Method and system for sterilization

Abstract

The sterilization method comprises preconditioning a sterilization apparatus including a sterilization chamber (102) containing an article (105) to be sterilized, the preconditioning comprising raising the temperature of a portion of the sterilization apparatus to a temperature greater than the maximum temperature of the article (105) to be sterilized, performing a sterilization phase (206) including a number of sterilization pulses (420, 440, 460), and performing an aeration phase (208) including a number of aeration pulses. The multiple aeration pulses include a primary aeration pulse comprising achieving (342) a first vacuum pressure in the sterilization chamber (102) below 65 kilopascals (650 millibars) and increasing (346) the pressure of the sterilization chamber (102) to a pressure greater than 70 kilopascals (700 millibars) after the first vacuum hold (344), and a secondary aeration pulse comprising achieving (322) a second vacuum pressure in the sterilization chamber (102) below 65 kilopascals (650 millibars) and adding (326) air to the sterilization chamber (102) while evacuating (328) the sterilizer after the second vacuum hold (324).

Description

[Technical field]

[0001] Various embodiments of the present disclosure relate to sterilization systems and methods for sterilization. More particularly, some embodiments of the present disclosure relate to systems and methods for chemical sterilization (e.g., wet chemical sterilization) of medical products, including terminal sterilization of drug delivery devices (e.g., pre-filled syringes) using a vaporized sterilant such as vaporized hydrogen peroxide. Additionally, embodiments of the present disclosure relate to systems and methods for monitoring and controlling the environment and / or conditions within a sterilization apparatus or sterilization process. [Background technology]

[0002] Chemical sterilization processes, such as those using ethylene oxide, vaporized hydrogen peroxide, vaporized peracetic acid, etc., offer many advantages, such as the ability to sterilize items at relatively low temperatures (e.g., below 50° C.) and without the need to enter a deep vacuum (e.g., pressures below 10 kilopascals (100 millibars)). Such sterilization processes can be particularly useful in sterilizing medical devices and products that are sensitive to extreme temperatures and / or pressures.

[0003] Processes using chemical sterilants include steps to ensure that the sterilant reaches all parts of the article that need to be sterilized and that, after sterilization has occurred, the sterilant has been removed from the article to an extent that ensures the safety and efficacy of the sterilized product. Removing the sterilant from the article is sometimes referred to as aerating the article. Additionally, sterilization processes could benefit from improvements that reduce the time and resources required to sterilize and aerate / dry the article.

[0004] In particular, the use of vaporized chemicals such as vaporized hydrogen peroxide can pose certain challenges: the distribution of the vaporized sterilant within the sterilization system, the behavior of the vaporized sterilant (e.g., condensation, evaporation, etc.), and the interaction of the vaporized sterilant with the items to be sterilized (e.g., adsorption to the materials of the items) can affect the efficacy of the vaporized sterilant and how easily it can be removed from the items. Summary of the Invention

[0005] An embodiment of the present disclosure may be directed to a method of sterilization. The method may include preconditioning a sterilization apparatus including a sterilization chamber with an article to be sterilized. Preconditioning the sterilization apparatus may include increasing the temperature of a portion of the sterilization apparatus to a temperature higher than a maximum temperature of the article to be sterilized. The method may further include performing a sterilization stage and performing an aeration stage. The sterilization stage may include a plurality of sterilization pulses. The aeration stage may include a plurality of aeration pulses, the plurality of aeration pulses including a primary aeration pulse and a secondary aeration pulse. The primary aeration pulse may include achieving a first vacuum pressure in the sterilization chamber, the first vacuum pressure being less than 650 millibars. The primary aeration pulse may further include increasing the pressure of the sterilization chamber to a pressure higher than 700 millibars after the first vacuum hold. The secondary aeration pulse may comprise achieving a second vacuum pressure in the sterilization chamber, the second vacuum pressure being less than 650 millibars. The secondary aeration pulse may further comprise adding air to the sterilization chamber after the second vacuum hold while evacuating the sterilizer.

[0006] In some embodiments, the method may further include adding dry air to the sterilization chamber after the sterilization step and before the aeration step. The multiple aeration pulses may include a first primary aeration pulse, followed by a first secondary aeration pulse, followed by a second primary aeration pulse, followed by a second secondary aeration pulse. The portion of the sterilization apparatus may include an inlet and, optionally, a conduit connecting a VHP injector to the inlet. Each sterilization pulse may include achieving a sterilization pressure in the sterilization chamber and adding vaporized hydrogen peroxide to the sterilization chamber when the pressure of the sterilization chamber is at the sterilization pressure. The sterilization pressure may be less than or equal to 65 kilopascals (650 millibars). The sterilization chamber may include a piston or diaphragm configured to adjust the pressure of the sterilization chamber. The method may further include generating a low frequency pressure wave using the piston or diaphragm after the sterilization pulse. The low frequency pressure waves may displace liquid hydrogen peroxide in contact with the item to be sterilized. The item to be sterilized may include a Tyvek® envelope.

[0007] In some embodiments of the present disclosure, the sterilization method may include performing a sterilization phase and performing an aeration phase. The sterilization phase may include a first, second, and third sterilization pulse. Each sterilization pulse may include achieving a sterilization pressure in the sterilization chamber and adding an amount of vaporized hydrogen peroxide to the sterilization chamber when the pressure in the sterilization chamber is at the sterilization pressure. The aeration phase may include achieving a vacuum pressure in the sterilization chamber, the vacuum pressure being less than 65 kilopascals (650 millibars). The aeration phase may further include adding air to the sterilization chamber after the vacuum hold while evacuating the sterilizer. The amount of vaporized hydrogen peroxide added to the sterilization chamber during one sterilization pulse may be sufficient to establish a lethal concentration of hydrogen peroxide in the 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.

[0008] In some embodiments, the method may further include repeating the first sterilization pulse at least once before the second sterilization pulse. The method may further 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 sterilization chamber volume. Each sterilization pulse may further include (i) adding gas into the sterilization chamber to increase the pressure to a holding pressure, and (ii) reducing the pressure of the sterilization chamber to the sterilization pressure. Step (i) may take more time than step (ii). The holding pressure may be greater than 70 kilopascals (700 millibars). 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 include maintaining 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 distribution manifold, an inlet and a chamber wall, and the method may further comprise maintaining a temperature of the chamber wall to be about the same as the temperature of the inlet or the temperature of the distribution manifold during the first, second and / or third sterilization pulses.

[0009] Further embodiments of the present 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 the sterilization chamber, the first amount being 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, the second amount being less than the first amount. Each third sterilization pulse may include adding a third amount of vaporized hydrogen peroxide to the sterilization chamber, the third amount being less than the second amount.

[0010] In some embodiments, the method may further comprise performing an aeration pulse. The aeration pulse may comprise the steps of (i) reducing the pressure of the sterilization chamber to a first venting pressure, and (ii) increasing the pressure of the sterilization chamber to a second venting pressure. The rate of pressure change in step (ii) may be at least 10 kilopascals (100 millibars) per minute greater than the rate of pressure change in step (i). The first venting pressure may be less than 65 kilopascals (650 millibars). The second venting pressure may be greater than 70 kilopascals (700 millibars). The method may further comprise removing moisture from the sterilization chamber prior to the venting step by passing the contents of the sterilization chamber through a condenser. The sterilization chamber may comprise an article, the article comprising a Tyvek material defining an interior of the article and an exterior of the article. After the plurality of third sterilization pulses, the concentration of hydrogen peroxide in the interior of the article may be approximately equal to the concentration of hydrogen peroxide in the exterior of the article.

[0011] The accompanying 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 the disclosure. Where appropriate, reference characters that refer to the same structures, components, materials and / or elements in different figures are similarly labeled. It is understood that various combinations of structures, components and / or elements other than those specifically shown are contemplated and that such combinations are within the scope of the disclosure.

[0012] Many inventions are described and illustrated herein. The described inventions are not limited to a single aspect or embodiment thereof, nor to any particular combination and / or permutation of such aspects and / or embodiments. Moreover, each of the described aspects of the invention and / or embodiments thereof can be used alone or in combination with one or more of the other aspects and / or embodiments of the described invention. For the sake of brevity, certain permutations and combinations are not discussed and / or not otherwise shown herein. In particular, an embodiment or implementation described herein as "exemplary" should not be construed as a preferred or advantageous embodiment or implementation, e.g., as preferred or advantageous over other embodiments or implementations, but rather, an embodiment or implementation described herein as "exemplary" is intended to reflect or indicate that the embodiment is an "example" embodiment. [Brief description of the drawings]

[0013] [Figure 1A] 1 is a schematic diagram of an exemplary sterilization system that may be used for sterilization of medical products. [Figure 1B] FIG. 1B is a schematic diagram showing an expanded view of a portion of the system shown in FIG. 1A. [Figure 2A] 1 is a process flow diagram of an exemplary method for sterilizing medical products using vaporized chemicals. [Figure 2B] 1 is a process flow diagram of an exemplary method for sterilizing medical products using vaporized chemicals. [Figure 3A] 1 is a process flow diagram of an exemplary method for performing a sterilization step. [Figure 3B] 1 is a process flow diagram of an exemplary method for performing a sterilization step. [Figure 4] 4 is a process flow diagram of an exemplary method for performing an aeration step. [Diagram 5] 4 is a process flow diagram of an exemplary method for performing another aeration stage. [Figure 6]FIG. 2 illustrates sterilization chamber pressure and article temperature during an exemplary sterilization method. [Figure 7] FIG. 2 illustrates sterilization chamber pressure and article temperature during an exemplary sterilization method. [Figure 8A] FIG. 2 illustrates sterilization chamber pressure and article temperature during an exemplary sterilization method. [Figure 8B] FIG. 2 illustrates sterilization chamber pressure and article temperature during an exemplary sterilization method. [Figure 9A] FIG. 2 illustrates sterilization chamber pressure and article temperature during an exemplary sterilization method. [Figure 9B] FIG. 2 illustrates sterilization chamber pressure and article temperature during an exemplary sterilization method. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] As used herein, the terms "comprises," "comprising," "include," "have," "with," or other variants thereof, are intended to cover the non-exclusive inclusion of aspects such that a process, method, article, or device comprising a list of elements need not include only those elements, but may include other elements not expressly listed or that are not inherent to such process, method, article, or device. The term "exemplary" is used in the sense of "example" and not "ideal." An embodiment described herein as exemplary should not be construed as preferred or advantageous over other embodiments. Furthermore, the terms "first," "second," and the like, used herein do not denote an order, quantity, or importance, but rather are used to distinguish one element from another. Similarly, relative orientation terms such as "front side," "top side," "back side," "bottom side," "upper," and "lower" refer to the depicted figures.

[0015] As used herein, the terms "about" and "approximately" are meant to allow for a possible deviation of ±10% of the stated numerical value. All measurements reported herein are understood to be modified by the term "about" or "approximately", whether or not those terms are explicitly used, unless expressly stated otherwise. As used herein, the singular forms "a", "an" and "the" include plural referents unless otherwise clear from the context. Furthermore, in the claims, values, limits and / or ranges refer to the values, limits and / or ranges ±10%.

