Method and system for sterilization

Abstract

A sterilization method comprising pre-conditioning a sterilization apparatus comprising a sterilization chamber (102) comprising a sterilization load (105), wherein pre-conditioning the sterilization apparatus comprises raising a temperature of a portion of the sterilization apparatus to a temperature greater than a maximum temperature of the sterilization load; performing a sterilization phase (206), wherein the sterilization phase (206) comprises a plurality of sterilization pulses (420, 440, 460); and performing an aeration phase (208), wherein the aeration phase (208) comprises a plurality of aeration pulses, wherein the plurality of aeration pulses comprises a primary aeration pulse comprising: reaching a first vacuum pressure (342) within the sterilization chamber, wherein the first vacuum pressure is less than 650 mbar; and after a first vacuum hold (344), raising a pressure (346) of the sterilization chamber (102) to a pressure greater than 700 mbar; and a secondary aeration pulse comprising: reaching a second vacuum pressure (322) within the sterilization chamber (102), wherein the second vacuum pressure is less than 650 mbar; and after a second vacuum hold (324), adding air (326) to the sterilization chamber (102) while venting the sterilization apparatus (328).

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 172,457, filed April 8, 2021, which is incorporated herein by reference in its entirety. Technical Field

[0003] Various embodiments of this disclosure relate to sterilization systems and methods for sterilization. More specifically, some embodiments of this disclosure relate to systems and methods for chemical sterilization (e.g., wet chemical sterilization) of medical products, including terminal sterilization using a drug delivery device employing a vaporized sterilizing agent such as vaporized hydrogen peroxide. Furthermore, embodiments of this disclosure relate to systems and methods for monitoring and controlling the environment and / or conditions within sterilization equipment or processes. Existing technology

[0004] Chemical sterilization processes, such as those using ethylene oxide, vaporized hydrogen peroxide, or vaporized peracetic acid, offer numerous advantages, including the ability to be performed at relatively low temperatures (e.g., below 50°C) without the need for deep vacuum (e.g., without reducing pressure to below 100 mbar). This type of sterilization can be particularly useful for sterilizing medical devices and products sensitive to extreme temperatures and / or pressures.

[0005] The process of using chemical sterilizing agents includes the following steps to ensure that the sterilizing agent reaches all parts of the load to be sterilized, and after sterilization, the sterilizing agent is removed from the load to a degree that ensures the safety and effectiveness of any sterilized product. Removing the sterilizing agent from the load can be referred to as aerating the load. Furthermore, the sterilization process can benefit from improvements in reducing the time and resources required for sterilizing and aerating / drying the load.

[0006] In particular, the use of vaporized chemicals such as vaporized hydrogen peroxide can pose certain challenges. The distribution of vaporized sterilizing agents in a sterilization system, their behavior (e.g., condensation, evaporation, etc.), and their interactions with the sterilization load (e.g., adsorption on the load material) can affect their effectiveness and the ease with which they can be removed from the load. Summary of the Invention

[0007] Embodiments of this disclosure pertain to a sterilization method. The method may include: pre-treating a sterilization apparatus, the sterilization apparatus including a sterilization chamber and a sterilization load. Pre-treating the sterilization apparatus may include raising the temperature of a portion of the sterilization apparatus to a temperature greater than the highest temperature of the sterilization load. The method may further include performing a sterilization phase and an aeration phase. The sterilization phase may include multiple sterilization pulses. The aeration phase may include multiple aeration pulses, wherein the multiple aeration pulses include primary aeration pulses and secondary aeration pulses. The primary aeration pulse may include reaching a first vacuum pressure within the sterilization chamber, wherein the first vacuum pressure is less than 650 mbar. The primary aeration pulse may further include, after maintaining the first vacuum, raising the pressure of the sterilization chamber to a pressure greater than 700 mbar. The secondary aeration pulse includes reaching a second vacuum pressure within the sterilization chamber, wherein the second vacuum pressure is less than 650 mbar. The secondary aeration pulse may further include, after maintaining the second vacuum, adding air to the sterilization chamber while simultaneously venting the sterilization apparatus.

[0008] In some embodiments, the method may further include adding dry air to the sterilization chamber after the sterilization phase and before the aeration phase. The plurality of aeration pulses may include a first primary aeration pulse, followed by a first-stage aeration pulse, followed by a second primary aeration pulse, and then a second-stage aeration pulse. A portion of the sterilization apparatus may include an inlet and optionally include conduit connecting a VHP injector to the inlet. Each sterilization pulse may include reaching a sterilization pressure within the sterilization chamber and, while the sterilization chamber is at that sterilization pressure, adding vaporized hydrogen peroxide to the sterilization chamber. The sterilization pressure may be less than or equal to 650 mbar. The sterilization chamber may include a piston or diaphragm configured to regulate the pressure within the sterilization chamber. The method may further include generating a low-frequency pressure wave using the piston or diaphragm after the sterilization phase. The low-frequency pressure wave moves liquid hydrogen peroxide in contact with the sterilization load. The sterilization load may include a Tyvek envelope.

[0009] In some embodiments of this disclosure, the sterilization method may include a sterilization phase and an aeration phase. The sterilization phase may include first, second, and third sterilization pulses. Each sterilization pulse may include reaching a sterilization pressure within the sterilization chamber and, while the sterilization chamber is at the sterilization pressure, adding a certain amount of vaporized hydrogen peroxide to the sterilization chamber. The aeration phase may include reaching a vacuum pressure within the sterilization chamber, wherein the vacuum pressure is less than 650 mbar. The aeration phase may also include adding air to the sterilization chamber after maintaining the vacuum, while simultaneously venting the sterilization equipment. The amount of vaporized hydrogen peroxide added to the sterilization chamber during the first sterilization pulse may be sufficient to establish a lethal concentration of hydrogen peroxide in the sterilization chamber. The amount of vaporized hydrogen peroxide added to the sterilization chamber during the second sterilization pulse may be less than the amount of vaporized hydrogen peroxide added to the sterilization chamber during the first sterilization pulse. The amount of vaporized hydrogen peroxide added to the sterilization chamber during the third sterilization pulse may be less than the amount of vaporized hydrogen peroxide added to the sterilization chamber during the second sterilization pulse.

[0010] In some embodiments, the method may further include repeating the first sterilization pulse at least once before the second sterilization pulse. The method may also include repeating the third sterilization pulse at least twice. The amount of vaporized hydrogen peroxide added to the sterilization chamber during the first sterilization pulse may include at least 0.1 moles of hydrogen peroxide per cubic meter of the sterilization chamber volume. Each sterilization pulse may further include: (i) adding gas to the sterilization chamber to raise the pressure to a holding pressure, and (ii) lowering the pressure of the sterilization chamber to the sterilization pressure. Step (i) may take longer than step (ii). The holding pressure may be greater than 700 mbar. Each sterilization pulse may further include maintaining the pressure of the sterilization chamber for a first holding time before step (i). Each sterilization pulse may further maintain the pressure of the sterilization chamber for a second holding time after step (ii). The second holding time may be longer than the first holding time. The sterilization chamber may include a dispensing manifold, an inlet, and a chamber wall, and the method may further include maintaining the temperature of the chamber wall approximately the same as the temperature of the inlet or the temperature of the dispensing manifold during the first, second, and third sterilization pulses.

[0011] Further embodiments of this disclosure may include a sterilization method comprising: a first sterilization pulse, a plurality of second sterilization pulses, and a plurality of third sterilization pulses. The first sterilization pulse may include adding a first amount of vaporized hydrogen peroxide to a sterilization chamber, wherein the first amount is sufficient to establish a lethal concentration of hydrogen peroxide in the sterilization chamber. Each second sterilization pulse may include adding a second amount of vaporized hydrogen peroxide to the sterilization chamber, wherein the second amount is less than the first amount. Each third sterilization pulse may include adding a third amount of vaporized hydrogen peroxide to the sterilization chamber, wherein the third amount is less than the second amount.

[0012] In some embodiments, the method may further include performing aeration pulses. An aeration pulse may include (i) reducing the pressure in the sterilization chamber to a first aeration pressure, and (ii) increasing the pressure in the sterilization chamber to a second aeration pressure. The rate of pressure change in step (ii) may be at least 100 mbar / min faster than the rate of pressure change in step (i). The first aeration pressure may be less than 650 mbar. The second aeration pressure may be greater than 700 mbar. The method may further include removing moisture from the sterilization chamber by passing the contents of the sterilization chamber through a condenser prior to the aeration phase. The sterilization chamber may include a load, wherein the load includes a Tyvek material defining the interior and exterior of the load. After a plurality of the third sterilization pulses, the hydrogen peroxide concentration inside the load may be substantially equal to the hydrogen peroxide concentration outside the load. Attached Figure Description

[0013] The drawings, which are incorporated in and constitute a part of this specification, illustrate various exemplary embodiments and, together with the description, serve to explain the principles of the disclosed embodiments. The drawings illustrate different aspects of this disclosure. Where appropriate, reference numerals illustrating similar structures, components, materials, and / or components are similarly labeled in the different drawings. It should be understood that, apart from those specifically shown, various combinations of structures, components, and / or components are contemplated and fall within the scope of this disclosure.

[0014] This document describes and illustrates numerous inventions. The described inventions are neither limited to any single aspect or implementation thereof, nor to any particular combination and / or arrangement of such aspects and / or implementations. Furthermore, each aspect of the described invention and / or its implementations may be used alone or in combination with one or more of the other aspects of the described invention and / or its implementations. For the sake of brevity, certain arrangements and combinations are not discussed and / or described separately herein. It is important to note that the embodiments or examples described herein as “exemplary” should not be construed as being superior or more advantageous than other embodiments; rather, they are intended to reflect or indicate “example” embodiments.

[0015] Figure 1A This is a schematic diagram of an exemplary sterilization system that can be used to sterilize medical products.

[0016] Figure 1B It is a display Figure 1A A schematic diagram of an enlarged view of a portion of the system shown.

[0017] Figure 2A and 2B This is a flowchart of steps in an exemplary method for sterilizing medical products using vaporized chemicals.

[0018] Figure 3A and 3BThis is a flowchart of the steps in an exemplary method for performing the sterilization phase.

[0019] Figure 4 This is a flowchart of the steps in an exemplary method for performing the aeration phase.

[0020] Figure 5 This is a flowchart of the steps in an exemplary method for performing another aeration phase.

[0021] Figure 6 , 7 8A, 8B, 9A and 9B show the sterilization chamber pressure and load temperature during an exemplary sterilization method. Specific Implementation

[0022] As used herein, the terms “comprising,” “including,” “having,” “possessing,” or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that includes a list of components need not include only those components, but may also include other components not expressly listed or components inherent to such a process, method, article, or apparatus. The term “exemplary” is used in the sense of “example” rather than “ideal.” Any implementation described herein as exemplary should not be construed as superior or more advantageous than other implementations. Furthermore, the terms “first,” “second,” etc., used herein do not indicate any order, quantity, or importance, but are used to distinguish one component from another. Similarly, relative orientation terms such as “front,” “top,” “rear,” “bottom,” “upper,” and “lower” are referenced relative to the described figures.

[0023] As used herein, the terms “about” and “approximately” are intended to describe a possible variation of ±10% in the specified values. All measurements reported herein should be understood to be modified by the terms “about” or “approximately”, whether or not these terms are explicitly used, unless otherwise expressly stated. As used herein, the singular forms “a” and “the” include plural indicators unless the context clearly specifies otherwise. Furthermore, in the claims, values, limits, and / or ranges refer to values, limits, and / or ranges of + / -10%.

