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 wide 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 certain 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 or therapeutic molecules and / or cells, such as prefilled syringes, and may not be suitable for AC sterilization.

[0005] ETO sterilization can be carried out at a lower temperature of 70°C or below, so it can be used for plastics. However, ETO is toxic at low concentrations and has an explosion risk, so it needs to be stored safely to avoid problems in terms of hygiene and safety, and there is a drawback that sufficient care is required in its handling. There is also a risk associated with the release of ETO gas from ETO-sterilized products. Also, when supplying ETO from a tank (cylinder) to a sterilization device via piping, it is necessary to measure the weight of the cylinder and constantly monitor for weight loss to prevent unexpected leakage from the piping etc. Unfortunately, ETO exposure has been associated with a suspected cancer risk both inside and near the sterilization facility.

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

[0007] A sterilization method is desired that can act on the details of the device, reduce the risks of toxicity and explosion, and be carried out at a lower temperature. SUMMARY OF THE INVENTION

[0008] The present disclosure provides, without limitation, a method for sterilizing devices such as medical devices. This summary is not intended to describe each or all implementations of the invention that are disclosed.

[0009] A first exemplary and non-limiting example has the form of a method for sterilizing a prefilled syringe, the method comprising placing the prefilled syringe in a sterilization chamber and performing a plurality of pulsed sterilization steps. Each pulsed sterilization step includes drying the sterilization chamber with the prefilled syringe therein, humidifying the sterilization chamber after drying the sterilization chamber to a target, evacuating the sterilization chamber to a target pressure after humidifying the sterilization chamber, introducing an amount of NO2 from a buffer tank selectively fluidly connected to the sterilization chamber into the sterilization chamber, introducing a preset amount of air through the buffer tank into the sterilization chamber to assist in flowing 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 residence pressure exceeds the target pressure by at least 150 Torr. Additionally or alternatively, the target pressure is in the range of about 200 to about 500 Torr, and the residence pressure is about 600 Torr. Additionally or alternatively, the sterilization chamber has a heat capacity sufficient to limit the change in temperature of the pre-filled syringe during the sterilization process to less than 5°C. Additionally or alternatively, the pre-filled syringe has contents such that the temperature of the pre-filled syringe does not change by more than 3°C during the sterilization process. Additionally or alternatively, the contents of the pre-filled syringe are maintained in the temperature range of 2 to 15°C. Additionally or alternatively, the concentration of NO2 when accumulated in the buffer chamber is about 100 times the concentration of NO2 after being introduced into the sterilization chamber. Additionally or alternatively, the resulting concentration of NO2 in the sterilization chamber during the residence step is in the range of 2 to 20 mg / L. Additionally or alternatively, the preset amount of air is in 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 residence 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, circulation means for recirculating the air within the chamber is provided, and the humidifying step and the step of introducing a certain amount of NO2 are performed by mixing with the recirculated air while the chamber is at a pressure lower than ambient pressure. Additionally or alternatively, the introduced NO2 is at least partially converted to other chemical products during sterilization, the other chemical products include at least HONO, and the method further includes monitoring the concentration of HONO during the sterilization process, comparing the concentration of HONO with one or more threshold values, and determining that the sterilization process is incomplete if the concentration of HONO does not meet the one or more threshold values. Additionally or alternatively, the step of introducing a certain amount of NO2 from a buffer tank into the sterilization chamber is performed by determining a first pressure within the sterilization chamber, monitoring a second pressure within 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] Another exemplary and non-limiting example has the form of a method for sterilizing a prefilled syringe, the method comprising placing the prefilled syringe in a sterilization chamber and performing a plurality of pulsed sterilization steps. Each pulsed sterilization step includes drying the sterilization chamber with the prefilled syringe inside, humidifying the sterilization chamber to a target humidity level after drying the sterilization chamber to a target, evacuating the sterilization chamber to a target pressure in the range of about 200 to about 500 Torr after humidifying the sterilization chamber, introducing an amount of NO2 from a buffer tank selectively fluidly connected to the sterilization chamber into the sterilization chamber, introducing a preset amount of air through the buffer tank into the sterilization chamber to assist in flowing NO2 from the buffer tank into the sterilization chamber, and holding the sterilization chamber at a residence pressure of about 600 Torr or more for a residence period after the preset amount of air has passed through the buffer tank. The concentration of NO2 in the sterilization chamber during the residence step is in the range of about 2 to 20 mg / L.

[0013] Additionally or alternatively, the residence pressure is at least 150 Torr above the target pressure. Additionally or alternatively, the concentration of NO2 when accumulated in the buffer chamber is about 100 times the concentration of NO2 after being introduced into the sterilization chamber. Additionally or alternatively, the preset amount of air is in the range of 4 to 8 times the volume of the buffer tank. Additionally or alternatively, the step of introducing an 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 have the form of a method for sterilizing an object, the method comprising placing the object in a sterilization chamber and performing a plurality of pulsed sterilization steps. Each pulsed sterilization step includes drying the sterilization chamber with the pre-filled syringe inside the sterilization chamber, humidifying the sterilization chamber after drying the sterilization chamber to a target, exhausting the sterilization chamber to a target pressure after humidifying the sterilization chamber, introducing a certain amount of NO2 from a buffer tank selectively fluidly connected to the sterilization chamber into the sterilization chamber, introducing a preset amount of air in the range of 4 to 8 times the volume of the buffer tank through the buffer tank into the sterilization chamber to assist the flow of NO2 from the buffer tank into the sterilization chamber, holding the sterilization chamber at a residence pressure for a residence period after the preset amount of air has passed through the buffer tank, and the concentration of NO2 in the sterilization chamber during the residence step is in the range of about 2 to 20 mg / L.

[0015] Additionally or alternatively, the step of introducing a certain amount of NO2 from the buffer tank into the sterilization chamber is performed by obtaining 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 residence 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 packaging.

