Sterilization method

Abstract

Embodiments of the present disclosure relate to systems and methods for applying vaporized chemicals to the sterilization of medical products. For example, embodiments of the present disclosure may relate to systems and methods for terminally sterilizing medical products using vaporized hydrogen peroxide (VHP). Embodiments of the present disclosure may relate to systems and methods for terminal sterilization of medical products such as prefilled syringes (PFS), for example.

Description

[0001] (Division of 201880020838.3)

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Application No. 62 / 477,030, filed on March 27, 2017, and U.S. Application No. 62 / 568,850, filed on October 6, 2017, both of which are incorporated herein by reference in their entirety. Field of the Invention

[0004] Various embodiments of the present disclosure are directed to systems and methods for sterilizing medical products. More specifically, specific embodiments of the present disclosure are directed to systems and methods for wet chemical sterilization of medical products, including terminal sterilization of prefilled syringes (or other prefilled drug delivery devices) using vaporized chemicals, such as vaporized hydrogen peroxide. BRIEF DESCRIPTION OF THE DRAWINGS

[0005] The accompanying drawings, which are incorporated into and constitute a part of this specification, illustrate various exemplary embodiments and, together with the description, are used to explain the principles of the disclosed embodiments. The accompanying drawings illustrate different aspects of the present disclosure, and, where appropriate, reference numerals illustrating similar structures, components, materials, and / or elements in different figures are similarly labeled. It should be understood that various combinations of structures, components, and / or elements other than those specifically illustrated are contemplated and within the scope of the present disclosure.

[0006] Many inventions are described and illustrated herein. The described invention is not limited to any single aspect nor to the embodiments thereof, nor to any combination and / or permutation of such aspects and / or embodiments. In addition, each of the aspects of the described invention and / or its embodiments may be employed alone or in combination with one or more of the other aspects of the described invention and / or its embodiments. For the sake of brevity, certain permutations and combinations are not discussed and / or illustrated separately herein. It is noteworthy that embodiments or implementations described herein as "exemplary" should not be construed as being superior or superior to, for example, other embodiments or implementations; rather, it is intended to reflect or indicate that one or more embodiments are one or more "example" embodiments.

[0007] Figure 1 is a schematic diagram of an exemplary sterilization system that may be used to sterilize medical products.

[0008] Figure 2 is a flow chart of steps in an exemplary method of sterilizing a medical product using vaporized chemicals.

[0009] FIG. 3A to FIG. 3Cis an additional flow chart of steps in an exemplary method of sterilizing a medical product using vaporized chemicals.

[0010] FIG. 4A to FIG. 4C is a schematic diagram of an exemplary sterilization system at various stages in an exemplary method of sterilizing a medical product using vaporized chemicals. DETAILED DESCRIPTION

[0011] As used herein, the terms "comprises," "comprising," "including," "have," "with," or any other variation thereof, are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that includes a series of elements need not include only those elements, but may also include other elements not expressly listed or inherent to such process, method, article, or apparatus. The term "exemplary" is used in the sense of "example" rather than "ideal." Any implementation described herein as exemplary should not be construed as superior or superior to other implementations. In addition, the terms "first," "second," and the like herein do not indicate any order, quantity, or importance, but are used to distinguish between individual elements. Similarly, terms of relative orientation, such as "front side," "top side," "back side," "bottom side," "upper," "lower," and the like, are mentioned with respect to the described figures.

[0012] As used herein, the terms "about" and "approximately" mean that possible variations of ±10% of the stated value are taken into account. Unless otherwise expressly stated, all measurements reported herein should be understood to be modified by the term "about", or the term "approximately", whether or not these terms are expressly used. As used herein, the singular forms "a", "an", and "the" include plural references unless the context clearly indicates otherwise. In addition, in the claims, values, limits, and / or ranges are intended to mean the stated values, limits, and / or ranges plus / minus 10%.

[0013] As used in the present disclosure, the term "sterilization" refers to the realization of suitable sterility levels for the drug substance or drug product prepared for commercial circulation and use. This sterility level can be defined in, for example, regulatory guidelines or regulations, such as the guidelines issued by the U.S. Food and Drug Administration (USFood and Drug Administration). In some embodiments, this sterility level can include, for example, a 6-log reduction of the microbial population of the biological indicator on the outer surface or inner surface (for example, the outer surface of a syringe or the inner surface of a blister package) of the drug product. In other embodiments, this sterility level can include, for example, a 9-log or 12-log reduction of the microbial population of the biological indicator. Sterilization refers to the realization of this suitable sterility level, while also realizing sufficiently low residual sterilization chemical content (for example, vaporized hydrogen peroxide, ethylene oxide, etc.) for commercial circulation and use. This low residual sterilization chemical content can also be defined in regulatory guidelines or regulations.

[0014] As used in this disclosure, the term "terminal sterilization" refers to sterilizing a pharmaceutical product in a container or package suitable for commercial distribution and use, such as in a primary packaging component or in both a primary packaging component and a secondary packaging component.

[0015] As used in this disclosure, the term "medical product" refers to a product that is used medically for living animals. The term "medical product" includes, for example, a pharmaceutical product, a formulated drug substance, a medical implant, a medical device, or a combination thereof. For example, the term "medical product" may refer to a syringe containing a formulated drug substance, such as a parenteral syringe or an ophthalmic syringe. Other exemplary medical products include, for example, suppository applicators and medications, transdermal drug delivery devices, medical implants, needles, cannulas, medical devices, and any other product that requires sterilization prior to intended medical use.

[0016] As used in this disclosure, the term "formulated drug substance" refers to a composition containing at least one active ingredient (e.g., a small molecule, protein, nucleic acid, or gene therapy agent) and excipients that is ready for pharmaceutical distribution and use. The formulated drug substance may include fillers, colorants, and other active or inactive ingredients.

[0017] As used in this disclosure, the term "drug product" refers to a dosage form containing a formulated drug substance, such as a final dosage form for an active ingredient. A drug product may include packaging, such as a bottle, vial, or syringe, for commercial distribution or use.

[0018] As used in this disclosure, the term "vaporized chemical" refers to a chemical that has been transformed into a substance that can be diffused or suspended in the air. In some cases, the vaporized chemical can be a chemical that is first combined with water and then transformed into a substance that can be diffused or suspended in the air.

[0019] As used in this disclosure, the term "fluid" refers to liquid, semi-liquid, vapor, or gas including oxygen, hydrogen, nitrogen, or a combination thereof.

[0020] Embodiments of the present disclosure relate to systems and methods for applying vaporized chemicals to the sterilization of medical products. For example, embodiments of the present disclosure may relate to systems and methods for terminally sterilizing medical products using vaporized hydrogen peroxide (VHP). More specifically, embodiments of the present disclosure may relate to systems and methods for terminal sterilization of medical products such as prefilled syringes (PFS), for example.

[0021] It is generally expected that exposure to the sterilization cycle will not have an adverse effect on the product being sterilized and that there is minimal risk of damage or alteration. Medical products that are subjected to terminal sterilization, such as PFS, may therefore require that the sterilization equipment, mechanical equipment, control devices, cycles and methods comply with certain restrictions and requirements in order to achieve proper sterilization and / or avoid damage to the medical product and / or device, formulated drug substance, drug product or other product. Such restrictions and requirements may include, for example:

[0022] The medical product and / or surrounding packaging may be sensitive to deep vacuum pressure during the sterilization cycle. For example, the PFS may include a pre-loaded plunger that is easily dislodged when exposed to a deep vacuum environment. In addition, the medical product may include fragile materials, such as glass, that may be affected by the deep vacuum environment.