[0024] As used in this disclosure, the term "sterilization" refers to achieving a level of sterility suitable for commercial distribution and use of a pharmaceutical substance or product. This level of sterility may be defined, for example, in regulatory guidelines or regulations, such as those issued by the U.S. Food and Drug Administration. In some embodiments, this level of sterility may include, for example, a 6-log reduction in the microbial community of a biological indicator placed on the outer or inner surface of the pharmaceutical product (e.g., the outer surface of a syringe or the inner surface of a blister pack). In other embodiments, this level of sterility may include, for example, a 9-log or 12-log reduction in the microbial community of a biological indicator. Sterilization means achieving this appropriate level of sterility while also achieving a sufficiently low level of residual sterilizing chemicals (e.g., vaporized hydrogen peroxide, ethylene oxide, etc.) for commercial distribution and use. This low level of residual sterilizing chemicals may also be defined in regulatory guidelines or regulations.

[0025] As used in this disclosure, the term "terminal sterilization" refers to the sterilization of a pharmaceutical product in a container or package, such as in a primary packaging assembly, or in both a primary and secondary packaging assembly, suitable for commercial distribution and use.

[0026] As used in this disclosure, the term "medical product" means a product intended for medical use in a live animal. The term "medical product" includes, for example, pharmaceutical products, formulations of pharmaceutical substances, medical implants, medical devices, or combinations thereof. For example, the term "medical product" may refer to a syringe containing a formulation of a pharmaceutical substance, such as a non-oral syringe or an ophthalmic syringe. Other exemplary medical products include, for example, suppository applicators and medications, percutaneous drug delivery devices, medical implants, needles, cannulas, medical devices, and any other products that require sterilization prior to their intended medical use.

[0027] As used in this disclosure, the term "formulation pharmaceutical substance" refers to a composition comprising at least one active ingredient (e.g., a small molecule, protein, nucleic acid, or gene therapy drug) and excipients, prepared for medical dispensing and use. Formulation pharmaceutical substances may include fillers, colorants, and other active or inactive ingredients.

[0028] As used in this disclosure, the term "pharmaceutical product" refers to a dosage form containing a pharmaceutical substance, such as the final dosage form of an active ingredient. Pharmaceutical products may include packaging intended for commercial distribution or use, such as bottles, vials, or syringes.

[0029] As used in this disclosure, the term "vaporized chemical" refers to a chemical that has been converted into a substance that can diffuse or suspend in the air. In some cases, a vaporized chemical may be a chemical that has combined with water and then converted into a substance that can diffuse or suspend in the air.

[0030] As used in this disclosure, the term "fluid" means liquid, semi-liquid, vapor, or gas, including oxygen, hydrogen, nitrogen, or combinations thereof.

[0031] Embodiments of this disclosure relate to systems and methods for using vaporized chemicals in a sterilization process, such as for sterilizing medical products. For example, embodiments of this disclosure may relate to systems and methods for terminal sterilization of medical products using vaporized hydrogen peroxide (VHP). More specifically, embodiments of this disclosure may relate to systems and methods for terminal sterilization, for example, of medical products such as pre-filled syringes (PFS).

[0032] It is generally expected that exposure to sterilization cycles is effective and without adverse effects, and that the risk of damage to or alteration of the load to be sterilized is minimized. Medical products undergoing terminal sterilization, such as PFS, may therefore require sterilization equipment, machinery, controls, cycles, and methods to address certain limitations and requirements in order to achieve proper sterilization and / or avoid damage to medical products and / or devices, pharmaceutical substances, pharmaceutical products, or other products. Such limitations and requirements may include, for example:

[0033] Medical products may be located in different parts of the sterilization chamber (e.g., quadrants or zones). During the sterilization cycle, these zones may experience conditions different from those in other parts of the chamber, such as temperature, pressure, water vapor concentration, humidity, or sterilizing agent concentration. These different conditions can affect sterilization efficacy. Maintaining a consistent environment throughout the sterilization chamber helps ensure that sterilization is adequate for all parts of the load.

[0034] The environment within a sterilization chamber can change during the sterilization cycle, affecting the movement, state, or efficacy of the sterilizing agent and / or fluids. For example, the pressure within the chamber can increase when a sterilizing agent is added. This pressure can affect the ratio of condensing to vaporizing sterilizing agents. Changes in temperature, humidity, or other environmental characteristics can also affect the behavior of the sterilizing agent within the chamber and any additional sterilizing agent added. Sterilization systems and methods that adapt to changes in the environment or climate within the sterilization chamber during the sterilization phase to maximize sterilization efficacy are beneficial. Systems and methods that adapt to changes in the environment or climate of an area to maximize aeration and drying in that area are also beneficial.

[0035] • Medical products may be densely packaged. For example, bulk-packaged medical products may contain a large quantity of fully assembled, packaged, and labeled medical products. In the case of terminal sterilization, the sterilizing agent may need to penetrate several layers of packaging material, container material, and / or label to effectively sterilize all aspects of the load and properly remove it from all aspects of the load. In some cases, the packaging may include semi-permeable materials selected for sterilizing agents used in specific stages (e.g., steam).

[0036] For certain types of sterilization, such as terminal sterilization, sterilizing agents may need to be sterilized by heating or by mass passing through a semipermeable membrane to sterilize the exterior of each medical product and the interior of its packaging components. The sterilizing agent may also need to be successfully removed, for example, by the semipermeable membrane, to avoid residue on the medical product. Permeation of the semipermeable membrane may only be feasible for specific forms of sterilizing agents, such as vapors or gases.

[0037] • Packaging for medical products must resist the penetration of sterilizing materials and / or be sensitive to temperature and pressure changes caused by sterilization. For example, syringes may be packaged in a plastic blister pack configured to contain the syringe and restrict its movement. Such blister packs may only be permeable to sterilizing materials and / or may be sensitive to pressure changes.

[0038] The use of a combination of vaporized chemical sterilizing agents (e.g., VHP) and vaporized water in an environment where temperature and pressure can be precisely controlled allows for specific environmental management to maximize contact between the sterilizing agent and the sterilized load during the sterilization phase, and / or to maximize removal of the sterilizing agent from the load during one or more subsequent aeration or drying phases. Some embodiments of this disclosure relate to the precise control of temperature, pressure, humidity, exposure time, and other environmental conditions. Environmental conditions can be adjusted in any part of the sterilization apparatus before, during, and / or after a sterilization process is performed using the apparatus. For example, the environment of one or more parts of the apparatus for introducing or removing sterilizing agents can be maintained or controlled within predetermined conditions. Therefore, embodiments of this disclosure can help improve the introduction and / or removal of chemical sterilizing agents in sterilization apparatus (e.g., between the sterilization apparatus and the outside of the apparatus, or between parts of the apparatus). Some embodiments of this disclosure can be used in conjunction with the disclosure of WIPO Publication No. WO2018 / 182,929, filed March 6, 2018, which is incorporated herein by reference in its entirety.

[0039] Several properties of vaporized chemical sterilizing agents may (positively or negatively) affect the safety, efficacy, efficiency, and other aspects of the sterilization process for medical products. For example:

[0040] • Chemical sterilizing agent vapors and water vapors in the environment may adsorb and / or condense on surfaces with relatively low ambient temperatures. For example, during the steam sterilization of PFS loads, “cold spots” created by the aqueous, high-heat-capacity, liquid products in each PFS can attract vapor adsorption and promote surface condensation. Furthermore, altering the ambient temperature (e.g., heating the sterilization chamber) can create relatively warm and cool areas in the environment, which in turn affects the relative temperature of the loads in these relatively warm or cool areas. For example, heating the sterilization chamber using a temperature control jacket can cause the chamber area closest to the jacket (e.g., the periphery of the chamber) to become hotter than areas further away from the jacket (e.g., the center of the chamber). Ambient heat in warmer areas can also cause some sterilized loads in these areas to become relatively hot. Chemical sterilizing agent vapors and water vapors may preferentially adsorb onto surfaces in areas with relatively low temperatures compared to the rest of the environment (“cold spots”); therefore, vaporized chemical sterilizing agents (e.g., VHPs) may not be uniformly distributed between relatively warm and cool areas. While cooler areas can be exposed to sterilizing agents more thoroughly, warmer areas can experience more thorough aeration and drying.

[0041] • Compared to water vapor, hydrogen peroxide preferentially adsorbs onto surfaces because it is denser and less volatile than water. In some cases, hydrogen peroxide and water vapor can be simultaneously adsorbed and condensed on surfaces. Compared to water vapor, hydrogen peroxide has a higher adsorption and condensation rate and percentage, and it is closer to the surface of the sterilization load than water vapor.

[0042] In sterilization environments, multiple adsorption layers can form on a single surface. In some cases, each adsorption layer and / or condensation layer farther from the surface may contain less hydrogen peroxide and more water vapor, thus creating a hydrogen peroxide to water gradient on the surface. Due to the thermodynamic behavior of a binary mixture of VHP and water vapor that is near or saturated (e.g., a binary mixture of hydrogen peroxide and water in vapor / liquid equilibrium), hydrogen peroxide can be preferentially adsorbed and condensed closer to the surface than water. The vapor / liquid equilibrium can be analogous to the gas / adsorbate equilibrium of a binary mixture of VHP and water vapor in sterilization applications.

[0043] • In some cases, condensed or adsorbed hydrogen peroxide may be difficult to remove from the surface. For example, the condensation of water vapor on condensed / adsorbed hydrogen peroxide, or the adsorption of water around condensed / adsorbed hydrogen peroxide, can trap hydrogen peroxide on the sterilization surface or otherwise inhibit its removal.

[0044] Pressure differences throughout the environment, such as within the sterilization chamber, can also affect the effectiveness of vaporized chemical sterilizers. For example, the sterilization effect may be greater at the compressed air injection point compared to the rest of the sterilization chamber. This is not theoretically limited, but could be due to the properties of the gas within the partially vacuumed chamber. When the chamber is filled with chemical sterilizer, the localized area at the compressed air injection point may experience a greater degree of pressure wave or pulse than areas farther away. This pressure wave can cause more condensation of the chemical sterilizer in the vicinity of the compressed air injection point.

[0045] In some cases, where it is desirable for a sterilizing agent to penetrate a semi-permeable membrane of a load to sterilize the internal area or volume covered by the membrane, a delay has been observed in the migration of at least a portion of the sterilizing agent across the load. For example, in sterilization loads comprising semi-permeable Tyvek membranes, the concentration of hydrogen peroxide inside the membrane, which is in equilibrium with the concentration of hydrogen peroxide outside the membrane, is delayed or slower. This delay or lag has not been observed with respect to water concentration. Therefore, the relative strength of the sterilizing agent to the load inside the semi-permeable membrane, or to a portion of the load (for part or all of a sterilization cycle), may be lower than the strength of the sterilizing agent outside the membrane.

[0046] • The rate of pressure increase during the introduction of vaporized sterilizing agent into the sterilization chamber can negatively impact sterilization efficacy. A certain degree of pressure increase can facilitate the introduction of the sterilizing agent into the loading material, promoting its adsorption. However, when the environment is at or near VHP saturation levels, excessive pressure increases can lead to, for example, violent condensation of the VHP, which may impair sterilization efficacy or subsequent aeration or drying efficiency. Allowing the ambient pressure to remain at a level where the vaporized sterilizing agent can condense over time may result in excessive condensation. Conversely, reducing the ambient pressure after introducing the vaporized sterilizing agent (e.g., VHP) allows more of the sterilizing agent to remain in the vapor phase, which can improve the agent's migration across the semipermeable membrane and achieve sterilization within the loading material.

[0047] During the sterilization phase (e.g., a sterilization pulse), the pressure increase can be faster than the pressure decrease (e.g., the rate of pressure increase during a sterilization pulse can be 150 mbar / min faster than the rate of pressure decrease during the same pulse). This can promote the movement of the sterilizing agent (e.g., promoting the movement of the sterilizing agent through one or more layers of packaging). During aeration, the opposite can be used to promote the movement of the sterilizing agent from inside the packaging layers to the outside of the packaging and through the exhaust port of the sterilization equipment. For example, the rate of pressure decrease during an aeration pulse can be 150 mbar faster than the rate of pressure increase during the same pulse. The increased chamber temperature can also improve the efficiency of aeration.