[0016] Another exemplary and non-limiting example has the form of a method for performing sterilization using NO2, the method comprising preparing a sterilization chamber containing a product to be sterilized by bringing the sterilization chamber to a known state; introducing a quantity of NO2 into the sterilization chamber together with air containing a quantity of moisture, wherein the air containing NO2 and the moisture interact within the sterilization chamber to produce a plurality of chemical products of the sterilization process; monitoring, using a chemical sensor, the concentration of at least one of the plurality of chemical products of the sterilization process during a dwell step after introducing the quantity of NO2 and the air containing the quantity of moisture into the chamber and before evacuating the chamber; comparing the monitored concentration to a process target; determining whether the dwell step has met or achieved a sterilization target; generating a warning to an operator or performing a corrective action if the dwell step has not met or achieved the sterilization target; and recording in a memory information indicating the success of the dwell step if the dwell step has met 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 with a process target is performed by comparing the concentration monitored over time with a modeled concentration model constructed during a validation and verification process, and the model is stored in the memory of a controller for the sterilization chamber. Additionally or alternatively, the step of performing the correction operation includes changing the state of the chamber during the residence step. Additionally or alternatively, the step of performing the correction operation includes storing information indicating that the residence step has failed, and repeating the preparing step, the introducing step, and the residence step. Additionally or alternatively, the step of performing the correction operation includes adjusting parameters used in subsequent iterations of the preparing step, the introducing step, and the residence step. Additionally or alternatively, the step of performing the correction operation includes changing the duration of the residence step, and changing the duration of the residence step may include extending or shortening the duration of the residence step.

Brief Description of the Drawings

[0018] The present invention can be more fully understood by considering the following detailed description of various embodiments in conjunction with the accompanying drawings.

Figure 1

Figure 2

Figure 3

Figure 4

Embodiments for Carrying Out the Invention

[0019] The present invention can follow various modifications and alternative forms, and its details are shown in the drawings by way of example 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 a person skilled 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 a numerical range 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, a person skilled 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 is to be read with reference to the drawings, in which like elements in different drawings are numbered the same. The detailed description and the drawings are not necessarily to scale, but show exemplary embodiments and are not intended to limit the scope of the invention. The exemplary embodiments shown are intended only as examples. Selected features of any exemplary embodiment may be incorporated into additional embodiments unless the contrary is expressly stated.

[0023] Nitrogen dioxide (hereinafter, NO2) has been found to exhibit a beneficial sterilizing effect. The purpose of the present disclosure is to provide, but not limited to, a sterilization method and system that can be used to sterilize articles such as scissors, forceps, needles, cannulas, surgical knives, tubes, drug delivery devices, filled syringes, empty syringes, staples, implantable medical devices (anchors, embolization coils, stents, catheters, ports, leads, implant tools, stimulation devices, pumps, ventricular assist devices, etc.), and other medical devices. Endoscopes and other visualization systems, balloon catheters, guide catheters, electrotherapy devices, stylets, implant 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 in part 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, etc. In some cases, different materials may be used for different parts of the sterilization chamber 10. The same or similar materials may 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 side 22 may include or be formed by a movable door 26 configured to open and close to enable access to the internal sterilization cavity 24 of the sterilization chamber 10 through the access opening 30. The internal sterilization cavity 24 may be defined by the respective inner surfaces of the walls 12, 14, 16, 18, 20, 22. The door 26 and / or the sterilization chamber 10 may include a sealing material 28 disposed 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 corrosion resistance and pressure resistance. In an exemplary embodiment, a fluorine-containing elastomer can be used for the sealing material 28. Although not explicitly shown, the door 26 may include a locking mechanism or interlock that prevents the door 26 from being opened under certain conditions. For example, when the concentration of NO2 gas is above a preset level (e.g., a level that may be harmful to the human body and / or exceeds the regulatory limit), the interlock can prevent the door 26 from being opened. In some cases, the interlock may communicate electronically with a NO2 sensor disposed within the sterilization cavity 24.

[0026] The internal sterilization cavity 24 may include one or more shelves 32 for disposing of the object to be sterilized 34. Although the sterilization chamber 10 is shown as including two shelves 32, the sterilization chamber 10 can include three or more or less than two shelves, as required. Further, it is contemplated that other mechanisms for receiving the object to be sterilized 34 can be used as desired. In one example, a plurality of hooks can be used to suspend a plurality of articles. In another example, a plurality of vertical racks or a plurality of slots may be provided for receiving a plurality of devices held in a vertical position. The racks, shelves, hooks or other receiving structures can be adapted to receive medical devices in an unpackaged or packaged form. For example, sterilization may be performed with the device held within a tray, with or without a gas permeable cover. In another example, the device is packaged for sterilization and loaded into a carton and box adapted for the NO2 process. These cartons and / or boxes may be transported on a pallet and placed on the pallet within the sterilization chamber 10.

[0027] It is further contemplated that the internal sterilization cavity 24 may have a volume in the range of about 20 liters (L) to 5000 L, although smaller or larger facilities are also possible. The sterilization chamber 10 may, in some examples, be portable, for example, may have a plurality of 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 facilities that require 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 about 20 - 25 L. A plurality of ports (not shown) may be provided for airtight connection to tubes, hoses, etc. that allow the introduction and removal of gas / fluid into the sterilization chamber, as desired. Chemical sensors, pressure sensors, temperature sensors, humidity sensors, and / or other sensors may be provided in or on the plurality of inner walls of the sterilization chamber 10, and electrical or other connections to such sensors may be routed along and / or through the plurality of walls and / or doors of the sterilization chamber, as desired. For example, the plurality of humidity sensors whose sensing elements are within the chamber or in fluid communication with the interior of the chamber may be based on any known detection technique, including but not limited to optics, resistance, capacitance, acoustics, resonance, etc. A plurality of 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 can include a humidification device 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 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 can include, optionally, a fan / blower coupled to a first pipe or conduit for drawing gas / air out of the sterilization cavity 24, the fan / blower providing an output that returns to the sterilization cavity 24 through a second pipe, the second pipe being in direct communication with the sterilization cavity 24 or communicating through a plenum separated from the remainder of the sterilization cavity 24 by, for example, a screen, grid, or diffuser. The circulation means can include, optionally, a scrubber as part of a recirculation loop, the scrubber being used to optionally remove a sterilant if the sterilant gas concentration within the sterilization chamber 10 exceeds a target or set value. The sterilization chamber 10 can be fluidly coupled to a gas supply system 110 for supplying a high concentration of NO2 to the sterilization cavity 24 of the sterilization chamber 10. Further, the sterilization system 100 can include an exhaust device 70 fluidly coupled to the sterilization chamber 10 for applying a vacuum or suction pressure to the sterilization cavity 24 of the sterilization chamber 10.