[0016] As used in this disclosure, the term "sterilization" refers to achieving an appropriate level of sterility for a formulated drug substance or drug product for commercial distribution and use. Such a level of sterility may be defined in regulatory guidelines or regulations, such as, for example, guidelines promulgated by the U.S. Food and Drug Administration. In some embodiments, such a level of sterility is achieved, for example, by achieving a sterility level of 10% or less of the microbial population of a biological indicator placed on the exterior or interior surface of the drug product (e.g., the exterior surface of a syringe or the interior surface of a blister pack). 6 In other embodiments, such sterility levels may include, for example, a 10-fold reduction in the microbial population of a biological indicator. 9 1 / 10 12 Sterilization may include a reduction to one-fifth of the concentration of sterilization chemicals. Sterilization relates to achieving such an adequate level of sterility, while still achieving sufficiently low levels of residual sterilizing chemicals (e.g., vaporized hydrogen peroxide, ethylene oxide, etc.) for commercial distribution and use. Such low levels of residual sterilizing chemicals may also be defined in regulatory guidelines or rules.

[0017] As used in this disclosure, the term "terminal sterilization" refers to the sterilization of a formulation in a container or package suitable for commercial distribution and use, such as in a primary packaging component or in both a primary and secondary packaging component.

[0018] As used in this disclosure, the term "medical product" refers to a product for medical use on a living animal. The term "medical product" includes, for example, a pharmaceutical formulation, a compounded drug substance, a medical implant, a medical device, or a combination thereof. For example, the term "medical product" may relate to a syringe containing a compounded drug substance, such as a parenteral or ophthalmic syringe. Other exemplary medical products include, for example, suppository applicators and medicaments, transdermal drug delivery devices, medical implants, needles, cannulas, medical devices, and other products that require sterilization prior to intended medical use.

[0019] As used in this disclosure, the term "compounded drug substance" refers to a composition containing at least one active ingredient (e.g., a small molecule, protein, nucleic acid, or gene therapy drug) and excipients, prepared for medical distribution and use. Compounded drug substances may include fillers, colorants, and other active or inactive ingredients.

[0020] As used in this disclosure, the term "formulation" refers to a dosage form that includes compounded drug substances, such as a finished dosage form for an active ingredient. The formulation may include packaging for commercial distribution or use, such as a bottle, vial, or syringe.

[0021] As used in this disclosure, the term "vaporized chemical" refers to a chemical that has been converted into a substance that can be dispersed or suspended in air. In some cases, the vaporized chemical may be a chemical that combines with water and then converted into a substance that can be dispersed or suspended in air.

[0022] As used in this disclosure, the term "fluid" refers to a liquid, semi-liquid, vapor, or gas, including oxygen, hydrogen, nitrogen, or combinations thereof. Embodiments of the present disclosure relate to systems and methods for using vaporized chemicals in sterilization processes, such as processes for sterilizing medical products. For example, embodiments of the present disclosure may relate to systems and methods for terminal sterilization of medical products using vaporized hydrogen peroxide (VHP). More particularly, embodiments of the present disclosure may relate to systems and methods for terminal sterilization of medical products, such as prefilled syringes (PFS).

[0023] In general, it is desired that exposure to a sterilization cycle be effective while having no adverse effects and minimizing the risk of damage or alteration to the items being sterilized. Thus, medical products that undergo terminal sterilization, such as PFS, may require sterilization equipment, machines, controls, cycles and methods to address certain constraints and requirements to achieve proper sterilization and / or to avoid damage to the medical products and / or devices, compounded drug substances, drug products or other products. Such constraints and requirements may include, for example:

[0024] Medical products may be placed in different portions (e.g., quadrants or zones) of the sterilization chamber that may experience conditions during the sterilization cycle that may differ from those in other portions of the chamber, such as temperature, pressure, water vapor concentration, humidity, or sterilant concentration. Such different conditions may affect sterilization efficacy. Maintaining a consistent environment throughout the sterilization chamber may be beneficial to ensure sufficient sterilization efficacy for all portions of the articles.

[0025] During a sterilization cycle, the environment within the sterilization chamber may change in ways that affect the movement, condition, or efficacy of the sterilant and / or fluids within the chamber. For example, the pressure within the chamber may increase as sterilant is added to the chamber. The pressure within the chamber may affect the ratio of condensed to vaporized sterilant. Changes in temperature, humidity, or other environmental characteristics may affect how the sterilant within the chamber and any additional sterilant added to the chamber behaves. Sterilization systems and methods adapted to maximize sterilization efficacy in response to changes in the environment or climate within the sterilization chamber during the sterilization phase may be beneficial. Systems and methods adapted to maximize aeration and drying of an area in response to changes in the environment or climate may also be beneficial.

[0026] Medical products may be densely packaged. For example, a packaged bulk medical product may contain a large amount of fully assembled, packaged, and labeled medical products. In the case of terminal sterilization, the sterilizing agent may need to pass through several layers of packaging materials, container materials, and / or labels to effectively sterilize and be properly removed from all aspects of the article. In some cases, the packaging may include semi-permeable materials that select for a particular phase (e.g., steam) of the sterilizing agent.

[0027] In the case of some types of sterilization, such as terminal sterilization, a sterilizing agent may need to be passed through a semipermeable membrane by heat or mass in order to sterilize the exterior of each medical product and the interior of the packaging element. To avoid remaining as a residue on the medical product, the sterilizing agent may further need to be successfully removed, for example through the semipermeable membrane. Passing through the semipermeable membrane may only be possible for certain forms of sterilizing agents, such as steam or gas.

[0028] Packaging for medical products may be resistant to penetration of sterilizing materials and / or may be sensitive to temperature and pressure changes caused by sterilization. For example, a syringe may be packaged in a plastic "blister" configured to contain the syringe and limit its movement. Such a blister may be only slightly permeable to the sterilizing material and / or may be sensitive to pressure changes.

[0029] The use of a combination of vaporized chemical sterilant (e.g., VHP) and vaporized water in an environment where temperature and pressure can be precisely controlled may allow specific management of the environment to maximize contact of the sterilant with the items to be sterilized during the sterilization stage and / or maximize removal of the sterilant from the items during one or more subsequent aeration or drying stages. Some embodiments of the present disclosure relate to precisely controlling temperature, pressure, humidity, exposure time, and other environmental conditions. Environmental conditions may be adjusted in any part of the sterilization apparatus before, during, and / or after a sterilization process is performed with the sterilization apparatus. For example, the environment of one or more parts of the sterilization apparatus where the sterilant is introduced or removed may be maintained or controlled to be within predetermined conditions. Thus, embodiments of the present disclosure may help improve the introduction and / or removal of chemical sterilant within the sterilization apparatus (e.g., between the sterilization apparatus and the outside of the sterilization apparatus, or between parts of the sterilization apparatus). Some embodiments of the present disclosure can be used in combination with the disclosure of WIPO International Publication No. WO 2018 / 182929, filed March 6, 2018, which is incorporated herein by reference in its entirety.

[0030] Several properties of vapor chemical sterilants can affect (positively or negatively) the safety, efficacy, efficiency and other aspects of the sterilization process for medical products. For example:

[0031] Chemical sterilant vapors and water vapor in the environment may adsorb to and / or condense on surfaces in the environment that have a relatively cooler temperature. For example, during steam sterilization of PFS articles, the "cold spots" created by the high heat capacity aqueous liquid products in each PFS may serve to attract vapor adsorption and promote surface condensation. Additionally, changing the temperature of the environment (e.g., heating the sterilization chamber) may create relatively warmer and cooler areas in the environment, which may affect the relative temperatures of the articles in the relatively warmer and cooler areas. For example, using a temperature-controlled jacket to heat the sterilization chamber may result in areas of the chamber closest to the jacket (e.g., the periphery of the chamber) being warmer than areas furthest from the jacket (e.g., the center of the chamber). The ambient heat in the warmer areas may also cause portions of the articles to be sterilized in those areas to be relatively warmer. Chemical sterilant vapors and water vapor may preferentially adsorb to surfaces in areas that have a relatively cooler temperature compared to the rest of the environment ("cold spots"), and therefore vaporized chemical sterilant (e.g., VHP) may not be distributed evenly between relatively warm and relatively cool areas. Cooler areas may receive more complete exposure to the sterilant, while warmer areas may experience more complete aeration and drying.

[0032] Because hydrogen peroxide is denser and less volatile than water, VHP may preferentially adsorb onto surfaces compared to water vapor. In some cases, hydrogen peroxide and water vapor may simultaneously adsorb and condense onto surfaces, with hydrogen peroxide adsorbing and condensing in greater amounts and at a higher percentage closer to the surfaces of items being sterilized than water vapor.

[0033] Multiple adsorbed layers may form on a single surface within a sterilization environment. In some cases, each adsorbed and / or condensed layer further from the surface may contain less hydrogen peroxide and more water vapor, such that a gradient of hydrogen peroxide relative to water is formed at the surface. Due to the thermodynamic behavior of near-saturated or saturated binary mixtures of VHP and water vapor (e.g., a binary mixture of hydrogen peroxide and water in vapor / liquid equilibrium), hydrogen peroxide may preferentially adsorb and condense near surfaces over water. For binary mixtures of VHP and water vapor in sterilization applications, the vapor / liquid equilibrium may be similar to the gas / adsorbate equilibrium.

[0034] In some cases, condensed or adsorbed hydrogen peroxide may be difficult to remove from a surface. For example, condensation of water vapor onto the condensed / adsorbed hydrogen peroxide, or adsorption of water around the condensed / adsorbed hydrogen peroxide, may trap the hydrogen peroxide on the sterilized surface or otherwise inhibit its removal.

[0035] Pressure differences throughout an environment, such as a sterilization chamber, can also affect the efficacy of vaporized chemical sterilants. For example, the sterilization efficacy at the compressed air injection point of a sterilization chamber may be greater than the rest of the chamber. Without being limited by theory, this may be due to the nature of the gases in the chamber at a partial vacuum. While the chamber is saturated with chemical sterilant, areas local to the compressed air injection point may experience pressure waves or pulses having a greater magnitude than areas more distant from the compressed air injection point. This pressure wave may cause greater condensation of the chemical sterilant in the area local to the compressed air injection point.

[0036] In some cases where it is desired for a sterilant to pass through a semipermeable membrane of an article to sterilize an interior area or volume covered by the semipermeable membrane, a delay in migration of at least a portion of the sterilant through the article has been observed. For example, in an article to be sterilized that includes a semipermeable Tyvek membrane, the hydrogen peroxide concentration inside the membrane was delayed or slower to equilibrate with the hydrogen peroxide concentration outside the membrane. No such delay or lag was observed for the water concentration. Thus, the relative strength of the sterilant for the article or portion of the article inside the semipermeable membrane may be lower (for part or all of the sterilization cycle) compared to the strength of the sterilant outside the membrane.

[0037] · The rate at which pressure increases during introduction of vaporized sterilant to the sterilization chamber can negatively affect sterilization efficacy. Pressure increases to a certain extent can promote adsorption of the sterilant to the articles and be to the benefit of the introduction of the sterilant to the articles. However, excessive pressure increases when the environment is at or near VHP saturation levels can result in, for example, aggressive condensation of VHP, which can compromise sterilization efficacy or subsequent aeration or drying efficacy. Allowing the pressure of the environment to be held at a level where the vaporized sterilant can condense over time can result in overcondensation of the vaporized sterilant. Conversely, reducing the pressure of the environment after introducing the vaporized sterilant (e.g., VHP) can allow more sterilant to remain in the vapor phase, which can improve the efficacy of the sterilant in migrating through the semipermeable membrane and achieving sterilization of the interior of the articles to be sterilized.