[0048] The saturation level of the sterilization chamber can also affect the rate or direction of pressure adjustment. For example, when the sterilization chamber is near saturation, pressure increases approaching atmospheric pressure should be avoided. Larger pressure changes can be used at lower sterilizing agent concentrations, while at higher concentrations, large pressure changes can lead to excessive condensation, thus reducing sterilization efficiency.

[0049] The sterilizing agent may also need to be successfully removed from the load to avoid residues on or within the medical product. For example, in embodiments using packaging that includes a semi-permeable membrane, permeation of the membrane may only be feasible for specific forms of sterilizing agents, such as vapors or gases. In some cases, stimulating mechanical movement of part or all of the load (e.g., rocking, rotating, agitating, etc.) can cause sterilizing agent molecules adhering to the load to detach and can promote aeration and removal of sterilizing agent from the load. Low-frequency pressure waves or sounds generated within the sterilization chamber (e.g., via diaphragms or pistons within the chamber) can remove sterilizing agent adhering to the load.

[0050] Increasing pressure immediately after a sterilization pulse can lead to unnecessary condensation and reduced aeration efficiency. To prevent excessive condensation, the humidity of the sterilization chamber can be reduced before aeration. For example, the contents of a closed system can be depressurized via a condenser (e.g., a desiccant wheel) to reduce ambient humidity. Alternatively, dry air can be injected before or during venting to reduce the overall humidity of the system.

[0051] The systems and methods disclosed herein can be advantageously used to improve the efficiency of sterilization, aeration, and / or drying cycles of vaporized chemical sterilizers. For example, the systems and methods disclosed herein can provide complete (e.g., 100%) sterilization of medical products using VHP, followed by complete (e.g., 100%) removal of VHP from the sterilized product. The systems and methods disclosed herein can, for example, improve sterilization efficiency, safety, and efficacy, and / or reduce sterilization cycle time. While aspects of this disclosure may be described in relation to the use of VHP in terminal sterilization in PFS, this disclosure is also contemplated for use in other environments (e.g., other products, clean areas, sterilization involving the addition / removal of vaporized chemicals in any environment, etc.) to move VHP with other chemical sterilizers.

[0052] This disclosure also considers the performance of "wet chemical sterilization," a method by which chemical sterilization can be achieved in the presence of water vapor. In some cases, the comparison between "wet chemical sterilization" and "chemical sterilization" may be similar to the comparison between "wet heat sterilization" and "heat sterilization." In some cases, wet chemical sterilization may be a more effective and efficient sterilization method than currently available chemical sterilization technologies, just as "wet heat sterilization" is considered more effective and efficient than "heat sterilization" alone in some situations.

[0053] "Wet chemical sterilization" can be performed when environmental conditions of relatively high chemical concentrations, water vapor concentrations, and pressures (e.g., above 400 mbar) work synergistically to force the chemicals and water vapor into a binary mixture. To achieve the required relatively high chemical concentrations, water vapor concentrations, and pressures, the area to be sterilized can be saturated with a combination of water vapor and sterilizing chemicals (e.g., VHP), thereby forcing the vapor to condense on the surface of the substrate. Most commercially available hydrogen peroxide is available and sold as aqueous liquid mixtures of varying concentrations (e.g., 3%, 15%, 35%, 59%); therefore, vaporizing hydrogen peroxide typically involves vaporizing water simultaneously.

[0054] Now refer to the diagram, Figure 1A An exemplary sterilization system 100 used in the methods of this disclosure is depicted schematically. It should be understood that the sterilization system 100 is merely exemplary, and the methods disclosed herein can be used in many other systems, environments, and / or parts thereof. The sterilization system 100 includes a sterilization chamber 102 surrounded by a temperature control jacket 104. The sterilization chamber 102 has an interior cavity including an upper interior 101 and a lower interior 103. The sterilization chamber 102 is configured to receive a sterilization load (e.g., a load including one or more products 105) for sterilization. An inlet conduit 134 fluidly connected to the sterilization chamber 102 is configured to allow various fluids to enter the sterilization chamber 102. The inlet conduit 134 may be connected to one or more distribution manifolds (e.g., diffuser plates, spray balls, or other structures configured to distribute gas throughout the chamber). Figure 1A and 1B In the example shown, the first distribution manifold 107a is located near the upper interior 101, while the second distribution manifold 107b is located near the lower interior 103. The distribution manifolds 107a and 107b, located on opposite sides of the sterilization chamber 102, promote the uniform distribution of sterilizing agents, air, or other introduced substances.

[0055] The inlet pipe 134 may be connected to both the first distribution manifold 107a and the second distribution manifold 107b. In some embodiments, the second distribution manifold 107b is connected to a different inlet pipe than the first distribution manifold 107a.

[0056] The second inlet pipe 135 is also fluidly connected to the sterilization chamber 102, and also allows fluid to enter the sterilization chamber 102 via inlet 109. For example, dry air from the dry air supply source 130 can be introduced into the sterilization chamber 102 via inlet 109.

[0057] Blower 106 is fluidly connected to sterilization chamber 102 via blower outlet conduit 108. Blower circulation conduit 118 is fluidly connected to blower 106 to allow fluid to flow from blower outlet conduit 108 to exhaust port 116, or back to sterilization chamber 102 via inlet conduit 134. In some embodiments, blower outlet conduit 108 may include or be coupled to condenser 147. Condenser 147 may include a dryer wheel or other configurations for removing water from fluid passing through blower outlet conduit 108. Exhaust valve 120 is located between blower circulation conduit 118 and exhaust port 116 and selectively closes or opens the connection between blower circulation conduit 118 and exhaust port 116. Recirculation valve 119 is located between blower circulation conduit 118 and inlet conduit 134 and selectively closes or opens the connection between blower 106 (e.g., via blower circulation conduit 118) and inlet conduit 134.

[0058] Blower 106 is capable of circulating air at a rate greater than 500 cubic feet per minute (cfm). In some embodiments, the air circulation rate maintained by blower 106 may be less than 1000 cfm. If blower 106 is moving too much fluid, the sterilizing agent will be displaced near distribution manifolds 107a, 107b, thereby reducing sterilization efficiency.

[0059] Vacuum pump 110 is fluidly connected to sterilization chamber 102 via vacuum conduit 112. Vacuum conduit 112 may include or be connected to catalytic converter 115. Vacuum valve 113 is located between sterilization chamber 102 and vacuum conduit 112, selectively allowing, partially allowing, or blocking flow from sterilization chamber 102 (e.g., through catalytic converter 115) to vacuum pump 110. Vacuum exhaust conduit 114 fluidly connects vacuum pump 110 to exhaust port 116.

[0060] The sterilization system 100 may include several air and / or steam supply sources from which fluid may be introduced into the sterilization chamber 102 via inlet conduits 134 or 135. A dry make-up air supply source 127 may be configured to supply dry make-up air to the sterilization chamber 102 via inlet conduit 134. In some embodiments, the dry make-up air supply source 127 is compressed dry air. A dry air valve 144 may be coupled to the fluid connection between the dry make-up air supply source 127 and the inlet conduit 134. The dry air valve 144 may selectively allow, partially allow, or block the flow of dry make-up air from the dry make-up air supply source 127 to the sterilization chamber 102 via inlet conduit 134.

[0061] The humid make-up air supply source 117 can be configured to supply humid make-up air (e.g., air with a higher humidity than the dry make-up air from the dry make-up air supply source 127) to the sterilization chamber 102 via inlet conduit 134. A humid air valve 124 can be coupled to the fluid connection between the humid make-up air supply source 117 and the inlet conduit 134. The humid air valve 124 can selectively allow, partially allow, or block the flow of humid make-up air from the humid make-up air supply source 117 to the sterilization chamber 102 via the inlet conduit 134.

[0062] The humidified supplemental air supply source 117 may be a supply source of any air (e.g., indoor air or compressed air) or other fluid external to the rest of the sterilization system 100. In some embodiments, the humidified supplemental air supply source 117 may be a supply source of "indoor air" surrounding the sterilization system 100, which may have already passed through an indoor filtration system. In some embodiments, the humidified supplemental air supply source 117 may include more water vapor than "indoor air". In some embodiments, the humidified supplemental air supply source 117 may be a supply source of filtered outdoor air.

[0063] A VHP injector 132, fluidly connected to inlet conduit 134, is configured to inject VHP into sterilization chamber 102 via inlet conduit 134. A VHP injector valve 128 is coupled to the fluid connection between VHP injector 132 and inlet conduit 134 and selectively allows, partially allows, or blocks the flow of VHP from VHP injector 132 to sterilization chamber 102 via inlet conduit 134.

[0064] VHP injector 132 may include a supply source of VHP or VHP and vaporized water, and may be configured to inject VHP or a combination of VHP and vaporized water into sterilization chamber 102 via, for example, inlet pipe 134. VHP injector 132 may be configured to inject steam into sterilization chamber 102 (or inlet pipe 134) at an adjustable concentration.

[0065] Depending on the positions of the dry air valve 144, the humid air valve 124, and the VHP injector valve 128, dry make-up air from dry make-up air supply source 127, humid make-up air from humid make-up air supply source 117, VHP from VHP injector 132, or a combination thereof, can enter the sterilization chamber 102 via inlet pipe 134. For example, during pretreatment, the humid air valve 124 can be positioned to block humid make-up air from humid make-up air supply source 117 from entering inlet pipe 134, the VHP injector valve 128 can be positioned to block VHP from VHP injector 132 from entering inlet pipe 134, and the dry air valve 144 can be positioned to allow dry make-up air to flow from dry make-up air supply source 127 to sterilization chamber 102 via inlet pipe 134. In this configuration, only dry make-up air flows to sterilization chamber 102, allowing for faster pretreatment.

[0066] In another configuration, the humid air valve 124 may be positioned to allow humid makeup air to flow from the humid makeup air supply source 117 to the sterilization chamber 102 (i.e., via inlet pipe 134), the VHP injector valve 128 may be positioned to allow VHP to flow from the VHP injector 132 to the sterilization chamber 102 (i.e., via inlet pipe 134), and the dry air valve 144 may be positioned to block the entry of dry makeup air from the dry makeup air supply source 127 into the inlet pipe 134. In such a configuration, the humid makeup air functions as a binding medium for introducing VHP into the sterilization chamber. Dry makeup air or a combination of dry makeup air and humid makeup air may also be used as a binding medium. Humid makeup air may be more effective as a binding medium than dry makeup air. After the VHP is introduced, moisture (e.g., water) in the humid makeup air used as a binding medium can be removed from the sterilization chamber 102 (e.g., via condenser 147).

[0067] An auxiliary dry air supply source 130, fluidly connected to inlet pipe 135, is configured to supply dry air to sterilization chamber 102 via inlet pipe 135. An auxiliary supply valve 126 is coupled to the fluid connection between the auxiliary dry air supply source 130 and inlet pipe 135 and is configured to selectively allow, partially allow, or block the flow of dry air from the auxiliary dry air source 130 to sterilization chamber 102 via inlet pipe 135.

[0068] The supplemental dry air supply 127 and the auxiliary dry air supply 130 may have the same or different compositions. One or both of the dry air supply sources 127 and 130 may be air supply sources with relatively low humidity, thus suitable for drying sterilization chamber 102 (e.g., a portion of sterilization chamber 102) and / or one or more blower outlet ducts 108, vacuum ducts 112, vacuum exhaust ducts 114, blower circulation ducts 118, and inlet ducts. For example, in some embodiments, the air in one or both of the dry air supply sources 127 and 130 may have a dew point of, for example, -10 degrees Celsius or lower, -40 degrees Celsius or lower, or between -10 degrees Celsius and -40 degrees Celsius. In some embodiments, one or both of the dry air supply sources 127 and 130 may be sources of hygienic dry air, such as air that has been sterilized or otherwise filtered to at least 0.2 microns. In some embodiments, one or both of the dry air supply sources 127 and 130 may be hermetically sealed air supply sources. In some embodiments, one or both of the dry air supply sources 127 and 130 may be compressed air supply sources.