[0029] The exhaust device 70 can be operably connected to the sterilization chamber 10 via a control valve 72 and a pump 74. Usually, the exhaust device 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 to the atmosphere. The detector may be arranged to detect NO2 and / or other process residues. One or more detectors can detect NO2 or other gases at the discharge section to determine whether the gas is safe to discharge to the atmosphere. If it is desirable to apply a vacuum to the sterilization cavity 24 of the sterilization chamber 10 to reduce the pressure in the sterilization cavity 24 or to exhaust the sterilization cavity 24 after the sterilization process, the control valve 72 can be opened to fluidly couple the sterilization cavity 24 and the pump 74. Next, the pump 74 can be operated to draw gas from the sterilization cavity 24 into the exhaust device 70. If NO2 gas is discharged from the sterilization cavity 24 after the sterilization process, it is conceivable that the exhaust gas can be treated before being discharged to the surrounding environment. For example, an ozonizer and a nitric acid filter may be provided downstream of the exhaust device 70 to treat the exhaust gas. The ozonizer can generate ozone that reacts with NO2 to generate dinitrogen pentoxide (N 2 O 5 ). Then, the dinitrogen pentoxide and nitric acid (generated in the sterilization cavity 24) are 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 may not react with nitric acid, but rather may adsorb nitric acid and release nitric acid at a slower rate to reduce the concentration of nitric acid to a safe level. Other approaches can be taken to scrub or remove NO2 from the exhaust gas in other ways. For example, the exhaust can be passed through water to generate nitric acid (HNO 3 ). Then, the nitric acid can be neutralized. In yet another example, molecular sieves can be used to capture and reuse NO2 gas.

[0030] The humidifying device 40 may be operably coupled to the sterilization cavity 24 of the sterilization chamber 10 and / or optionally operably coupled to a pre-chamber (or buffer tank) 65 or buffer tank 130 that is fluidly coupled to the sterilization cavity 24. The humidifying device 40 coupled to the pre-chamber 65 or buffer tank 130 may be omitted in some examples. In some cases, the recirculation loop 75 may allow steam to be slowly added to the sterilization cavity 24 to avoid local concentration of the steam. For example, the evaporator of the humidifying device 40 may be fluidly coupled to the sterilization cavity 24 of the sterilization chamber 10, the pre-chamber 65, and / or the buffer tank 130. The humidifying device may use a steam source instead of an evaporator as needed. The circulation means 60 can draw air, steam, etc. from the sterilization cavity into the pre-chamber 65 or buffer tank 130 and push additional air, steam, etc. back into the sterilization cavity 24. The recirculation loop 75 mixes the air (humidity) containing the introduced moisture with dry air and operates to avoid local high concentrations. It is conceivable that a NO2 supply source determines which of the pre-chamber 65 or buffer tank 130 is used. For example, when NO2 is supplied into the canister 55, the pre-chamber 65 can be used. When a gas supply system 110 is used to generate NO2, 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 as exemplary examples to illustrate two or more ways to generate NO2 gas and introduce it into the sterilization chamber 10.

[0031] In some exemplary examples, the process gas is added using a recirculation loop, for example, mixing the air recirculated from the sterilization chamber with the added dry air, moisture-containing air, NO2, or other process gas before returning it to the sterilization chamber. Such addition of gas to the chamber via the recirculation loop may be performed in a process below ambient pressure. A blower that can provide recirculation, particularly in a sanitary environment, can be specially designed to do so.

[0032] The evaporator includes a stainless - steel pipe around which an electric heater is wound, and insulation may cover the heater and the pipe. Water can be put into the evaporator and heated by the electric heater in the range of about 50°C to about 80°C to generate steam. In some cases, an ultrasonic humidifier may be used. Then, the steam is introduced into the sterilization cavity 24 under reduced pressure (e.g., less than 500 millibars (mbar) or 0.5 atm) to humidify the sterilization cavity 24. It is conceivable that the steam can be introduced into the sterilization cavity 24 which is in a completely dry state generated by applying a vacuum to the sterilization cavity 24 before introducing the water vapor. Drying the sterilization cavity 24 may result in less residual water and, thus, may enable a better prediction / estimation of how much water is added to the sterilization cavity 24. For example, by introducing water into a completely pre - dried chamber, process control is improved. By starting from a dry state, the relationship of the ideal gas law (PV = nRT) combined with pressure sensors and temperature sensors can make it possible to calculate an accurate measured value of the introduced molar amount. The added water can be measured as grams of water per volume, or relative humidity at a specific temperature (e.g., g / m3, or X%RH @ Y°C). This can create a known state to control the process and prevent / limit condensation. For example, excess steam can penetrate the cardboard and / or saturate the cardboard. Further, by placing the sterilization cavity 24 in a completely dry state, the amount of water vapor introduced into the sterilization cavity 24 can be determined by measuring the value of the pressure increase in the sterilization cavity 24 due to humidification. It is conceivable that the pressure in the sterilization cavity 24 can be measured using a pressure sensor (not explicitly shown) positioned within or on the walls of the sterilization cavity 24. Thus, a specific humidity level within the sterilization 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, by filling the stainless - steel pipe with stainless - steel pellets, the heat capacity (and thus the humidifying capacity) of the humidifying device 40 can be increased.In some examples, a humidity sensor may be provided.

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

[0034] The plurality of walls of the sterilization chamber 10 may be insulated, if desired, to allow for further control of the temperature inside those walls. The temperature may also be controlled by controlling the pressure within the sterilization chamber, for example, by pumping in large amounts of air or steam to raise both the pressure and the temperature within the sterilization chamber. A heater within the chamber 10 or a heater associated with the chamber 10 can be provided together with a cooling device. Cooling and heating can also be performed using a heat pump. Cooling may be performed, if necessary, using, for example, a Peltier thermoelectric cooler, or a refrigerant system. If room temperature is sufficient, cooling and / or warming can be achieved by circulating air against the outside of the chamber, assuming that the thermal conductivity of the plurality of walls of the chamber is high. The chamber 10 can be provided with a heat sink device for dissipating temperature changes, such as one or more metal blocks that come into contact with the plurality of walls defining the chamber and that can function to rapidly dissipate temperature changes. Such a heat sink may be removable.