[0038] During the sterilization phase (e.g., a sterilization pulse), the pressure may increase faster than the pressure decreases (e.g., the rate of pressure increase during a sterilization pulse may be 15 kPa (150 mbar) / min higher than the rate of pressure decrease during the same pulse). This may facilitate the movement of the sterilant (e.g., through one or more packaging layers). The reverse may be used during venting to facilitate the movement of sterilant from within the packaging layers to the exterior of the package and through the exhaust of the sterilizer. For example, the rate of pressure decrease during a vent pulse may be 15 kPa (150 mbar) faster than the rate of pressure increase during the same pulse. Elevated chamber temperature may also increase the venting efficiency.

[0039] The saturation level of the sterilization chamber may also be factored into the rate or direction of pressure adjustment. For example, pressure increases close to atmospheric pressure should be avoided while the sterilization chamber is close to saturation. For example, lower sterilant concentrations may be used with larger pressure changes, whereas large pressure changes at high sterilant concentrations may cause over-condensation and reduce the efficiency of sterilization.

[0040] · To avoid remaining as a residue on or in the medical product, the sterilizing agent may further need to be successfully removed from the article. For example, in embodiments utilizing packaging that includes a semipermeable membrane, passage through the semipermeable membrane may only be possible for the sterilizing agent in a particular form, such as a steam or gas. In some cases, stimulating mechanical movement (e.g., rocking, rotating, agitating, etc.) of some or all of the article may dislodge sterilant molecules attached to the article and may facilitate aeration and removal of the sterilant from the article. Low frequency pressure waves or sound waves generated within the sterilization chamber (e.g., via a diaphragm or piston located within the chamber) may dislodge sterilant attached to the article.

[0041] Immediately increasing pressure following a sterilization pulse may result in unwanted condensation, which may result in less effective aeration. The humidity of the sterilization chamber may be reduced prior to aeration to prevent over-condensation. For example, the contents of the closed system may be passed through a condenser (e.g., a desiccant wheel) to reduce the humidity of the environment. Additionally or instead, dry air may be injected prior to or during evacuation to reduce the overall humidity of the system.

[0042] The systems and methods disclosed herein can be advantageously used in improving the efficacy of sterilization, aeration and / or drying cycles involving vaporized chemical sterilants. 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 products. The systems and methods disclosed herein can, for example, increase the efficiency, safety and efficacy of sterilization and / or reduce sterilization cycle time. Although embodiments of the present disclosure may be described with respect to the use of VHP in terminal sterilization of a PFS, the present disclosure also contemplates the use of the techniques and systems herein for the transfer of VHP and other chemical sterilants in other contexts (e.g., sterilization of other products, cleaning of areas, adding / removing vaporized chemicals to the environment, etc.).

[0043] The present disclosure also contemplates the practice of "wet chemical sterilization," where chemical sterilization may be achieved in the presence of water vapor. In some cases, a comparison of "wet chemical sterilization" to "chemical sterilization" may be similar to a comparison of "moist heat sterilization" to "heat sterilization." Just as "moist heat sterilization" is considered more effective and efficient than "heat sterilization" alone in some cases, in some cases wet chemical sterilization may be a more effective and efficient means of achieving sterilization than currently existing chemical sterilization techniques.

[0044] "Wet chemical sterilization" can occur when environmental conditions of relatively high chemical concentrations, high water vapor concentrations, and high pressures (e.g., greater than 40 kilopascals (400 millibars)) act in concert to force the chemicals and water vapor to behave as a binary mixture. To achieve the desired relatively high chemical concentrations, high water vapor concentrations, and high pressures, the area to be sterilized may be saturated with a combination of water vapor and sterilizing chemicals (e.g., VHP), forcing the vapor to condense on the surfaces of the items. Most commercially available hydrogen peroxide is available and sold as an aqueous liquid mixture in various concentrations (e.g., 3%, 15%, 35%, 59%), and thus converting the hydrogen peroxide to vapor generally involves the simultaneous evaporation of water.

[0045] Turning now to the figures, FIG. 1A shows a schematic diagram of an exemplary sterilization system 100 for use in the methods of the present disclosure. It should be understood that the sterilization system 100 is merely an example, and that the methods disclosed herein can be used in many other systems, environments, and / or portions thereof. The sterilization system 100 includes a sterilization chamber 102 surrounded by a temperature controlled 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 an article to be sterilized (e.g., an article 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., a diffuser plate, spray ball, or other structure configured to distribute gas throughout the chamber). 1A and 1B, a first distribution manifold 107a is located near the upper interior 101 and a second distribution manifold 107b is located near the lower interior 103. Locating the distribution manifolds 107a, 107b on opposite sides of the sterilization chamber 102 may promote even distribution of the sterilant, air or other materials introduced.

[0046] The inlet conduit 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 conduit than the first distribution manifold 107a.

[0047] A second inlet conduit 135 is also fluidly connected to the sterilization chamber 102 to allow fluid to enter the sterilization chamber 102 via the inlet 109. For example, dry air from a dry air source 130 may be introduced into the sterilization chamber 102 via the inlet 109.

[0048] A blower 106 is fluidly connected to the sterilization chamber 102 via a blower outlet conduit 108. A blower circulation conduit 118 is fluidly connected to the blower 106 for transferring fluid from the blower outlet conduit 108 towards the exhaust conduit 116 or for transferring fluid from the blower outlet conduit 108 back towards the sterilization chamber 102 via the inlet conduit 134. In some embodiments, the blower outlet conduit 108 may include or be coupled to a condenser 147. The condenser 147 may include a desiccating wheel or other structure configured to remove water from the fluid passing through the blower outlet conduit 108. An exhaust valve 120 is disposed between the blower circulation conduit 118 and the exhaust conduit 116 and selectively closes or opens the connection between the blower circulation conduit 118 and the exhaust conduit 116. A recirculation valve 119 is disposed between the blower circulation conduit 118 and the inlet conduit 134 and selectively closes or opens the connection between the blower 106 and the inlet conduit 134 (e.g., via the blower circulation conduit 118).

[0049] The blower 106 may circulate air at a flow rate greater than 500 cubic feet per minute (cfm). In some embodiments, the air circulation flow rate maintained by the blower 106 may be less than 1000 cfm. If the blower 106 is moving too much fluid, it will displace the sterilant near the distribution manifolds 107a, 107b, which reduces sterilization efficiency.

[0050] A vacuum pump 110 may be fluidly connected to the sterilization chamber 102 via a vacuum conduit 112. The vacuum conduit 112 may include or be connected to a catalytic converter 115. A vacuum valve 113 disposed between the sterilization chamber 102 and the vacuum conduit 112 may selectively allow, partially allow, or block flow from the sterilization chamber 102 (e.g., through the catalytic converter 115) to the vacuum pump 110. A vacuum exhaust conduit 114 fluidly connects the vacuum pump 110 to an exhaust 116.

[0051] The sterilization system 100 may include several sources of air and / or steam from which fluids may be introduced to the sterilization chamber 102 via the inlet conduit 134 or the inlet conduit 135. A dry make-up air source 127 may be configured to supply dry make-up air to the sterilization chamber 102 via the inlet conduit 134. In some embodiments, the dry make-up air source 127 is compressed dry air. A dry air valve 144 may be coupled to the fluid connection between the dry make-up air source 127 and the inlet conduit 134. The dry air valve 144 may selectively enable, partially enable, or block the flow of dry make-up air from the dry make-up air source 127 to the sterilization chamber 102 via the inlet conduit 134.

[0052] The wet make-up air source 117 may be configured to supply wet make-up air (e.g., air with more moisture than the dry make-up air from the dry make-up air source 127) to the sterilization chamber 102 via the inlet conduit 134. A wet air valve 124 may be coupled to the fluid connection between the wet make-up air source 117 and the inlet conduit 134. The wet air valve 124 may selectively allow, partially allow, or block the flow of wet make-up air from the wet make-up air source 117 to the sterilization chamber 102 via the inlet conduit 134.

[0053] The moist makeup air source 117 may be, for example, a source of air (e.g., room air or compressed air) or other fluid external to the rest of the sterilization system 100. In some embodiments, the moist makeup air source 117 may be a source of "room air" surrounding the sterilization system 100, which may have been passed through an indoor filtration system. In some embodiments, the moist makeup air source 117 may contain more water vapor than "room air." In some embodiments, the moist makeup air source 117 may be a source of filtered outside air.

[0054] A VHP injector 132 fluidly connected to the inlet conduit 134 is configured to inject VHP into the sterilization chamber 102 via the inlet conduit 134. A VHP injector valve 128 is coupled to the fluid connection between the VHP injector 132 and the inlet conduit 134 and selectively allows, partially allows, or blocks the flow of VHP from the VHP injector 132 to the sterilization chamber 102 via the inlet conduit 134.

[0055] VHP injector 132 may include a source of VHP or a source of VHP and vaporized water and may be configured to inject VHP or a combination of VHP and vaporized water into the sterilization chamber 102, for example, via inlet conduit 134. VHP injector 132 may be configured to inject steam into the sterilization chamber 102 (or into inlet conduit 134) at an adjustable concentration.

[0056] Depending on the positions of the dry air valve 144, the wet air valve 124 and the VHP injector valve 128, dry make-up air from the dry make-up air source 127, wet make-up air from the wet make-up air source 117, VHP from the VHP injector 132, or a combination thereof may enter the sterilization chamber 102 via the inlet conduit 134. For example, during preconditioning, the wet air valve 124 may be in a position such that wet make-up air from the wet make-up air source 117 is blocked from entering the inlet conduit 134, the VHP injector valve 128 may be in a position such that VHP from the VHP injector 132 is blocked from entering the inlet conduit 134, and the dry air valve 144 may be in a position such that dry make-up air flows from the inlet dry make-up air source 127 via the inlet conduit 134 into the sterilization chamber 102. In such a configuration, only dry make-up air flows into the sterilization chamber 102, which allows for faster preconditioning.

[0057] In another configuration, the wet air valve 124 may be in a position to allow wet make-up air to flow from the wet make-up air source 117 to the sterilization chamber 102 (i.e., via inlet conduit 134), the VHP injector valve 128 may be in a position to allow VHP to flow from the VHP injector 132 to the sterilization chamber 102 (i.e., via inlet conduit 134), and the dry air valve 144 may be in a position to prevent dry make-up air from the dry make-up air source 127 from entering the inlet conduit 134. In such a configuration, the wet make-up air may function as a bonding medium to carry the VHP to the sterilization chamber. Dry make-up air or a combination of dry make-up air and wet make-up air may be used as a bonding medium. Wet make-up air may be more effective as a bonding medium than dry make-up air. Moisture (e.g., water) from the wet make-up air used as a bonding medium may be removed from the sterilization chamber 102 (e.g., via condenser 147) after the VHP is introduced.

[0058] An auxiliary dry air source 130 fluidly connected to the inlet conduit 135 may be configured to supply dry air to the sterilization chamber 102 via the inlet conduit 135. An auxiliary source valve 126 is coupled to the fluid connection between the auxiliary dry air source 130 and the inlet conduit 135 and configured to selectively allow, partially allow, or block the flow of dry air from the auxiliary dry air source 130 to the sterilization chamber 102 via the inlet conduit 135.

