sterilization method

Abstract

Provided are a method and a system for sterilizing a medical device including, but not limited to, a prefilled syringe. The method for sterilizing a prefilled syringe may include placing the prefilled syringe in a sterilization chamber and performing a plurality of pulsed sterilization steps. Each pulsed sterilization step may include drying the sterilization chamber, humidifying the sterilization chamber, evacuating the sterilization chamber to a target pressure, introducing an amount of NO2 into the sterilization chamber from a buffer tank selectively fluidly connected to the sterilization chamber, introducing a preset amount of air into the sterilization chamber through the buffer tank to assist in flowing NO2 from the buffer tank into the sterilization chamber, and holding the sterilization chamber at a retention pressure for a retention period after the preset amount of air has passed through the buffer tank.

Description

Technical Field

[0001] The present invention generally relates to a sterilization method, and more particularly to a sterilization method using NO2 gas.

Background Art

[0002] A variety of medical devices have been developed for medical use. Some devices can be fully implanted to replace or repair bone in the bloodstream or other locations within the body (e.g., orthopedic implants, stents, and various electrical stimulators). Other devices (e.g., endoscopes, catheters, and guidewires) are introduced into the body in a single procedure and then removed from there. Still other devices are used to introduce substances into the body or extract substances from the body (e.g., syringes). Still other products are used to repair the body or treat it in other ways (e.g., sutures and various staples).

[0003] Conventionally, as sterilization methods for medical instruments, high-pressure steam sterilization (hereinafter simply referred to as "AC sterilization") and ethylene oxide gas sterilization (hereinafter simply referred to as "ETO sterilization") have been widely used. Gamma radiation can also be used for a range of devices.

[0004] AC is a sterilization method that exposes the object to be sterilized to a high temperature of about 121 to 135 °C, and is widely used for medical instruments made of materials such as metal and glass. However, since sterilization is performed under high-temperature conditions, there is a drawback that the object to be sterilized is limited. For example, heat-sensitive materials such as some plastics cannot be sterilized by AC. Some products may contain heat-sensitive substances such as prefilled syringes or therapeutic molecules and / or cells, and may not be suitable for AC sterilization.

[0005] ETO sterilization can be performed at lower temperatures below 70°C, making it suitable for use with plastics. However, ETO is toxic at low concentrations and poses an explosive risk, requiring careful storage and handling to ensure hygiene and safety. There are also risks associated with the release of ETO gas from ETO-sterilized products. Furthermore, when supplying ETO from a tank (cylinder) to a sterilization device via piping, it is necessary to constantly monitor the weight of the cylinder to prevent unexpected leaks from the piping. Unfortunately, ETO exposure has been associated with a suspected cancer risk both within and near sterilization facilities.

[0006] In addition to these sterilization methods, hydrogen peroxide sterilization is also used. Compared to ETO, hydrogen peroxide is easier to use and manage, and is useful from a safety standpoint. However, because hydrogen peroxide is used in the form of hydrogen peroxide vapor at or near its saturation partial pressure, it is necessary to compensate for the non-uniform vapor distribution throughout the sterilization chamber, making it difficult to scale up this sterilization method.

[0007] There is a need for a sterilization method that can act on the intricate details of the device, reduce the risk of toxicity and explosion, and be performed at lower temperatures. [Overview of the project]

[0008] This disclosure provides, but is not limited to, methods for sterilizing devices such as medical devices. This summary is not intended to describe each disclosed embodiment or all implementations of the present invention.

[0009] A first exemplary and non-limiting example is a method for sterilizing a pre-filled syringe, comprising: placing the pre-filled syringe in a sterilization chamber; and performing a number of pulse sterilization steps. Each pulse sterilization step includes: drying the sterilization chamber with the pre-filled syringe inside; humidifying the sterilization chamber after it has been dried to a target; evacuating the sterilization chamber to a target pressure after it has been humidified; introducing a certain amount of NO2 into the sterilization chamber from a buffer tank selectively fluid-coupled to the sterilization chamber; introducing a preset amount of air into the sterilization chamber through the buffer tank to assist in the flow of NO2 from the buffer tank into the sterilization chamber; and holding the sterilization chamber at a residence pressure for a residence period after the preset amount of air has passed through the buffer tank.

[0010] Additionally or alternatively, the retention pressure is at least 150 Torr above the target pressure. Additionally or alternatively, the target pressure is in the range of about 200 to about 500 Torr, and the retention pressure is about 600 Torr. Additionally or alternatively, the sterilization chamber has sufficient heat capacity to limit the temperature change of the prefilled syringe during the sterilization process to less than 5°C. Additionally or alternatively, the prefilled syringe has contents that do not change the temperature of the prefilled syringe by more than 3°C during the sterilization process. Additionally or alternatively, the contents of the prefilled syringe are maintained in the temperature range of 2 to 15°C. Additionally or alternatively, the concentration of NO2 accumulated in the buffer chamber is about 100 times the concentration of NO2 after it is introduced into the sterilization chamber. Additionally or alternatively, the resulting concentration of NO2 in the sterilization chamber during the retention process is in the range of 2 to 20 mg / L. Additionally or alternatively, the preset amount of air is within the range of 4 to 8 times the volume of the buffer tank. Additionally or alternatively, the preset amount of air is dry air. Additionally or alternatively, the method may include, following the retention step, flowing air into the sterilization chamber while monitoring the residual gas in the chamber using a residual gas sensor until the residual gas concentration falls below a preset safety threshold.

[0011] Additionally or alternatively, a circulation means is provided for recirculating the air in the chamber, and the humidifying step and the step of introducing a certain amount of NO2 are carried out by mixing with the recirculating air while the chamber is at a pressure lower than the ambient pressure. Additionally or alternatively, the introduced NO2 is at least partially converted into other chemical products during sterilization, the other chemical products comprising at least HONO, and the method further includes monitoring the concentration of HONO during the sterilization process, comparing the concentration of HONO to one or more thresholds, and determining that the sterilization process is incomplete if the concentration of HONO does not meet the one or more thresholds. Additionally or alternatively, the step of introducing a certain amount of NO2 from a buffer tank into the sterilization chamber is carried out by determining a first pressure in the sterilization chamber, monitoring a second pressure in the buffer tank, adding air to the buffer tank until the second pressure exceeds the first pressure, and opening a valve between the buffer tank and the sterilization chamber.

[0012] Other exemplary and non-limiting examples include a method for sterilizing pre-filled syringes, the method comprising placing the pre-filled syringes in a sterilization chamber and performing a number of pulse sterilization steps. Each pulse sterilization step includes: drying the sterilization chamber with the prefilled syringe inside; humidifying the sterilization chamber to a target humidity level after drying it to a target level; exhausting the sterilization chamber to a target pressure in the range of approximately 200 to approximately 500 Torr after humidifying it; introducing a certain amount of NO2 into the sterilization chamber from a buffer tank selectively fluid-connected to the sterilization chamber; introducing a preset amount of air into the sterilization chamber through the buffer tank to assist in the flow of NO2 from the buffer tank into the sterilization chamber; and maintaining the sterilization chamber at a residence pressure of approximately 600 Torr or more for a residence period after the preset amount of air has passed through the buffer tank, wherein the concentration of NO2 in the sterilization chamber during the residence step is in the range of approximately 2 to 20 mg / L.

[0013] Additionally or alternatively, the retention pressure is at least 150 Torr above the target pressure. Additionally or alternatively, the concentration of NO2 accumulated in the buffer chamber is about 100 times the concentration of NO2 after it is introduced into the sterilization chamber. Additionally or alternatively, the preset amount of air is within the range of 4 to 8 times the volume of the buffer tank. Additionally or alternatively, the process of introducing a certain amount of NO2 from the buffer tank into the sterilization chamber is performed by determining a first pressure in the sterilization chamber, monitoring a second pressure in the buffer tank, adding air to the buffer tank until the second pressure exceeds the first pressure, and opening a valve between the buffer tank and the sterilization chamber.