[0069] The sterilization system 100 can be configured to operate sterilization cycles at various temperatures and pressures within the sterilization chamber 102 for various durations and / or time intervals. In some embodiments, the temperature, pressure, and time intervals at which the sterilization system 100 can operate sterilization cycles can be selectively and individually modified and customized. Furthermore, the temperature, pressure, and time intervals can be adjusted during sterilization cycles, for example, to improve the distribution, migration, and / or removal of the sterilizing agent.

[0070] The sterilization system 100 can be configured to control the environment inside the sterilization chamber 102, including temperature, pressure, humidity, atmosphere, fluid intake, and fluid discharge. Mechanisms for temperature control include: temperature regulation of the input fluid flow and / or recirculated fluid flow, temperature regulation of the sterilization chamber itself, and temperature modulation of other components of the system 100 (e.g., inlet pipe 134, blower outlet pipe 108, vacuum pump 110, temperature control jacket 104, blower circulation pipe 118, blower 106, recirculation valve 119, humid make-up air supply source 117, dry make-up air supply source 127, VHP injector 132, humid air valve 124, dry air valve 144, VHP injector valve 128, distribution manifolds 107a, 107b). The sterilization chamber 102 (e.g., a portion of the sterilization chamber 102, such as the upper interior 101 or the lower interior 103) may include or be fluidly connected to one or more pistons 150 or diaphragms, which may be actuated, inflated, deflated, or otherwise altered to regulate the pressure of the sterilization chamber 102 without introducing or removing material. One or more pistons 150 or diaphragms may be configured to generate pressure waves or generate low-frequency pulses. These pressure waves and pulses may be used to influence (e.g., promote) the condensation of the sterilizing agent on the surface of the load.

[0071] Furthermore, the sterilization system 100 may include any suitable number and location of sensors configured to sense, for example, temperature, pressure, flow rate, chemical concentration, or other parameters of the entire sterilization system 100, including the sterilization chamber 102, temperature control jacket 104, blower 106, vacuum pump 110, and / or pipes 108, 112, 114, 118, and 134. Such sensors may be configured to transmit sensed data to, for example, a controller 140 and / or a human-machine interface.

[0072] The sterilization chamber 102 may be a sealable cavity defining its interior, including an upper interior 101 and a lower interior 103. The sterilization chamber 102 may be opened to an open configuration, allowing one or more items, such as product 105, to be placed therein as part of a load for sterilization and to be removed after sterilization. In some embodiments, the sterilization chamber 102 may have an operating direction, for example, with the upper interior 101 positioned above the lower interior 103, allowing material to fall from the vicinity of the upper interior 101 towards the lower interior 103 (e.g., under gravity). The sterilization chamber 102 may have one or more conveying devices to which one or more inlet pipes 134 and 135 may be connected. As shown in FIG1, for example, distribution manifolds 107a and 107b are two such conveying devices. Distribution manifolds 107a and 107b can be configured to disperse gas, vapor, or liquid in the sterilization chamber 102 in a given configuration, such as a flow or uniform spray through the sterilization chamber 102. For example, distribution manifold 107a can distribute gas, vapor, or liquid through the upper interior 101, and distribution manifold 107b can distribute gas, vapor, or liquid through the lower interior 103. Inlet 109 is another such delivery device. Inlet 109 can also be configured to disperse gas, vapor, or liquid in the sterilization chamber 102 in a given configuration, such as a flow or uniform spray through the upper interior 101 or another portion of the sterilization chamber 102.

[0073] In some embodiments, the distribution manifold (e.g., distribution manifold 107a) may be configured to disperse gas, vapor, or liquid into the sterilization chamber 102 in one configuration, such as as a uniform spray, and the inlet 109 may be configured to disperse gas or vapor into the sterilization chamber 102 in different configurations, such as as a flow. In some embodiments, the inlet 109 may be absent, and inlet conduits 134 and 135 may be connected to one or more distribution manifolds 107a, 107b.

[0074] The temperature control jacket 104 can be made of any material surrounding the sterilization chamber 102, and is configured to, or effectively provide, temperature control for the environment within the sterilization chamber 102. In some embodiments, for example, the temperature control jacket 104 can be a water jacket surrounding the sterilization chamber 102. In such embodiments, the temperature and / or flow rate of the water or other liquid passing through the temperature control jacket 104 can be controlled by, for example, a temperature controller 140.

[0075] Product 105 may be any article or articles suitable for sterilization using sterilization system 100. In some embodiments, product 105 may be a primary package, a secondary package, or both of a medical product. In some embodiments, product 105 may be a medical product having moving parts or other components sensitive to deep vacuum environments, such as environments with pressures less than about 100 mbar. In some embodiments, product 105 may be, for example, a container filled with a volumetric pharmaceutical substance. For example, product 105 may be a vial or PFS. In some embodiments, product 105 may include a semi-permeable package, such as a semi-permeable membrane, or be covered by a semi-permeable membrane, through which vapor or gas can pass. In further embodiments, product 105 may be or may include a medical product sensitive to high temperatures, such as above 30°C. Such medical products may include, for example, pharmaceutical substances or other compositions sensitive to high temperatures, such as proteins (e.g., antibodies or enzymes), fragments thereof, any antigen-binding molecules, nucleic acids, blood, blood components, vaccines, allergens, gene therapy drugs, tissues, other biological agents, etc. For example, product 105 may be a packaged PFS containing a pharmaceutical substance including an antibody or adeno-associated virus (AAV). In some embodiments, product 105 may include a pharmaceutical product comprising, for example, a large molecule with a molecular weight of 30 kDa or greater.In some embodiments, product 105 may include ingredients such as aflibercept, alorocumab, abicipar pegol, bevacizumab, brolucizumab, conbercept, dupilumab, evolocumab, tocilizumab, certolizumab, abatacept, rituximab, infliximab, ranibizumab, sarilumab, adalimumab, anakinra, trastuzumab, pegfilgrastim, interferon beta-1a, and insulin glargine. glargine (rDNA source), epoetin alpha, darbepoetin, filigrastim, golimumab, etanercept, antigen-binding fragments of any of the above, or combinations of such binding domains, such as bispecific antibodies against VEGF or angiopoietin-2.

[0076] In some embodiments, product 105 may include therapeutic products for ophthalmic diseases, including those for treating patients with neovascular (wet) age-related macular degeneration (AMD), macular edema following retinal vein occlusion (RVO), diabetic macular edema (DME), and diabetic retinopathy (DR). In particular, macromolecular and small molecule antagonists of VEGF and / or ANG-2, such as aflibercept, ranibizumab, bevacizumab, conbercept, OPT-302, RTH258 (brolocizumab), PEGylated abizia (a PEGylated ankylosing repeat protein (DARPin)), RG7716, or fragments thereof, may be included in product 105 at any concentration. In some embodiments, product 105 may be a product for cosmetic application or medical dermatology such as the treatment or diagnosis of allergic reactions.

[0077] Blower 106 may be a blower that, for example, forcibly draws steam and gas from the lower interior 103 of sterilization chamber 102 via blower outlet pipe 108, optionally via condenser 147, and reintroduces the steam and gas into the upper interior 101 of sterilization chamber 102 via inlet pipe 134 (or alternatively, draws the steam and gas to exhaust port 116 via exhaust valve 120 and catalytic converter 121). In some embodiments, blower 106 may be outside sterilization chamber 102, as shown in FIG1. ​​In other embodiments, blower 106 may be located inside sterilization chamber 102. In some embodiments, blower 106 may be configured to draw steam and gas from the lower interior 103 of sterilization chamber 102 and reintroduce the steam and gas into the upper interior 101 with sufficient force to create a steam and gas flow from the upper interior 101 to the lower interior 103 of sterilization chamber 102. This flow can be termed "turbulence." In some embodiments, the force at which the blower 106 can operate may be adjustable (e.g., via controller 140), thereby producing a more turbulent (e.g., more powerful) or less turbulent flow of steam and gas within the sterilization chamber 102. In some embodiments, the blower 106 may be configured to generate a stronger force than, for example, a vacuum pump 110 to draw in steam and gas.

[0078] Vacuum pump 110 may be a vacuum pump capable of drawing gas from the interior of sterilization chamber 102 (e.g., lower interior 103) via vacuum conduit 112 and catalytic converter 115 to exhaust port 116, thereby creating a vacuum within sterilization chamber 102 and / or within a closed system comprising sterilization chamber 102 and, for example, blower 106. Vacuum pump 110 may be fluidly connected to exhaust port 116 via, for example, vacuum exhaust conduit 114. In some embodiments, exhaust port from vacuum pump 110 and blower 106 may be separate rather than integrated.

[0079] In some embodiments, the vacuum function can also be performed, or alternatively, by, for example, a blower 106, which can selectively circulate steam and gas out of or into the sterilization chamber 102 via an exhaust valve 120, toward the exhaust port 116. The exhaust valve 120 can be selectively opened or closed, thereby allowing or preventing gas or steam from flowing from the blower circulation duct 118 to the exhaust port 116 or to the inlet duct 134 for reintroduction into the sterilization chamber 102. The exhaust valve 120 can be manually controlled or controlled, for example, by a controller 140.

[0080] Catalytic converter 115, catalytic converter 121, or both may be any catalytic converter known in the art, for example, suitable for converting toxic gases or vaporized fluids circulating within sterilization system 100 into less toxic gases or vapors during sterilization cycles. For example, catalytic converters 115, 121 may be configured to convert VHP into water vapor, oxygen, and / or other non-toxic fluids.

[0081] The controller 140 is connected to one or more other components of the sterilization system 100, such as the sterilization chamber 102, temperature control jacket 104, blower 106, VHP injector 132, humid make-up air supply 117, dry make-up air supply 127, auxiliary dry air supply 130, vacuum pump 110, piston 150, catalytic converters 115 and 121, condenser 147, distribution manifolds 107 and 107b, pipes 112, 108, 118, 134, and 135, valves 113, 119, 120, 124, 126, and 144, and / or any other component of the sterilization system 100. Some or all aspects of the sterilization system 100 may be controlled by, for example, the controller 140. For example, controller 140 may be associated with one or more valves 113, 119, 120, 124, 126, 144, and may be configured to control, adjust, and / or monitor the position of one or more valves 113, 119, 120, 124, 126, 144. Alternatively, one or more valves 113, 119, 120, 124, 126, 144 may be manually operated.

[0082] The controller 140 may be, for example, an analog or digital controller configured to alter environmental aspects of the sterilization chamber 102, such as the internal temperature of one or more of the sterilization chamber 102 and / or the blower 106, vacuum pump 110, air supply source 117, dry air supply source 130, VHP injector 132, exhaust port 116, valves 113, 119, 120, 124, 126 and 128, catalytic converters 115 and 121, ducts 108, 112, 114, 116, 118 and 134, and any and / or other aspects of the sterilization system 100. In some embodiments, the sterilization system 100 may be controlled by multiple controllers 140. In other embodiments, the sterilization system may have only one controller 140. In some embodiments, the controller 140 may be a digital controller, such as a programmable logic controller.

[0083] In some embodiments, the controller 140 may be pre-programmed to perform one or more sterilization, aeration, drying, and / or cleaning cycles using the sterilization system 100. In some embodiments, the sterilization system 100 may be executed by a controller having one or more human machine interface (HMI) components configured to allow a user to input or change desired parameters of the cycle, which may be executed by a controller on or operatively coupled to the sterilization system 100. Therefore, in some embodiments, the HMI component may be used to program a custom cycle for execution by the sterilization system 100. For example, in some embodiments, the sterilization system 100 may be controlled by a controller connected to, for example, a calculator, tablet computer, or handheld device with a display. Such a display may include options such as selecting or changing desired temperature, pressure, time, VHP intake, dry air intake, compressed air or room air intake, etc., for one or more steps of the cycle.