[0059] The dry make-up air source 127 and the auxiliary dry air source 130 may have the same composition or may have different compositions. One or both dry air sources 127, 130 may be a source of air having a relatively low humidity such that the air may be used to dry the sterilization chamber 102 (e.g., a portion of the sterilization chamber 102) and / or one or more of the blower outlet conduit 108, the vacuum conduit 112, the vacuum exhaust conduit 114, the blower circulation conduit 118, and the inlet conduit. For example, in some embodiments, the air of one or both dry air sources 127, 130 may include a dew point of, for example, -10 degrees Celsius or less, a dew point of -40 degrees Celsius or less, or a dew point between -10 degrees Celsius and -40 degrees Celsius. In some embodiments, one or both dry air sources 127, 130 may be a source of sanitary dry air, such as sterilized air or otherwise air that has been filtered to at least 0.2 microns. In some embodiments, one or both dry air sources 127, 130 may be a sealed source of air. In some embodiments, one or both dry air sources 127, 130 may be a source of compressed air.

[0060] The sterilization system 100 may be configured to run sterilization cycles in the sterilization chamber 102 at various temperatures and pressures and for various durations and / or time intervals. In some embodiments, the temperatures, pressures and time intervals at which the sterilization system 100 may run a sterilization cycle may be selectively and individually altered and customized. Additionally, the temperatures, pressures and time intervals may be adjusted during a sterilization cycle, for example, to provide improved distribution, transfer and / or removal of the sterilant.

[0061] The sterilization system 100 may be configured to control the environment inside the sterilization chamber 102, including temperature, pressure, humidity, atmosphere, fluid intake and fluid exit. Mechanisms for controlling temperature include temperature regulation of the input and / or recirculating fluid streams, temperature regulation of parts of the sterilization chamber itself, and temperature regulation of other components of the system 100 (e.g., intake conduit 134, blower outlet conduit 108, vacuum pump 110, temperature control jacket 104, blower circulation conduit 118, blower 106, recirculation valve 119, wet make-up air source 117, dry make-up air source 127, VHP injector 132, wet 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 that operate to regulate the pressure in the sterilization chamber 102 without the introduction or removal of substances and may expand, collapse, or otherwise be altered. The one or more pistons 150 or diaphragms may be configured to create pressure waves or to generate low frequency pulses. These pressure waves and pulses can be used to affect (e.g., promote) condensation of a sterilant on the surfaces of articles.

[0062] Additionally, the sterilization system 100 may include any suitable number and location of sensors configured to sense temperature, pressure, flow rate, chemical concentration or other parameters throughout the sterilization system 100, including, for example, the sterilization chamber 102, the temperature control jacket 104, the blower 106, the vacuum pump 110, and / or any of the conduits 108, 112, 114, 118 and 134. Such sensors may be configured to transmit sensed data, for example, to the controller 140 and / or a human machine interface.

[0063] The sterilization chamber 102 may be a sealable chamber defining an interior including an upper interior 101 and a lower interior 103. The sterilization chamber 102 may be openable to an open configuration such that one or more items, e.g., a product 105, may be placed inside as part of an article for sterilization and removed following sterilization. In some embodiments, the sterilization chamber 102 may have an operational orientation, e.g., such that the upper interior 101 is disposed above the lower interior 103 and such that material may fall (e.g., under gravity) from near the upper interior 101 toward the lower interior 103. The sterilization chamber 102 may have one or more delivery devices to which one or more of the inlet conduits 134 and 135 may be connected. As shown in FIG. 1, for example, distribution manifolds 107a, 107b are two such delivery devices. The distribution manifolds 107a, 107b may be configured to distribute the gas, vapor or liquid into the sterilization chamber 102 in a given shape, such as a stream or a uniform spray across the sterilization chamber 102. For example, the distribution manifold 107a may distribute the gas, vapor or liquid across the upper interior 101, and the distribution manifold 107b may distribute the gas, vapor or liquid across the lower interior 103. The inlet 109 is another such delivery device. The inlet 109 may also be configured to distribute the gas, vapor or liquid into the sterilization chamber 102 in a given shape, such as a stream or a uniform spray across the upper interior 101 or another portion of the sterilization chamber 102.

[0064] In some embodiments, a distribution manifold (e.g., distribution manifold 107a) may be configured to distribute gas, vapor or liquid into sterilization chamber 102 in one shape, such as a uniform spray, and inlet 109 may be configured to distribute gas or vapor into sterilization chamber 102 in a different shape, such as a stream. In some embodiments, inlet 109 may not be present and both inlet conduits 134 and 135 may be connected to one or more distribution manifolds 107a, 107b.

[0065] The temperature control jacket 104 may be a material that surrounds the sterilization chamber 102 and that is configured or effective to provide temperature control to the environment inside the sterilization chamber 102. In some embodiments, for example, the temperature control jacket 104 may be a water jacket that surrounds the sterilization chamber 102. In such embodiments, the temperature and / or flow rate of water or other liquid passing through the temperature control jacket 104 may be controlled, for example, by the controller 140.

[0066] The product 105 may be any one or more items of goods suitable for sterilization using the sterilization system 100. In some embodiments, the product 105 may be a medical product in a primary package, a secondary package, or both. In some embodiments, the product 105 may be a medical product having moving parts or parts that are otherwise sensitive to a deep vacuum environment, such as an environment having a pressure below about 10 kilopascals (100 millibars). In some embodiments, the product 105 may be a container filled with a volume of, for example, a compounded drug substance. For example, the product 105 may be a vial or a PFS. In some embodiments, the product 105 may include or be covered by a semi-permeable packaging, such as a semi-permeable membrane through which vapor or gas can pass. In further embodiments, the product 105 may be or include a product that is sensitive to high temperatures, for example, temperatures above 30°C. Such medical products may include compounded drug substances or other compositions that may be sensitive to high temperatures, such as, for example, proteins (e.g., antibodies or enzymes), fragments thereof, any antigen-binding molecules, nucleic acids, blood, blood components, vaccines, allergens, gene therapy drugs, tissues, other biologics, etc. For example, the product 105 may be a packaged PFS that includes a compounded drug substance that includes an antibody or an adeno-associated virus (AAV). In some embodiments, the product 105 may include a formulation that includes a large molecule, e.g., a molecule with a molecular weight of 30 kDa or greater.In some embodiments, the product 105 may be, for example, aflibercept, alirocumab, abicipar pegol, among others. pegol, bevacizumab, brolucizumab, conbercept, dupilumab, evolocumab, tocilizumab, certolizumab, abatacept, rituximab, infliximab, ranibizumab, sarilumab, adalimumab, anakinra, trastuzumab, pegfilgrastim, interferon beta-1a, insulin glargine [rDNA origin], epoetin alfa 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.

[0067] In some embodiments, the products 105 may include products for the treatment of ocular diseases, including for the treatment of 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, any concentration of large and small molecule antagonists of VEGF and / or ANG-2 may be included in product 105, such as aflibercept, ranibizumab, bevacizumab, conbercept, OPT-302, RTH258 (brolucizumab), abicipar pegol (a pegylated designed ankyrin repeat protein (DARPin), RG7716, or fragments thereof. In some embodiments, product 105 may be a product for cosmetic or medical dermatology applications, such as treatment or diagnosis of allergic responses.

[0068] The blower 106 may be, for example, a blower capable of forcefully drawing steam and gas from the lower interior 103 of the sterilization chamber 102 through a blower outlet conduit 108, optionally through a condenser 147, and reintroducing said steam and gas to the upper interior 101 of the sterilization chamber 102 via an inlet conduit 134 (or alternatively drawing such steam and gas through an exhaust valve 120 and a catalytic converter 121 to an exhaust 116). In some embodiments, as shown in FIG. 1, the blower 106 may be external to the sterilization chamber 102. In other embodiments, the blower 106 may be disposed within the sterilization chamber 102. In some embodiments, the blower 106 may be configured to draw steam and gas from the lower interior 103 of the sterilization chamber 102 and reintroduce said steam and gas to the upper interior 101 with sufficient force to create a flow of steam and gas from the upper interior 101 to the lower interior 103 of the sterilization chamber 102. This flow may be referred to as a "turbulent flow." In some embodiments, the force with which the blower 106 may operate may be adjustable (e.g., via the controller 140) in a manner that may produce a more turbulent (e.g., more forceful) 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 to pull steam and gas, e.g., a stronger force than the vacuum pump 110.

[0069] The vacuum pump 110 may be a vacuum pump capable of drawing gases from the interior of the sterilization chamber 102 (e.g., lower interior 103) through a vacuum conduit 112 and a catalytic converter 115 towards an exhaust 116, thereby creating a vacuum within the sterilization chamber 102 and / or within a closed system including the sterilization chamber 102 and, for example, a blower 106. The vacuum pump 110 may be fluidly connected to the exhaust 116, for example, via a vacuum exhaust conduit 114. In some embodiments, the exhaust from the vacuum pump 110 and the exhaust from the blower 106 may be separate instead of being combined together.

[0070] In some embodiments, vacuum type functions may additionally or instead be performed by, for example, the blower 106 which may selectively circulate steam and gases into and out of the sterilization chamber 102 through an exhaust valve 120 towards an exhaust 116. The exhaust valve 120 may be selectively opened or closed to allow or prevent the flow of gases or steam from the blower circulation conduit 118 towards the exhaust 116, or from the blower circulation conduit 118 towards an inlet conduit 134 for reintroduction to the sterilization chamber 102. The exhaust valve 120 may be manually controlled or may be controlled, for example, by a controller 140.

[0071] Catalytic converter 115, catalytic converter 121, or both, may be any catalytic converter known in the art suitable for converting, for example, toxic gaseous or vaporized fluids circulating within sterilization system 100 into less toxic gases or vapors, for example, during a sterilization cycle. For example, catalytic converters 115, 121 may be configured to convert VHP into water vapor, oxygen, and / or other non-toxic fluids.

[0072] A controller 140 is connected to one or more other components of the sterilization system 100, such as the sterilization chamber 102, the temperature control jacket 104, the blower 106, the VHP injector 132, the wet make-up air source 117, the dry make-up air source 127, the auxiliary dry air source 130, the vacuum pump 110, the piston 150, the catalytic converters 115, 121, the condenser 147, the distribution manifolds 107, 107b, the conduits 112, 108, 118, 134, 135, the valves 113, 119, 120, 124, 126, 144 and / or other components of the sterilization system 100. Some or all aspects of the sterilization system 100 may be controllable by the controller 140, for example. For example, the controller 140 may be in communication with one or more of the valves 113, 119, 120, 124, 126, 144 and may be configured to control, regulate, and / or monitor the position of the one or more of the valves 113, 119, 120, 124, 126, 144. Additionally or alternatively, one or more of the valves 113, 119, 120, 124, 126, 144 may be manually operated.

[0073] The controller 140 may be an analog or digital controller configured to modify aspects of the environment of the sterilization chamber 102, such as, for example, the temperature or pressure inside the sterilization chamber 102 and / or one or more of the blower 106, the vacuum pump 110, the air supply 117, the dry air supply 130, the VHP injector 132, the exhaust 116, one or more of the valves 113, 119, 120, 124, 126 and 128, one or more of the catalytic converters 115, 121, one or more of the conduits 108, 112, 114, 116, 118 and 134, as well as any and / or other aspects of the sterilization system 100. In some embodiments, the sterilization system 100 may be controllable 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.