[0023] Medical products, compositions contained in medical products, and / or the surrounding environment may be adversely affected by extreme temperatures during sterilization cycles. For example, products containing liquid formulations (e.g., liquid medications in PFS) may be unstable when heated to the higher temperatures to which the products may be exposed during a typical sterilization cycle. For example, medications in such liquid formulations may denature, become inactivated, or otherwise altered when exposed to and / or heated to high temperatures.

[0024] Medical products may be densely packaged; for example, a bulk package of medical products may contain a large number of fully assembled, packaged and labeled medical products. In the case of terminal sterilization, the sterilant may need to traverse several layers of packaging materials, container materials and / or labeling.

[0025] • In the case of some types of sterilization, such as terminal sterilization, the sterilant may need to cross a semi-permeable membrane, either by heat or by mass, to sterilize the exterior of each medical product as well as the interior of the packaging element.

[0026] Packaging for medical products may be resistant to penetration by sterilization 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' that is configured to contain the syringe and restrict its movement. Such a blister may be only slightly permeable to sterilization materials, and / or may be sensitive to pressure changes.

[0027] Medical products can be sealed using temperature or pressure sensitive components. For example, PFS can be sealed using a semi-permeable membrane 'lid'.

[0028] Chemical sterilization including wet chemical sterilization can provide the advantages of some of the features of processing the above-mentioned medical product sterilization.For example, the sterilization performed using the combination of VHP and vaporized water can be advantageously performed at a relatively low temperature, thereby eliminating the need for exposing the medical product to destructive high temperatures. However, due to, for example, incomplete sterilization is achieved by the sterilization cycle, the sterilization cycle cannot be operated within the permissible temperature and / or pressure range of the medical product, and it is difficult to remove toxic residual VHP and / or the sterilization time is long from the sterilized article, indicating that the evidence of the successful application of VHP sterilization technology in terminal sterilization (for example, the terminal sterilization of PFS) is very limited. Ethylene oxide (" EtO ") is a feasible alternative to VHP, and is known to be an effective agent for sterilizing articles sensitive to high temperature and high pressure. However, EtO is more toxic to humans than VHP, and therefore presents health and safety issues during and after its use in the sterilization system.

[0029] For at least the above reasons, it may be desirable to more successfully apply VHP to the terminal sterilization of medical products. Such behavior may be desirable despite achieving relative sterilization "cycle efficiencies" (e.g., (1) a reduction in overall sterilization cycle time, and / or (2) a reduction in the extremes of the temperature at which the sterilization cycle operates). There is potentially significant value associated with the successful application of VHP in terminal sterilization (e.g., of PFS), and there is improved cycle efficiency when VHP is applied to the terminal sterilization of PFS. Potential value can be obtained by minimizing risk to the product and commercially by allowing a greater total throughput of medical products (e.g., PFS) per unit time.

[0030] Several aspects of VHP sterilization may affect (positively or negatively) the safety, efficacy, efficiency, and other aspects of the sterilization process used for medical products. For example:

[0031] Vaporized sterilization chemicals such as VHP may be stored as aqueous liquid mixtures, may be vaporized in the presence of water, and / or may otherwise be present in an environment with water vapor. Under some sterilization conditions, the vaporized sterilization chemical may not behave like a dry gas and / or an ideal gas. For example, VHP may not completely dissociate from water vapor in a sterilization chamber; instead, VHP may behave like a binary mixture of VHP and water vapor.

[0032] During some or all of the sterilization cycle, chemical sterilant vapor and water vapor in the sterilization chamber may adsorb onto and / or condense on surfaces having a lower temperature than the ambient temperature in the sterilization chamber. For example, during steam sterilization of a PFS load, "cold spots" created by aqueous, high heat capacity liquid products in each PFS may be used to induce vapor adsorption and promote surface condensation. Once in proximity to a surface, chemical sterilant vapor and water vapor may adsorb onto the surface due to the chemical properties of the steam itself, the operating conditions inside the chamber during sterilization, and the lower temperature on the surface of the PFS load compared to the rest of the chamber environment.

[0033] During some or all sterilization cycles, VHP may be preferentially adsorbed onto surfaces compared to water vapor due to the fact that hydrogen peroxide has a greater density and lower volatility than water. In some cases, VHP and water vapor may simultaneously adsorb and condense on surfaces, with the amount and percentage of VHP adsorbed and condensed being greater than that of water vapor and closer to the surface of the sterilization load than water vapor.

[0034] During some or all sterilization cycles, multiple adsorbed layers may form on the surface of the PFS load. In some cases, each adsorbed and / or condensed layer further from the surface may contain less VHP and more water vapor, so that a gradient of VHP to water is formed on the surface. Due to the thermodynamic behavior of a binary mixture of VHP and water vapor near or at saturation (vapor / liquid equilibrium), VHP may preferentially adsorb to the surface of the load and condense closer to the surface. The vapor / liquid equilibrium may be similar to the gas / adsorbate equilibrium of a binary mixture of VHP and water vapor in a sterilization application.

[0035] During or after a VHP sterilization cycle, condensed / adsorbed hydrogen peroxide can be difficult to remove from surfaces that the hydrogen peroxide has sterilized due in part to condensation of water vapor on the condensed hydrogen peroxide, and adsorption of water around the condensed hydrogen peroxide, which can trap the hydrogen peroxide in locations on the sterilized surface.

[0036] The systems and methods disclosed herein can be advantageously used to successfully sterilize medical products while reducing the impact and / or risk of the sterilization process on the products being sterilized. For example, the systems and methods disclosed herein can provide for comprehensive (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, improve the efficiency, safety, and effectiveness of sterilization, and / or reduce sterilization cycle time. In addition, while various aspects of the present disclosure may be described with respect to the use of VHP in the final sterilization of PFS, sterilization of other medical products is also contemplated by the present disclosure.

[0037] The present disclosure also contemplates the performance of "wet chemical sterilization," by which chemical sterilization can be achieved in the presence of water vapor. The comparison of "wet chemical sterilization" to "chemical sterilization" can be similar in some cases to the comparison of "moist heat sterilization" to "heat sterilization." In some cases, wet chemical sterilization can be a more effective and efficient means of achieving sterilization than currently existing chemical sterilization technologies, just as "moist heat sterilization" is considered more effective and efficient than "heat sterilization" alone in some cases.

[0038] "Wet chemical sterilization" can occur when environmental conditions of relatively high chemical concentration, high water vapor concentration, and high pressure (e.g., greater than 400 millibars) work together to force the chemical and water vapor to behave like a binary mixture. In order to achieve the desired relatively high chemical concentration, high water vapor concentration, and high pressure, the sterilization chamber (e.g., sterilization chamber 102) can be saturated with a combination of water vapor and a sterilizing chemical (e.g., VHP), so that the vapor condenses on the surface of the "load" or one or more items to be sterilized (e.g., product 105). Most commercially available hydrogen peroxide is available and sold as an aqueous liquid mixture at different concentrations (e.g., 3%, 15%, 35%, 59%), and therefore the vaporized hydrogen peroxide typically also includes vaporized water. When using VHP, since VHP has a higher density than water vapor, VHP can condense on the surface of one or more items to be sterilized in preference to water vapor.