[0084] Figure 1B An enlarged view of sterilization chamber 102 is depicted. Sterilization chamber 102 can be used as an exemplary environment to which many aspects of this disclosure are applicable. However, it should be understood that sterilization chamber 102 is merely exemplary, and aspects of this disclosure are applicable to many other environments.

[0085] Variations in temperature, pressure, humidity, and air / fluid flow can characterize different parts of the sterilization chamber 102. For example, a temperature control jacket 104 may be configured to control the temperature within the sterilization chamber 102, but it can have a more direct impact on the periphery of the sterilization chamber 102 than on the more central portion of the chamber. As previously mentioned, the temperature control jacket 104 can more directly affect the temperature of the product 105 (i.e., the load) closer to the periphery of the sterilization chamber 102 than the temperature closer to the center, resulting in the product 105 closer to the periphery being, for example, warmer than the product 105 in the center.

[0086] As another example, the distribution manifolds 107a, 107b and / or inlet 109 may have surface temperatures different from the average internal temperature of the sterilization chamber 102 (e.g., they may be cooler or warmer than the average internal temperature of the sterilization chamber 102). Furthermore, during operation of system 100, the distribution manifolds 107a, 107b, inlet 109, diaphragm (not shown), and / or piston 150 may create relatively high-pressure localized areas around them when they inject fluid into the sterilization chamber 102 or generate pressure waves. This may result in more fluid condensation in areas closer to the pressure wave source compared to more distant areas. For example, sterilizing agent dispersed from one of the distribution manifolds 107a, 107b is more likely to condense on product 105 closer to the distribution manifolds 107a, 107b than on product 105 further away.

[0087] As previously described, product 105 may include one or more semi-permeable membranes through which vapor or gas can flow, such as covers used in the packaging of medical devices or pharmaceuticals. In some cases, the semi-permeable membrane may prevent liquid from passing through. In some embodiments, it is necessary to sterilize the areas on both sides of the semi-permeable membrane.

[0088] Figure 2A , 2BDocuments 3A, 3B, 4, and 5 depict flowcharts of the stages and steps in a sterilization method according to this disclosure. As those skilled in the art will recognize, some stages and / or steps may be omitted, combined, and / or performed out of order while remaining consistent with this disclosure. In some embodiments, the time and / or steps may be run using, for example, sterilization system 100 or variations thereof. Alternatively or additionally, it is desirable that stages and / or steps be applicable to other environments in which vaporized sterilizing agents are operated. It will be appreciated that the following stages and steps can be performed using customizable and controllable aspects of sterilization system 100. For example, in some embodiments, controller 140 may be used to direct, adjust, or modify temperature, pressure, time, etc., in a series of sterilization steps, setpoints, and stages that can be performed by sterilization system 100. Furthermore, although these stages and steps described below are described with respect to sterilization system 100, those skilled in the art will understand that these stages and steps may be performed by another sterilization system or another system capable of performing these steps.

[0089] Figure 2A A flowchart depicts a series of steps in a method 200 for sterilization in a sterilization system such as sterilization system 100. According to step 206, a sterilization stage can be performed. According to step 208, a first aeration stage can be performed. According to step 210, a second aeration stage can be performed.

[0090] Prior to performing the steps of method 200, a sterilization load, such as product 105, may be placed within a sterilization chamber, such as sterilization chamber 102, of a sterilization system, such as sterilization system 100. The sterilization environment of the closed system includes, for example, sterilization chamber 102, blower outlet duct 108, blower 106, blower circulation duct 118, inlet duct 134, condenser 147, and any components connecting these parts may then be sealed. In some cases, a leak test may be performed within the sterilization environment of the closed system. A leak test may include, for example, creating a vacuum via the closed system. A vacuum may be created by, for example, discharging gases and vapors from the closed system using a vacuum pump 110. During the leak test, blower 106 may be operated, thereby circulating any remaining air through the closed system and creating a homogeneous environment. A leak test can be performed in part in this manner to verify that a suitable vacuum can be maintained within the closed system.

[0091] In some embodiments, the sterilization system (e.g., sterilization system 100) may be pretreated. Pretreatment may include, for example, raising the temperature of the closed system to a temperature to be maintained during the sterilization phase (e.g., between about 25°C and about 50°C). In some embodiments, the pretreatment run time may be longer than that performed during standard chemical sterilization, which allows more time to reduce any temperature differences between environments within the closed system (including, for example, sterilization chamber areas such as sterilization chamber 102). Alternatively or additionally, pretreatment may include, for example, pairing the temperature of a temperature control jacket (e.g., temperature control jacket 104) with the temperature of inlets such as distribution manifolds 107a, 107b, and / or inlet 109, before or during method 200. By “pairing” the temperature of the temperature control jacket with the inlet temperature, it means that the temperature control jacket is programmed to maintain the same or similar temperature as the inlet surface within the sterilization chamber. This can be advantageous because the inlet (e.g., distribution manifolds 107a, 107b, and / or inlet 109) can typically be colder than other parts of the sterilization chamber due to the temperature of, for example, the sterilizing agent, compressed air, or other fluids flowing through it. Additionally, when the temperature control jacket heats the sterilization chamber 102, the periphery of the chamber (e.g., the portion of sterilization chamber 102 closest to the temperature control jacket) can be hotter than the center of the sterilization chamber (e.g., the portion furthest from the temperature control jacket). Therefore, pairing the temperature control jacket with the inlet temperature can reduce the temperature difference throughout the sterilization chamber. In some embodiments, the temperature control jacket can be paired, for example, by setting the temperature control jacket to a known inlet temperature during a sterilization cycle. In some embodiments, the temperature control jacket can be paired by, for example, by experimentally determining the inlet temperature during one or more sterilization cycles and setting the temperature control jacket to that temperature. In other embodiments, a digital thermometer may be configured to contact or be near an inlet (e.g., distribution manifolds 107a, 107b, or inlet 109) to transmit temperature information to a controller (e.g., controller 140). For example, one or more thermometers or temperature sensors may transmit temperature information to controller 140 on alert, periodically, continuously, or dynamically (e.g., periodically based on monitoring conditions of the chamber during a sterilization cycle).

[0092] The controller 140 can also be configured to sense the temperature at or near the inlet (e.g., distribution manifolds 107a, 107b, or inlet 109). Since the surface temperatures of distribution manifolds 107a, 107b, and inlet 109 are typically lower than the average internal temperature of the sterilization chamber 102, pairing the temperature of the temperature control jacket 104 with the temperature of the inlet (e.g., distribution manifolds 107a, 107b, or inlet 109) can correct for some temperature differences present throughout the sterilization chamber, which in turn can help distribute the sterilizing agent throughout the sterilization chamber.

[0093] It is also conceivable that, in some embodiments, maintaining a temperature difference between the sterilization load and the surrounding enclosed system, creating a "cold spot," can be advantageous. For example, controlled condensation of vaporized sterilization chemicals (e.g., VHP) at the "cold spot" of the load can concentrate the sterilization chemicals on the load and cause the chemicals to diffuse more effectively into the load, thereby reducing the total amount of sterilization chemicals required to achieve effective sterilization in sterilization chamber 102. In such embodiments, reducing pretreatment time or eliminating pretreatment altogether can be advantageous.

[0094] According to step 206, a sterilization phase can be performed. The sterilization phase may include, for example, initiating the circulation of fluid through the sterilization system, reaching a vacuum level, injecting vaporized chemicals into the sterilization chamber, maintaining a post-injection hold, injecting gas into the sterilization chamber to transition to a shallower vacuum, and maintaining a post-transition hold. The sterilization phase according to step 206 can be repeated multiple times using similar or different vacuum levels, volumes of vaporized chemicals, and / or holding times. Figure 3A and 3B The sterilization stage according to step 206 is described in more detail.

[0095] According to step 208, a first aeration stage can be performed. The first aeration stage may include, for example, reaching a vacuum level, maintaining a vacuum level, breaking the vacuum level, and aerating and venting the system. The first aeration stage can be performed multiple times. Figure 4 The first aeration stage according to step 208 is described in more detail.

[0096] According to step 210, a second aeration stage can be performed. The second aeration stage may include, for example, reaching a vacuum level, maintaining a vacuum level, and breaking the vacuum level. The second aeration stage can be performed multiple times. Figure 5 The second aeration stage according to step 210 is described in more detail below.

[0097] Steps 208 and / or 210 may be performed multiple times. Furthermore, while in some embodiments step 208 may be performed before step 210, in alternative embodiments step 210 may be performed before step 208. In some embodiments, steps 208 or 210 may be completely omitted.

[0098] Figure 2BA flowchart depicts a series of steps in a method 250 for sterilization in a sterilization system such as sterilization system 100. According to step 252, a localized climate forsterilization can be maintained. According to step 254, a sterilization phase can be performed. According to step 256, a first localized climate for aeration can be maintained. According to step 258, a first aeration phase can be performed. According to step 260, a second localized climate for aeration can be maintained. According to step 262, a second aeration phase can be performed.

[0099] Prior to performing the steps of method 250, the sterilization load can be placed in a sealable sterilization chamber, a leak test can be performed, and the sterilization system can be pretreated as described above regarding method 200. Sterilization stage 254, the first aeration stage 258, and the second aeration stage 262 can be performed in any manner suitable for sterilization stage 206, the first aeration stage 208, and the second aeration stage 210, respectively. Steps 258 and / or 262 can be performed multiple times. Furthermore, although in some embodiments step 258 may be performed before step 262, in alternative embodiments step 258 may be performed before step 262. In some embodiments, steps 258 or 262 may be completely omitted.

[0100] Steps 254, 258, and 262 may precede the step of maintaining a local climate. Maintaining a local climate typically refers to ensuring that one or more areas within a sterilization system (e.g., sterilization system 100) exhibit conditions (e.g., temperature, pressure, water vapor concentration, sterilizing agent concentration, etc.) suitable for the steps to be performed in the sterilization process. Maintaining a consistent or targeted local climate can contribute to strong sterilization and aeration effects. A local climate may attract or repel sterilizing agents to one or more specific locations within the system. If controlled, such a local climate can help achieve the desired sterilization level. For example, the inlet and / or trolley supporting the sterilization load may be heated to prevent sterilizing agent condensation. The load itself (e.g., packaging) may be kept at a temperature below the trolley temperature to attract VHP or promote adhesion and condensation. Larger loads may also be used to reduce peak load temperatures.

[0101] Furthermore, maintaining a local climate can help distribute or remove sterilizing agents from more difficult locations within the sterilization system, thereby reducing the amount of "overkill" required to sterilize or aerate these locations. Directing sterilizing agents to areas previously proven difficult to meet sterilization criteria (e.g., biological indicator metrics) can normalize sterilization in those areas without requiring additional sterilizing agents. Similarly, removing sterilizing agents from previously difficult-to-aerate locations reduces the total aeration and drying time in the methods described herein.

[0102] like Figure 2B As shown, a localized sterilization climate can be maintained, such as in step 252. This may include using, for example, a temperature difference to draw the sterilizing agent to an area within the system. In some embodiments, this may be achieved by altering the temperature of one or more locations to lower the temperature of the location where the sterilizing agent should be moved. For example, because the heating elements are located on the periphery of the chamber (e.g., temperature control jacket 104 of system 100), the periphery of the sterilization chamber may be hotter than the center of the chamber. Maintaining a localized climate for sterilization on the periphery of the sterilization chamber may therefore include lowering the temperature on the periphery of the sterilization chamber by, for example, lowering the target temperature of the heating elements (e.g., temperature control jacket 104). According to step 254, maintaining the localized climate for sterilization according to step 252 may continue throughout the execution of the sterilization phase.