[0074] In some embodiments, the controller 140 may be preprogrammed 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 controllable by a controller having one or more human machine interface ("HMI") elements that may be configured to allow a user to input or modify desired parameters for a cycle that may be performable by a controller on the sterilization system 100 or a controller operably coupled to the sterilization system 100. Thus, in some embodiments, the HMI elements may be used to program customized cycles for performance by the sterilization system 100. For example, in some embodiments, the sterilization system 100 may be controllable by a controller connected to, for example, a computer, tablet or handheld device having a display. Such a display may include options to select or modify, for example, a desired temperature, pressure, time, amount of VHP intake, amount of dry air, compressed air or room air intake, etc. for one or more steps of the cycle.

[0075] 1B shows an expanded view of the sterilization chamber 102. The sterilization chamber 102 can serve as an example environment in which many aspects of the present disclosure may be applicable. However, it should be understood that the sterilization chamber 102 is merely an example, and that aspects of the present disclosure may be applicable in many other environments.

[0076] Variations in temperature, pressure, humidity and air / fluid flow rates may characterize different portions of the sterilization chamber 102. For example, the temperature control jacket 104 may be configured to control the temperature within the sterilization chamber 102, but may have a more direct effect on the periphery of the sterilization chamber 102 than on the more central portions of the interior of the sterilization chamber 102. As previously explained, the temperature control jacket 104 may have a more direct effect on the temperature of the products 105 (i.e., articles) closer to the periphery of the sterilization chamber 102 than the temperature of the products 105 (i.e., articles) closer to the center of the sterilization chamber 102, such that the products 105 closer to the periphery may, for example, be warmer than the products 105 in the center.

[0077] As another example, the distribution manifolds 107a, 107b and / or the inlet 109 may have a surface temperature that is 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). Additionally, during operation of the system 100, the distribution manifolds 107a, 107b, the inlet 109, the diaphragm (not shown) and / or the piston 150 may create localized areas of relatively high pressure around them as they inject fluid into the sterilization chamber 102 or create pressure waves. This may cause greater fluid condensation in areas closer to the source of the pressure wave compared to areas further away. For example, sterilant dispersed from one of the distribution manifolds 107a, 107b may be more likely to condense on products 105 located closer to the distribution manifolds 107a, 107b than on products 105 that are further away.

[0078] As previously described, the product 105 may include one or more semi-permeable membranes through which vapor or gas may flow, such as a cover on a package for a medical device or formulation. In some cases, the semi-permeable membrane may not allow liquids to pass through it. In some embodiments, sterilization of the areas on both sides of the semi-permeable membrane is desired.

[0079] 2A, 2B, 3A, 3B, 4 and 5 show a flow diagram of steps and processes of a method for sterilization according to the present disclosure. As will be appreciated by those skilled in the art, some steps and / or processes may be omitted, combined, and / or performed in a different order while remaining consistent with the present disclosure. In some embodiments, the steps and / or processes may be performed, for example, using sterilization system 100 or variations of sterilization system 100. Additionally or alternatively, the steps and / or processes may be applicable in other environments where operation of a vaporized sterilant is desirable. It will be appreciated that customizable and controllable aspects of sterilization system 100 may be used to perform the steps and processes described below. For example, in some embodiments, controller 140 may be used to direct, regulate and modify temperatures, pressures, timing, etc. in a series of sterilization steps, set points and stages that can be performed by sterilization system 100. Additionally, although the steps and processes described below are described with respect to sterilization system 100, one of ordinary skill in the art will understand that the steps and processes may be performed by another sterilization system or another system having the capability to perform those steps.

[0080] 2A shows a flow diagram of 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 step may be performed. According to step 208, a first aeration step may be performed. According to step 210, a second aeration step may be performed.

[0081] Prior to the execution of the steps of method 200, an article to be sterilized, such as product 105, may be placed in a sterilization chamber, such as sterilization chamber 102, of a sterilization system, such as sterilization system 100. A closed system sterilization environment, including, for example, sterilization chamber 102, blower outlet conduit 108, blower 106, blower circulation conduit 118, inlet conduit 134, condenser 147, and elements connecting these components, may then be sealed. In some cases, a leak test may be performed on the closed system sterilization environment. The leak test may include, for example, creating a vacuum throughout the closed system. This vacuum may be created by evacuating gases and vapors from the closed system using, for example, vacuum pump 110. The blower 106 may be running during the leak test to circulate remaining air through the closed system and create a homogenous environment. The leak test may be performed in this manner, in part, to ensure that an adequate vacuum can be maintained within the closed system.

[0082] In some embodiments, a sterilization system (e.g., sterilization system 100) may be preconditioned. Preconditioning may include, for example, raising the temperature of the closed system to a temperature intended to be maintained during the sterilization phase (e.g., between about 25° C. and about 50° C.). In some embodiments, preconditioning may be performed for a longer period of time than is performed in a standard chemical sterilization procedure, which may allow more time for the temperature difference between the environments within the closed system (including, for example, areas of the sterilization chamber, such as sterilization chamber 102) to decrease. Alternatively or in addition, preconditioning may include, for example, pairing the temperature of a temperature-controlled jacket (e.g., temperature-controlled jacket 104) with the temperature of an inlet, such as distribution manifold 107a, distribution manifold 107b, and / or inlet 109, prior to or for the duration of method 200. "Pairing" the temperature of the temperature-controlled jacket with the temperature of the inlet means that the temperature-controlled jacket is programmed to maintain the same or similar temperature as the surface temperature of the inlet inside the sterilization chamber. This may be advantageous. This is because the inlets (e.g., distribution manifolds 107a, 107b and / or inlet 109) may generally be cooler than other parts of the sterilization chamber due to, for example, the temperature of the sterilant, compressed air or other fluid moving through those parts. Additionally, when the temperature controlled jacket warms the sterilization chamber 102, the periphery of the chamber (e.g., the portion of the sterilization chamber 102 closest to the temperature controlled jacket) may be warmer than the center of the sterilization chamber (e.g., the portion furthest from the temperature controlled jacket). Thus, pairing the temperature controlled jacket with the temperature of the inlet may reduce the temperature difference across the sterilization chamber. In some embodiments, the temperature controlled jacket may be paired, for example, by setting the temperature controlled jacket to a known temperature of the inlet during a sterilization cycle. In some embodiments, the temperature controlled jacket may be paired, for example, by empirically determining the temperature of the inlet during one or several sterilization cycles and setting the temperature controlled jacket to that temperature.In other embodiments, a digital thermometer may be disposed in contact with or near an inlet (e.g., distribution manifold 107a, 107b or inlet 109) and may relay 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 when prompted, periodically, continuously or dynamically (e.g., periodically based on monitored conditions of the chamber during a sterilization cycle).

[0083] The controller 140 may then set the temperature control jacket to the temperature sensed at or near the inlet (e.g., distribution manifold 107a, 107b or inlet 109). Because the surface temperatures of the distribution manifolds 107a, 107b and inlet 109 may generally be cooler than the average interior temperature of the sterilization chamber 102, pairing the temperature of the temperature control jacket 104 with the temperature of the inlet (e.g., distribution manifold 107a, 107b or inlet 109) may correct any temperature differences that exist throughout the sterilization chamber, which may aid in the distribution of the sterilant throughout the sterilization chamber.

[0084] It is also contemplated that in some embodiments, it may be advantageous to maintain a temperature differential between the articles to be sterilized and the surrounding closed system, creating a "cold spot." For example, controlled condensation of a vaporized sterilization chemical (e.g., VHP) on the "cold spot" of the articles may concentrate the sterilization chemical on the articles, which may lead to more efficient diffusion of the chemical into the articles, thus reducing the total amount of sterilization chemical required within the sterilization chamber 102 to achieve effective sterilization. In such embodiments, it may be advantageous to reduce the time of preconditioning or eliminate preconditioning altogether.

[0085] A sterilization step may be performed according to step 206. The sterilization step may include, for example, initiating circulation of fluids through the sterilization system, achieving a vacuum level, injecting a vaporized chemical to the sterilization chamber, maintaining a post-injection hold, injecting gas to the sterilization chamber to transition to a shallower vacuum, and maintaining a post-transition hold. The sterilization step according to step 206 may be repeated multiple times using similar or different vacuum levels, vaporized chemical volumes, and / or hold times. The sterilization step according to step 206 is shown in further detail in Figures 3A and 3B.

[0086] A first venting stage may be performed according to step 208. The first venting stage may include, for example, achieving a vacuum level, holding the vacuum level, breaking the vacuum level, and venting and exhausting the system. The first venting stage may be performed multiple times. The first venting stage according to step 208 is shown in further detail in FIG. 4.

[0087] A second venting stage may be performed according to step 210. The second venting stage may include, for example, achieving a vacuum level, holding the vacuum level, and breaking the vacuum level. The second venting stage may be performed multiple times. The second venting stage according to step 210 is shown in further detail in FIG. 5.

[0088] Step 208 and / or step 210 may be performed multiple times. Additionally, in some embodiments step 208 may be performed before step 210, while in alternative embodiments step 210 may be performed before step 208. In some embodiments, step 208 or step 210 may be eliminated entirely.

[0089] 2B shows a flow diagram of 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 for sterilization may be maintained. According to step 254, a sterilization phase may be performed. According to step 256, a first localized climate for aeration may be maintained. According to step 258, a first aeration phase may be performed. According to step 260, a second localized climate for aeration may be maintained. According to step 262, a second aeration phase may be performed.

[0090] As described above with respect to method 200, prior to the performance of the steps of method 250, the items to be sterilized may be placed in a sterilization chamber, which may be sealed, a leak test may be performed, and the sterilization system may be preconditioned. Sterilization step 254, first vent step 258, and second vent step 262 may be performed in a manner appropriate for sterilization step 206, first vent step 208, and second vent step 210, respectively. Step 258 and / or step 262 may be performed multiple times. Furthermore, in some embodiments step 258 may be performed before step 262, while in alternative embodiments step 258 may be performed before step 262. In some embodiments step 258 or step 262 may be eliminated entirely.

[0091] Prior to each of steps 254, 258, and 262, a step of maintaining a localized climate may be performed. Maintaining a localized climate generally refers to ensuring that one or more areas within a sterilization system (e.g., sterilization system 100) exhibit suitable conditions (e.g., temperature, pressure, water vapor concentration, sterilant concentration, etc.) for subsequent steps in the sterilization method. Maintaining a consistent or targeted localized climate may aid in robust sterilization and aeration efficacy. The localized climate may attract or repel sterilant to one or more specific locations within the system. If controlled, such a localized climate may aid in achieving a desired level of sterilization. For example, the inlet and / or the cart supporting the articles to be sterilized may be heated to prevent condensation of the sterilant. The articles themselves (e.g., packaging) may be kept at a cooler temperature than the cart to attract VHP or promote adhesion and condensation. Additionally, larger articles may be used to lower peak article temperatures.