[0039] It should be recognized herein that a portion of a sterilization load having a lower temperature than the surrounding sterilization environment (e.g., the ambient temperature of the sterilization chamber 102) can act as a "cold spot" that attracts steam condensation on a surface area of ​​the load. If specific "cold spots" within the load are located inside a package that requires steam to travel through a semipermeable membrane, these "cold spots" can advantageously attract vaporized VHP to condense to the surface area surrounding the "cold spots," thereby creating a higher density of condensed VHP areas of the load and promoting diffusion of the sterilization chemical across the semipermeable membrane it contacts. On the other hand, it should be recognized that if the "cold spot" is too cold, that is, there is an excessively large temperature difference (δ) between the load or a portion of the load and the surrounding sterilization environment (e.g., the environment of the sterilization chamber 102), the presence of the "cold spot" can prevent the VHP from being distributed and penetrating the entire load. It should be recognized, therefore, that a balanced temperature difference is required between the temperature of the sterilization environment (e.g., sterilization chamber 102) and the temperature of a "cold spot" on the item to be sterilized (e.g., product 105) so that the VHP is drawn to condense at the "cold spot" without adversely affecting short-term diffusion across the load.

[0040] Now refer to the accompanying drawings, Figure 1 An exemplary sterilization system 100 is shown in diagrammatic form. The sterilization system 100 includes a sterilization chamber 102, which is surrounded by a temperature control jacket 104. The sterilization chamber 102 has an internal cavity, which includes an upper interior 101 and a lower interior 103. The sterilization chamber 102 is configured to accommodate 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 via a distribution manifold 107 in the sterilization chamber 102. A second inlet conduit 135 is also fluidly connected to the sterilization chamber 102, also allowing fluids to enter the sterilization chamber 102 via an inlet 109. A blower 106 is fluidly connected to the sterilization chamber 102 via a blower outlet conduit 108. The blower circulation conduit 118 fluidly connects the blower 106 to move fluid from the blower outlet conduit 108 toward the exhaust pipe 116, or back toward the sterilization chamber 102 via the inlet conduit 134. The exhaust valve 120 is located between the blower circulation conduit 118 and the exhaust pipe 116, and selectively closes or opens the connection between the blower circulation conduit 118 and the exhaust pipe 116. The recirculation valve 119 is located between the blower circulation conduit and the inlet conduit 134, and selectively closes or opens the connection between the blower circulation conduit 118 and the inlet conduit 134. The vacuum pump 110 is also fluidly connected to the sterilization chamber 102 via the vacuum conduit 112 and the catalytic converter 115. The vacuum valve 113 is located on the vacuum conduit 112, and selectively allows, partially allows, or blocks flow from the sterilization chamber 102 through the catalytic converter 115 and the vacuum pump 110. A vacuum exhaust conduit 114 fluidly connects the vacuum pump 110 to an exhaust pipe 116 .

[0041] Several fluid supplies are also fluidly connected to the sterile chamber 102 via the inlet conduit 134 or the inlet conduit 135. The air supply 117 is configured to supply air to the sterile chamber 102 via the inlet conduit 134. The air valve 124 is coupled to the fluid connection between the air supply 117 and the inlet conduit 134, and selectively allows, partially allows, or prevents air from flowing from the air supply 117 to the sterile chamber 102 via the inlet conduit 134. In addition, a VHP injector 132 fluidly connected to the inlet conduit 134 is configured to inject VHP into the sterile chamber 102 via the inlet conduit 134. The 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 prevents VHP from flowing from the VHP injector 132 to the sterile chamber 102 via the inlet conduit 134. In addition, a dry air supply 130 fluidly connected to the inlet conduit 135 is configured to supply dry air to the sterile chamber 102 via the inlet conduit 135. The dry air supply valve 126 is coupled to the fluid connection between the dry air supply 130 and the inlet conduit 135 and is configured to selectively allow, partially allow, or prevent dry air from flowing from the dry air supply 130 to the sterilization chamber 102 via the inlet conduit 134. The 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 air supply 117, the dry air supply 130, and / or any other components of the sterilization system 100.

[0042] The sterilization system 100 can be configured to run a sterilization cycle at various temperatures and pressures and in various durations and / or time intervals within the sterilization chamber 102. In some embodiments, the temperature, pressure, and time interval at which the sterilization system 100 can run a sterilization cycle can be selectively and individually modified and customized. The sterilization system 100 can be configured to control the environment in the interior of the sterilization chamber 102, including temperature, pressure, humidity, atmosphere, the amount of fluid introduced via, for example, an inlet conduit 134, one or more via a temperature or pressure control device, and / or the outflow of fluid via, for example, a blower outlet conduit 108 and / or a vacuum conduit 112. Additionally, the sterilization system 100 may include any suitable number and location of sensors configured to sense, for example, temperature, pressure, flow, chemical concentration, or other parameters throughout the sterilization system 100, including in 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 to, for example, the controller 140 and / or a human-machine interface.

[0043] The sterilization chamber 102 can be a sealable chamber defining an interior including an upper interior 101 and a lower interior 103. The sterilization chamber 102 can be open to an open configuration so that one or more items, such as product 105, can be placed inside as part of a load for sterilization and can be removed after sterilization. In some embodiments, the sterilization chamber 102 can, for example, have an operating orientation so that the upper interior 101 is located above the lower interior 103 and so that materials can fall from near the upper interior 101 toward the lower interior 103 (e.g., under the action of gravity). The sterilization chamber 102 can have one or more conveying devices, and one or more of the inlet conduits 134 and the inlet conduits 135 can be connected to the one or more conveying devices. As shown in FIG. Figure 1 As shown, for example, the distribution manifold 107 is one such delivery device. The distribution manifold 107 can be configured to disperse gas, steam, or liquid into the sterilization chamber 102 in a given configuration, such as a flow or uniform spray across the upper interior 101 of the sterilization chamber 102. The inlet 109 is another such delivery device. The inlet 109 can also be configured to disperse gas, steam, or liquid into the sterilization chamber 102 in a given configuration, such as a flow or uniform spray across the upper interior 101. In some embodiments, the distribution manifold 107 can be configured to disperse gas, steam, or liquid into the sterilization chamber 102 in a configuration, such as a uniform spray, and the inlet 109 can be configured to disperse gas or steam into the sterilization chamber 102 in a different configuration, such as in a flow configuration. In some embodiments, the inlet 109 may not be present, and both inlet conduits 134 and 135 can be connected to the distribution manifold 107.

[0044] The temperature control jacket 104 can be any material surrounding the sterilization chamber 102 that is configured or effective to provide temperature control of the environment inside the sterilization chamber 102. In some embodiments, for example, the temperature control jacket 104 can be a water jacket surrounding the sterilization chamber 102. In such embodiments, the temperature and / or flow rate of water or other liquid passing through the temperature control jacket 104 can be controlled by, for example, the controller 140.

[0045] The product 105 can be any one or more articles suitable for sterilization using the sterilization system 100. In some embodiments, the product 105 can be a medical product in primary packaging, secondary packaging, or both. In some embodiments, the product 105 may be a medical product having one or more active parts that are additionally sensitive to a deep vacuum environment, such as an environment with a pressure less than about 100 millibars. The product 105 can therefore be, for example, a container filled with a certain volume of a prepared drug substance, such as a vial or PFS. In other embodiments, the product 105 can be or include a medical product that is sensitive to, for example, a high temperature higher than 30°C. Such a medical product can include, for example, a prepared drug substance or other compositions that may be sensitive to high temperatures, such as proteins (e.g., antibodies or enzymes), nucleic acids, blood, blood components, vaccines, allergen preparations, gene therapy agents, tissues, other biological substances, etc. For example, the product 105 can be a packaged PFS containing a prepared drug substance including an antibody.