[0014] Other exemplary and non-limiting examples include a method for sterilizing an object, comprising placing the object in a sterilization chamber and performing a number of pulsed sterilization steps. Each pulsed sterilization step includes drying the sterilization chamber with the prefilled syringe inside; humidifying the sterilization chamber after it has been dried to a target level; evacuating the sterilization chamber to a target pressure after it has been humidified; introducing a certain amount of NO2 into the sterilization chamber from a buffer tank selectively fluid-coupled to the sterilization chamber; introducing a preset amount of air, ranging from 4 to 8 times the volume of the buffer tank, through the buffer tank into the sterilization chamber to assist in the flow of NO2 from the buffer tank into the sterilization chamber; and maintaining the sterilization chamber at a residence pressure for a residence period after the preset amount of air has passed through the buffer tank, wherein the concentration of NO2 in the sterilization chamber during the residence step is in the range of approximately 2 to 20 mg / L.

[0015] Additionally or alternatively, the process of introducing a certain amount of NO2 from a buffer tank into a sterilization chamber is performed by determining a first pressure in the sterilization chamber, monitoring a second pressure in the buffer tank, adding air to the buffer tank until the second pressure exceeds the first pressure, and opening a valve between the buffer tank and the sterilization chamber. Additionally or alternatively, the dwell pressure is at least 150 Torr above the target pressure. Additionally or alternatively, the object is a medical device. Additionally or alternatively, the medical device is placed in a package.

[0016] Other exemplary and non-limiting examples include a method for sterilizing using NO2, the method comprising: preparing a sterilization chamber for containing products to be sterilized by placing the sterilization chamber in a known state; introducing a certain amount of NO2 together with a certain amount of moisture-containing air into the sterilization chamber, wherein the NO2 and the moisture-containing air interact within the sterilization chamber to produce a plurality of chemical products of the sterilization process; using a chemical sensor to monitor the concentration of at least one of the plurality of chemical products of the sterilization process during a retention step after the introduction of the certain amount of NO2 and the moisture-containing air into the chamber and before exhausting the chamber; comparing the monitored concentration with a process target; determining whether the retention step has reached or achieved a sterilization target; generating a warning to the operator or performing a corrective action if the retention step has not reached or failed to achieve the sterilization target; and recording information in memory indicating the success of the retention step if the retention step has reached or achieved the sterilization target.

[0017] Additionally or alternatively, the step of using a chemical sensor to monitor the concentration of at least one of the plurality of chemical products includes detecting the concentration of HONO in the sterilization chamber. Additionally or alternatively, the step of comparing the monitored concentration to a process target is performed by comparing the concentration monitored over time with a modeled concentration model constructed during the validation and verification process, the model of which is stored in the memory of the controller for the sterilization chamber. Additionally or alternatively, the step of performing the corrective action includes changing the state of the chamber during the retention step. Additionally or alternatively, the step of performing the corrective action includes storing information indicating that the retention step has failed and repeating the preparation step, the introduction step, and the retention step. Additionally or alternatively, the step of performing the corrective action includes adjusting parameters used in subsequent iterations of the preparation step, the introduction step, and the retention step. Additionally or alternatively, the step of performing the corrective operation may include changing the duration of the dwell step, and changing the duration of the dwell step may include extending or shortening the duration of the dwell step. [Brief explanation of the drawing]

[0018] The present invention can be more fully understood by considering the following detailed descriptions of various embodiments in conjunction with the accompanying drawings. [Figure 1] Figure 1 is a schematic perspective view of an exemplary sterilization chamber. [Figure 2] Figure 2 is a block diagram of an exemplary sterilization system and gas supply system. [Figure 3] Figure 3 is a block diagram of an exemplary method for sterilizing an object. [Figure 4] Figure 4 is an exemplary block diagram of residence period monitoring and correction processing. [Modes for carrying out the invention]

[0019] The present invention can follow various modifications and alternative forms, the details of which are shown in the drawings as examples and will be described in detail. However, it should be understood that the intention is not to limit the aspects of the present invention to the specific embodiments described. On the contrary, it is intended to cover all modifications, equivalents, and alternatives within the spirit and scope of the present invention.

[0020] In this specification, all numerical values are considered to be modified by the term "about", whether or not explicitly indicated. The term "about" generally refers to a range of numerical values that one of ordinary skill in the art would consider to be equivalent to the recited value (e.g., having the same function or result). In many cases, the term "about" can be shown to include numerical values rounded to the nearest significant digit. The recitation of numerical ranges by endpoints includes all numbers within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, and 5). Although some preferred dimensions, ranges, and / or values for various components, features, and / or specifications are disclosed, one of ordinary skill in the art triggered by this disclosure will understand that the desired dimensions, ranges, and / or values can deviate from those explicitly disclosed.

[0021] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly indicates otherwise. As used in this specification and the appended claims, the term "or" is generally used in the sense of "and / or" unless the context clearly indicates otherwise.

[0022] The following detailed description should be read with reference to the drawings, and similar elements in different drawings are numbered the same. The detailed description and drawings are not necessarily to a certain scale and illustrate exemplary embodiments, and are not intended to limit the scope of the invention. The exemplary embodiments shown are intended for illustrative purposes only. Selected features of any exemplary embodiment may be incorporated into additional embodiments unless otherwise expressly stated to the contrary.

[0023] Nitrogen dioxide (NO2) is known to exhibit beneficial sterilization effects. The object of this disclosure is to provide sterilization methods and systems that can be used to sterilize articles such as scissors, forceps, needles, cannulas, surgical scalpels, tubes, drug delivery devices, filled syringes, empty syringes, staples, implantable medical devices (such as anchors, embolization coils, stents, catheters, ports, leads, implantable tools, stimulating devices, pumps, ventricular assist devices, etc.), and other medical devices. Endoscopes and other visualization systems, balloon catheters, guide catheters, electrotherapy devices, stylets, implantable tools, filters, baskets, and other medical devices may also be sterilized by the methods described herein.

[0024] The object to be sterilized can be considered to be placed within a sterilization chamber. FIG. 1 is a schematic view of an exemplary sterilization chamber 10. In the illustrated embodiment, the sterilization chamber 10 (in a closed configuration) includes an upper wall 12, a bottom wall 14 facing the upper wall 12, a first side surface 16, a second side surface 18 facing the first side surface 16, a rear surface 20, and a front surface 22 facing the rear surface 20. The sterilization chamber 10 is formed at least partially from a material that is less likely to be corroded and / or degraded by a NO2 sterilization environment. For example, the sterilization chamber 10 may be formed from stainless steel, nickel-chromium alloy, unsaturated polyester resin, or the like. In some cases, different materials may be used for different parts of the sterilization chamber 10. The same or similar materials may also be used in a pre-chamber and / or a buffer tank, which will be further described below. The sterilization chamber 10 is described and illustrated as having a generally rectangular prism shape, but the sterilization chamber 10 may have any desired shape, such as spherical or cylindrical, although not limited thereto. Although not explicitly shown, the sterilization chamber 10 may be fixed or connected to a base so that the sterilization chamber 10 is stably supported.

[0025] The front section 22 may include or be formed by a movable door 26 configured to open and close to allow access to the internal sterilization cavity 24 of the sterilization chamber 10 through an access opening 30. The internal sterilization cavity 24 may be defined by the inner surfaces of the respective walls 12, 14, 16, 18, 20, and 22. The door 26 and / or the sterilization chamber 10 may include a sealing material 28 positioned around the access opening 30. The sealing material 28 can provide an airtight seal when the door 26 is in a closed configuration (not explicitly shown). In some embodiments, the sealing material 28 may be selected for its corrosion resistance and pressure resistance. In exemplary embodiments, a fluorine-containing elastomer may be used for the sealing material 28. Although not explicitly shown, the door 26 may include a locking mechanism or interlock to prevent the door 26 from being opened under certain conditions. For example, if the concentration of NO2 gas exceeds a preset level (e.g., a level that could be harmful to the human body and / or a level that exceeds regulatory limits), the interlock can prevent the door 26 from being opened. In some cases, the interlock may communicate electronically with a NO2 sensor located inside the sterile cavity 24.

[0026] The internal sterilization cavity 24 may include one or more shelves 32 for arranging the objects to be sterilized 34. Although the sterilization chamber 10 is shown to include two shelves 32, the sterilization chamber 10 may include three or more or fewer than two shelves as needed. Furthermore, other mechanisms for receiving the objects to be sterilized 34 may be used as desired. In one example, multiple hooks may be used to suspend multiple items. In another example, multiple vertical racks or multiple slots may be provided to receive multiple devices held in a vertical position. Racks, shelves, hooks or other receiving structures may be adapted to receive medical devices in an unpackaged or packaged form. For example, sterilization may be performed with the devices held in trays, with or without gas-permeable covers. In another example, the devices are packaged for sterilization and loaded into cartons and boxes that conform to the NO2 process. These cartons and / or boxes may be transported on pallets and placed on the pallets within the sterilization chamber 10.