[0092] Additionally, maintaining a localized climate can aid in distributing or removing sterilant to more difficult locations within the sterilization system, thus reducing the amount of "overkill" required to sterilize or vent those locations. Attracting sterilant to locations that have previously proven to struggle to pass sterilization standards (e.g., biological indicator standards) can standardize sterilization of that zone without the need to add more sterilant. Similarly, removing sterilant from previously difficult to vent locations can reduce overall aeration and drying times in the methods described herein.

[0093] As shown in FIG. 2B, a localized climate for sterilization may be maintained, for example, at step 252. This may include drawing sterilant to an area in the system, for example, using a temperature differential. In some embodiments, this may be accomplished by changing the temperature of one or more locations to lower the temperature of the location to which the sterilant is to travel. For example, the periphery of the sterilization chamber may be warmer than the center of the chamber due to heating elements (e.g., temperature-controlled jacket 104 of system 100) positioned around the periphery of the chamber. Thus, maintaining a localized climate for sterilization at the periphery of the sterilization chamber may include lowering the temperature at the periphery of the sterilization chamber, for example, by lowering the target temperature of the heating elements (e.g., temperature-controlled jacket 104). Maintaining a localized climate for sterilization, as per step 252, may continue throughout the performance of the sterilization stage, as per step 254.

[0094] According to step 256, a first localized climate for aeration may be maintained, and according to step 260, a second localized climate for aeration may be maintained. Each of the first localized climate for aeration and the second localized climate for aeration may include, for example, increasing the temperature of the location within the sterilization system, decreasing the humidity of the location within the sterilization system, etc. Each of the first localized climate and the second localized climate may be maintained during the first aeration stage 258 and the second aeration stage 262, respectively.

[0095] 3A is a flow diagram of a sterilization step 300, such as the sterilization step described with respect to step 206 of sterilization method 200 or step 254 of method 250. Prior to the sterilization step 300, an item to be sterilized (e.g., product 105) may be introduced to the sterilization chamber 102. According to step 302, a vacuum level may be achieved. According to step 304, a vaporized chemical may be injected into the sterilization chamber. According to step 306, a 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, a post-injection hold may be maintained. The sterilization step 300 may be repeated multiple times, such as 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, for example, 2, 3, 4, 5, 6, 7, or 8 times. A single repetition of a sterilization step (eg, sterilization step 300) may be referred to as a "pulse."

[0096] As part of the sterilization phase 300 , turbulent flow may be initiated and maintained within the sterilization system 100 . According to step 302, a vacuum level may be established within the sterilization chamber 102 of the sterilization system 100. The vacuum level may be between about 40 kilopascals (400 mbar) and about 70 kilopascals (700 mbar), such as, for example, between about 45 kilopascals (450 mbar) and about 65 kilopascals (650 mbar) or between about 45 kilopascals (450 mbar) and about 55 kilopascals (550 mbar). For example, the vacuum may be about 45 kilopascals (450 mbar), about 50 kilopascals (500 mbar), about 55 kilopascals (550 mbar), or about 60 kilopascals (600 mbar). The vacuum may promote a higher concentration of the sterilization chemical on the items to be sterilized, and extending the time that the closed system is held at a deeper vacuum increases the exposure of the items to be sterilized to the sterilization chemical.

[0097] 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, for example, having a hydrogen peroxide concentration of between about 5% and about 75% by weight. In some embodiments, the vaporized chemical may be a vaporized aqueous hydrogen peroxide solution, for example, having a hydrogen peroxide concentration of between about 10% and about 65% by weight, between about 15% and about 60% by weight, between about 30% and about 60% by weight, between about 30% and about 60% by weight, or between about 45% and about 60% by weight. In some embodiments, the vaporized chemical may be a vaporized aqueous hydrogen peroxide solution, for example, having a hydrogen peroxide concentration of between about 35% by weight (and a water concentration of 65% by weight). In further embodiments, the vaporized chemical may be a vaporized aqueous hydrogen peroxide solution, for example, having a hydrogen peroxide concentration of between about 59% by weight (and a water concentration of 41% by weight).

[0098] In some embodiments, the VHP dosage may be, for example, between about 50 g and about 700 g of aqueous VHP. For example, the VHP dosage may be between about 50 g and about 600 g, between about 100 g and about 600 g, between about 300 g and about 550 g, or between about 450 g and about 550 g. For example, the VHP dosage 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 dosage may be based on the volume or amount of articles to be sterilized inside the sterilization chamber 102. For example, if several formulations, such as prefilled syringes, are sterilized in the sterilization chamber 102, the infusion supply of VHP may be between about 0.01 grams and about 0.15 grams per unit of formulation inside the sterilization chamber 102, such as between about 0.01 grams and about 0.10 grams of VHP, e.g., about 0.015 grams, 0.02 grams, 0.025 grams, 0.03 grams, 0.04 grams, 0.05 grams, 0.06 grams, 0.07 grams, 0.08 grams, 0.09 grams, 0.1 grams, or 0.11 grams per formulation. In other embodiments, the infusion supply of VHP may be based on the volume of the sterilization environment, such as the interior of the sterilization chamber 102. For example, the infusion supply of VHP may be between about 7 grams and 105 grams per cubic meter of sterilization chamber volume (between about 0.2 grams and 3.0 grams per cubic foot of volume). For example, the VHP injection rate may be between about 7 and 70 grams per cubic meter (between about 0.2 and 2.0 grams per cubic foot), such as about 8.8 grams, about 18 grams, about 26 grams, about 35 grams, about 42 grams, about 49 grams, about 53 grams, about 56 grams, about 63 grams, or about 70 grams per cubic meter (about 0.25 grams, about 0.50 grams, about 0.75 grams, about 1.0 grams, about 1.2 grams, about 1.4 grams, about 1.5 grams, about 1.6 grams, about 1.8 grams, or about 2.0 grams per cubic foot). In some embodiments, the VHP injection rate may be based on the amount of VHP injected into the sterilization chamber in a previous iteration of the sterilization stage 300.For example, a first portion of VHP may be injected into the sterilization chamber in a first iteration of the sterilization phase 300. A second portion of VHP may be injected into the sterilization chamber in a second iteration of the sterilization phase 300, the second portion being less than the first portion, based on the portion injected in the first iteration. A third portion of VHP may be injected into the sterilization chamber in a third iteration of the sterilization phase 300, the third portion being less than the second portion, based on the combined portions injected in the first and second iterations.

[0099] In some embodiments, the injection supply of VHP may be based on a combination of the amount of VHP already in the sterilization chamber and the desired increase in pressure caused by injection of additional VHP into the sterilization chamber. The desired increase in pressure caused by injection of VHP into the sterilization chamber may be inversely related to the amount of hydrogen peroxide already present in the sterilization chamber. Advantageously, a lower increase in pressure as the amount of VHP in the sterilization chamber increases may help reduce unwanted condensation of VHP that may be caused by an excessive increase in pressure. Unwanted condensation of VHP may result in reduced sterilization efficiency and reduced aeration efficacy.

[0100] According to step 306, a post-injection hold may be maintained. During the post-injection hold, turbulent flow is maintained through the closed system including the sterilization chamber 102 and the blower 106. No fluid is added or removed from the closed system in which turbulent flow is maintained. The time for which the post-injection hold is maintained (or the "post-injection hold time") may be selected to allow the vaporized sterilization chemical to contact the articles for a sufficient time without allowing the vaporized sterilization chemical to condense. In some embodiments, the post-injection hold time may be between about 2 minutes and about 20 minutes. In some embodiments, the post-injection hold time may 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 may 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 manner, the need to add excess VHP to the system to ensure contact of the VHP with the articles to be sterilized may be avoided.

[0101] According to step 308, a gas may be injected into the sterilization chamber to transition to a shallower vacuum (i.e., higher pressure) within the sterilization chamber. The gas may be any suitable gas capable of breaking or weakening the vacuum within the sterilization chamber 102. In some embodiments, the gas may be a nitrogen-containing gas (e.g., a commercial source of nitrogen only or primarily) or a dry gas, such as air, for example, having a dew point of -10°C or less. The use of a dry gas may be selected to allow sufficient air exchange and reduced humidity within the sterilization chamber to further avoid unwanted condensation. In some embodiments, the gas may be injected from a dry air source 130. The gas may be injected at a volume to achieve a pressure of between about 50 kilopascals (500 millibars) and about 110 kilopascals (1100 millibars), such as between about 55 kilopascals (550 millibars) and about 100 kilopascals (1000 millibars), between about 60 kilopascals (600 millibars) and about 100 kilopascals (1000 millibars), between about 70 kilopascals (700 millibars) and about 90 kilopascals (900 millibars) or between about 75 kilopascals (750 millibars) and about 85 kilopascals (850 millibars). For example, this second post-injection pressure may be about 70 kilopascals (700 millibars), about 75 kilopascals (750 millibars), about 80 kilopascals (800 millibars), about 85 kilopascals (850 millibars), or about 90 kilopascals (900 millibars). If the article to be sterilized includes a semi-permeable membrane through which it is desired that the sterilant pass, the increase in pressure caused by step 308 may serve to aid in the migration of the sterilant through such semi-permeable membrane.

[0102] According to step 310, a post-transition hold may be maintained. During this post-transition hold, the pressure achieved during step 308 may be maintained for, for example, at least about 5 minutes, at least about 10 minutes, or at least about 15 minutes. In some embodiments, this second post-injection pressure may be maintained for a time period 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.

[0103] In some embodiments, the number of times the sterilization step 300 may be repeated (e.g., number of pulses) may be inversely proportional to the time the post-injection hold is maintained in each repetition. For example, if the post-injection hold is maintained for a short time (e.g., 10 minutes), steps 210 through 216 may be repeated more times. In some embodiments, the post-injection hold is maintained for a longer time (e.g., 15-20 minutes) to increase the time the items to be sterilized are exposed to the sterilizing chemical in each repetition of the sterilization step 300. In further embodiments, the number of times the sterilization step 300 may be repeated may depend on the desired total amount of VHP for the sterilization process. In some embodiments, for example, a total amount of at least 200 g of VHP may be desired. For example, in some embodiments, a total amount of at least 250 g of VHP may be desired. In some embodiments, a total amount of between about 200 g and about 700 g of VHP may be desired. In some embodiments, the number of times the sterilization step 300 may be repeated may depend on a combination of factors to ensure complete penetration of the VHP through the items to be sterilized and to ensure sufficient contact time between the hydrogen peroxide and the items to enable sterilization.

[0104] 3B is a flow diagram of a sterilization phase 400 that includes multiple sterilization pulses 420, 440, 460, each of which may include a different amount of VHP injected into the sterilization chamber, may include different hold times and pressure changes, and may be performed once or multiple times. According to step 402, an initial vacuum level may 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 pressure in the 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 chemical may be injected into the sterilization chamber (step 422), 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).

[0105] As previously explained, the pressure increase caused by each sterilization pulse (pulses 420, 440, 460) may reflect the existing concentrations of sterilant and water (e.g., hydrogen peroxide) in the sterilization chamber. When the existing concentrations are lower (or zero), such as before pulse 420, a larger increase in pressure may be used to maximize the rate at which the sterilant is introduced to the articles. Thus, the first amount of vaporized chemical introduced according to step 422 may be greater than the second or third amounts of vaporized chemical introduced according to steps 442 or 462.