[0046] The blower 106 can be, for example, a blower capable of forcibly drawing steam and gases from the lower interior 103 of the sterilization chamber 102 through the blower outlet duct 108 and reintroducing the steam and gases back into the upper interior 101 of the sterilization chamber 102 via the inlet duct 134 (or alternatively, drawing such steam and gases through the exhaust valve 120 and the catalytic converter 121 to the exhaust pipe 116). The blower 106 can be any device or mechanism configured or effective to perform such a function. For example, the blower 106 can have an impeller and rotating blades, or rotating vanes, that are configured to draw steam and gases from the lower interior 103 out of the blower outlet duct 108, through the blower circulation duct 118 and draw the steam and gases back into the upper interior 101 of the sterilization chamber 102 via the inlet duct 134. In some embodiments, as Figure 1 As shown, the blower 106 can be outside the sterilization chamber 102. In other embodiments, the blower 106 can be arranged in the sterilization chamber 102. In some embodiments, the blower 106 can be configured to extract steam and gas from the lower interior 103 of the sterilization chamber 102 with a force sufficient to generate a steam and gas flow from the upper interior 101 of the sterilization chamber 102 to the lower interior 103, and the steam and gas are introduced back to the upper interior 101. This flow can be referred to as "turbulence". In some embodiments, the force by which the blower 106 can operate may be adjustable (via, for example, a controller 140) so that more turbulent (for example, more intense) or less turbulent steam and gas flow can be generated in the sterilization chamber 102. In some embodiments, the blower 106 can be configured to generate a more powerful force than, for example, a vacuum pump 110 to extract steam and gas.

[0047] The vacuum pump 110 may be a vacuum pump capable of drawing gas from the interior of the sterilization chamber 102 (e.g., the lower interior 103), passing through the vacuum conduit 112 and the catalytic converter 115 and drawing the gas toward the exhaust pipe 116, thereby creating a vacuum within the sterilization chamber 102 and / or a closed system containing the sterilization chamber 102 and, for example, the blower 106. In some embodiments, the vacuum pump 110 may have a pump wheel, rotating blades, or vanes that are configured to draw vapor and gas toward the exhaust pipe 116. The vacuum pump 110 may be fluidly connected to the exhaust pipe 116 via, for example, a vacuum exhaust conduit 114. In some embodiments, the exhaust from the vacuum pump 110 and the blower 106 may be separated rather than combined into one.

[0048] In some embodiments, vacuum type functions may also or alternatively be performed by, for example, a blower 106, which may selectively circulate steam and gases into and out of the sterilization chamber 102, or out of the sterilization chamber 102, through a discharge valve 120 and toward the discharge conduit 116. The discharge valve 120 may be selectively opened or closed to permit or prevent gas or steam from flowing from the blower circulation conduit 118 toward the discharge conduit 116, or toward the inlet conduit 134 for reintroduction into the sterilization chamber 102. The discharge valve 120 may be manually controlled, or may be controlled by, for example, a controller 140.

[0049] The sterilization system 100 may include several air and / or steam supplies by which fluids may be introduced into the sterilization chamber 102 via an inlet conduit 134 or an inlet conduit 135. For example, the air supply 117 may be any air supply (e.g., room air, or compressed dry air) or other fluids from the rest of the sterilization system 100 externally. In some embodiments, the air supply 117 may be a "room air" supply surrounding the sterilization system 100, which may have passed through an indoor filtration system. In some embodiments, the air supply 117 may include more water vapor than "room air". In some embodiments, the air supply 117 may be a filtered outdoor air supply. An air valve 124 coupled to the fluid connection between the air supply 117 and the inlet conduit 134 may be configured to selectively allow, partially allow, or prevent air from flowing from the air supply 117 via the inlet conduit 134 to the sterilization chamber 102, thereby controlling the amount of air introduced into the enclosed portion of the sterilization system 100. The air valve 124 may be manually controllable and / or controllable by, for example, the controller 140 .

[0050] The dry air supply 130 can be an air supply with relatively low humidity, so that it can be used to dry the interior of, for example, the sterilization chamber 102 and / or one or more of the conduits 108, 112, 114, 118, and 134. In some embodiments, for example, the air in the dry air supply 130 can include a dew point of, for example, -10°C or lower, -40°C or lower, or any temperature between -10°C and -40°C. In some embodiments, the dry air supply 130 can be a clean dry air supply, such as air that has been sterilized or otherwise filtered to at least 0.2 microns. In some embodiments, the dry air supply 130 can be a sealed air supply. In some embodiments, the dry air supply 130 can be a compressed air supply. The dry air supply valve 126 coupled to the fluid connection between the dry air supply 130 and the inlet conduit 135 can be configured to selectively allow, partially allow, or prevent dry air from the dry air supply 130 via the inlet conduit 135 to flow to the sterilization chamber 102. Dry air supply valve 126 may be manually controllable and / or may be controlled by, for example, controller 140. In some embodiments, dry air supply 130 may be connected to inlet conduit 134 instead of inlet conduit 135. In other embodiments, air supply 117 may supply any type of air that dry air supply 130 comprises.

[0051] The VHP injector 132 may include a supply of VHP, or VHP and vaporized water, and may be configured to inject the VHP or a combination of VHP and vaporized water into the sterilization chamber 102 via, for example, an inlet conduit 134. The VHP injector 132 may be configured to inject steam into the sterilization chamber 102 at an adjustable concentration. The VHP injector valve 128 may be coupled to a fluid connection between the VHP injector 132 and the inlet conduit 134, and may be configured to selectively allow or prevent VHP from flowing from the VHP injector 132 via the inlet conduit 134 to the sterilization chamber 102. The VHP injector valve 128 may be manually controllable and / or may be controlled by, for example, a controller 140. The dry air supply valve 126 and the VHP injector valve 128 may also be used in conjunction to allow a desired combination of dry air and vaporized VHP / water to enter the sterilization chamber 102 via the inlet conduit 134.

[0052] The catalytic converter 115 and the catalytic converter 121 can be any catalytic converter known in the art to be suitable for converting a toxic gaseous or vaporized fluid, such as one that circulates within the sterilization system 100 during a sterilization cycle, into a gas or vapor of low toxicity. For example, the catalytic converters 115, 121 can be configured to convert the VHP injected into the sterilization system 100 via the VHP injector 132 into water vapor, oxygen, or other non-toxic fluids.

[0053] Some or all aspects of the sterilization system 100 may be controlled by, for example, a controller 140. The controller 140 may be, for example, an analog or digital controller configured to change various aspects of the sterilization chamber 102 environment, such as the internal temperature or pressure of 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 pipe 116, one or more of the valves 113, 119, 120, 124, 126, and 128, one or more of the catalyst converters 115, 121, one or more of the conduits 108, 112, 114, 116, 118, and 134, and any and / or other aspects of the sterilization system 100. In some embodiments, the sterilization system 100 may be controlled by multiple controllers 140. In other embodiments, the sterilization system may have only one controller 140. In some embodiments, the controller 140 may be a digital controller, such as a programmable logic controller.