[0027] The internal sterilization cavity 24 may further be thought to have a volume in the range of approximately 20 liters (L) to 5000 L, although smaller or larger equipment is also possible. In some examples, the sterilization chamber 10 may be portable and may have, for example, multiple wheels that allow the sterilization chamber 10 to be moved, and may have a sterilization cavity volume of 100 L or less. That is, sterilization may be performed in industrial equipment that requires a large space, as well as in smaller, self-contained, and / or portable units. In some examples, the portable chamber may have a volume in the range of approximately 20 to 25 L. Multiple ports (not shown) may be provided, if desired, for airtight connections to pipes, hoses, etc., that allow for the introduction and removal of gas / fluid into and out of the sterilization chamber. Chemical sensors, pressure sensors, temperature sensors, humidity sensors, and / or other sensors may be provided in or on multiple internal walls of the sterilization chamber 10, and electrical or other connections to such sensors may be routed, if desired, along and through multiple walls and / or doors of the sterilization chamber. For example, multiple humidity sensors, whose detection elements are located within the chamber or in fluid communication with the inside of the chamber, may be based on any known detection technique, including but not limited to optical, resistive, capacitive, acoustic, and resonant sensors. Multiple sensors for detecting one or more of the chemical products of the sterilization process may be provided at one or more locations within the sterilization chamber, for example, NO, HONO, N2O3, and / or NO2 may be monitored.

[0028] Figure 2 is a schematic block diagram of an exemplary sterilization system 100, an exemplary first gas supply system 110, and an exemplary second gas supply system 45. In addition to the sterilization chamber 10, the sterilization chamber 10 may include a humidifier 40 for controlling the humidity within the sterilization cavity 24 of the sterilization chamber 10, a temperature control device 50 for controlling the temperature within the sterilization cavity 24 of the sterilization chamber 10, and a circulation means 60 for dispersing gas to obtain a uniform chemical and temperature distribution within the sterilization cavity 24 of the sterilization chamber 10. The circulation means may optionally include a fan / blower coupled to a first pipe or conduit for drawing gas / air out of the sterilization cavity 24, which provides output returning to the sterilization cavity 24 through a second pipe, which may lead directly into the sterilization cavity 24 or through a plenum separated from the rest of the sterilization cavity 24 by, for example, a screen, grid, or diffuser. The circulation means may, if necessary, include a scrubber as part of the recirculation loop, which can be used to selectively remove sterilant when the sterilization gas concentration in the sterilization chamber 10 exceeds a target or set value. The sterilization chamber 10 may be fluid-coupled to a gas supply system 110 for supplying high concentrations of NO2 to the sterilization cavity 24 of the sterilization chamber 10. Furthermore, the sterilization system 100 may include an exhaust device 70 fluid-coupled to the sterilization chamber 10 for applying vacuum or suction pressure to the sterilization cavity 24 of the sterilization chamber 10.

[0029] The exhaust system 70 can be operably connected to the sterilization chamber 10 via a control valve 72 and a pump 74. Typically, the exhaust system 70 may include a blower, a scrubber, and one or more detectors. In one example, the exhaust may be drawn by a blower into a drum carrying a reactive material that removes NO2 and other contaminants before being discharged into the atmosphere. Detectors may be positioned to detect NO2 and / or other process residues. One or more detectors may detect NO2 or other gases at the discharge point to determine whether the gas is safe to discharge into the atmosphere. If it is desirable to apply a vacuum to the sterilization cavity 24 of the sterilization chamber 10 to reduce the pressure inside the sterilization cavity 24 or to evacuate the sterilization cavity 24 after sterilization, the control valve 72 can be opened to fluidly couple the sterilization cavity 24 with the pump 74. The pump 74 can then be operated to draw gas from the sterilization cavity 24 into the exhaust system 70. If NO2 gas is discharged from the sterile cavity 24 after sterilization, the exhaust gas may be treated before being discharged into the surrounding environment. For example, an ozonizer and a nitric acid filter may be installed downstream of the exhaust system 70 to treat the exhaust gas. The ozonizer may produce ozone, which reacts with NO2 to produce nitrogen pentoxide (N2O5). The nitrogen pentoxide and nitric acid (generated in the sterile cavity 24) are then absorbed by the nitric acid filter. In some cases, the nitric acid filter may include layers of sodium permanganate (NaMnO4) and activated carbon. The activated carbon does not have to react with nitric acid; rather, it may adsorb nitric acid and release it at a slower rate than reducing the nitric acid concentration to a safe level. Other approaches can be taken to scrub or otherwise remove NO2 from the exhaust gas. For example, the exhaust can be passed through water to produce nitric acid (HNO3). The nitric acid can then be neutralized. In yet another example, molecular sieves can be used to capture and reuse NO2 gas.

[0030] The humidifier 40 may be operably coupled to the sterile cavity 24 of the sterilization chamber 10, and / or optionally operably coupled to a pre-chamber (or buffer tank) 65 or buffer tank 130 fluid-coupled to the sterile cavity 24. The humidifier 40 coupled to the pre-chamber 65 or buffer tank 130 may be omitted in some examples. In some cases, a recirculation loop 75 may allow steam to be slowly added to the sterile cavity 24 to avoid localized concentration of steam. For example, the evaporator of the humidifier 40 may be fluid-coupled to the sterile cavity 24 of the sterilization chamber 10, the pre-chamber 65, and / or the buffer tank 130. The humidifier may use a steam source instead of an evaporator if necessary. The circulation means 60 can draw air, steam, etc. from the sterile cavity into the pre-chamber 65 or buffer tank 130 and push additional air, steam, etc. back into the sterile cavity 24. The recirculation loop 75 operates to mix the introduced moisture-containing air with dry air to avoid localized high concentrations. The NO2 supply source may determine whether the spare chamber 65 or the buffer tank 130 is used. For example, if NO2 is supplied into the canister 55, the spare chamber 65 can be used. If NO2 is generated using the gas supply system 110, the buffer tank 130 can be used. In some examples, only one of the first and second gas supply systems 45,110 is provided in a given system. Both are shown in illustrative examples and illustrate two or more methods for generating NO2 gas and introducing it into the sterilization chamber 10.

[0031] In some exemplary cases, process gases are added using a recirculation loop, for example, mixing recirculated air from a sterilization chamber with added dry air, moisture-containing air, NO2, or other process gases before returning to the sterilization chamber. Such addition of gas to the chamber via a recirculation loop may be carried out at a process pressure below ambient pressure. Blowers capable of providing recirculation, particularly in a sanitary environment, can be specially designed to do so.

[0032] The evaporator includes stainless steel piping with an electric heater wrapped around it, and insulation may cover the heater and piping. Water can be placed in the evaporator and heated with the electric heater to a range of about 50°C to about 80°C to generate steam. In some cases, an ultrasonic humidifier may be used. The steam can then be introduced into the sterile cavity 24 under reduced pressure (e.g., less than 500 millibars (mbar) or 0.5 atm) to humidify the sterile cavity 24. The steam may be introduced into the sterile cavity 24 which is in a completely dry state, created by applying a vacuum to the sterile cavity 24 before introducing the steam. Drying the sterile cavity 24 may result in less residual water, and thus may allow for better prediction / estimation of how much water has been added to the sterile cavity 24. For example, process control is improved by introducing water into a completely pre-dried chamber. By starting from a dry state, the relationship of the ideal gas law (PV=nRT) combined with pressure and temperature sensors may allow for the calculation of an accurate measurement of the amount of molars introduced. The added water can be measured as grams of water per volume or as relative humidity at a specific temperature (e.g., g / m³, or X%RH @ Y°C). This allows for the creation of known conditions to control the process and prevent / limit condensation. For example, excess steam can penetrate and / or saturate cardboard. Furthermore, by placing the sterile cavity 24 in a completely dry state, the amount of water vapor introduced into the sterile cavity 24 can be determined by measuring the value of the pressure increase within the sterile cavity 24 due to humidification. The pressure within the sterile cavity 24 may be measured using a pressure sensor (not explicitly shown) positioned within or on the wall of the sterile cavity 24. Thus, a specific humidity level within the sterile cavity 24 can be obtained by controlling the heating level of the electric heater and the amount of water in the evaporator. In some cases, the heat capacity (and therefore humidification capacity) of the humidifier 40 can be increased by filling stainless steel piping with stainless steel pellets.In some examples, a humidity sensor may be provided.