[0103] A first local climate for aeration can be maintained according to step 256, and a second local climate for aeration can be maintained according to step 260. Each of the first and second local climates for aeration may include, for example, increasing the temperature at a location within the sterilization system or decreasing the humidity at a location within the sterilization system. The first and second local climates can each be maintained during the first aeration phase 258 and the second aeration phase 262, respectively.

[0104] Figure 3AThis is a flowchart of sterilization stage 300, such as step 206 of sterilization method 200 or step 254 of method 250. Prior to sterilization stage 300, a sterilization load (e.g., product 105) may be introduced into sterilization chamber 102. According to step 302, a vacuum level can be achieved. According to step 304, vaporized chemicals may be injected into the sterilization chamber. According to step 306, post-injection hold may be maintained. According to step 308, gas may be injected into the sterilization chamber to transition to a shallower vacuum. According to step 310, post-injection hold may be maintained. Sterilization stage 300 may be repeated multiple times, for example, between 2 and 15 times, between 2 and 12 times, between 2 and 10 times, between 2 and 8 times, between 2 and 6 times, between 2 and 5 times, or between 2 and 4 times, such as 2, 3, 4, 5, 6, 7, or 8 times. A single iteration of a sterilization phase (e.g., sterilization phase 300) can be referred to as a "pulse".

[0105] As part of the sterilization stage 300, turbulence can be initiated and maintained in the sterilization system 100.

[0106] According to step 302, a vacuum level can be achieved within the sterilization chamber 102 of the sterilization system 100. The vacuum level can be, for example, between about 400 mbar and about 700 mbar, such as between about 450 mbar and about 650 mbar, or between about 450 mbar and about 550 mbar. For example, the vacuum can be about 450 mbar, about 500 mbar, about 550 mbar, or about 600 mbar. This vacuum can promote a higher concentration of sterilizing chemicals on the sterilization load, and extending the time the closed system maintains a deeper vacuum will increase the exposure of the sterilization load to the sterilizing chemicals.

[0107] According to step 304, a vaporized chemical may be injected into the sterilization chamber. In some embodiments, the vaporized chemical may include VHP. In some embodiments, the vaporized sterilization chemical may be a vaporized aqueous hydrogen peroxide solution having a hydrogen peroxide concentration, for example, between about 5% and about 75% by weight. In some embodiments, the vaporized chemical may be a vaporized aqueous hydrogen peroxide solution having a hydrogen peroxide concentration, for example, between about 10% and about 65% by weight, between about 15% and about 60% by weight, or between about 45% and about 60% by weight. In some embodiments, the vaporized chemical may be vaporized aqueous hydrogen peroxide having a concentration of about 35% hydrogen peroxide (and 65% water) by weight. In a further embodiment, the vaporized chemical may be vaporized aqueous hydrogen peroxide having a concentration of about 59% hydrogen peroxide (and 41% water) by weight.

[0108] In some embodiments, the VHP injection supply may be, for example, between about 50 g and about 700 g of aqueous VHP. For example, the VHP injection supply may be between about 50 g and about 600 g, about 100 g and about 600 g, about 300 g and about 550 g, or about 450 g and about 550 g. For example, the VHP injection supply may be about 100 g, about 200 g, about 300 g, about 400 g, about 450 g, about 475 g, about 500 g, about 525 g, about 550 g, about 600 g, or about 650 g. In some embodiments, the VHP injection supply may be quantified based on the volume or amount of the load to be sterilized within the sterilization chamber 102. For example, if a number of pharmaceutical products, such as pre-filled syringes, are to be sterilized in sterilization chamber 102, the injected VHP supply may be between approximately 0.01 and approximately 0.15 grams of VHP per unit of pharmaceutical product within sterilization chamber 102, for example, between approximately 0.01 and approximately 0.10 grams of VHP, such as approximately 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.04 g, 0.05 g, 0.06 g, 0.07 g, 0.08 g, 0.09 g, 0.1 g, or 0.11 g / pharmaceutical. In other embodiments, the injected VHP supply may be quantified based on the volume of the sterilization environment, such as the interior of sterilization chamber 102. For example, the injected VHP supply may be approximately 0.2 to 3.0 g / cubic foot of volume within the sterilization chamber. For example, the VHP injection supply can be between approximately 0.2 and approximately 2.0 grams per cubic foot, such as approximately 0.25 grams, approximately 0.50 grams, approximately 0.75 grams, approximately 1.0 gram, approximately 1.2 grams, approximately 1.4 grams, approximately 1.5 grams, approximately 1.6 grams, approximately 1.8 grams, or approximately 2.0 grams per cubic foot. In some embodiments, the VHP injection supply can be based on the amount of VHP injected into the sterilization chamber in a previous iteration of sterilization stage 300. For example, a first amount of VHP can be injected into the sterilization chamber in the first iteration of sterilization stage 300. In the second iteration of sterilization stage 300, a second amount of VHP, less than the first amount, can be injected into the sterilization chamber based on the amount injected in the first iteration. In the third iteration of sterilization stage 300, a third amount of VHP, less than the second amount, can be injected into the sterilization chamber based on a combination of the amounts injected in the first and second iterations.

[0109] In some implementations, the VHP injection supply can be based on a combination of the amount of VHP already present in the sterilization chamber and the desired pressure increase caused by injecting additional VHP into the sterilization chamber. The desired pressure increase caused by injecting VHP into the sterilization chamber can be inversely proportional to the amount of hydrogen peroxide already present in the sterilization chamber. Advantageously, as the amount of VHP in the sterilization chamber increases, a lower pressure increase helps reduce undesirable VHP condensation that may be caused by excessive pressure increase. Undesirable VHP condensation can lead to reduced sterilization efficiency and reduced aeration efficiency.

[0110] According to step 306, a post-injection hold can be maintained. During the post-injection hold, turbulence is maintained by a closed system including sterilization chamber 102 and blower 106. No fluid is added to or removed from the closed system maintaining turbulence. The duration of the post-injection hold (or "post-injection hold time") can be selected to allow sufficient time for the vaporized sterilizing chemicals to contact the load without condensation. In some embodiments, the post-injection hold time can be between about 2 minutes and about 20 minutes. In some embodiments, the post-injection hold time can be at least about 5 minutes, at least about 10 minutes, or at least about 15 minutes. In some embodiments, the post-injection hold time can be between about 5 minutes and about 20 minutes, between about 8 minutes and about 20 minutes, between about 10 minutes and about 20 minutes, or between about 10 minutes and about 15 minutes. In this way, it is avoided that excessive VHP needs to be added to the system to ensure its contact with the sterilized load.

[0111] According to step 308, gas may be injected into the sterilization chamber to transition to a shallower vacuum (i.e., a higher pressure) within the sterilization chamber. The gas may be any suitable gas capable of disrupting or reducing the vacuum in sterilization chamber 102. In some embodiments, the gas may be a dry gas, such as a nitrogen-containing gas (e.g., a commercially available product that supplies only or primarily nitrogen), or air having a dew point of, for example, -10°C or lower. The use of a dry gas may be chosen to allow for adequate air exchange and reduce humidity within the sterilization chamber, thereby further avoiding unnecessary condensation. In some embodiments, the gas may be injected from a dry air supply source 130. A volume of gas may be injected to achieve a pressure between approximately 500 mbar and approximately 1100 mbar, for example, between approximately 550 mbar and approximately 1000 mbar, between approximately 600 mbar and approximately 1000 mbar, between approximately 700 mbar and approximately 900 mbar, or between approximately 750 mbar and approximately 850 mbar. For example, the pressure after the second injection can be approximately 700 mbar, approximately 750 mbar, approximately 800 mbar, approximately 850 mbar, or approximately 900 mbar. In cases where the sterilization load includes a semi-permeable membrane through which the sterilizing agent is desired to pass, the pressure increase resulting from step 308 can be used to facilitate the migration of the sterilizing agent through the semi-permeable membrane.

[0112] According to step 310, a post-transition hold can be maintained. During the post-transition hold, the pressure reached during step 308 can be maintained, for example, for at least about 5 minutes, at least about 10 minutes, or at least about 15 minutes. In some embodiments, the second post-injection pressure can be maintained between about 5 minutes and about 20 minutes, between about 8 minutes and about 20 minutes, between about 10 minutes and about 20 minutes, or between about 10 minutes and about 15 minutes.

[0113] In some embodiments, the number of repeatable sterilization phase 300 (e.g., the number of pulses) may be inversely proportional to the post-injection hold time in each repeat. For example, if the post-injection hold time is short (e.g., 10 minutes), steps 210 to 216 may be repeated more times. In some embodiments, the post-injection hold may be maintained for a longer period (e.g., 15 to 20 minutes) to increase the time the sterile load is exposed to the sterilizing chemicals in each repeat of sterilization phase 300. In further embodiments, the number of repeatable sterilization phase 300 may depend on the total amount of VHP used in the sterilization process. In some embodiments, for example, it may be necessary to inject a total amount of at least 200 g of VHP. For example, in some embodiments, it may be necessary to inject a total amount of at least 250 g. In some embodiments, it may be necessary to inject a total amount of VHP between about 200 g and about 700 g. In some embodiments, the number of repeatable sterilization phase 300 may depend on a combination of factors that ensure complete penetration of VHP through the sterile load and ensure sufficient contact time between hydrogen peroxide and the load to allow sterilization.

[0114] Figure 3B This is a flowchart of a sterilization phase 400 comprising multiple sterilization pulses 420, 440, and 460. Each sterilization pulse may include injecting different amounts of VHP into the sterilization chamber, may include different holding times and pressure variations, and may be performed once or multiple times. According to step 402, an initial vacuum level can be achieved. During pulse 420, a first amount of vaporized chemical may be injected into the sterilization chamber (step 422), a first post-injection hold may be maintained (step 424), gas may be injected into the sterilization chamber to increase the pressure in the sterilization chamber (step 426), and a first post-transition hold may be maintained (step 428). During pulse 440, a second amount of vaporized chemical may be injected into the sterilization chamber (step 422), a second post-injection hold may be maintained (step 424), gas may be injected into the sterilization chamber to increase the pressure in the chamber (step 426), and a second post-transition hold may be maintained (step 428). During pulse 460, a third amount of vaporized chemicals may be injected into the sterilization chamber (step 422), and a third post-injection hold may be maintained (step 424). Gas may be injected into the sterilization chamber to increase the pressure in the chamber (step 426), and a third post-transition hold may be maintained (step 428).

[0115] As previously described, the pressure increase caused by each sterilization pulse (pulses 420, 440, 460) reflects the existing concentrations of sterilizing agent and water (e.g., hydrogen peroxide) in the sterilization chamber. When the existing concentration is low (or zero), for example before pulse 420, a greater pressure increase can be used to maximize the rate at which the sterilizing agent is introduced into the load. Therefore, the first amount of vaporized chemical introduced according to step 422 can be greater than the second or third amount of vaporized chemical introduced according to steps 442 or 462.

[0116] In cases where sterilizing agents are expected to pass through a semipermeable membrane (e.g., a Teflon membrane covering a medical device or product), delays in the transport of some sterilizing agents (e.g., hydrogen peroxide) across the membrane have been observed. Furthermore, in some sterilization cycles, the concentration of hydrogen peroxide in areas blocked by the semipermeable membrane has been observed to be generally lower (or “weaker”) than in areas not blocked by the semipermeable membrane. Water does not exhibit this transport delay or weakening. As a result, the strength and efficacy of the sterilizing agent (particularly the strength and efficacy of hydrogen peroxide) in areas blocked by the semipermeable membrane may be reduced. The third amount of vaporized chemical introduced according to step 462 can particularly help overcome this transport delay and weakened sterilizing agent concentration. The third amount of vaporized chemical may be less than the first amount of vaporized chemical introduced according to step 422 or the second amount of vaporized chemical introduced according to step 424 to avoid a rapid increase in pressure and excessive condensation that could hinder the migration of the sterilizing agent through the semipermeable membrane.