[0054] In some embodiments, the controller 140 can be pre-programmed to perform one or more sterilization cycles using the sterilization system 100. In some embodiments, the sterilization system 100 can be controlled by a controller having one or more human-machine interface ("HMI") elements, which can be configured to allow a user to input or change the desired parameters of a sterilization cycle, which can be performed by the controller on the sterilization system 100 or operably coupled to the sterilization system. Therefore, in some embodiments, the HMI element can be used to program a customized sterilization cycle for the sterilization system 100 to perform. For example, in some embodiments, the sterilization system 100 can be controlled by a controller connected to, for example, a computer, a tablet computer, or a handheld device with a display. Such a display may include, for example, options for selecting or changing the desired temperature, pressure, time, VHP introduction amount, etc. for one or more steps of the sterilization cycle.

[0055] Figure 2 and FIG. 3A to FIG. 3C A flow chart showing the stages and steps in a sterilization method according to the present disclosure is shown. As one of ordinary skill in the art will recognize, the steps may be omitted, combined, and / or performed out of sequence while remaining consistent with the present disclosure. Figure 2 and FIG. 3A to FIG. 3C In some embodiments, the sterilization system 100 or a variation of the sterilization system 100 may be used to perform Figure 2 and FIG. 3A to FIG. 3C It will be recognized that in order to implement Figure 2 and FIG. 3A to FIG. 3CThe stages and steps shown may utilize customizable and controllable aspects of the sterilization system 100. For example, in some embodiments, the controller 140 may be employed to direct, adjust, or modify a series of sterilization steps, set points, and stages that may be performed by the sterilization system 100. Additionally, although the sterilization system 100 is described with respect to FIG. Figure 2 and FIG. 3A to FIG. 3C The stages and steps described in the present invention are described herein, but a person of ordinary skill in the art will understand that these stages and steps can be performed by another sterilization system, or another system capable of performing the steps.

[0056] Figure 2 A flow chart showing a series of steps in a sterilization method 200 according to the present disclosure in a sterilization system such as the sterilization system 100. According to step 202, a leak test can be performed on the sterilization system 100. According to step 204, the sterilization system 100 can be preconditioned. According to step 206, a sterilization phase can be performed. According to step 208, a first ventilation phase can be performed. According to step 208, a second ventilation phase can be performed.

[0057] Prior to performing the steps of method 200, a sterilization load such as product 105 may be placed within a sterilization chamber such as sterilization chamber 102 of a sterilization system such as sterilization system 100. A closed system sterilization environment may then be sealed, including sterilization chamber 102, blower outlet duct 108, blower 106, blower circulation duct 118, inlet duct 134, and any elements connecting these components.

[0058] According to step 202, a leak test can be performed on the closed system sterilization environment. The leak test can include, for example, creating a vacuum in the entire closed system. The vacuum can be created by, for example, using a vacuum pump 110 to exhaust gases and steam from the closed system. During the leak test, the blower 106 can be in operation so that any remaining air is circulated through the closed system and a homogenous environment is created. In order to verify that a suitable vacuum can be maintained in the closed system, a leak test can be performed in this way to some extent. In addition, including air in the entire closed system in the leak test and circulating air through the entire closed system can help increase the heat transfer coefficient between the environment in the closed system and the load to be sterilized, which can help balance the temperature between the environment in the closed system and the load to be sterilized before sterilization.

[0059] According to step 204, the sterilization system (e.g., sterilization system 100) can be pre-conditioned. Pre-conditioning can include, for example, increasing 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, pre-conditioning can be performed over a longer time than that performed in a standard chemical sterilization procedure, which can allow more time to reduce any temperature difference between the environment in the closed system (including, for example, the environment of the sterilization chamber 102) and the load to be sterilized. In some embodiments, pre-conditioning can be performed for about 15 minutes to about two hours, such as about 20 minutes to about 1.5 hours, about 25 minutes to about 1 hour, about 30 minutes to about 1 hour, about 30 minutes to about 45 minutes, about 45 minutes to about 1 hour, such as about 30 minutes, about 40 minutes, about 45 minutes or about 1 hour. Preconditioning according to step 204 may also include operating at or near atmospheric pressure, for example, between about 400 mbar and about 700 mbar, between about 500 mbar and about 700 mbar, between about 500 mbar and about 600 mbar, between about 800 mbar and about 1000 mbar, or between about 900 mbar and about 1100 mbar. The operation of the preconditioning step at or near atmospheric pressure may promote convective heat transfer from the chamber environment to the load, thereby helping to minimize the temperature difference between the chamber environment and the load. In addition, the blower 106 may be operated during preconditioning according to step 204, which may contribute to a higher heat transfer coefficient, and therefore a potentially faster temperature balance between the closed system including the environment of the sterilizing chamber 102 and the load to be sterilized. The temperature balance between the closed system and the load to be sterilized may allow a "cold spot", or a position on or in the load with a temperature cooler than the majority of the load and / or the surrounding environment to warm up. For example, the liquid contents of the PFS may absorb heat more slowly than its non-liquid packaging, thereby acting as a "cold spot" within the load containing the PFS. Reducing such cold spots by balancing the temperatures in the closed system and the load to be sterilized can advantageously allow vaporized sterilization chemicals (e.g., VHP) to diffuse evenly throughout the sterilization chamber 102, across the load to be sterilized, and / or diffuse through permeable membranes and barriers in the load to be sterilized. However, it may be desirable to maintain a certain temperature difference between the closed system and the "cold spot" to promote preferential surface adsorption and condensation of VHP and water vapor onto the load to be sterilized.

[0060] As discussed elsewhere herein, it is also contemplated that maintaining a "cold spot" via maintaining a temperature differential between the load to be sterilized and the surrounding closed system may also have advantages in some embodiments; for example, controlled condensation of vaporized sterilization chemical (e.g., VHP) at a "cold spot" of the load to be sterilized may concentrate the sterilization chemical on the load and diffuse the chemical into the load more efficiently, thereby reducing the total amount of sterilization chemical required to achieve effective sterilization in the sterilization chamber 102. In such embodiments, preconditioning according to step 204 may be performed for a shorter amount of time and / or in a shallow vacuum created by, for example, the vacuum pump 110, in order to allow or maintain a "cold spot" within the load to be sterilized.

[0061] According to step 206, a sterilization phase may be performed. The sterilization phase may include, for example, starting the circulation of fluid through the sterilization system, achieving a vacuum, injecting vaporized chemicals into the sterilization chamber, maintaining a post-injection hold, injecting gas into the sterilization chamber to transition to a shallower vacuum, and maintaining a post-transition hold. The sterilization phase according to step 206 may be repeated multiple times. Figure 3A The sterilization phase according to step 206 is shown in more detail in FIG.

[0062] According to step 208, a first ventilation stage may be performed. The first ventilation stage may include, for example, achieving a vacuum, maintaining a vacuum, breaking a vacuum, and ventilating and exhausting the system. The first ventilation stage may be performed multiple times. Figure 3B The first ventilation phase according to step 208 is shown in more detail in FIG.

[0063] According to step 210, a second ventilation stage may be performed. The second ventilation stage may include, for example, achieving a vacuum, maintaining a vacuum, and breaking a vacuum. The second ventilation stage may be performed multiple times. Figure 3C The second ventilation phase according to step 210 is shown in more detail in FIG.

[0064] Both steps 208 and 210 may be performed multiple times. Additionally, while in some embodiments, step 208 may be performed before step 210, in alternative embodiments, step 210 may be performed before step 208.