[0033] The temperature control device 50 may include rubber heaters fixed to multiple walls within the sterile cavity 24. In other examples, temperature-controlled water may flow through channels or tubes in contact with multiple walls of the chamber. This may allow heating and / or cooling of the sterile cavity 24. The amount of heat generated in the rubber heater and / or through the temperature-controlled water may be controlled to provide a desired temperature within the sterile cavity 24. For example, a thermocouple placed in the sterile cavity 24 or attached to the rubber heater may be operably coupled to the temperature control device 50 to provide the temperature control device 50 with the current temperature of the sterile cavity 24. The temperature control device 50 may then increase or decrease the power to the rubber heater to raise or lower the temperature to a desired setpoint temperature. In some cases, the temperature within the sterile cavity 24 may be in the range of about 10°C to about 90°C. However, other temperatures may be used as needed.

[0034] Multiple walls of the sterilization chamber 10 may be insulated, if desired, to allow for further control of the temperature inside the walls. Temperature may also be controlled by controlling the pressure inside the sterilization chamber, for example by introducing a large volume of air or steam to increase both the pressure and temperature inside the sterilization chamber. Heaters inside or associated with the chamber 10 may be provided together with a cooling device. Cooling and heating may also be performed using a heat pump. Cooling may be performed using, if necessary, a Peltier thermoelectric cooler or a refrigerant system. If room temperature is sufficient, cooling and / or heating can be achieved by circulating air to the outside of the chamber, assuming that the multiple walls of the chamber have high thermal conductivity. The chamber 10 may be provided with a heat sink device for dissipating temperature changes, such as one or more metal blocks in contact with the multiple walls defining the chamber, which can function to rapidly dissipate temperature changes. Such heat sinks may be removable.

[0035] The circulation means 60 may be configured to circulate gas / vapor within the sterile cavity 24 and / or via the recirculation loop 75 to provide a uniform gas concentration throughout the sterile cavity 24 and to mitigate humidity. Instantaneous mixing is ensured by injecting the gas, especially gases that may condense, into the flow provided by the recirculation loop. Water and / or sterilizing gas (such as NO2, but others may be used in the apparatus / system as shown) may be injected into the recirculation loop 75 near the outlet of the loop 75 to ensure proper mixing. Furthermore, external recirculation of the gas (e.g., outside the sterile cavity 24) may be important for gases that are close to saturation or gases that need to be mixed if additional gases are added. For example, the circulation means 60 can reduce fluctuations in sterilizing gas concentration and / or relative humidity that may occur due to temperature differences within the sterile cavity 24. In some cases, the gas within the sterile cavity 24 may be removed using a bellows pump and reintroduced into the sterile cavity 24. However, other circulation means may be used as needed. For example, a fan may be provided within the sterile cavity 24 to provide a uniform temperature distribution, gas concentration, and / or relative humidity level. Alternatively or additionally, the sterile gas may be dispersed by the convection of the sterile gas heated by the temperature control device 50. Furthermore, good mixing can be provided before the gas concentration is measured by measuring the gas in the recirculation loop 75. Real-time gas measurement and control or a similar method can be utilized by injecting the gas closer to the outlet side of this circuit (e.g., the pre-chamber 65 or buffer tank 130) and measuring it on the inlet side (e.g., downstream of valve 134, which can be a two-way or three-way valve depending on which sterile gas source(s) are included). This may be important for cycles performed at ambient pressure and / or near ambient pressure, such as those used in pre-filled syringes. A humidifier may be located at position 40', rather than at other positions 40, or in addition to other positions 40, to allow injection in the circulation means 60.

[0036] A certain amount of high-concentration NO2 gas can be supplied to the sterile cavity 24 via an exemplary first gas supply system 110 or an exemplary second gas supply system 45. It is conceivable that one or both of the first or second gas supply systems 110, 45 may be coupled to the sterile cavity 24. The first gas supply system 110 can generate NO2, and the second gas supply system 45 can utilize a NO2 canister or cylinder 55.

[0037] Typically, the second gas supply system 45 may include a canister or cylinder 55 containing liquid NO2 and a pre-chamber 65. The pre-chamber 65 may be used to measure the amount of NO2 gas supplied to the sterile cavity 24. For example, the pre-chamber 65 can be evacuated and then NO2 added from cylinder 55 to the pre-chamber 65 using a control valve that opens and closes rapidly with a low duty cycle (e.g., 10 milliseconds open, 3 seconds closed). The pre-chamber 65 may optionally include one or more of a pressure sensor, a chemical sensor, a temperature sensor, a humidity sensor, or other sensors. Several exemplary systems and methods for introducing a sterilizer into a pre-chamber are described in U.S. Patent No. 8,703,066 (Title: STERILIZATION SYSTEM AND METHOD) and U.S. Patent No. 8,017,074 (Title: STERILIZATION SYSTEM AND METHOD) by the same applicant, the contents of which are incorporated herein by reference. Next, the pressure in the pre-chamber 65 is measured, and the number of moles of NO2 added can be determined using the law of ideal gases, corrected to account for the fact that NO2 is not an ideal gas. Alternatively or additionally, the NO2 concentration can be determined using a measuring system. For example, an infrared detector or a visible light detector can determine the NO2 concentration in real time. A valve placed between the cylinder 55 and the pre-chamber 65 may be adjusted to prevent the NO2 from boiling. In some cases, two valves may be present between the pre-chamber 65 and the sterile cavity 24 to control the pumping rate of the pre-chamber 65. The concentration of NO2 in the pre-chamber 65 can be in the range of 50 to 150 times, or about 100 times, the concentration of NO2 after introduction into the sterile cavity 24. In some embodiments, the pre-chamber 65 may have a volume in the range of about 0.5% to about 2.0% of the size of the sterile cavity 24. The smaller volume of the reserve chamber 65 may help ensure that the pressure inside the sterile cavity 24 remains below atmospheric pressure when NO2 is added to the sterile cavity 24.Therefore, if there is a leak in the sterilization chamber 10, air is moved from the outside of the sterilization cavity 24 to the inside of the cavity 24 to ensure that no harmful gases leak out of the sterilization cavity 24.

[0038] Typically, the first gas supply system 110 may include a NO2 gas generation system 120 including a pre-chamber or buffer tank 130, a flow resistive portion 140, a plasma generator 150, and a circulation device 160. To generate a continuous circulation path, the flow resistive portion 140 may be fluid-coupled downstream of the buffer tank 130 (e.g., via piping), the plasma generator 150 may be fluid-coupled downstream of the flow resistive portion 140, the circulation device 160 may be fluid-coupled downstream of the plasma generator 150, and the buffer tank 130 may be fluid-coupled downstream of the circulation device 160.

[0039] A mixed gas containing nitrogen and oxygen may be introduced into the NO2 gas generation system 120 through the air inlet section 170. The nitrogen and oxygen may be dried using the gas drying means 180 before being introduced into the buffer tank 130. The buffer tank 130 may optionally include one or more of the following sensors: a pressure sensor, a chemical sensor, a temperature sensor, a humidity sensor, or other sensors. The circulation device 160 can be operated to circulate the mixture of nitrogen and oxygen through the buffer tank 130, the flow resistance section 140, the plasma generator 150, and the circulation device 160 to produce NO2. In some embodiments, the plasma generator 150 may be replaced by a cylinder of liquid NO2. Alternatively or additionally, NO may be introduced into the NO2 gas generation system. NO2 is then produced by oxidation of NO in the buffer tank 130 (or other chambers along the loop), as outlined below.

[0040] A strong electric field is formed in the plasma generation section of the plasma generator 150. The nitrogen and oxygen in the mixed gas undergo dielectric breakdown when excited by the strong electric field (for example, from DC to microwave frequencies), and are transitioned from a molecular state to a low-temperature (non-equilibrium plasma) state. Gases in a low-temperature state are highly reactive with other gases in a low-temperature state or in a molecular state. Therefore, when a mixed gas mainly containing nitrogen and oxygen is introduced into the plasma generation section 150, a portion of it is converted into nitrogen oxides such as nitric oxide (Equation 1) and nitrogen dioxide (Equation 2), or ozone (Equation 3). The circulating mixed gas (NOx mixed gas) is depressurized as it passes through the flow resistance section 140, allowing it to be more stably displaced into a low-temperature plasma state within the plasma generation section 150.