[0035] Circulation means 60 may be configured to circulate gas / vapor within the sterilization cavity 24 and / or via a recirculation loop 75 to provide a uniform gas concentration throughout the sterilization cavity 24 and to moderate humidity. By injecting gas, particularly gas that may condense, into the flow provided by the recirculation loop, instantaneous mixing is ensured. Water and / or a sterilizing agent gas (such as NO2, although others may be used in the apparatus / system as shown) may be injected near the outlet of loop 75 into the recirculation loop 75 to ensure proper mixing. Further, external recirculation of the gas (e.g., external to the sterilization cavity 24) may be important for gases that are near saturation or for gases that need to be mixed when additional gas is added. For example, the circulation means 60 can reduce variations in the sterilizing gas concentration and / or relative humidity that may occur due to temperature differences within the sterilization cavity 24. In some cases, the gas within the sterilization cavity 24 may be removed using a bellows pump and reintroduced into the sterilization cavity 24. However, other circulation means may be used as needed. For example, a fan may be provided within the sterilization cavity 24 to provide a uniform temperature distribution, gas concentration, and / or relative humidity level. Alternatively or additionally, the sterilizing gas may be dispersed by the convection of the sterilizing gas heated by the temperature control device 50. Further, by measuring the gas within the recirculation loop 75, good mixing can be provided before the gas concentration is measured. By injecting gas closer to the outflow side of this circuit (e.g., the prechamber 65 or the buffer tank 130) and measuring on the inflow side (e.g., downstream of the valve 134 which can be a two-way valve or a three-way valve depending on which sterilizing gas source(s) are included), real-time gas measurement and control or something close to it can be utilized. This can be important for cycles that are performed at ambient pressure and / or a pressure close to ambient pressure, such as those used for prefilled syringes. The humidifier may be located at position 40' instead of or in addition to other positions 40 to enable injection by the circulation means 60.

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

[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 sterilization cavity 24. For example, an adjustment valve that rapidly opens and closes at a low duty cycle (e.g., 10 milliseconds open, 3 seconds closed) can be used to evacuate the pre-chamber 65 and then add NO2 from the cylinder 55 to the pre-chamber 65. 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. Some exemplary systems and methods for introducing a sterilant into a pre-chamber are described in U.S. Patent No. 8,703,066 (Title of Invention: STERILIZATION SYSTEM AND METHOD) and U.S. Patent No. 8,017,074 (Title of Invention: 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 ideal gas law corrected considering that NO2 is not an ideal gas. Alternatively or additionally, a measurement system can be used to determine the NO2 concentration. For example, an infrared detector or a visible light detector can determine the NO2 concentration in real time. The valve disposed between the cylinder 55 and the pre-chamber 65 can be adjusted to prevent NO2 from boiling. In some cases, there may be two valves between the pre-chamber 65 and the sterilization cavity 24 to control the evacuation 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 sterilization cavity 24. In some embodiments, the pre-chamber 65 can have a volume in the range of about 0.5% to about 2.0% of the size of the sterilization cavity 24. The smaller volume of the pre-chamber 65 can help ensure that the pressure in the sterilization cavity 24 remains below atmospheric pressure when NO2 is added to the sterilization 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 gas leaks from the sterilization cavity 24.

[0038] Typically, the first gas supply system 110 may include a NO2 gas generation system 120 including a preliminary chamber or buffer tank 130, a flow resistive portion 140, a plasma generator 150, and a circulation device 160. To create a continuous circulation path, the flow resistive portion 140 may be fluidly coupled (e.g., via piping) downstream of the buffer tank 130, the plasma generator 150 may be fluidly coupled downstream of the flow resistive portion 140, the circulation device 160 may be fluidly coupled downstream of the plasma generator 150, and the buffer tank 130 may be fluidly 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 portion 170. The nitrogen and oxygen may be dried using gas drying means 180 before being introduced into the buffer tank 130. The buffer tank 130 may optionally include one or more of a pressure sensor, a chemical sensor, a temperature sensor, a humidity sensor, or other sensors. The circulation device 160 can be operated to circulate a mixture of nitrogen and oxygen through the buffer tank 130, the flow resistive portion 140, the plasma generation section 150, and the circulation device 160 to generate NO2. In some embodiments, the plasma generation section 150 may be replaced by a cylinder of liquid NO2. Alternatively or additionally, NO may be introduced into the NO2 gas generation system. Then, NO2 is generated by oxidation of the NO in the buffer tank 130 (or other chamber along the loop), as outlined below.

[0040] A strong electric field is formed in the plasma generation section of the plasma generator 150. The mixed gas of nitrogen and oxygen undergoes dielectric breakdown when excited by a strong electric field (for example, from direct current to microwave frequency), causing a transition from the molecular state to the low-temperature (non-equilibrium plasma) state. The gas in the low-temperature state has high reactivity with other gases in the low-temperature state or the molecular state. Therefore, when a mixed gas mainly containing nitrogen and oxygen is introduced into the plasma generation section 150, a part of it is converted into nitrogen oxides such as nitrogen monoxide (Equation 1) and nitrogen dioxide (Equation 2), or ozone (Equation 3). Since the circulating mixed gas (NOx mixed gas) is depressurized when passing through the flow resistance section 140, it can be more stably displaced into the low-temperature plasma state within the plasma generation section 150.

[0041] N 2 +O 2 →2NO Equation 1 N 2 +2O 2 →2NO 2 Equation 2 3O 2 →2O 3 Equation 3 It should be noted that the conversion ratio according to Equation 1 is the largest. A part of the NO generated according to Equation 1 combines with oxygen in the low-temperature plasma state in the plasma generation section and is converted into NO2 as shown in Equation 4.

[0042] 2NO+O 2 →2NO 2 Equation 4 The NOx mixed gas containing NO2 thus generated circulates within the NO2 gas generation system 120 or stays in the buffer tank 130 by being pressurized by the circulation device 160. During that time, the NO generated according to Equation 1 reacts step by step with oxygen in the NOx mixed gas or ozone generated according to Equation 3 and is further converted into NO2 as shown in Equation 5 and Equation 6. As a result, the NO2 concentration increases as the mixed gas continues to circulate.

[0043] 2NO+O 2 →2NO 2 Equation 5 NO+O3 → NO 2 + O 2 Formula 6 The ozone generated according to Formula 3 reacts with nitrogen in the NOx mixed gas to generate NO as shown in Formula 7.