[0065] Figure 3A 2 is a flow chart of a sterilization stage 300 that can be performed as step 206 of the sterilization method 200. Prior to the sterilization stage 300, a sterilization load (e.g., product 105) can be introduced into the sterilization chamber 102. According to step 302, a vacuum can be achieved. According to step 304, a vaporized chemical can be injected into the sterilization chamber. According to step 306, a post-injection hold can be maintained. According to step 308, a gas can be injected into the sterilization chamber to convert to a shallower vacuum. According to step 310, a post-injection hold can be maintained.

[0066] As part of the sterilization stage 300 , turbulent flow may be initiated and maintained in the sterilization system 100 .

[0067] According to step 302, a vacuum can be achieved in the sterilization chamber 102 of the sterilization system 100. The vacuum can be, for example, between about 400 mbar and about 700 mbar, such as between about 450 mbar and about 650 mbar or between about 450 mbar and about 550 mbar. For example, the vacuum can be about 450 mbar, about 500 mbar, about 550 mbar, or about 600 mbar. Such a vacuum can promote a high concentration of sterilizing chemicals on the sterilizing load, and extending the amount of time that the closed system remains in a deeper vacuum increases the exposure of the sterilizing load to the sterilizing chemicals.

[0068] According to step 304, vaporized chemicals can be injected into the sterilization chamber. In some embodiments, vaporized chemicals can include VHP. In some embodiments, vaporized sterilization chemicals can be vaporized hydrogen peroxide aqueous solution with, for example, a concentration of hydrogen peroxide between about 5 wt % and about 75 wt %. In some embodiments, vaporized chemicals can be vaporized hydrogen peroxide aqueous solution with following concentration: for example, hydrogen peroxide between about 10 wt % and about 65 wt %, hydrogen peroxide between about 15 wt % and about 60 wt %, hydrogen peroxide between about 30 wt % and about 60 wt %, hydrogen peroxide between about 30 wt % and about 60 wt %, or hydrogen peroxide between about 45 wt % and about 60 wt %. In some embodiments, vaporized chemicals can be vaporized aqueous hydrogen peroxide with about 35 wt % hydrogen peroxide (and 65 wt % water). In other embodiments, vaporized chemicals can be vaporized aqueous hydrogen peroxide with about 59 wt % hydrogen peroxide (and 41 wt % water).

[0069] In some embodiments, the VHP supply of injection can be, for example, about 50g to about 700g of aqueous VHP. For example, the VHP supply of injection can be about 50g to about 600g, about 100g to about 600g, about 300g to about 550g or about 450g to about 550g. For example, the VHP supply of injection can be about 100g, about 200g, about 300g, about 400g, about 450g, about 475g, about 500g, about 525g, about 550g, about 600g or about 650g. In some embodiments, the VHP supply of injection can be quantitative based on the volume or amount of the load sterilized inside sterilizing chamber 102. For example, if a number of drug products, such as prefilled syringes, are to be sterilized in sterilization chamber 102, the VHP supply for injection may be about 0.01 to about 0.15 grams of VHP, such as about 0.01 to about 0.10 grams of VHP, such as 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 unit of drug product inside sterilization chamber 102. In other embodiments, the VHP supply for injection may be quantified based on the volume of the sterilization environment, such as the interior of sterilization chamber 102. For example, the VHP supply for injection may be about 0.2 to 3.0 grams per cubic foot of volume in the sterilization chamber. For example, the injected VHP supply can be about 0.2 to about 2.0 grams per cubic foot, such as 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.

[0070] In some embodiments, step 210 may also include injecting dry air into the sterilization system from, for example, the dry air supply 130 to create a desired balance between the concentrations of vaporized chemicals and water vapor at different pressures inside the chamber.

[0071] According to step 306, it is possible to maintain the injection back maintenance.During the injection back maintenance period, turbulence is maintained by a closed system comprising sterilizing chamber 102 and blower 106.Do not add or remove fluid to the closed system wherein maintaining turbulence.The time (or "hold time after injection") maintained after the injection can be selected to allow the sterilizing chemicals of vaporization to have enough time to contact the load to be sterilized.In some embodiments, the holding time after the injection can be about 2 minutes to about 20 minutes.In some embodiments, the holding time after the injection can be at least about 5 minutes, at least about 10 minutes or at least about 15 minutes.In some embodiments, the holding time after the injection can be about 5 minutes to about 20 minutes, about 8 minutes to about 20 minutes, about 10 minutes to about 20 minutes or about 10 minutes to about 15 minutes.In this way, it is possible to avoid the need to add excessive VHP to the system to ensure that it contacts with the sterilization load.

[0072] According to step 308, gas can be injected into the sterilization chamber to convert to a shallower vacuum (i.e., a higher pressure) in the sterilization chamber. The gas can be any suitable gas capable of destroying or reducing the vacuum in the sterilization chamber 102. In some embodiments, the gas can be a dry gas, such as a gas containing nitrogen (e.g., a commercially available supply of only nitrogen or mainly nitrogen), or air having a dew point of, for example, -10°C or less. In some embodiments, the gas can be injected from a dry air supply 130. The gas can be injected by volume to achieve a pressure between about 500 mbar and about 1100 mbar, such as between about 550 mbar and about 1000 mbar, between about 600 mbar and about 1000 mbar, between about 700 mbar and about 700 mbar and about 900 mbar, or between about 750 mbar and about 850 mbar. For example, the second post-injection pressure may be about 700 mbar, about 750 mbar, about 800 mbar, about 850 mbar, or about 900 mbar.

[0073] The post-transition hold may be maintained according to step 310. During the post-transition hold, the pressure achieved during step 308 may be maintained, for example, for at least about 5 minutes, at least about 10 minutes, or at least about 15 minutes. In some embodiments, the second post-injection pressure may be maintained for about 5 minutes to about 20 minutes, about 8 minutes to about 20 minutes, about 10 minutes to about 20 minutes, or about 10 minutes to about 15 minutes.

[0074] The steps of sterilization stage 300 can be repeated, for example, 1 to 10 times, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10 times. This can help ensure complete sterilization of the sterilization load in sterilization chamber 102. In some embodiments, the number of times that sterilization stage 300 can be repeated can be inversely proportional to the time maintained after injection in each repetition. For example, if the time maintained after injection is shorter (for example, 10 minutes), steps 210 to 216 can be repeated more times. In some embodiments, the injection is maintained for a longer period of time (for example, 15-20 minutes) to increase the time that the sterilization load is exposed to sterilization chemicals in each repetition of sterilization stage 300. In other embodiments, the number of times that sterilization stage 300 can be repeated can depend on the desired VHP total amount of the sterilization process. In some embodiments, for example, the injection of at least 200g of VHP total amount may be desired. For example, in some embodiments, the total amount injection of at least 250g may be desired. In some embodiments, injection of a total amount of between about 200 g and about 700 g of VHP may be desirable.

[0075] Figure 3B is a flow chart of a first venting stage 320 that can be performed as step 208 of the sterilization method 200 after performing one or more iterations of the sterilization stage according to step 206. According to step 322, a vacuum can be achieved. According to step 324, the vacuum can be maintained. According to step 326, the vacuum can be broken. According to step 328, the sterilization system (e.g., the sterilization system 100) can be ventilated and exhausted.