[0041] N2+O2→2NO Equation 1 N2+2O2→2NO2 formula 2 3O2 → 2O3 formula 3 Note that the conversion ratio according to Equation 1 is the largest. A portion of the NO generated according to Equation 1 is converted to NO2 by combining with oxygen in the low-temperature plasma state in the plasma generation section, as shown in Equation 4.

[0042] 2NO+O2→2NO2 formula 4 The NOx mixed gas containing the NO2 thus produced is pressurized by the circulation device 160 and circulates within the NO2 gas production system 120, or remains in the buffer tank 130. Meanwhile, the NO produced according to Equation 1 reacts stepwise with oxygen in the NOx mixed gas or ozone produced according to Equation 3, and is further converted to NO2 as shown in Equations 5 and 6. As a result, the NO2 concentration increases as the mixed gas continues to circulate.

[0043] 2NO+O2→2NO2 formula 5 NO+O3→NO2+O2 formula 6 The ozone generated according to Equation 3 reacts with nitrogen in the NOx mixed gas to produce NO, as shown in Equation 7.

[0044] N2+2O3→2NO+2O2 formula 7 This NO is also converted to NO2 by reactions according to equations 5 and 6. In this way, the dry mixed gas circulates within the NO2 gas generation system 120 by the operation of the circulation device 160, generating a NOx mixed gas containing NO and NO2, which are produced when nitrogen and oxygen, which have transitioned to a low-temperature plasma (non-equilibrium plasma) state as they pass through the plasma generator 150, react. NO is converted to NO2 by reacting with oxygen and ozone in the NOx mixed gas, and the NO2 concentration increases stepwise. As a result, a high-concentration NO2 gas with a NO2 concentration of 5,000 to 100,000 ppm is produced. The NO2 concentration can be determined using a measurement system. For example, an infrared detector or a visible light detector can determine the NO2 concentration in real time.

[0045] A buffer tank 130 is used to temporarily store the high-concentration NO2 produced. The buffer tank 130 may be connected to the sterile cavity 24 of the sterilization chamber 10 via a gas supply line 132. A control valve 134, which is in fluid communication with the gas supply line 132, can be selectively opened to allow gas to flow from the buffer tank 130 to the sterile cavity 24 of the sterilization chamber 10. To assist in the mixing and introduction of the high-concentration NO2, an additional amount of dry air can be introduced into the buffer tank 130 to flush the high-concentration NO2 into the sterilization chamber. In some embodiments, the buffer tank 130 may have a volume ranging from about 0.5% to about 2.0% of the size of the sterile cavity 24. In one example, the chamber may have a volume of about 40 L, and the sterile cavity 24 may have a volume ranging from 2000 to 5000 L. The concentration of NO2 in the buffer tank 130 can be in the range of 50 to 150 times, or approximately 100 times, the concentration of NO2 after introduction into the sterile cavity 24. A smaller volume of the buffer tank 130 may help ensure that the pressure inside the sterile cavity 24 remains below atmospheric pressure when NO2 is added to the sterile cavity 24. Therefore, in the event of a leak in the sterile chamber 10, air is moved from the outside of the sterile cavity 24 to the inside of the cavity 24 to ensure that no harmful gases leak out of the sterile cavity 24.

[0046] The rinse step can, for example, involve introducing a certain amount of air into the buffer tank 65 / 130 and then into the sterilization chamber through the gas supply line 132. The amount of air to be rinsed is in the range of 1 to 10 times the volume of the buffer tank (determined relative to the internal pressure of the sterilization chamber itself). In some examples, the rinsed volume may be approximately 4 to 8 times the volume of the buffer tank 65 / 130, or approximately 6 times the volume of the buffer tank 65 / 130, again relative to the internal pressure of the sterilization chamber itself. A dry air source, such as indicated by "66", can be coupled to either of the buffer tanks 65 / 130 for this purpose.

[0047] In another example, as preparation for the introduction of NO2 from the pre-chamber and / or buffer tank 65 / 130 into the sterilization chamber 10, the buffer tank may be at least partially pressurized by adding either fresh air or dry air. In one example, before opening the control valve 134 to release the mixed NO2 and air from the buffer tank 130 into the sterilization chamber 10, air may be added to the buffer tank 65 / 130 by process control until the pressure in the buffer tank exceeds the pressure in the sterilization chamber. Using the order of these steps is optional and may be useful in preventing backflow of air from the sterilization chamber and moisture-containing air in the passage from the buffer tank to the sterilization chamber. Next, in the flow step, additional air is injected into the buffer tank. In the flow step, (ambient or pre-dried) air may be added until the pressure in the sterilization chamber increases by a preset value, such as 20 Torr. This pressure increase may be used to monitor the amount of ambient or dry air added. Air may be added in multiple flow cycles to increase the pressure.

[0048] The buffer tank 130 can also be coupled to a vacuum pump or to a pump 74 and exhaust system 70 via a separate gas supply line 136 and control valve 138. If it is desirable to empty the buffer tank 130, the control valve 138 can be opened to fluidly couple the buffer tank 130 with the pump 74. The pump 74 can then be operated to draw the gas from the buffer tank 130 into the exhaust system 70. If NO2 gas is discharged from the buffer tank 130, it is conceivable that the exhaust gas may be treated before being discharged into the ambient environment. For example, an ozone generator and a nitric acid filter may be provided to treat the exhaust gas. The ozone generator may produce ozone that reacts with NO2 to produce dinitrogen pentoxide (N2O5). The dinitrogen pentoxide and nitric acid (if present) are then absorbed by a nitric acid filter. As previously mentioned, other methods for removing NO2 from the exhaust gas flow may be used. The goal may be to reach an acceptable threshold of NO2 concentration based on applicable regulations to ensure that the hazards during implementation are minimized. The objective may also be chosen to limit the introduction of NO2 into the general environment. Using a similar process, the reserve chamber 65 can be emptied as needed.

[0049] In the illustrated example, the humidifier 40, temperature control device 50, circulation device 60, gas supply line 132, and control valve 72 are each connected to the sterilization chamber 10 by themselves. In other examples, fewer such connections to the sterilization chamber 10 are provided. For example, articles 40 and 50 can be coupled to the circulation device 60 so that, if desired, four ports are provided (two for the circulation device 60 and one for the gas supply line 132 and control valve 72). In other examples, the sterilization chamber has fewer ports, such as two or even a single port. In some examples, two ports are provided, one for allowing fluid / gas to be introduced and the other for allowing fluid / gas to be discharged, and so multiple steps related to exhausting the chamber can be carried out in a continuous manner using one port for fluid entry and another port for fluid discharge. These are merely examples, and any desired number of ports can be provided.

[0050] In some examples, the controller 80 may be provided in the form of a microcontroller, microprocessor, ASIC (application-specific integrated circuit), or computer, and may have multiple inputs for receiving diagnostic signals from pressure and / or temperature sensors, any flow monitors, chemical and humidity sensors, etc., and may also control various valves, circulation, heating and / or cooling devices, etc., throughout the system. In a particular example, an NO2 sensor may be provided in the sterilization chamber to monitor the actual NO2 concentration during the sterilization process, and the controller 80 may record the output of the NO2 sensor at various stages, including before a certain amount is introduced, when a certain amount is introduced, during retention, and after discharge.

[0051] The memory associated with the controller 80 can store multiple machine-executable instructions for monitoring and controlling the ongoing process of the sterilizer. In an alternative configuration, one or more communication ports such as USB, infrared, or other coupling ports, or wireless communication subsystems (such as WiFi, Bluetooth®, RF, or cellular) may be used, which may be provided to allow the system to connect to a local or remote computer as needed. Although the controller 80 is shown as part of the sterilization system 100, it should be understood that the controller 80 may also be coupled to multiple components of the gas supply systems 45,110 to acquire diagnostic information and / or control the operation of those components.