[0044] N 2 + 2O 3 → 2NO + 2O 2 Formula 7 This NO is also converted to NO2 by the reactions according to Formulas 5 and 6. In this way, as the dried mixed gas circulates in the NO2 gas generation system 120 by the operation of the circulation device 160, a NOx mixed gas containing NO and NO2 generated by the reaction of nitrogen and oxygen that has shifted to the low-temperature plasma (non-equilibrium plasma) state when passing through the plasma generator 150 is generated. NO is converted to NO2 by reacting with oxygen and ozone in the NOx mixed gas, and the concentration of NO2 increases step by step. As a result, a high-concentration NO2 gas with a NO2 concentration of 5,000 to 100,000 ppm is generated. 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] The buffer tank 130 is used to temporarily store the generated high-concentration NO₂. The buffer tank 130 may be connected to the sterilization cavity 24 of the sterilization chamber 10 via a gas supply line 132. A control valve 134 in fluid communication with the gas supply line 132 can be selectively opened to allow gas to flow from the buffer tank 130 into the sterilization cavity 24 of the sterilization chamber 10. To assist in the mixing and introduction of high-concentration NO₂, an additional amount of dry air can be introduced into the buffer tank 130 to flow the high-concentration NO₂ into the sterilization chamber. In some embodiments, the buffer tank 130 can have a volume in the range of about 0.5% to about 2.0% of the size of the sterilization cavity 24. In one example, the chamber can have a volume of about 40 L, and the sterilization cavity 24 can have a volume in the range of 2000 to 5000 L. The concentration of NO₂ in the buffer tank 130 can be in the range of 50 to 150 times, or about 100 times, the concentration of NO₂ after introduction into the sterilization cavity 24. The smaller volume of the buffer tank 130 can help ensure that the pressure in the sterilization cavity 24 remains below atmospheric pressure when NO₂ is added to the sterilization cavity 24. Thus, 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 harmful gases do not leak from the sterilization cavity 24.

[0046] The rinse step can, for example, introduce a certain amount of air into the buffer tank 65 / 130 and introduce it into the sterilization chamber through the gas supply line 132. The amount of air introduced can range from 1 to 10 times the volume of the buffer tank (determined relative to the pressure inside the sterilization chamber itself). The rinsing volume can, in some examples, be about 4 to 8 times, or about 6 times, the volume of the buffer tank 65 / 130, again determined relative to the pressure inside 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 preliminary 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, air can be added to the buffer tank 65 / 130 by process control until the pressure in the buffer tank exceeds the pressure of the sterilization chamber before opening the control valve 134 to release the mixed NO2 and air from the buffer tank 130 into the sterilization chamber 10. The order of these steps can be arbitrary and can be useful for preventing the air from the sterilization chamber and the air containing moisture from flowing back in the passage from the buffer tank to the sterilization chamber. Next, in the filling step, additional air is injected into the buffer tank. In the filling step, air (ambient or pre-dried) can be added until the pressure in the sterilization chamber increases by a preset value such as 20 Torr. This increase in pressure may be used to monitor the amount of ambient air or dry air added. The air may be added in multiple filling cycles to increase the pressure.

[0048] The buffer tank 130 can also be coupled to a vacuum pump or to the pump 74 and the exhaust device 70 via another gas supply line 136 and a 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 and the pump 74. Next, the pump 74 can be operated to draw gas from the buffer tank 130 into the exhaust device 70. If NO2 gas is discharged from the buffer tank 130, it is conceivable that the exhaust gas can be treated before being discharged to the ambient environment. For example, an ozone generator and a nitric acid filter may be provided to treat the exhaust gas. The ozone generator can generate ozone that reacts with NO2 to produce dinitrogen pentoxide (N2O5). Thereafter, the dinitrogen pentoxide and nitric acid (if present) are absorbed by the nitric acid filter. As described above, other methods of removing NO2 from the exhaust gas stream may be used. The goal can be to reach an acceptable threshold of NO2 concentration based on applicable regulations in order to ensure that the risk during implementation is minimized. The goal may also be selected to limit the introduction of NO2 into the general environment. A similar process can be used to empty the pre-chamber 65 as needed.

[0049] In the illustrated example, the humidifying device 40, the temperature control device 50, the circulation device 60, the gas supply line 132, and the control valve 72 are each connected to the sterilization chamber 10 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 such that, if desired, four ports (two for the circulation device 60, one for the gas supply line 132 and the control valve 72) are provided. 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 to allow fluid / gas to be introduced and the other to allow fluid / gas to be discharged, and thus, the multiple steps associated with evacuating the chamber can be performed 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, a microprocessor, an ASIC (application specific integrated circuit), or a computer, and has a plurality of inputs for receiving diagnostic signals from pressure and / or temperature sensors, any flow monitoring devices, chemical and humidity sensors, etc., and may also control various valves, circulation, heating and / or cooling devices, etc. throughout the system. As a specific example, a 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 being introduced, during residence, and after discharge.

[0051] The memory associated with the controller 80 can store a plurality of machine-executable instructions for monitoring and controlling the ongoing process of the sterilizer. In an alternative form, one or more communication ports such as USB, infrared, or other coupling ports, or a wireless communication subsystem (such as WiFi, Bluetooth®, RF, cellular, etc.) can be used, which can be provided to enable the system to be connected 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 can also be coupled to a plurality of components of the gas supply systems 45, 110 to obtain diagnostic information and / or control the operation of its components.

[0052] In one example, the controller 80 can be used to obtain and record process control signals associated with each step of the sterilization method. Such a controller 80 can also store a model 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, it is expected that the humidity sensor will detect an increasing humidity as water vapor is introduced into the chamber, and the inability of the humidity sensor to return a signal that matches the stored model indicates a failure, and a warning signal will be generated by the system. Similarly, modeling can provide an indication of the expected multiple NO2 levels within the sterilization chamber at various times during the process, and discrepancies can be identified by comparing the detected values with the values of the process model in addition to comparing with a threshold regarding the performance of the actual process. That is, for example, any leakage in the sterilization chamber can be observed by maintaining the system at a relatively low pressure for a period during the conditioning stage when the sterilization chamber is being dried. Pressure, temperature, and / or NO2 levels are monitored when the sterilant is introduced into the interior of the sterilization chamber, and the correct operation of multiple control valves and the free flow within the associated multiple gas lines from the buffer tank 130 to the sterilization chamber 10 can be inspected.

[0053] The process control model can also be used to predict and manage the system process. For example, by modeling temperature or pressure changes, the controller 80 can open or close valves or other actuators, or turn heating devices on or off to prevent overshoot before the detected pressure, temperature, humidity, and / or chemical concentration reaches the desired target.