[0076] According to step 322, a vacuum can be achieved in the sterilization chamber 102 while also injecting dry gas into the sterilization chamber 102 near the upper interior 101 of the sterilization chamber 102, such as via the distribution manifold 107 or the inlet 109. The dry gas may include, for example, oxygen and / or nitrogen. The dry gas may have, for example, a dew point of -10°C or lower. The dry gas may be injected from, for example, a dry air supply 130. While the dry gas is injected into the sterilization chamber 102, a vacuum may be drawn by, for example, a vacuum pump 110 via a vacuum conduit 112, a catalytic converter 115, and a vacuum exhaust conduit 114. The vacuum may be drawn at a rate greater than the injection rate of the dry gas so that a vacuum may be gradually achieved. The vacuum may be, for example, between about 500 mbar and about 850 mbar, such as between about 500 mbar and about 800 mbar, between about 550 mbar and about 750 mbar, or between about 600 mbar and about 700 mbar. For example, the vacuum level can be 500 mbar, 550 mbar, 600 mbar, 650 mbar, or 700 mbar. Injecting the dry gas near the upper interior 101 of the sterilization chamber 102 while achieving the desired vacuum level reduces the concentration of VHP and water vapor at the upper interior 101 of the chamber, and promotes the movement of denser molecules in the sterilization chamber toward the lower interior (e.g., lower interior 103) of the sterilization chamber 102, and to some extent out of the sterilization system 100 through the vacuum exhaust conduit 114.

[0077] According to step 324, the injection of dry gas can be stopped, and the vacuum can be maintained, for example, for about 1 minute to about 20 minutes, such as about 2 minutes to about 20 minutes, about 5 minutes to about 20 minutes, about 5 minutes to about 15 minutes, or about 5 minutes to about 10 minutes. For example, the vacuum can be maintained for about 2, 5, 8, 10, or 15 minutes. Maintaining the vacuum can continue to promote the settling of denser molecules (e.g., sterilizing chemical molecules) downward toward the lower interior 103 of the sterilization chamber 102, and away from the sterilization load.

[0078] According to step 326, vacuum can be broken near the upper interior 101 of sterilizing chamber 102 by adding more dry gas via, for example, distribution manifold 107 or inlet 109. Dry gas of a volume sufficient to achieve higher pressure can be added. Higher pressure can be, for example, 50 to 200 mbar higher than the vacuum achieved in step 322. Vacuum can be, for example, between about 550 mbar and about 1000 mbar, such as between about 550 mbar and about 850 mbar, between about 600 mbar and about 700 mbar, or between about 650 mbar and about 750 mbar. For example, vacuum can be about 550 mbar, 600 mbar, 650 mbar, 700 mbar, 750 mbar, or 800 mbar. Adding more dry gas may continue to force the sterilization chemical to settle into the lower interior 101 of the sterilization chamber 102 , thereby moving the sterilization chemical away from the sterilization load and positioning it for removal via the vacuum duct 112 or the blower outlet duct 108 .

[0079] According to step 328, the sterilization system (e.g., sterilization system 100) can be ventilated and exhausted. During this step, the blower 106 can be turned on while closing the recirculation valve 119 and opening the discharge valve 120, so that the blower 106 draws fluid from the interior of the sterilization chamber 102 and discharges the fluid through the discharge pipe 116 via the catalytic converter 121. Since the blower outlet conduit 108 is connected to the sterilization chamber 102 at the lower interior 103 of the sterilization chamber 102, the denser fluid (such as sterilizing chemicals) that has settled to the lower interior 103 can be removed by this step. Air (e.g., from the air supply 117) can be simultaneously allowed to be discharged into the sterilization chamber 102 so that the pressure in the sterilization chamber 102 returns to atmospheric pressure or near it.

[0080] The first aeration stage 320 can be repeated, for example, 1 to 35 times, such as 2, 5, 10, 15, 17, 19, 22, 25, 27, 29, 30, 32 or 35 times. The repetition of the first aeration stage 320 can ensure that most of the sterilization chemicals (e.g., VHP) are removed from the sterilization system 100.

[0081] Figure 3C is a flow chart of a second ventilation stage 340 that can be performed as step 210 of the sterilization method 200. According to step 342, a vacuum can be achieved. According to step 344, the vacuum can be maintained. According to step 346, the vacuum can be broken.

[0082] According to step 342, vacuum can be achieved in sterilizing chamber 102. Similar to the first ventilation stage, the vacuum achieved in this stage can be, for example, between about 500 mbar and about 850 mbar, such as between about 500 mbar and about 800 mbar, between about 550 mbar and about 750 mbar or between about 600 mbar and about 700 mbar. For example, the vacuum can be 500 mbar, 550 mbar, 600 mbar, 650 mbar or 700 mbar. Achieving vacuum can promote the removal of moisture in sterilizing chamber 102 and therefore sterilizing load. Therefore, the sterilizing load can be dried.

[0083] According to step 344, the vacuum degree can be maintained for example from about 1 minute to about 20 minutes, such as from about 2 minutes to about 20 minutes, from about 5 minutes to about 20 minutes, from about 5 minutes to about 15 minutes, or from about 5 minutes to about 10 minutes. For example, the vacuum degree can be maintained for about 2, 5, 8, 10 or 15 minutes. Maintaining the vacuum degree can continue to promote the removal of moisture in the sterilizing chamber 102 and therefore the sterilizing load. Therefore, the sterilizing load can be further dried. In some embodiments, step 344 can be omitted.

[0084] According to step 346 , the vacuum in the sterilization chamber 102 may be broken or raised to a higher pressure by adding dry gas from, for example, the dry air supply 130 .

[0085] The second ventilation stage 340 can be repeated, for example, 1 to 50 times, such as 2, 5, 10, 15, 20, 25, 30, 35, 38, 40, 42, 45, 47, 49 or 50 times. The repetition of the second ventilation stage 340 can ensure drying of the sterilization chamber 102 and the sterilization load.

[0086] As has been previously described, the second aeration stage 340 may be performed before or after the first aeration stage 320. The first aeration stage 320 may ensure that, for example, the concentration of a sterilization chemical (e.g., VHP) in the sterilization chamber 102 is relatively low, and the second aeration stage 340 may ensure that the sterilization load is dry and may also remove residual sterilization chemicals remaining in the sterilization chamber 102 after the first aeration stage 320. In the case where the second aeration stage 340 is performed after the first aeration stage 320, the first aeration stage may ensure that the concentration of a sterilization chemical (e.g., VHP) in the sterilization chamber 102 is relatively low, so that when the sterilization chamber 102 and the sterilization load are dried in the second aeration stage 340, there is little need to remove residual sterilization chemicals from the sterilization system 100.

[0087] FIG. 4A to FIG. 4CThe sterilization system 100 is shown in diagrammatic form and specifically shows which components of the sterilization system 100 may be activated, opened, or turned on (as opposed to deactivated, closed, or disconnected) during stages 300, 320, and 340. For clarity, the controller 140 and thermal jacket 104 are not shown.