[0052] For example, a controller 80 can be used to acquire and record process control signals associated with each step of the sterilization method. Such a controller 80 can also store models that can be compared with the process control signals. For example, a system model can be used to predict the responses of various sensors to multiple process steps. That is, a humidity sensor is expected to detect rising humidity as water vapor is introduced into the chamber, and if the humidity sensor fails to return a signal that matches the stored model, it indicates a malfunction, and a warning signal will be generated by the system. Similarly, modeling can provide indications of multiple expected NO2 levels in the sterilization chamber at various points in the process, and discrepancies can be identified by comparing the detected values ​​with the values ​​in the process model, in addition to comparing them with thresholds relating to the actual process performance. That is, for example, any leak in the sterilization chamber can be observed by holding the system at a relatively low pressure for a period during the adjustment phase in which the sterilization chamber is dried. Pressure, temperature, and / or NO2 levels are monitored as the sterilizing agent is introduced into the sterilization chamber, and the correct operation of multiple control valves and free flow in the relevant multiple gas lines from the buffer tank 130 to the sterilization chamber 10 can be checked.

[0053] Process control models can also be used to predict and manage system processes. For example, by modeling temperature or pressure changes, the controller 80 can prevent overshoot by opening or closing valves or other actuators, or by turning heating devices on or off, before the detected pressure, temperature, humidity, and / or chemical concentration reach a desired target.

[0054] Figure 3 is an exemplary flowchart of a method 200 for sterilizing an object using a sterilization system 100. First, the object to be sterilized 34 is placed in the sterile cavity 24 of the sterilization chamber 10. In one example, the object 34 may be a filled syringe. The filled syringe may contain contents in its barrel. For example, the contents may contain a therapeutic agent. The sterilization process may be carried out so that the temperature of the contents of the syringe does not change by more than ±5°C or more than ±3°C. In other examples, the sterilization process may be carried out without considering temperature changes of the object to be sterilized, or with a wider tolerance, or with the aim of actually changing the temperature of the object 34. In some cases, the temperature of the contents may be maintained within a temperature range of about 15–25°C. Once the object is placed in the sterile cavity 24, the door 26 of the sterilization chamber 10 may be closed and locked. The sterile cavity 24 is then dried using a series of exhaust and filling steps, as shown in block 204. By drying the sterile cavity 24, it is possible to provide a controlled starting point or controlled process conditions for each "pulse" of the sterilization process, as will be described in more detail herein.

[0055] Once the sterile cavity 24 is in a known state, as shown in block 206, the sterile cavity 24 is humidified in a controlled manner using a series of exhaust and filling steps until a target relative humidity is reached. The target relative humidity may be, for example, in the range of approximately 25% to approximately 90%, or approximately 40% to approximately 80%, or approximately 80%, but is not limited. The target relative humidity may be influenced by several process factors, including the surface temperature and pressure used, and in some examples, the target relative humidity may be chosen to prevent condensation during all stages of the sterilization process. In some cases, the relative humidity may be monitored using an IR or visible light detector.

[0056] Next, the chamber is depressurized to the target pressure, as shown in block 208. Target pressure P TWhen performing this method using a pre-filled syringe, the range may be, for example, 200 Torr to 500 Torr. In some cases, P T This may be in the range of approximately 450 Torr. If humidification is performed before adding NO2, this can be achieved by recirculating the gas from the sterile chamber through a humidifying element as shown at 40'. If several preceding steps are performed to keep the dry chamber under reduced pressure, the additional depressurization step in 208 may be optionally omitted.

[0057] Next, as shown in block 210, a certain amount of NO2 is introduced into the sterile cavity 24. The NO2 can be introduced from one of the gas supply systems 45, 110 using a separate, smaller pre-chamber 65 or buffer tank 130, as described above. In some examples, the sterile cavity 24 can have a volume in the range of approximately 20 L to 5000 L, and the buffer tank 130 of the corresponding pre-chamber has a volume in the range of approximately 4 L to 60 L. Other volumes can be used as needed.

[0058] As mentioned above, the concentrated mass of NO2 is at the target pressure P of the sterile cavity 24. TThe NO2 is placed in the pre-chamber 65 or buffer tank 130 at a lower pressure, and the lower pressure in the pre-chamber 65 or buffer tank 130 is selected to maintain the NO2 in the buffer tank 130 in its gaseous state and prevent condensation. The pre-chamber 65 or buffer tank 130 can then be pressurized by adding ambient air or dry air until the pressure in the pre-chamber 65 or buffer tank 130 becomes higher than the pressure inside the sterile cavity 24. The valve 134 is then opened to release the mixed NO2 and air in the pre-chamber 65 or buffer tank 130 into the sterile cavity 24. The concentration of NO2 can be measured using multiple IR detectors or multiple visible light detectors. The added air is then flowed through the pre-chamber 65 or buffer tank 130 into the sterile cavity 24, as shown in block 212. The volume of air added at the resident pressure may be approximately six times the volume of the pre-chamber 65 or buffer tank 130, thus ensuring the mixing of NO2 and its complete introduction into the sterile cavity 24.

[0059] Steps 210 and 212 involve adding a certain amount of air and NO2 to the sterile cavity 24, thereby reducing the stagnation pressure P of the sterile cavity 24. dIn some cases, the dwelling pressure may be in the range of approximately 550 to 650 Torr, for example, within the range of approximately 600 Torr, for example, between 500 Torr and ambient pressure, or even higher than ambient pressure, for example, up to approximately ambient pressure + 100 Torr. The dwelling pressure can also be understood in relation to ambient pressure and may be in the range of approximately 200 Torr lower than ambient pressure to approximately 100 Torr higher than ambient pressure, or in the range of approximately 100 Torr lower than ambient pressure to ambient pressure. In some cases, the dwelling pressure is at least approximately 150 Torr above the target pressure. In some cases, the dwelling pressure is ambient pressure, which may be the average ambient pressure at that location, or may be determined by sensing the ambient pressure using an external pressure sensor. The amount of NO2 introduced in step 210 may be sufficient to result in a NO2 concentration in the sterile cavity 24 in the range of approximately 2 to 20 milligrams (mg / L) per liter. However, the concentration of NO2 in the buffer tank 130 can be several times higher than the resulting concentration of NO2 in the sterile cavity 24. For example, assuming that the sterile chamber 10 has a volume of 4000 L and the buffer tank has a volume of 40 L, the concentration of NO2 in the buffer tank 130 can be in the range of 200 mg / L to achieve a concentration of 2 mg / L in the sterile cavity 24, or 2000 mg / L to achieve a concentration of 20 mg / L in the sterile cavity 24. Other values ​​may be used. Specific process parameters vary depending on the device to be sterilized, which includes multiple characteristics such as surface contour, material, material compatibility, whether there are moving parts that may move due to pressure changes, and the resistance of materials to heat, pressure, humidity, and NO2 itself, as well as any substances contained within the sterilized object (pharmaceuticals, biologics, etc.).

[0060] The sterile cavity 24 can be maintained in a stable state for a predetermined residence time, as shown in block 214. For example, the humidity, NO2 concentration, and air in the sterile cavity 24 can be maintained for a period ranging from approximately 4 to 15 minutes. However, residence times of less than 4 minutes or more than 15 minutes may be used as needed. After vacuum is applied in step 208, each of steps 210 and 212 brings the pressure in the sterile cavity 24 to a target pressure P T From the stagnant pressure P d Note that the pressure should be increased to this level. As a result, the target pressure in process 208 is not the same as the pressure in the sterile cavity 24 during the retention process 214.

[0061] At the end of any given retention process, the chamber is evacuated, and the discharged NO2 is scrubbed and removed from the exhaust gas. Process 220 is repeated for multiple pulses, as shown in block 216. The number of pulses may range from 2 to 8. However, in some cases, there may be only one pulse, or there may be more than eight pulses, as desired. If additional pulses are required in the sterilization routine, the process returns to process 204, again returning the sterilization cavity 24 to a known state. When the process returns to block 204, the evacuating and refilling process performed discharges any NO2 remaining in the sterilization chamber from the previous retention process (214), and the resulting exhaust gas needs to be treated to reduce the amount of discharged NO2 to an environmentally acceptable level.