[0117] In view of the above principles, in some embodiments, the first amount of sterilizing agent injected according to step 422 may be greater than the second amount of sterilizing agent injected according to step 442, and the second amount of sterilizing agent injected according to step 442 may be greater than the third amount of sterilizing agent injected according to step 462. For example, the first amount of sterilizing agent may be a large dose (e.g., a large amount) to establish a lethal concentration in the sterilization chamber, the second amount (e.g., a medium amount) may be selected to maintain the concentration and meet the holding time requirements, and the third amount (e.g., a small amount) may be selected to overcome the delay in sterilizing agent transport and the weakening of penetration through the semipermeable membrane.

[0118] For example, a large quantity may include 15 grams of 35% by weight of H2O2 per cubic meter of sterilization chamber volume, a medium quantity may include 7.5 grams of 35% by weight of H2O2 per cubic meter of sterilization chamber volume, and a small quantity may be 0.5 grams of 35% by weight of H2O2 per cubic meter of sterilization chamber volume.

[0119] The duration of each post-injection hold (424, 444, 464) may depend on the volume of vaporized sterilizing agent in the sterilization chamber prior to the post-injection hold, and the pressure within the sterilization chamber prior to the post-injection hold. In some embodiments, each post-injection hold (424, 444, 464) may be shorter than the time required for the vaporized sterilizing agent to condense within the sterilization chamber. This allows more sterilizing agent to remain in vapor form when gas is injected into the sterilization chamber according to steps 426, 446, 466. For example, each post-injection hold (424, 444, 464) may have a duration of ten minutes or less, such as eight minutes or less, six minutes or less, four minutes or less, three minutes or less, or less than three minutes.

[0120] The duration of each post-transition hold (428, 448, 468) is sufficient to expose the surfaces within the sterilization chamber to the sterilizing agent, thereby effectively sterilizing these surfaces. For example, each post-transition hold (428, 448, 468) may have a duration of 10 minutes or less, such as 8 minutes or less, 6 minutes or less, 4 minutes or less, 3 minutes or less, or less than 3 minutes. In some embodiments, the post-transition hold may be stopped after approximately half of the peak VHP concentration has been reached.

[0121] As previously described, each of pulses 420, 440, and 460 may be performed once or multiple times. In some embodiments, pulse 420 may be performed once, and pulses 440 and 460 may each be performed multiple times. For example, pulse 420 may be repeated once or twice, pulse 440 may be repeated once or twice, and pulse 460 may be repeated 2 to 10 times. In some embodiments, pulse 440 or pulse 460 may be canceled from sterilization stage 400. For sterilization loads comprising more semipermeable membranes or VHP-resistant materials, more pulses 420 comprising large doses of sterilizing agent may be used.

[0122] During the sterilization phases, such as sterilization phases 206, 254, 300, and / or 400, it may be beneficial to regulate the rate of pressure change so that the pressure decrease is slower than the pressure increase. For example, steps 304, 308, 422, 426, 442, 446, 462, and 466, which include or cause a pressure increase within the sterilization chamber (e.g., adding fluid, breaking a vacuum, or via a diaphragm or piston 150 within sterilization chamber 102), may include a situation where the pressure within the sterilization chamber is increased more rapidly than the pressure decrease in step 302 or 402, which includes reaching a vacuum level. This can facilitate the permeation of the sterilizing agent through the sterilization chamber and the load, including the portion of the load enclosed within a semi-permeable membrane.

[0123] Figure 4 This is a flowchart of the first aeration stage 320, which can be performed as step 208 of sterilization method 200, after one or more repeated sterilization stages are performed according to step 206. According to step 322, a vacuum level can be reached. According to step 324, the vacuum level can be maintained. According to step 326, the vacuum level can be broken. According to step 328, the sterilization system (e.g., sterilization system 100) can be aerated and vented.

[0124] According to step 322, a vacuum level can be achieved in sterilization chamber 102 while dry gas is injected, for example, via distribution manifold 107a or inlet 109, into the vicinity of the upper interior 101 of sterilization chamber 102 and / or via distribution manifold 107b into the vicinity of the lower interior 103 of sterilization chamber 102. The dry gas facilitates air exchange without promoting condensation of the sterilizing agent. The dry gas may include, for example, oxygen and / or nitrogen. The dry gas may have a dew point of, for example, -10°C or lower. The dry gas may be injected from, for example, an auxiliary dry air supply source 130 or a dry supplement air supply source 127. While the dry gas is injected into sterilization chamber 102, a vacuum can be evacuated, for example, via vacuum pump 110 through vacuum conduit 112, catalytic converter 115, and vacuum exhaust conduit 114. The vacuum level can be gradually achieved by evacuating at a rate faster than the dry gas injection rate. For example, the vacuum level can be between approximately 500 mbar and approximately 850 mbar, such as between approximately 500 mbar and approximately 800 mbar, between approximately 550 mbar and approximately 750 mbar, or between approximately 600 mbar and approximately 700 mbar. For example, the vacuum level can be 500 mbar, 550 mbar, 600 mbar, 650 mbar, or 700 mbar. Injecting dry gas near the upper interior 101 of the sterilization chamber 102 while achieving the desired vacuum level reduces the condensation of VHP and water vapor in the upper interior 101 of the chamber and promotes the movement of denser molecules in the sterilization chamber toward the lower interior (e.g., lower interior 103) of the sterilization chamber 102, and to some extent exits the sterilization system 100 via the vacuum exhaust duct 114.

[0125] According to step 324, the injection of dry gas can be stopped and the vacuum level can be maintained, for example, between about 1 minute and about 20 minutes, such as between about 2 minutes and about 20 minutes, between about 5 minutes and about 20 minutes, between about 5 minutes and about 15 minutes, or between about 5 minutes and about 10 minutes. For example, the vacuum level can be maintained for about 2, 5, 8, 10, or 15 minutes. Maintaining the vacuum level can continue to promote the downward settling of denser molecules (e.g., sterilizing chemical molecules) toward the lower interior 103 of the sterilization chamber 102, away from the sterilization load.

[0126] According to step 326, the vacuum level can be disrupted by adding more dry gas near the upper interior 101 of the sterilization chamber 102 via, for example, distribution manifold 107a or inlet 109, or by adding more dry gas near the lower interior 103 of the sterilization chamber 102 via distribution manifold 107b. A sufficient volume of dry gas can be added to achieve a higher pressure. For example, the higher pressure can be 50 to 200 mbar higher than the vacuum level achieved in step 322. Adding more dry gas can further force the sterilizing chemicals to settle into the lower interior 101 of the sterilization chamber 102, thereby moving them away from the sterilization load and positioning them for removal via vacuum conduit 112 or blower outlet conduit 108.

[0127] According to step 328, the sterilization system (e.g., sterilization system 100) can be aerated and vented. During this step, when the recirculation valve 119 is closed and the vent valve 120 is open, the blower 106 can be turned on, causing the blower 106 to draw fluid from the sterilization chamber 102 and discharge it through the catalytic converter 121 and vent through the vent 116. Because the blower outlet pipe 108 is connected to the sterilization chamber 102 at the lower interior 103, denser fluids (such as sterilization chemicals) that have settled into the lower interior 103 can be removed by this step. Air (e.g., from a humid make-up air supply source 117 or a dry make-up air supply source 127) can also be allowed to be discharged into the sterilization chamber 102, thereby restoring the pressure in the sterilization chamber 102 to or near atmospheric pressure.

[0128] The first aeration phase 320 can be repeated, for example, between 1 and 35 times, such as 2, 5, 10, 15, 17, 19, 22, 25, 27, 29, 30, 32, or 35 times. Repeating the first aeration phase 320 ensures that most sterilization chemicals (e.g., VHP) are removed from the sterilization system 100.

[0129] Figure 5 This is a flowchart of the second aeration stage 340, which can be performed as step 210 of sterilization method 200. According to step 342, a vacuum level can be achieved. According to step 344, the vacuum level can be maintained. According to step 346, the vacuum level can be broken.

[0130] According to step 342, a vacuum level can be achieved in sterilization chamber 102. Similar to the first aeration stage, the vacuum level achieved in this stage can be, for example, between about 500 mbar and about 850 mbar, such as between about 500 mbar and about 800 mbar, about 550 mbar and about 750 mbar, or about 600 mbar and about 700 mbar. For example, the vacuum level can be 500 mbar, 550 mbar, 600 mbar, 650 mbar, or 700 mbar. Achieving the vacuum level facilitates the removal of moisture from sterilization chamber 102 and from the sterilization load. Therefore, the sterilization load can be dried.

[0131] According to step 344, the vacuum level can be maintained, for example, between about 1 minute and about 20 minutes, for example, between about 2 minutes and about 20 minutes, between about 5 minutes and about 20 minutes, between about 5 minutes and about 15 minutes, or between about 5 minutes and about 10 minutes. For example, the vacuum level can be maintained for about 2, 5, 8, 10, or 15 minutes. Maintaining the vacuum level can continue to promote the removal of moisture from the sterilization chamber 102 and from the sterile load. Therefore, the sterile load can be further dried. In some embodiments, step 344 can be omitted.

[0132] According to step 346, the vacuum level in sterilization chamber 102 can be disrupted or increased to a higher pressure by adding dry gas from, for example, auxiliary dry air supply source 130 and / or dry supplement air supply source 127.

[0133] The second aeration phase 340 can be repeated, for example, between 1 and 50 times, such as 2, 5, 10, 15, 20, 25, 30, 35, 38, 40, 42, 45, 47, 49, or 50 times. The repetition of the second aeration phase 340 ensures the dryness of the sterilization chamber 102 and the sterilization load.

[0134] As previously described, the second aeration stage 340 can be performed before or after the first aeration stage 320. The first aeration stage 320 ensures, for example, a relatively low concentration of sterilizing chemicals (e.g., VHP) in the sterilization chamber 102, and the second aeration stage 340 ensures the sterilization load is dried and also removes residual sterilizing chemicals in the sterilization chamber 102 after the first aeration stage 320. When the second aeration stage 340 is performed after the first aeration stage 320, the first aeration stage ensures a relatively low concentration of sterilizing chemicals (e.g., VHP) in the sterilization chamber 102, so that when the sterilization chamber 102 and the sterilization load are dried in the second aeration stage 340, it is almost unnecessary to remove sterilizing chemical residues from the sterilization system 100.

[0135] In some embodiments, prior to performing the first aeration stage 320 or the second aeration stage 340, it may be desirable to achieve and / or maintain a suitable local climate for aeration, as previously described with respect to steps 258 and 262 of the sterilization method 250.

[0136] In some embodiments, pressure increases to atmospheric pressure can be avoided before performing the first aeration stage 320 or the second aeration stage 340, when the concentration of the sterilizing agent in the sterilization chamber is at or near saturation (e.g., after the sterilization stage is completed). Immediately increasing the pressure to atmospheric pressure when the sterilization chamber is saturated or near saturation with the sterilizing agent may cause unnecessary condensation of the sterilizing agent, resulting in reduced aeration efficiency.

[0137] Before or during the first aeration stage 320 or the second aeration stage 340, repeated inflection changes in pressure (e.g., suction and pressurization) can facilitate physical movement of packaging components such as sleeves, caps, and films. Physical movement of a portion of the sterilized load can help remove sterilizing agents adhering to the load, thereby promoting effective aeration.

[0138] Furthermore, the temperature in the sterilization chamber or sterilization system can be increased before or during the first aeration stage 320 or the second aeration stage 340. This can improve aeration efficiency.

[0139] Furthermore, during the aeration phases (e.g., aeration phases 208, 210, 258, 262, 320, 340), it is beneficial to regulate the rate of pressure change so that the pressure increase is slower than the pressure decrease. For example, steps 322, 328, and 342, which include reaching a vacuum level and aerating / venting the system, may include a faster reduction in pressure within the sterilization chamber compared to the pressure increase in steps 326 and 346, which include breaking the vacuum level. This can facilitate the removal of sterilizing agents from the sterilization chamber and the load.