[0088] Figure 4A Various components of the sterilization system 100 are shown in diagrammatic form at different stages of activation or deactivation during the sterilization stage 300. As shown, during the sterilization stage 300, the blower outlet duct 108, the blower circulation duct 118, the blower 106, and the recirculation valve 119 remain open, connected, or activated throughout the sterilization stage 300. The air supply 117, the air supply valve 124, the exhaust valve 120, and the catalytic converter 121 remain closed, disconnected, or deactivated throughout the sterilization stage 300. The remaining components are sometimes opened, connected, or activated during the sterilization stage 300. The following table indicates when these components are opened, connected, or activated:

[0089] Table 1

[0090]

[0091] Figure 4B The various components of the sterilization system 100 during the first ventilation stage 320 are shown in diagram form. As shown, the VHP injector 132, the VHP injector valve 128, and the recirculation valve 119 remain disconnected or closed during the first ventilation stage 320. The remaining components are sometimes opened, turned on, or activated during the first ventilation stage 320 as indicated in the following table:

[0092] Table 2

[0093]

[0094] Figure 4C Various components of the sterilization system 100 are shown in diagrammatic form during the second ventilation stage 340. As shown, during the second ventilation stage 340, the air supply 117, the air supply valve 124, the VHP injector, the VHP injector valve 128, the exhaust valve 120, and the catalytic converter 121 remain closed. The blower outlet duct 108, the blower 108, the blower circulation duct 118, the recirculation valve 119, the inlet 134, and the distribution manifold 107 remain open during the ventilation stage 340. The remaining components are sometimes opened, switched on, or activated during the ventilation stage 340. The following table indicates when these components are opened, switched on, or activated:

[0095] Table 3

[0096]

[0097] In some embodiments, any or all of the above steps and stages can be automatically performed by the sterilization system 100 as directed by, for example, the controller 140, which can be programmed or otherwise configured in advance by, for example, a user. The sterilization methods disclosed herein can be characterized as "limited overkill" sterilization methods because the sterilization methods can ensure sterilization of a load, such as a PFS, while minimizing the impact of the sterilization method on the product.

[0098] The above description is illustrative and is not intended to be restrictive. Without departing from the general scope of the present invention, a person of ordinary skill in the art may make numerous modifications and / or changes. For example, and as described, the above embodiments (and / or aspects thereof) may be used in combination with each other. In addition, without departing from the scope of the present invention, parts of the above embodiments may be removed. In addition, without departing from the scope thereof, modifications may be made to adapt specific situations or materials to the teachings of various embodiments. After reviewing the above description, many other embodiments will also be apparent to a person of ordinary skill in the art.

Claims

1. A method for sterilizing a syringe containing a drug, the sterilization method comprising: generating turbulence in a chamber containing a primary packaging component including said syringe; as well as While maintaining the turbulence, pulsating sterilization is performed, the pulsating sterilization comprising: Achieving a vacuum level within the chamber; introducing vaporized hydrogen peroxide (VHP) into the chamber; removing the VHP from the lower interior of the chamber and reintroducing the VHP into the upper interior of the chamber; and introducing a dry gas into the chamber, wherein the dry gas has a dew point of -10°C or less, Therein a coagulation layer is formed on the primary packaging element.

2. The sterilization method according to claim 1, wherein the drug is an antibody.

3. The sterilization method of claim 1, wherein the primary packaging component comprises a semipermeable membrane.

4. The sterilization method of claim 1, wherein the coagulation layer comprises a first portion in contact with the primary packaging component and a second portion not in contact with the primary packaging component; and a hydrogen peroxide concentration in the first portion is greater than a hydrogen peroxide concentration in the second portion.

5. The sterilization method of claim 1, wherein the dry gas is introduced at least 5 minutes after the VHP is introduced.

6. The sterilization method of claim 5, wherein the dry gas comprises nitrogen.

7. The sterilization method of claim 1, wherein the condensation layer comprises hydrogen peroxide and water.

8. The sterilization method of claim 1, wherein the syringe is a first syringe among a plurality of syringes; During sterilization, the plurality of syringes are within the chamber; and Introducing VHP into the chamber comprises introducing about 0.01 to about 0.10 grams of VHP per syringe into the chamber.

9. A method for sterilizing a syringe containing a drug, the sterilization method comprising: generating turbulence in a chamber containing the injector; and While maintaining the turbulence, pulsating sterilization is performed, the pulsating sterilization comprising: Maintaining the sterilization pressure in the chamber for at least 5 minutes; introducing vaporized hydrogen peroxide (VHP) into the chamber; allowing the VHP to circulate within the chamber for at least 5 minutes, said allowing the VHP to circulate within the chamber comprising removing the VHP from the lower interior of the chamber and reintroducing the VHP into the upper interior of the chamber; and A dry gas is introduced into the chamber, wherein the dry gas has a dew point of -10°C or less.

10. The sterilization method of claim 9, wherein the dry gas comprises nitrogen.

11. The sterilization method of claim 9, wherein the sterilization pressure is between about 400 mbar and about 800 mbar.

12. The sterilization method according to claim 9, wherein the pulsating sterilization is a first pulsating sterilization, and the sterilization method further comprises performing a second pulsating sterilization.

13. The sterilization method of claim 9, wherein reintroducing the VHP into the chamber comprises introducing about 0.2 to about 3.0 grams of VHP per cubic foot of chamber volume.

14. The sterilization method according to claim 9, wherein the dry gas is a first dry gas having a dew point of -10°C or lower, and the sterilization method further comprises performing pulsating ventilation, the pulsating ventilation comprising: achieving a first ventilation pressure of between about 400 mbar and about 800 mbar in the chamber; increasing the pressure within the chamber to a second ventilation pressure that is greater than the first ventilation pressure; and While indoor air, air having a dew point of -10°C or less, or a second dry gas having a dew point of -10°C or less is introduced into the chamber, gas is simultaneously exhausted from the chamber.

15. The sterilization method according to claim 9, wherein: During pulsation sterilization, a condensation layer forms within the chamber.

16. A method for sterilizing a syringe containing a drug, the sterilization method comprising: placing a primary packaging component of the syringe in the chamber; Creating turbulence in the chamber; and While maintaining the turbulence, pulsating sterilization is performed, the pulsating sterilization comprising: maintaining the sterilization pressure within the chamber for at least 5 minutes, wherein the sterilization pressure is between about 400 mbar and about 800 mbar; introducing vaporized hydrogen peroxide (VHP) into the chamber; allowing the VHP to circulate within the chamber for at least 5 minutes, wherein allowing the VHP to circulate within the chamber comprises removing the VHP from the lower interior of the chamber and reintroducing the VHP into the upper interior of the chamber; and introducing a dry gas into the chamber, wherein the dry gas has a dew point of -10°C or less; Therein, during the pulsation sterilization, a condensation layer is formed on the primary packaging component.

17. The sterilization method of claim 16, further comprising maintaining a temperature between about 25°C and about 60°C within the chamber while performing the pulsation sterilization.

18. The sterilization method according to claim 16, wherein the dry gas is a first dry gas having a dew point of -10°C or lower, the sterilization method further comprising performing pulsating ventilation, the pulsating ventilation comprising: achieving a first ventilation pressure of between about 400 mbar and about 800 mbar in the chamber; increasing the pressure within the chamber to a second ventilation pressure that is greater than the first ventilation pressure; and While indoor air, air having a dew point of -10°C or less, or a second dry gas having a dew point of -10°C or less is introduced into the chamber, gas is simultaneously exhausted from the chamber.

19. The sterilization method of claim 18, wherein the first dry gas, the second dry gas, or both comprise nitrogen.

20. The sterilization method of claim 18, wherein the pulsating sterilization is a first pulsating sterilization, the pulsating ventilation is a first pulsating ventilation, and the sterilization method further comprises performing a second pulsating sterilization, performing a second pulsating ventilation, or both.

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