[0054] Figure 3 is an exemplary flowchart of a method 200 for sterilizing an object using the sterilization system 100. First, the object 34 to be sterilized is placed within the sterilization cavity 24 of the sterilization chamber 10. In one example, the object 34 can be a filled syringe. The filled syringe can contain contents within its barrel. For example, the contents can include a therapeutic agent. The sterilization process may be performed such 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 performed without considering temperature changes of the object to be sterilized, or with a wider allowable change, or with the aim of actually changing the temperature of the object 34. In some cases, the temperature of the contents can be maintained within a temperature range of about 15 - 25°C. When the object is placed within the sterilization cavity 24, the door 26 of the sterilization chamber 10 can be closed and locked. Next, as shown in block 204, a series of evacuation and filling steps are used to dry the sterilization cavity 24. Drying the sterilization cavity 24 can provide a controlled starting point, or controlled process conditions for each "pulse" of the sterilization process, as described in more detail herein.

[0055] When the sterilization cavity 24 reaches a known state, as shown in block 206, the sterilization cavity 24 is humidified in a controlled manner using a series of evacuation and filling steps until a target relative humidity is reached. The target relative humidity can be, for example, but not limited to, within the range of about 25% - about 90%, or about 40% - about 80%, or about 80%. The target relative humidity may be affected by a plurality of process factors including the surface temperature and pressure used, and in some examples, the target relative humidity may be selected 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, as shown in block 208, the chamber is depressurized to a target pressure. The target pressure P TWhen implementing this method using a prefilled syringe, for example, it can be in the range of 200 Torr to 500 Torr. In some cases, P T may be in the range around about 450 Torr. When humidified before adding NO2, the humidification can be achieved by recirculating the gas from the sterilization chamber through a humidification element as indicated by 40’. If a plurality of preceding steps are performed to keep the dried chamber under reduced pressure, the additional pressure reduction step at 208 may optionally be omitted.

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

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

[0059] Steps 210 and 212 add a certain amount of air and NO2 to the sterilization cavity 24, resulting in the resident pressure P of the sterilization cavity 24 dWithin a range of about 600 Torr, for example, within the range of 500 Torr to ambient pressure, or even above ambient pressure, for example, in some examples where it reaches up to about ambient pressure + 100 Torr, the residence pressure may be in the range of about 550 to about 650 Torr. The residence pressure is also understood with respect to ambient pressure and can be in the range from a pressure about 200 Torr lower than ambient pressure to a pressure about 100 Torr higher than ambient pressure, or in the range from a pressure about 100 Torr lower than ambient pressure to ambient pressure. In some examples, the residence pressure is at least about 150 Torr above the target pressure. In some examples, the residence pressure is ambient pressure, and the ambient pressure may be the average ambient pressure at that location, or may be determined by detecting 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 within the sterilization cavity 24 in the range of about 2 to 20 milligrams per liter (mg / L). However, the concentration of NO2 in the buffer tank 130 can be several times higher than the resulting concentration of NO2 in the sterilization cavity 24. For example, assuming that the sterilization 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 range from 200 mg / L to achieve a concentration of 2 mg / L in the sterilization cavity 24, or from 2000 mg / L to achieve a concentration of 20 mg / L in the sterilization 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 profile, material, material compatibility, whether there are movable parts that may move due to pressure changes, the resistance of the material of the object to be sterilized and any substances (pharmaceuticals, biologics, etc.) contained within the object to be sterilized to heat, pressure, humidity, and NO2 itself.

[0060] The sterilization cavity 24 can be maintained in a steady state for a preset residence time, as shown in block 214. For example, the humidity, NO2 concentration, and air within the sterilization cavity 24 can be maintained for a period ranging from about 4 minutes to 15 minutes. However, if necessary, a residence time less than 4 minutes or exceeding 15 minutes may be used. After vacuum is applied in step 208, it should be noted that each of steps 210 and 212 raises the pressure within the sterilization cavity 24 from the target pressure P T to the hold pressure P d . As a result, the target pressure in step 208 is not the same as the pressure within the sterilization cavity 24 during the hold step 214.

[0061] At the end of any given hold step, the chamber is evacuated and the NO2 discharged is scrubbed and removed from the exhaust gas. The process 220 is repeated for a plurality of pulses, as shown in block 216. The number of pulses may range from 2 to 8 pulses. However, in some cases, optionally, only one pulse may be present, or more than 8 pulses may be present. When additional pulses are required in the sterilization routine, the process returns to step 204 to bring the sterilization cavity 24 back to a known state again. When the process returns to block 204, the evacuation and refill steps performed discharge the NO2 remaining in the sterilization chamber in the previous hold step (214), and it is necessary to treat the resulting exhaust gas to reduce the amount of NO2 discharged to an environmentally acceptable level.

[0062] When the sterilization routine is completed (e.g., when Process 220 is repeated for a preset number of pulses), as shown in Block 218, the sterilization cavity 24 can be purged and vented. The sterilization cavity 24 may be vented by a series of exhaust or incoming air passing through the sterilization cavity 24. For example, an amount of air can be drawn through the sterilization cavity 24. To purge the sterilization cavity 24, the mixed gas is discharged through the exhaust device 70, and NO2 and nitric acid can be scrubbed before the mixed gas is released into the ambient environment. If desired, the purge and vent process 218 may include changing the temperature of the object to be sterilized, such as by using heated or cooled air during multiple purge steps and by heating or cooling multiple walls of the sterilization chamber. The purge and vent 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 following the dwell step. For example, a NO2 sensor in the chamber or a NO2 sensor in a flow path associated with the chamber, such as in the exhaust flow path, may be used to monitor the NO2 level during venting until such level falls below the threshold.

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

[0064] In some examples, the success of the process can be monitored based on the concentration of chemical reaction byproduct species. For example, N2O3 is a harmful molecule that reacts with DNA / RNA strands after passing through the cell membrane and destroys them. For example, to form N2O3, the species required for its formation are NO and HONO. The concentrations of NO, HONO, N2O3, and / or others can be monitored to determine whether N2O3 was present at a sufficient concentration to sterilize the object(s) within the sterilization cavity 24.