[0062] Once the sterilization routine is complete (for example, when process 220 is repeated for a preset number of pulses), the sterilization cavity 24 may be purged and ventilated, as shown in block 218. The sterilization cavity 24 may be ventilated by a series of exhaust or incoming air passing through the sterilization cavity 24. For example, a certain amount of air may be drawn through the sterilization cavity 24. To purge the sterilization cavity 24, a gas mixture may be discharged through the exhaust device 70 and scrubbed for NO2 and nitric acid before the gas mixture is released into the ambient environment. If desired, the purging and venting process 218 may include altering the temperature of the object to be sterilized, such as by using heated or cooled air during multiple purging steps and by heating or cooling multiple walls of the sterilization chamber. Following the retention step, the purging and venting process 218 may include flowing air into the sterilization chamber while monitoring the residual gas in the chamber using a residual gas sensor until the residual gas concentration falls below a preset safety threshold. For example, NO2 levels in the vent may be monitored using an NO2 sensor inside the chamber, or an NO2 sensor in a flow path related to the chamber, such as in the exhaust flow path, until such levels fall below a threshold.

[0063] Alternative approaches may follow similar processes as shown, but with certain modifications. The sterilization chamber may function as a decontamination isolator. With respect to such processes, the method shown in Figure 3 can be applied as described above, although some exceptions may exist. The product to be decontaminated is applied in block 202 and may or may not be in a prefilled syringe. In 204, one or more drying cycles are performed, which may include following a process similar to that described above. Next, multiple humidification cycles are performed in block 206. The exhaust step 208 may be omitted, and in block 210, NO2 is added using a process similar to that described above. To introduce NO2, slightly pressurized air or a blower (10-100 Torr higher than ambient and / or higher than the detected or calculated chamber pressure) can be used to introduce dry air into the pre-chamber between blocks 210 and 212. Next, the retention step 214 can be performed at ambient pressure. By returning to block 204, additional pulses can be executed in block 216. Finally, the system is purged in block 218.

[0064] In some cases, the success of a process can be monitored based on the concentration of chemical reaction byproduct species. For example, N2O3 is a harmful molecule that, after crossing the cell membrane, reacts with DNA / RNA strands and destroys them. For instance, the species required to form N2O3 are NO and HONO. By monitoring the concentrations of NO, HONO, N2O3, and / or others, it can be determined whether N2O3 was present in a concentration sufficient to sterilize the object(s) in the sterile cavity 24.

[0065] In exemplary examples, process monitoring within a sterilization chamber may include monitoring one or more of NO, HONO, N2O3, and / or NO2 within the sterilization chamber during multiple processes as illustrated. In one example, during the retention process in 214, one or more of the concentrations of NO, HONO, N2O3, and / or NO2 within the chamber are monitored using sensors. For example, the NO2 concentration may be monitored against a target concentration, for example, within the range of 2 to 20 mg / L, but not limited to. In a specific example, HONO is monitored during the retention process, and the concentration of HONO is expected to change during the retention process as the retention period progresses. In some examples, a model of the expected HONO concentration can be constructed for a particular sterilization process during validation and verification (V / V) of the sterilization process. For example, a test run of the sterilization process may be performed, followed by inspection and / or testing of the products to be sterilized to determine whether the sterilization process performed as expected. The HONO models constructed during such V / V activities may be stored in the memory of the system controller 80 (Figure 2) and used to determine whether a particular execution of these processes conforms to multiple system monitoring requirements. Using such modeling may enable the elimination of or reduction of reliance on biological process monitors, which can be costly to create, store, and inspect after use. Alternatively, the HONO concentration may be compared to a threshold (such as the average over all or part of the residence period, or the peak or minimum concentration, or the concentration at the end of the residence period). Monitoring of NO, N2O3 may be performed using a similar approach instead.

[0066] Parameterized process monitoring (using multiple measurements, but not in addition to, biological sample material), such as monitoring the concentration of one or more of NO2, NO, HONO, and / or N2O3 during sterilization, may be used in several ways. For example, in block 216, to determine whether more pulses are needed, the controller may determine whether one or more of the preceding iterations or the target number met the target concentration and / or correlated with a stored model of NO, HONO, N2O3, and / or NO2 concentrations, and if not, another pulse may be requested. During residence period 214, if the monitored parameter does not match its target, it may be possible to add one or more substances to the chamber in small pulses, such as through a pre-chamber / buffer chamber, by introducing additional NO2 or moisture-containing air. Similarly, partial ventilation of the chamber can be performed to reduce the concentration of chemicals or humidity within the chamber. In another example, additional fresh or dry air can be added to the chamber to reduce the concentration of chemicals and / or humidity within the chamber, or otherwise to more closely match the target. In one example, both ventilation and the addition of dry air can be achieved.

[0067] In some examples, the temperature or pressure inside the chamber may be raised or lowered to affect the rate of chemical reactions inside the chamber, typically increasing the temperature speeds up the reactions and cooling the chamber slows them down. Rather than adding or removing substances from the chamber, an expandable bladder inside or on the chamber wall may be expanded or contracted to regulate the pressure inside the chamber (by decreasing or increasing the volume within the enclosed space). A circulating blower may be adjusted in response to tracked chemical or humid conditions inside the chamber, for example, if the NO2 concentration remains relatively high but the HONO concentration does not match the model, the blower may be started or its speed increased to promote additional mixing inside the chamber, thereby improving the rate of the chemical reaction that generates HONO. These are just a few examples of the steps that can be taken to adjust or correct the HONO concentration in the chamber, or the concentration of another sterilizer and / or chemical product in the sterilization process, in response to sensor output indicating that HONO does not match the modeled parameter trend and / or does not match the target.

[0068] Rather than doing anything to adjust the concentration of the monitored parameter, the residence period itself may be adjusted by adding more residence time if the concentration falls below the desired target, or by shortening the residence time if the concentration exceeds the target or reaches the target faster than modeled. In some examples, corrective actions may be taken outside of the specific residence process being monitored, such as adjusting the concentration, temperature, humidity, or pressure for use in subsequent residence processes for the same set of products to be sterilized, or for use in the sterilization of subsequent products. In yet another example, the monitored parameter can be used to trigger an alert to the operator if one or more system components are not functioning as expected, for example, suggesting a clogged valve, a non-functioning actuator, or other malfunction or performance degradation.

[0069] Figure 4 shows an exemplary example. During the retention process 300, process parameters are monitored 310. In 312, multiple sensors are used to monitor multiple parameters (humidity, temperature, concentration of NO2, NO, HONO, H2NO3 or any other sterilizer, and / or chemical markers of the sterilization process) and in 314, they are compared to a stored target and / or model. The comparison may be a simple comparison to the target, or it may involve tracking (recording) trends or deviations from the target using standard statistics (such as determining whether the process remains within the standard deviation of the process parameters). If the monitored parameters are out of range, above or below the target, or tracking (recording) or showing a trend away from the model and / or target, corrections may be made in 316. The corrections 316 may include a wide range of steps, depending on the many types of sterilization that may be used and the many resulting processes, some of which are described in the preceding description. Since steps 312, 314, and 318 are used to monitor the process and generate or trigger one or more warnings regarding chamber operability, the status of the sterilization process, or the success / failure of a particular iteration / retention step in the sterilization process, correction 316 may be omitted in some examples. The monitored data, comparison with targets, trends and / or models, and / or any correction steps performed are then stored in memory at 318 and may become part of a history file of the product(s) being sterilized. Finally, when the residence period ends, the process optionally proceeds from block 310 to 320 to determine whether further pulses are needed. The stored data from block 318 may be used to determine whether more pulses are needed.

[0070] Some specific examples of products that can be sterilized, and the sterilization considerations that apply, are as follows: Prefilled syringes may be sterilized several times using the NO2 sterilization process as described above. The process may be carried out at a temperature close to room temperature (i.e., 10–30°C, or more narrowly, in the range of 15–25°C), depending on how easily the contents of the syringe decompose due to the applicable temperature. The syringe typically has a barrel and a plunger associated with the barrel, and the plunger is movable relative to the barrel so that low pressures (such as below 100 Torr or below 200 Torr, depending on the design) are avoided. In one example, the pressure in step 208 may be in the range of 350–500 Torr, and some amount of NO2 and air is added in 210,212 to achieve a NO2 concentration of 2–40 mg / L in the sterilization chamber at a pressure of approximately 550–650 Torr.

[0071] Implantable electrical stimulation devices such as pacemakers, defibrillators, or nerve stimulators may also be sterilized. Such systems typically have ports for receiving lead wires, the ports being enclosed by a plastic material such as epoxy, and multiple silicone components being used to insulate multiple parts of the ports. Such systems are often housed in a metallic canister, for example, made of titanium, and the metallic canister is coated with a coating such as titanium nitride, iridium oxide, or any other suitable coating. Other materials may include polysulfone, silicone rubber, and / or silicone medical adhesives and / or biodegradable materials.