[0106] In cases where it is desired for the sterilant to pass through a semipermeable membrane (e.g., a Tyvek membrane covering a medical device or product), delayed transport of some sterilants (e.g., hydrogen peroxide) across the membrane has been observed. Additionally, in some sterilization cycles, it has been observed that the hydrogen peroxide concentration in areas blocked by the semipermeable membrane is generally lower (or "faded") than in areas not blocked by the semipermeable membrane. Water does not exhibit such delayed transport or decay. As a result, the strength and efficacy of the sterilant (and particularly the strength and efficacy of hydrogen peroxide) in the areas blocked by the semipermeable membrane may be reduced. The third amount of vaporized chemical introduced according to step 462 may, among other things, help overcome this transport delay and the faded sterilant concentration. To avoid causing an aggressive build-up of pressure and over-condensation that may impede the transfer of the sterilant across the semipermeable membrane, 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.

[0107] Given the principles described above, in some embodiments, the first amount of sterilant injected according to step 422 may be greater than the second amount of sterilant injected according to step 442, which may be greater than the third amount of sterilant per step 462. For example, the first amount of sterilant may be a bolus (e.g., large amount) to establish a lethal concentration in the sterilization chamber, the second amount (e.g., medium amount) may be chosen to maintain that concentration and meet hold time requirements, and the third amount (e.g., small amount) may be chosen to overcome transport delays and attenuation of the sterilant across the semipermeable membrane.

[0108] For example, a large amount may include 15 grams of 35% H2O2 by weight per cubic meter of sterilization chamber volume, a medium amount may include 7.5 grams of 35% H2O2 by weight per cubic meter of sterilization chamber volume, and a small amount may be 0.5 grams of 35% H2O2 by weight per cubic meter of sterilization chamber volume.

[0109] The time for each post-injection hold 424, 444, 464 may depend on the volume of vaporized sterilant in the sterilization chamber prior to that post-injection hold, and the pressure in the sterilization chamber prior to that post-injection hold. In some embodiments, each post-injection hold 424, 444, 464 may be shorter than the time required for condensation of the vaporized sterilant in the sterilization chamber. This may allow more of the sterilant 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 10 minutes or less, such as, for example, 8 minutes or less, 6 minutes or less, 4 minutes or less, 3 minutes or less, or less than 3 minutes.

[0110] The time for each post-transition hold 428, 448, 468 may be sufficient to expose surfaces within the sterilization chamber to the sterilant to effectively sterilize such 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 cease after reaching about half of the peak VHP concentration.

[0111] As previously discussed, each of pulses 420, 440, and 460 may be performed one 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 one or two times, pulse 440 may be repeated one or two times, and pulse 460 may be repeated two to ten times. In some embodiments, pulse 440 or pulse 460 may be eliminated from sterilization stage 400. For articles to be sterilized that contain more semipermeable membranes or semipermeable materials that are resistant to VHP saturation, more pulses 420 containing larger boluses of sterilant may be used.

[0112] During a sterilization step, such as sterilization step 206, sterilization step 254, sterilization step 300 and / or sterilization step 400, it may be beneficial to moderate the rate at which pressure changes are accomplished so that pressure drops more slowly than pressure increases. For example, steps 304, 308, 422, 426, 442, 446, 462 and 466, which include or result in increasing pressure in the sterilization chamber (e.g., by adding fluid, breaking vacuum, or by a diaphragm or piston 150 in the sterilization chamber 102), may include increasing the pressure in the sterilization chamber faster than the pressure is reduced in steps 302 or 402, which include achieving a vacuum level. This may encourage penetration of the sterilant throughout the sterilization chamber and the article, including the portion of the article enclosed within the semipermeable membrane.

[0113] 4 is a flow diagram of a first venting step 320 that may be performed as step 208 of the sterilization method 200 after performing one or more iterations of the sterilization step according to step 206. According to step 322, a vacuum level may be achieved. According to step 324, a vacuum level may be maintained. According to step 326, a vacuum level may be broken. According to step 328, air may be vented to and exhausted from a sterilization system (e.g., sterilization system 100).

[0114] According to step 322, a vacuum level may be achieved within the sterilization chamber 102 while also injecting a dry gas into the sterilization chamber 102, such as via distribution manifold 107a or inlet 109, near the upper interior 101 of the sterilization chamber 102, and / or via distribution manifold 107b near the lower interior 103 of the sterilization chamber 102. The dry gas may help to allow air exchange without promoting condensation of the sterilant. 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 less. The dry gas may be injected, for example, from the auxiliary dry air source 130 or the dry make-up air source 127. While the dry gas is being injected into the sterilization chamber 102, a vacuum may be pulled, for example by vacuum pump 110, through vacuum conduit 112, catalytic converter 115, and vacuum exhaust conduit 114. This vacuum may be pulled at a rate greater than the rate of injection of the dry gas, so that the vacuum level is gradually achieved. The vacuum level may be between about 50 kilopascals (500 millibars) and about 85 kilopascals (850 millibars), such as between about 50 kilopascals (500 millibars) and about 80 kilopascals (800 millibars), between about 55 kilopascals (550 millibars) and about 75 kilopascals (750 millibars), or between about 60 kilopascals (600 millibars) and about 70 kilopascals (700 millibars). For example, the vacuum level may be 50 kilopascals (500 millibars), 55 kilopascals (550 millibars), 60 kilopascals (600 millibars), 65 kilopascals (650 millibars), or 70 kilopascals (700 millibars). Injecting dry gas near the upper interior 101 of the sterilization chamber 102 while achieving the desired vacuum level reduces condensation of VHP and water vapor in the upper interior 101 of the chamber and encourages the migration of higher density molecules within the sterilization chamber towards the lower interior (e.g., lower interior 103) of the sterilization chamber 102 and, to some extent, out of the sterilization system 100 through the vacuum exhaust conduit 114.

[0115] According to step 324, the injection of drying gas may be stopped and the vacuum level may be maintained for a time period between about 1 minute and about 20 minutes, such as, 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 may be maintained for about 2, 5, 8, 10 or 15 minutes. Maintaining the vacuum level may continue to promote sedimentation of denser molecules (e.g., sterilization chemical molecules) away from the articles to be sterilized toward the lower interior 103 of the sterilization chamber 102.

[0116] According to step 326, the vacuum level may be broken by adding more dry gas near the upper interior 101 of the sterilization chamber 102, for example via the distribution manifold 107a or inlet 109, or by adding dry gas near the lower interior 103 of the sterilization chamber 102 via the distribution manifold 107b. A volume of dry gas sufficient to achieve a higher pressure may be added. This higher pressure may be, for example, 5.0 kilopascals (50 millibars) to 20 kilopascals (200 millibars) higher than the vacuum level achieved in step 322. Adding more dry gas may continue to force the sterilization chemical to settle in the lower interior 101 of the sterilization chamber 102, thus displacing the sterilization chemical from the articles to be sterilized and positioning the sterilization chemical for removal via the vacuum conduit 112 or the blower outlet conduit 108.

[0117] According to step 328, air may be vented to and exhausted from the sterilization system (e.g., sterilization system 100). During this step, the blower 106 may be turned on so that it draws fluid from within the sterilization chamber 102 and exhausts it through the exhaust 116 and through the catalytic converter 121 while the recirculation valve 119 is closed and the exhaust valve 120 is open. The blower outlet conduit 108 is connected to the sterilization chamber 102 at the lower interior 103 of the sterilization chamber 102 so that any denser fluids (such as sterilizing chemicals) that have settled in the lower interior 103 may be removed by this step. At the same time, air (e.g., from the wet make-up air source 117 or the dry make-up air source 127) may be allowed to enter the sterilization chamber 102 in such a manner that the pressure within the sterilization chamber 102 returns to atmospheric or near atmospheric pressure.

[0118] The first aeration stage 320 may be repeated between 1 and 35 times, such as, for example, 2, 5, 10, 15, 17, 19, 22, 25, 27, 29, 30, 32 or 35 times. The repetition of the first aeration stage 320 may ensure that a majority of the sterilization chemical (e.g., VHP) is removed from the sterilization system 100.

[0119] 5 is a flow diagram of a second venting stage 340 that may be performed as step 210 of the sterilization method 200. According to step 342, a vacuum level may be established. According to step 344, the vacuum level may be maintained. According to step 346, the vacuum level may be broken.

[0120] According to step 342, a vacuum level may be achieved within the sterilization chamber 102. As with the first aeration stage, the vacuum level achieved in this stage may be between about 50 kilopascals (500 mbar) and about 85 kilopascals (850 mbar), such as, for example, between about 50 kilopascals (500 mbar) and about 80 kilopascals (800 mbar), between about 55 kilopascals (550 mbar) and about 75 kilopascals (750 mbar), or between about 60 kilopascals (600 mbar) and about 70 kilopascals (700 mbar). For example, the vacuum level may be 50 kilopascals (500 mbar), 55 kilopascals (550 mbar), 60 kilopascals (600 mbar), 65 kilopascals (650 mbar), or 70 kilopascals (700 mbar). Achieving a vacuum level may facilitate removing moisture from the sterilization chamber 102, and therefore from the items to be sterilized. Thus, the items to be sterilized may dry out.

[0121] According to step 344, the vacuum level may be maintained for a time period between about 1 minute and about 20 minutes, such as, 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 may be maintained for about 2, 5, 8, 10, or 15 minutes. Maintaining the vacuum level may continue to facilitate removing moisture from the sterilization chamber 102 and, therefore, from the items to be sterilized. Thus, the items to be sterilized may become further dried. In some embodiments, step 344 may be omitted.

[0122] According to step 346, the vacuum level within the sterilization chamber 102 may be broken or increased to a higher pressure by adding dry gas, for example from the auxiliary dry air source 130 and / or the dry make-up air source 127.

[0123] The second aeration stage 340 may be repeated between 1 and 50 times, such as, for example, 2, 5, 10, 15, 20, 25, 30, 35, 38, 40, 42, 45, 47, 49 or 50 times. The repetition of the second aeration stage 340 may ensure drying of the sterilization chamber 102 and the items to be sterilized.

[0124] As previously described, the second aeration stage 340 may be performed before or after the first aeration stage 320. The first aeration stage 320 may, for example, ensure that the concentration of the sterilization chemical (e.g., VHP) in the sterilization chamber 102 is relatively low, and the second aeration stage 340 may ensure that the items to be sterilized are dried and may also remove residual sterilization chemical remaining in the sterilization chamber 102 after the first aeration stage 320. If the second aeration stage 340 is performed after the first aeration stage 320, the first aeration stage may ensure that the concentration of the sterilization chemical (e.g., VHP) in the sterilization chamber 102 is relatively low, such that when the sterilization chamber 102 and the items to be sterilized are dried in the second aeration stage 340, little need remains to remove residual sterilization chemical from the sterilization system 100.

[0125] In some embodiments, it may be desirable to achieve and / or maintain a local climate suitable for aeration prior to performing the first aeration stage 320 or the second aeration stage 340, as previously described with respect to steps 258 and 262 of the sterilization method 250.

[0126] In some embodiments, increasing the pressure to atmospheric pressure may be avoided while the concentration of sterilant in the sterilization chamber is at or near the saturation point (e.g., after a sterilization stage is completed) before performing the first venting stage 320 or the second venting stage 340. Immediately increasing pressure to atmospheric pressure when the sterilization chamber is saturated or nearly saturated with sterilant may cause unnecessary condensation of the sterilant and subsequent less effective venting.