[0065] In an exemplary example, process monitoring in the sterilization chamber may include monitoring one or more of NO, HONO, N2O3, and / or NO2 in the sterilization chamber during a plurality of processes as exemplified. In one example, during the residence step at 214, one or more of the concentrations of NO, HONO, N2O3, and / or NO2 in the chamber are monitored using a sensor. For example, the NO2 concentration may be monitored against a target concentration in the range of, for example, but not limited to, 2 to 20 mg / L. A specific example is to monitor HONO during the residence step, and the concentration of HONO is expected to change during the residence process as the residence period progresses. In some examples, a model of the expected HONO concentration can be constructed for a specific sterilization process during validation and verification (V / V) of the sterilization process. For example, a test run of the sterilization process is performed, and then inspection and / or testing of the product to be sterilized is performed to determine whether the sterilization process was carried out as expected. The HONO model constructed during such V / V activities is stored in the memory of the system controller 80 (Figure 2) and may be used to determine whether a specific execution of these processes complies with a plurality of system monitoring requirements. Using such a model ring may make it possible to eliminate or reduce the dependence on a biological process monitor that may be costly to create, store, and inspect after use. Alternatively, the concentration of HONO may be compared with a threshold value (such as an average during all or part of the residence period, or a peak or minimum concentration, or a concentration at the end of the residence period). Monitoring of NO and N2O3 may be performed using a similar approach instead.

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

[0067] In some examples, the temperature or pressure within the chamber may be raised, lowered, or adjusted to affect the rate of a chemical reaction within the chamber. Typically, increasing the temperature causes the chemical reaction to speed up, and cooling the chamber causes the chemical reaction to slow down. Instead of adding or removing substances from the chamber, a bladder that is expandable within the chamber or in the walls of the chamber may be expanded or contracted to adjust the chamber internal pressure (by reducing or increasing the volume within the enclosed space), and the pressure may be adjusted. A circulation blower may be adjusted in response to a tracked (recorded) chemical or humidity state within the chamber. For example, if the concentration of NO2 remains relatively high but the HONO concentration does not match the model, additional mixing within the chamber may be promoted, and the blower may be activated or its speed increased to thereby improve the rate of the chemical reaction that generates HONO. These are merely examples of a number of steps that can be taken to adjust or correct the concentration of HONO within the chamber, or the concentration of another sterilant and / or chemical product of the sterilization process, in response to sensor outputs indicating that the HONO does not match the modeled parameter trends and / or does not meet the target.

[0068] Rather than doing something to adjust the concentration of the parameter being monitored, the residence time itself may be adjusted by adding more residence time if the concentration is 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 action may be taken outside of the specific residence step being monitored, such as by adjusting the concentration, temperature, humidity, or pressure for use in a subsequent residence step for the same set of products to be sterilized or for use in the sterilization of subsequent products. In yet other examples, the monitored parameter may be used to trigger a warning to the operator that one or more system components are not operating as expected, for example, a clogged valve, a non-functional actuator, or other failure or performance degradation.

[0069] Figure 4 shows an exemplary example. During the residence step 300, monitoring 310 of process parameters is performed. At 312, multiple sensors are used to monitor multiple parameters (humidity, temperature, NO2, NO, HONO, H2NO3, or the concentration of any other sterilant, and / or a chemical marker of the sterilization process), and at 314, they are compared with the stored targets and / or models. The comparison may be a simple comparison against the target, or may involve using standard statistics to track (record) trends or deviations from the target (such as determining whether the process stays within the standard deviation of the process parameters). If the monitored parameters are out of range, above or below the target, or deviate from or show a trend away from the model and / or target, at 316, corrections may be made. Correction 316 may include a wide range of steps according to many types of sterilization that can be used, as well as many processes that can result. Some correction actions are described in the foregoing description. Steps 312, 314, and 318 are used to monitor the process and generate or trigger one or more warnings regarding the operability of the chamber, the state of the sterilization process, or the success / failure of a particular iteration / residence step in the sterilization process. In some examples, correction 316 may be omitted. The monitored data, comparison with the target, trends and / or models, and / or any correction steps taken are then stored in memory at 318 and can become part of the history file of the product(s) being sterilized. Finally, when the residence period ends, the process optionally proceeds from block 310 and determines at 320 whether further pulses are required. The stored data from block 318 can be used when determining whether more pulses are needed.

[0070] Some specific examples of products that can be sterilized, and the sterilization considerations applied, are as follows. The prefilled syringe may be sterilized several times as described above using the NO2 sterilization process. The process can be carried out at a temperature close to room temperature (i.e., in the range of 10 - 30 °C, or more narrowly 15 - 25 °C), depending on how readily 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 since the plunger is movable relative to the barrel, 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 an amount of NO2 and air are added at 210, 212 to achieve a NO2 concentration in the sterilization chamber of 2 - 40 mg / L at a pressure of about 550 - 650 Torr.

[0071] Implanted electrical stimulation devices such as pacemakers, defibrillators, or nerve stimulators may also be sterilized. Such systems typically have a port for receiving a lead wire, the port is surrounded by a plastic material such as epoxy, and a plurality of silicone components are used to insulate the plurality of parts of the port. Such systems are often housed, for example, in a metallic canister 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] A stent delivery system for delivering a heart stent can also be sterilized. The stent delivery system can include an elongate catheter having at one or more inflatable balloons at its distal end that carry an expandable metal stent, and the stent 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 lubricious materials, lower humidity levels may be required. In some cases, it may be necessary to protect therapeutic agents during the sterilization process. For example, an additional layer or coating of a therapeutic agent may be provided on the device.

[0073] Other exemplary devices can include orthopedic-related devices, intramedullary nails, pedicle screws, custom implants, 3D printed implants, metallic implants (including but not limited to nitinol, titanium, chromium, tantalum markers), polymeric implants (including polyethylene (PE), polyetheretherketone (PEEK), polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), poly(caprolactone-co-lactide) (PCLA)), or combinations thereof. The specific water activity level of metal nitrates can be considered for use 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 NO2 release in the immediate vicinity of the sterilization chamber. In some examples, as a way to monitor for NO2 leakage, a NO2 sensor may be provided outside the sterilization chamber, and NO2 leakage can impair the actual sterilization process itself and pose a potential danger to operators in the area. As described above, in some examples, the pressure may be above ambient levels during the sterilization process, in which case an external NO2 sensor may be used, the space provided by the sterilization chamber may be sealed, or alternatively, it may be ventilated using the assistance of a scrubber that removes NO2 from the air exiting the chamber.

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

[0076] Products that require refrigeration can be sterilized within the NO2 chamber. In one example, products stored at a low temperature for storage purposes in the range of, for example, 1°C to 15°C can be sterilized using the NO2 sterilization process without the need to warm the product to room temperature. Such prior heating is required in other sterilization processes, significantly delaying the processing time, exposing the product to high temperatures, accelerating its degradation, and / or shortening the shelf life.