[0072] Stent delivery systems for delivering cardiac stents can also be sterilized. These systems may include an elongated catheter having one or more inflatable balloons at its distal end, carrying an expandable metal stent, which is coated with a soluble drug coating. Resorbable stents, including poly(L-lactide) (PLLA), poly-D,L-lactide (PDLLA), iron, zinc, magnesium, their alloys, and / or others, can be sterilized. For lubricating materials, lower humidity levels may be required. In some cases, it may be necessary to protect the therapeutic agent during the sterilization process. For example, an additional layer or coating of therapeutic agent may be provided on the device.

[0073] Other exemplary devices may include orthopedic devices, intramedullary nails, pedicle screws, custom implants, 3D printed implants, metal implants (including, but not limited to, nitinol, titanium, chromium, and tantalum markers), polymeric implants (including polyethylene (PE), polyetheretherketone (PEEK), polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), and poly(caprolactone-co-lactide) (PCLA)), or combinations thereof. The specific water activity level of a metal's nitrate may be used as an indicator of whether a particular metal can be sterilized in a NO2 environment.

[0074] The pressure is typically maintained below atmospheric pressure during sterilization to avoid the release of NO2 in the immediate vicinity of the sterilization chamber. In some examples, NO2 sensors may be installed outside the sterilization chamber as a way to monitor for NO2 leaks, which can impair the actual sterilization process itself and pose a potential danger to workers in that area. As mentioned above, in some examples, the pressure may be above ambient level during the sterilization process, in which case external NO2 sensors may be used, and the space provided by the sterilization chamber may be sealed or, alternatively, ventilated with the aid of a scrubber to remove NO2 from the air exiting the chamber.

[0075] Many products may be held in trays, which are covered with a gas-permeable material such as spunbond high-density polyethylene or polypropylene fiber (e.g., Tyvek®), although other materials may be used. Paper can be used, but it may yellow during the NO2 sterilization process, and sterilized products are not expected to have a "weathered" appearance, which is generally undesirable. However, coated paper, lacquered cardboard, and / or labels can be used without yellowing.

[0076] Products requiring refrigeration can be sterilized in an NO2 chamber. For example, products stored at low temperatures for preservation purposes, such as in the range of 1°C to 15°C, can be sterilized using the NO2 sterilization process without the need to warm the products to room temperature. Such preheating is required in other sterilization processes, significantly delaying processing time, exposing the products to high temperatures, accelerating their deterioration, and / or shortening their shelf life.

[0077] For NO2 sterilization of refrigerated products, the walls of the sterilization chamber may be optionally cooled by circulating a cooling fluid through them, as described above. Referring again to Figure 3, the product is removed from the cold storage and placed in the sterilization chamber 202, where it is processed through the drying process 204 described above. Specifically, the pressure inside the chamber is reduced to, for example, a pressure in the range of around 350 Torr, dry air is introduced to return the pressure to 500 Torr, and all (optionally) chamber walls are kept at a low temperature, for example, 1°C to 15°C. After several drying cycles (any of 1 to 60 drying cycles may be performed), a dose of moisture-containing air is introduced into the chamber 206, maintaining a relative humidity in the range of, for example, about 25% to about 90%, or about 40% to about 80%. To prevent or avoid localized condensation, humidification can be carried out in a series of iterations, such as by removing the air to reach the target vacuum (which also cools the chamber), introducing a certain amount of water vapor mixed with air (which temporarily warms the chamber), and repeating this process.

[0078] Next, the cooled and humidified chamber receives a certain amount of NO2 at 210, and a reserve chamber or buffer tank of NO2 is filled with dry air. These steps increase the pressure inside the sterile chamber and also temporarily raise the temperature inside the chamber. Then, a retention step 214 is performed, and the process can be repeated until a sufficient number of pulses 216 are completed, at which point the chamber is purged and ventilated (218). The process may require a longer retention period (214) than required at higher temperatures, or a higher NO2 concentration, or more pulses 216 may be required. Such a process can be carried out using pre-filled syringes containing products that require low-temperature conditions for reasons such as shelf life or efficacy. Some examples may include various vaccines, biological products, and drugs, including certain ophthalmic products. Even when the sterilization chamber process requires more time when carried out at low temperatures, the overall sterilization time can be reduced by avoiding preheating and subsequent cooling of the products (which can take up to 72 hours for palletized products), and also avoid product degradation and / or reduced shelf life due to prolonged time outside of refrigerated storage.

[0079] In some examples, the piping to and from the chamber may be temperature-controlled. For example, when delivering moisture-containing air and / or water vapor to the chamber, the walls of the piping may be heated to prevent condensation on the piping within the piping (in this case, the flow may be at a higher pressure than the pressure assumed throughout the chamber). In some examples, the supply of dry air provided to the chamber may be delivered after passing through cooled piping or after passing dry air through a heat exchanger to cool the injected air, thereby assisting temperature control within the chamber.

[0080] It should be understood that this disclosure is illustrative in many respects. Modifications can be made to details, particularly shape, size, and sequence of processes, without exceeding the scope of the invention. This may include, to a suitable extent, using any feature of one exemplary embodiment in other embodiments. Naturally, the scope of the invention is defined by the language expressed in the appended claims.

Claims

1. A method for sterilizing pre-filled syringes, The pre-filled syringe is placed inside the sterile chamber, The system includes performing multiple pulse sterilization steps, and each pulse sterilization step is: The sterilization chamber is dried with the pre-filled syringe placed inside it. After drying the sterilization chamber to the target level, the sterilization chamber is humidified. After humidifying the sterilization chamber, the sterilization chamber is evacuated to the target pressure. A certain amount of NO2 is introduced into the sterilization chamber from a buffer tank selectively fluid-connected to the sterilization chamber, In order to assist in the flow of NO2 from the buffer tank into the sterilization chamber, a predetermined amount of air is introduced into the sterilization chamber through the buffer tank, A method comprising: after the predetermined amount of air has passed through the buffer tank, maintaining the sterilization chamber at a residence pressure at least 150 Torr above the target pressure for a residence period.

2. The method according to claim 1, wherein the target pressure is in the range of about 200 to about 500 Torr, and the stagnant pressure is about 600 Torr.

3. The method according to claim 1 or 2, wherein the sterilization chamber has sufficient heat capacity to suppress the temperature change of the prefilled syringes during the plurality of pulse sterilization steps to less than 5°C.

4. The method according to claim 1 or 2, wherein the concentration of NO2 when accumulated in the buffer tank is approximately 100 times the concentration of NO2 after it has been introduced into the sterilization chamber.

5. The method according to claim 4, wherein the resulting concentration of NO2 in the sterilization chamber during the holding process is in the range of 2 to 20 mg / L.

6. The method according to claim 1 or 2, wherein the preset amount of air is within the range of 4 to 8 times the volume of the buffer tank.

7. A circulation means is provided for recirculating the air inside the sterilization chamber. The method according to claim 1 or 2, wherein the humidification step and the step of introducing a certain amount of NO2 are performed by mixing at least one of the moisture-containing air and NO2 with the recirculating air while the sterilization chamber is at a pressure lower than the ambient pressure.

8. The introduced NO2 is at least partially converted into other chemical products during sterilization, and these other chemical products include at least HONO. The aforementioned method, Monitoring the concentration of HONO during the aforementioned multiple pulse sterilization steps, The concentration of the aforementioned HONO is compared with one or more thresholds, If the concentration of HONO does not meet one or more thresholds, it is determined that the sterilization method is incomplete. The method according to claim 1 or 2, further comprising performing at least one additional pulsed sterilization step in response to determining that the sterilization method is incomplete.

9. Introducing a certain amount of NO2 from the buffer tank into the sterilization chamber is To determine the first pressure inside the sterilization chamber, Monitoring the second pressure in the buffer tank, Adding air to the buffer tank until the second pressure exceeds the first pressure, The method according to claim 1 or 2, which is carried out by opening a valve between the buffer tank and the sterilization chamber.

10. The method according to claim 1, wherein the volume of the buffer tank is in the range of about 0.5% to about 2% of the volume of the sterilization chamber.

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