[0140] In some embodiments, any or all of the above steps and stages may be performed automatically by a sterilization system (e.g., sterilization system 100) instructed by, for example, controller 140, which may be programmed or otherwise pre-configured by, for example, a user. The sterilization method disclosed herein may be referred to as a “limited overkill” sterilization method because it ensures sterilization of loads such as PFS while minimizing the impact of the sterilization method on the product.

[0141] This document has described several sterilization and aeration stages. It should be understood that the characteristics, methods, or steps of any sterilization stage can be applied to any other sterilization method described herein. Similarly, the characteristics, methods, or steps of any aeration stage described herein can be applied to any other aeration stage.

[0142] Example

[0143] The following examples are intended to illustrate the content of this disclosure and are not inherently limiting. It should be understood that this disclosure includes additional aspects and implementations consistent with the foregoing description and the following examples.

[0144] Example 1

[0145] In one example, a sterilization load comprising 24 biological indicators was loaded into a sterilization chamber and a sterilization method was performed. The sterilization method included a leak test, a pretreatment phase, a sterilization phase with one sterilization pulse, and two aeration phases. Table 1 summarizes the exact parameters of the sterilization method.

[0146] Table 1

[0147]

[0148] During the sterilization method of Example 1, the pressure in the sterilization chamber and the temperature of the load were measured and shown. Figure 6 .

[0149] Example 2

[0150] In another example, a sterilization load comprising 20 biological indicators was loaded into a sterilization chamber and sterilization was performed. The sterilization method included a leak test, a pretreatment phase, and a sterilization phase with two sterilization pulses. Table 2 summarizes the exact parameters of the sterilization method. The temperature of the sterilization load was monitored to ensure it did not exceed 33°C.

[0151] Table 2

[0152]

[0153] During the sterilization method of Example 2, the pressure in the sterilization chamber and the temperature of the load were measured and shown. Figure 7 .

[0154] Example 3

[0155] The sterilization load, comprising 24 biological indicators, was loaded into the sterilization chamber and sterilization was performed. The sterilization method included a leak test, a pretreatment phase, a sterilization phase with two sterilization pulses, and two aeration phases. Table 3 summarizes the exact parameters of the sterilization method.

[0156] Table 3

[0157]

[0158]

[0159] During the sterilization method of Example 3, the pressure in the sterilization chamber and the temperature of the load were measured and shown. Figure 8A.

[0160] Example 4

[0161] The sterilization load, comprising 24 biological indicators, was loaded into the sterilization chamber and sterilization was performed. The sterilization method included a leak test, a pretreatment phase, a sterilization phase with two sterilization pulses, and two aeration phases. Table 4 summarizes the exact parameters of the sterilization method.

[0162] Table 4

[0163]

[0164]

[0165] During the sterilization method of Example 4, the pressure in the sterilization chamber and the temperature of the load were measured and shown. Figure 8B .

[0166] Example 5

[0167] The sterilization load, comprising 24 biological indicators, was loaded into the sterilization chamber and sterilization was performed. The sterilization method included a leak test, a pretreatment phase, a sterilization phase with three sterilization pulses, and two aeration phases. Table 5 summarizes the exact parameters of the sterilization method.

[0168] Table 5

[0169]

[0170]

[0171] During the sterilization method of Example 5, the pressure in the sterilization chamber and the temperature of the load were measured and shown in [the table / document]. Figure 9A .

[0172] Example 6

[0173] The sterilization load, comprising 24 biological indicators, was loaded into the sterilization chamber and sterilization was performed. The sterilization method included a leak test, a pretreatment stage, a sterilization stage with three sterilization pulses, and two aeration stages. Table 6 summarizes the exact parameters of the sterilization method.

[0174] Table 6

[0175]

[0176]

[0177] During the sterilization method of Example 6, the pressure in the sterilization chamber and the temperature of the load were measured and shown. Figure 9B .

[0178] The efficacy and sterilization efficiency of the sterilization protocols from Examples 1 to 6 were evaluated using chemical indicators, biological indicators, temperature loggers, humidity loggers, VHP monitors, and a handheld Dragar VHP monitoring device. These results are summarized in Table 7.

[0179] Table 7

[0180]

[0181] As shown in Table 7, sterilization methods comprising multiple sterilization pulses prevented the growth of biological indicators. Although not shown in Table 7, each exemplary sterilization method also resulted in a residual VHP of less than 1.0 parts per million. Based on data observed from the exemplary sterilization methods, effective sterilization was determined to be achieved using at least 300 g of 57 wt% H2O2 solution and a sterilization time of 1 hour at a cycling temperature below 35°C and a vacuum pressure greater than 480 mbar. This is a more efficient sterilization protocol than previous methods requiring at least 500 g of 57 wt% H2O2 solution and a sterilization time of at least 2 hours and 15 minutes. Compared to methods known in the art, this more efficient protocol means that more loads (e.g., more pre-filled syringes containing drugs) can be sterilized per hour.

[0182] The above descriptions and examples are illustrative and not limiting. For example, and as already described, the above embodiments (and / or aspects thereof) can be used in combination with each other.

Claims

1. A sterilization method, comprising: Pre-treatment of sterilization equipment, the sterilization equipment including a sterilization chamber including a sterilization load, wherein pre-treatment of the sterilization equipment includes raising the temperature of a portion of the sterilization equipment to a temperature greater than the highest temperature of the sterilization load, the portion of the sterilization equipment including an inlet and a conduit connecting a VHP injector to the inlet; Perform a sterilization phase, which includes multiple sterilization pulses; as well as The aeration phase is performed, which includes multiple aeration pulses, including primary aeration pulses and secondary aeration pulses. The primary aeration pulse includes: A first vacuum pressure is reached in the sterilization chamber, wherein the first vacuum pressure is 500 to 850 millibars; and After the initial vacuum period, the pressure in the sterilization chamber is increased to a level greater than 700 mbar; and This secondary aeration pulse includes: A second vacuum pressure is achieved within the sterilization chamber, wherein the second vacuum pressure is less than 650 mbar; and After the second vacuum is maintained, air is added to the sterilization chamber while the sterilization equipment is vented.

2. The sterilization method of claim 1, wherein the plurality of aeration pulses includes a first primary aeration pulse, followed by a first secondary aeration pulse, followed by a second primary aeration pulse, and then a second secondary aeration pulse.

3. The sterilization method of claim 1, wherein each sterilization pulse comprises: The sterilization pressure is reached in the sterilization chamber; as well as When the sterilization chamber is at the sterilization pressure, vaporized hydrogen peroxide is added to the sterilization chamber.

4. The sterilization method according to claim 3, wherein the sterilization pressure is less than or equal to 650 mbar.

5. The sterilization method as described in claim 1, further comprising: Dry air is added to the sterilization chamber after the sterilization stage and before the aeration stage.

6. The sterilization method of claim 1, wherein the sterilization chamber includes a piston or diaphragm configured to regulate the pressure of the sterilization chamber, and the method further includes: After the sterilization stage, a low-frequency pressure wave is generated using the piston or the diaphragm.

7. The sterilization method of claim 6, wherein the low-frequency pressure wave moves the liquid hydrogen peroxide in contact with the sterilization load.

8. The sterilization method of claim 1, wherein the sterilization loading material comprises a Tefal envelope.

9. A sterilization method, characterized in that... include: Pre-treating a sterilization device, the sterilization device including a sterilization chamber including a sterilization load, wherein pre-treating the sterilization device may include raising the temperature of a portion of the sterilization device to a temperature greater than the highest temperature of the sterilization load, wherein the portion of the sterilization device includes an inlet and a conduit connecting a VHP injector to the inlet; The sterilization phase includes a first sterilization pulse, a second sterilization pulse, and a third sterilization pulse, wherein each of the sterilization phases includes: Sterilization pressure is reached in the sterilization chamber; and When the sterilization chamber is under sterilization pressure, a certain amount of vaporized hydrogen peroxide is added to the sterilization chamber; and The aeration phase includes: A vacuum pressure is achieved within the sterilization chamber, wherein the vacuum pressure is less than 650 mbar; and After maintaining the vacuum, air is added to the sterilization chamber, and the sterilization equipment is vented. The amount of vaporized hydrogen peroxide added to the sterilization chamber during the first sterilization pulse is sufficient to establish a lethal concentration of hydrogen peroxide in the sterilization chamber. The amount of vaporized hydrogen peroxide added to the sterilization chamber during the second sterilization pulse is less than the amount of vaporized hydrogen peroxide added to the sterilization chamber during the first sterilization pulse; and The amount of vaporized hydrogen peroxide added to the sterilization chamber during the third sterilization pulse is less than the amount of vaporized hydrogen peroxide added to the sterilization chamber during the second sterilization pulse.

10. The method of claim 9, wherein, The first sterilization pulse is repeated at least once before the second sterilization pulse.

11. The method of claim 9, wherein the third sterilization pulse is repeated at least twice.

12. The method of claim 9, wherein the amount of vaporized hydrogen peroxide added to the sterilization chamber during the first sterilization pulse comprises at least 0.1 moles of hydrogen peroxide per cubic meter of the sterilization chamber volume.

13. The method of claim 9, wherein each of the sterilization pulses further comprises: (i) Gas is added to the sterilization chamber to increase the pressure to a holding pressure, wherein the holding pressure is greater than 700 mbar; as well as (ii) Reduce the pressure of the sterilization chamber to the sterilization pressure.

14. The method of claim 13, wherein step (i) takes more time than step (ii).

15. The method of claim 14, wherein each of the sterilization pulses further comprises: Before step (i), the pressure in the sterilization chamber is maintained for a first holding time; After step (ii), the pressure in the sterilization chamber is maintained for a second holding time; The second holding time is longer than the first holding time.

16. The method of claim 9, wherein the sterilization chamber includes a distribution manifold, an inlet, and a chamber wall, and the method further includes: During the first sterilization pulse, the second sterilization pulse, and the third sterilization pulse, the temperature of the chamber wall is maintained to be approximately the same as the temperature of the inlet or the temperature of the distribution manifold.

17. A sterilization method, characterized in that... include: Pre-treating a sterilization device, the sterilization device including a sterilization chamber including a sterilization load, wherein pre-treating the sterilization device may include raising the temperature of a portion of the sterilization device to a temperature greater than the highest temperature of the sterilization load, wherein the portion of the sterilization device includes an inlet and a conduit connecting a VHP injector to the inlet; The first sterilization pulse includes adding a first amount of vaporized hydrogen peroxide to the sterilization chamber, wherein the first amount is sufficient to establish a lethal concentration of hydrogen peroxide in the sterilization chamber; Multiple second sterilization pulses, wherein each second sterilization pulse includes adding a second amount of vaporized hydrogen peroxide to the sterilization chamber, wherein the second amount is less than the first amount; as well as Multiple third sterilization pulses, wherein each third sterilization pulse includes adding a third amount of vaporized hydrogen peroxide to the sterilization chamber, wherein the third amount is less than the second amount.

18. The method of claim 17, wherein the sterilization chamber includes a loading material, and the loading material includes a Teflon material defining the interior and exterior of the loading material; and After multiple third sterilization pulses, the hydrogen peroxide concentration inside the load is approximately equal to the hydrogen peroxide concentration outside the load.

19. The method of claim 17, further comprising executing an aeration pulse, comprising: (i) Reduce the pressure in the sterilization chamber to a first aeration pressure, wherein the first aeration pressure is less than 650 mbar; as well as (ii) Increase the pressure of the sterilization chamber to a second aeration pressure, wherein the second aeration pressure is greater than 700 mbar; The rate of pressure change in step (ii) is at least 100 mbar / min faster than the rate of pressure change in step (i).

20. The method of claim 19, further comprising removing moisture from the sterilization chamber by passing the contents of the sterilization chamber through a condenser prior to the aeration stage.

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