[0077] For the NO2 sterilization of refrigerated products, the walls of the sterilization chamber may optionally be cooled by circulating a cooling fluid through those walls, as described above. Referring again to FIG. 3, the product is removed from the low temperature storage and placed in the sterilization chamber 202 and processed through the drying process 204 described above. In particular, the pressure in the chamber is reduced to a pressure in the range of, for example, around 350 Torr, dry air is introduced to return the pressure to 500 Torr, and all (optionally) the walls of the chamber are maintained at a low temperature of, for example, 1°C to 15°C. (Any of 1 to 60 drying cycles may be performed.) After a plurality of drying cycles, a dose of humidity containing a certain amount of moisture is introduced into the chamber 206 while 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 local condensation, air is removed to reach the target vacuum state (which will also cool the chamber), a dose of water vapor mixed with air is introduced (which will temporarily warm the chamber), and humidification can be performed by a series of iterations such as repeating this process.

[0078] Next, the cooled and humidified chamber receives a quantity of NO2 at 210, and dry air is flowed into the NO2 pre-chamber or buffer tank. These steps increase the pressure within the sterilization chamber and also temporarily raise the temperature within the chamber. Next, a dwell 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 vented (218). The process may require a longer dwell period (214) than needed at a higher temperature, or a higher NO2 concentration, or more pulses 216 may be required. Such a process can be carried out, for example, using prefilled syringes containing products that require low temperature conditions for reasons such as shelf life, effectiveness, etc. Some examples can include various vaccines, biological products, drugs, etc., including certain ophthalmic products. Even when the sterilization chamber process requires more time when carried out at low temperature, the overall sterilization time can be shortened by avoiding preheating and subsequent cooling of the products (which can take up to 72 hours for palletized products), and also avoiding product degradation and / or shortening of the shelf life due to increased time outside refrigerated storage.

[0079] The piping to and from the chamber may be temperature controlled in some examples. For example, when delivering air and / or water vapor containing moisture 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 can be carried out at a pressure higher than the pressure assumed throughout the chamber). In some examples, the supply of dry air provided to the chamber is delivered after passing through cooled piping or after passing the dry air through a heat exchanger to cool the injected air, which may assist in temperature control within the chamber.

[0080] It should be understood that the present disclosure is merely illustrative in many respects. Without departing from the scope of the present invention, changes may be made in details, particularly in the shape, size, and order of steps. This may include, within appropriate limits, using any of the features of one exemplary embodiment in other embodiments. Of course, the scope of the present invention is defined by the language expressed in the appended claims.

Claims

1. A method for sterilizing a prefilled syringe, comprising: placing the prefilled syringe in a sterilization chamber; and performing a plurality of pulsed sterilization steps, each pulsed sterilization step comprising: drying the sterilization chamber with the prefilled syringe therein; after drying the sterilization chamber to a target, humidifying the sterilization chamber; after 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 after the preset amount of air has passed through the buffer tank, holding the sterilization chamber at a residence pressure for a residence period.

2. The method of claim 1, wherein the residence pressure is at least 150 Torr above the target pressure.

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

4. The method according to any one of claims 1 to 3, wherein the sterilization chamber has a heat capacity sufficient to keep a change in temperature of the prefilled syringe during the sterilization process below 5°C.

5. The method according to any one of claims 1 to 4, wherein the concentration of NO2 when accumulated in the buffer chamber is about 100 times the concentration of NO2 after being introduced into the sterilization chamber.

6. The method of claim 5, wherein the resulting concentration of NO2 in the sterilization chamber during the residence step is in the range of 2 to 20 mg / L.

7. The method according to any one of claims 1 to 6, wherein the preset amount of air is in the range of 4 to 8 times the volume of the buffer tank.

8. Circulation means is provided for recirculating the air in the chamber The step of humidifying and the step of introducing a certain amount of NO₂ are performed by mixing at least one of air containing moisture and NO₂ with the recirculated air while the chamber is at a pressure lower than the ambient pressure, according to any one of claims 1 to 7.

9. The introduced NO₂ is at least partially converted into other chemical products during sterilization, and the other chemical products include at least HONO. The method includes monitoring the concentration of HONO during the sterilization process, comparing the concentration of HONO with one or more threshold values, and determining that the sterilization process is incomplete when the concentration of HONO does not meet the one or more threshold values, according to any one of claims 1 to 8.

10. The introduction of the certain amount of NO₂ from the buffer tank into the sterilization chamber is 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, according to any one of claims 1 to 9.

11. A method for performing sterilization using NO₂, comprising preparing a sterilization chamber for accommodating a product to be sterilized by placing the sterilization chamber in a known state, introducing a certain amount of NO₂ together with air containing a certain amount of moisture into the sterilization chamber, wherein the NO₂ and the air containing moisture interact within the sterilization chamber to generate a plurality of chemical products of the sterilization process, after introducing the certain amount of NO₂ and the air containing the certain amount of moisture into the chamber and before exhausting the chamber, using a chemical sensor to monitor the concentration of at least one of the plurality of chemical products of the sterilization process during a residence step, comparing the monitored concentration with a process target, determining whether the residence step has reached or achieved a sterilization target, and generating a warning to an operator or performing a corrective action when the residence step has not reached or achieved the sterilization target. When the residence step has achieved or has achieved the sterilization target, recording information indicating the success of the residence step in a memory. A method comprising this.

12. The step of using a chemical sensor to monitor the concentration of at least one of the plurality of chemical products The method according to claim 11, comprising detecting the concentration of HONO in the sterilization chamber.

13. The step of comparing the monitored concentration with the process target is performed by comparing the concentration monitored over time with a modeled concentration model constructed during the validation and verification process. The method according to claim 11 or 12, wherein the model is stored in the memory of a controller for the sterilization chamber.

14. The step of performing the corrective action The method according to any one of claims 11 to 13, comprising changing the state of the chamber during the residence step.

15. The step of performing the corrective action Storing information indicating that the residence step has failed The method according to any one of claims 11 to 14, comprising repeating the preparing step, the introducing step, and the residence step.

16. The step of performing the corrective action The method according to any one of claims 11 to 15, comprising adjusting parameters used in subsequent repetitions of the preparing step, the introducing step, and the residence step.

17. The step of performing the corrective action The method according to any one of claims 11 to 16, comprising changing the duration of the residence step.

Images