[0127] Repeated modulation of pressure changes (e.g., evacuating and pressurizing) may be advantageous to cause physical movement of packaging components such as envelopes, covers and membranes prior to or during the first aeration stage 320 or second aeration stage 340. Physical movement of parts of the article after sterilization may help dislodge sterilant adhering to the article, thus facilitating effective aeration.

[0128] Additionally, the temperature within the sterilization chamber or system may be increased prior to or during the first aeration stage 320 or the second aeration stage 340. This may increase the aeration efficiency.

[0129] Additionally, during the venting phases (e.g. venting phases 208, 210 258, 262, 320, 340), it may be beneficial to adjust the rate at which pressure changes are accomplished so that the pressure increases slower than the pressure decreases. For example, steps 322, 328 and 342, which involve achieving a vacuum level and venting / evacuating the system, may involve lowering the pressure in the sterilization chamber faster than the pressure increases in steps 326 and 346, which involve breaking the vacuum level. This may facilitate removal of sterilant from the sterilization chamber and articles.

[0130] In some embodiments, some or all of the above-described processes and steps may be performed automatically by a sterilization system (e.g., sterilization system 100) as directed, for example, by the controller 140, which may be pre-programmed or otherwise pre-configured, for example, by a user. The sterilization methods disclosed herein may be considered "limited overkill" sterilization methods, in the sense that they ensure sterility of an article, for example an article of PFS, while minimizing the impact of the sterilization method on the product.

[0131] A number of sterilization and aeration stages are described herein. It should be understood that the characteristics, methods, or steps of any one of the sterilization stages may be applied to the other sterilization methods described herein. Similarly, the characteristics, methods, or steps of any one of the aeration stages may be applied to the other aeration stages.

[0132] (Example) The following examples are intended to illustrate the present disclosure without limiting it in nature, and it is understood that the present disclosure encompasses additional aspects and embodiments consistent with the foregoing description and the following examples.

[0133] Example 1 In one example, the sterilization target items containing 24 biological indicators were loaded into the sterilization chamber and a sterilization method was performed. The sterilization method included a leak test, a preconditioning phase, a sterilization phase with one sterilization pulse, and two aeration phases. The exact parameters for the sterilization method are summarized in Table 1.

[0134] [Table 1]

[0135] The pressure in the sterilization chamber and the temperature of the articles during the sterilization method of Example 1 were measured and are shown in FIG. Example 2 In another example, an item to be sterilized containing 20 biological indicators was loaded into a sterilization chamber and a sterilization method was performed. The sterilization method included a leak test, a preconditioning phase, and a sterilization phase with two sterilization pulses. The exact parameters for the sterilization method are summarized in Table 2. The temperature of the item to be sterilized was monitored to ensure that it did not exceed 33°C.

[0136] [Table 2]

[0137] The pressure in the sterilization chamber and the temperature of the articles during the sterilization method of Example 2 were measured and are shown in FIG. Example 3 The sterilization target items containing 24 biological indicators were loaded into the sterilization chamber and the sterilization method was carried out. The sterilization method included a leak test, a preconditioning phase, a sterilization phase with two sterilization pulses, and two aeration phases. The exact parameters for the sterilization method are summarized in Table 3.

[0138] [Table 3]

[0139] The pressure in the sterilization chamber and the temperature of the articles during the sterilization method of Example 3 were measured and are shown in Figure 8A. Example 4 The sterilization target items containing 24 biological indicators were loaded into the sterilization chamber and the sterilization method was carried out. The sterilization method included a leak test, a preconditioning phase, a sterilization phase with two sterilization pulses, and two aeration phases. The exact parameters for the sterilization method are summarized in Table 4.

[0140] [Table 4]

[0141] The pressure in the sterilization chamber and the temperature of the articles during the sterilization method of Example 4 were measured and are shown in Figure 8B. Example 5 The sterilization target items containing 24 biological indicators were loaded into the sterilization chamber and the sterilization method was carried out. The sterilization method included a leak test, a preconditioning phase, a sterilization phase with three sterilization pulses, and two aeration phases. The exact parameters for the sterilization method are summarized in Table 5.

[0142] [Table 5]

[0143] The pressure in the sterilization chamber and the temperature of the articles during the sterilization method of Example 5 were measured and are shown in Figure 9A. Example 6 The sterilization target items containing 24 biological indicators were loaded into the sterilization chamber and the sterilization method was carried out. The sterilization method included a leak test, a preconditioning phase, a sterilization phase with three sterilization pulses, and two aeration phases. The exact parameters for the sterilization method are summarized in Table 6.

[0144] [Table 6]

[0145] The pressure in the sterilization chamber and the temperature of the articles during the sterilization method of Example 6 were measured and are shown in Figure 9B. The efficacy and sterilization efficiency of the sterilization protocols from Examples 1-6 were evaluated using chemical indicators, biological indicators, temperature and humidity recorders, VHP monitors, and a handheld Drager VHP monitoring device. A summary of these results is shown in Table 7.

[0146] [Table 7]

[0147] As shown in Table 7, the sterilization methods including multiple sterilization pulses prevented biological indicators from growing. Although not shown in Table 7, each of the exemplary sterilization methods resulted in less than 1.0 ppm residual VHP. Based on the data observed from these exemplary sterilization methods, it was determined that effective sterilization could be achieved using a cycle temperature below 35° C., a vacuum pressure above 48 kilopascals (480 millibar), at least 300 g of 57 wt % H2O2 solution, and a sterilization time of 1 hour. This is a more efficient sterilization protocol than previous methodologies that required at least 500 g of 57 wt % H2O2 solution and at least 2 hours and 15 minutes of sterilization time. This more efficient protocol means that more items (e.g., more pre-filled syringes containing medicine) can be sterilized per hour compared to methods known in the art.

[0148] The above description and examples are by way of illustration and not by way of limitation. For example, as explained, the above-described embodiments (and / or aspects thereof) can be used in combination with each other.

Claims

1. preconditioning a sterilization apparatus including a sterilization chamber containing an article to be sterilized, said preconditioning comprising raising a temperature of a portion of the sterilization apparatus to a temperature greater than a maximum temperature of the article to be sterilized; performing a sterilization step comprising a plurality of sterilization pulses; performing an aeration phase including a plurality of aeration pulses; wherein the plurality of ventilation pulses comprises: establishing a first vacuum pressure in the sterilization chamber, the first vacuum pressure being between 50 and 85 kilopascals (500 and 850 millibars); and increasing the pressure in the sterilization chamber to greater than 70 kilopascals (700 millibars) after the first vacuum hold. A primary ventilation pulse comprising: establishing a second vacuum pressure within the sterilization chamber, the second vacuum pressure being less than 65 kilopascals (650 millibars); and adding air to the sterilization chamber after the second vacuum hold while evacuating the sterilization apparatus. A secondary ventilation pulse comprising The sterilization method comprises:

2. 2. The sterilization method of claim 1, wherein the multiple aeration pulses include a first primary aeration pulse, followed by a first secondary aeration pulse, followed by a second primary aeration pulse, followed by a second secondary aeration pulse.

3. 2. The sterilization method of claim 1, wherein the portion of the sterilization apparatus includes an inlet and a conduit connecting a VHP injector to the inlet.

4. Each sterilization pulse: establishing a sterilization pressure in the sterilization chamber; adding vaporized hydrogen peroxide to the sterilization chamber while the pressure in the sterilization chamber is at the sterilization pressure; The sterilization method of claim 1 , comprising:

5. 5. The sterilization method of claim 4, wherein the sterilization pressure is less than or equal to 65 kilopascals (650 millibars).

6. adding dry air to the sterilization chamber after the sterilization step and before the aeration step. The sterilization method of claim 1 further comprising:

7. the sterilization chamber includes a piston or diaphragm configured to adjust the pressure in the sterilization chamber, the method comprising: generating low frequency pressure waves using said piston or diaphragm after said sterilization step. The sterilization method of claim 1 further comprising:

8. 8. The method of claim 7, wherein the low frequency pressure waves displace liquid hydrogen peroxide in contact with the items to be sterilized.

9. 10. The method of claim 1, wherein the item to be sterilized comprises a Tyvek envelope.

10. performing a sterilization step, the sterilization step including first, second and third sterilization pulses, each sterilization pulse comprising: achieving a sterilization pressure in the sterilization chamber; and adding a quantity of vaporized hydrogen peroxide to the sterilization chamber when the pressure in the sterilization chamber is at the sterilization pressure. said performing step comprising: performing an aeration step, establishing a vacuum pressure within the sterilization chamber, said vacuum pressure being less than 65 kilopascals (650 millibars); and adding air to the sterilization chamber after the vacuum is applied while the sterilizer is being evacuated. the performing step comprising: Equipped with 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 within the 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; 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; Sterilization method.

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

12. 11. The sterilization method of claim 10, wherein the third sterilization pulse is repeated at least two times.

13. 11. The sterilization method of claim 10, 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 volume of the sterilization chamber.

14. Each sterilization pulse: (i) adding gas into the sterilization chamber to increase the pressure to a holding pressure, said holding pressure being greater than 70 kilopascals (700 millibars); (ii) reducing the pressure in the sterilization chamber to the sterilization pressure; The sterilization method of claim 10, further comprising:

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

16. Each sterilization pulse: prior to step (i), maintaining pressure in the sterilization chamber for a first hold time; maintaining the pressure in the sterilization chamber for a second hold time after step (ii); Further equipped with the second retention time is longer than the first retention time; The sterilization method according to claim 15.

17. the sterilization chamber includes a distribution manifold, an inlet and a chamber wall, the method comprising: maintaining the temperature of the chamber walls approximately the same as the temperature of the inlet or the temperature of the distribution manifold during the first, second and third sterilization pulses. The sterilization method of claim 10, further comprising:

18. a first sterilization pulse comprising adding a first amount of vaporized hydrogen peroxide to a sterilization chamber, said first amount being sufficient to establish a lethal concentration of hydrogen peroxide within said sterilization chamber; a plurality of second sterilization pulses, each second sterilization pulse including adding a second amount of vaporized hydrogen peroxide to the sterilization chamber, the second amount being less than the first amount; a plurality of third sterilization pulses, each third sterilization pulse including adding a third amount of vaporized hydrogen peroxide to the sterilization chamber, the third amount being less than the second amount; A sterilization method comprising:

19. the sterilization chamber comprising an article, the article comprising a Tyvek material defining an interior of the article and an exterior of the article; after the third plurality of sterilization pulses, a concentration of hydrogen peroxide in the interior of the article is approximately equal to a concentration of hydrogen peroxide in the exterior of the article; 19. The sterilization method according to claim 18.

20. (i) reducing the pressure in the sterilization chamber to a first venting pressure, said first venting pressure being less than 65 kilopascals (650 millibars); (ii) increasing the pressure in the sterilization chamber to a second venting pressure, said second venting pressure being greater than 70 kilopascals (700 millibars); [0033] Further comprising the step of performing an aeration pulse, comprising: the rate of pressure change in step (ii) is at least 10 kilopascals (100 millibars) per minute higher than the rate of pressure change in step (i); 19. The sterilization method according to claim 18.

21. 21. The sterilization method of claim 20, further comprising the step of removing moisture from the sterilization chamber prior to the venting step by passing the contents of the sterilization chamber through a condenser.

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