Noxilizer has developed a room temperature sterilization process for medical devices that is based on nitrogen dioxide (NO2) gas. Currently, industrial sterilizers and contract sterilization services using NO2 gas are being offered to medical device manufacturers for terminal sterilization during the manufacturing process. A hospital model is also being developed for use in the clinical setting as a means of sterilizing reusable medical devices. As such, designers should be aware of this technology today for disposable and implantable devices, and also in the future for reusable devices sterilized in hospitals using NO2 gas sterilizers. At present, the terminal sterilization market for medical devices is primarily serviced by ethylene oxide (EO) gas or radiation processes, with gamma accounting for the majority of radiation sterilization. In this article, NO2 sterilization is discussed in the context of other gas sterilization processes, but it may also be applicable to devices that are sterilized with gamma.
NO2 is a rapid and effective sterilant, as demonstrated using a broad range of microorganisms. The most resistant organism is the spore-former, Geo bacillus stearothermophilus, which is also the biological indicator for both steam and vapor hydrogen peroxide sterilization. It is a well-characterized biological indicator organism and, as can be seen in Figure 1, NO2 provides a log-linear population reduction as exposure time is increased. This log-linear response allows for a model around which the sterilization cycle for a given device may be developed. With most medical devices, a sterility assurance level (SAL) of 10-6 can be achieved with 20 to 40 minutes of exposure time to the NO2 sterilant.
All gas sterilizers face challenges in addressing the wide variety of medical devices that are being produced today, or will be developed in the future. The first challenge is the fact that the gaseous sterilant needs to contact all of the device surfaces that require sterilization. There fore, the packaging and device design must permit gas access. For the device, this means avoiding closed spaces and mated surfaces. For the packaging, gas access is typically achieved through the use of porous packaging that provides a sterile barrier for the finished device. Tyvek® has been an industry standard in sterile barrier packaging for years because it allows ready gas diffusion in and out of the package. Tyvek pouches are compatible with EO, hydrogen peroxide (H2O2), steam, and NO2 sterilization. Additionally, EO can diffuse through polymers in order to sterilize within non-porous polymeric packaging. Sterilant access to all device surfaces can be ensured during the design process by allowing for paths through which the NO2 can flow, either under vacuum or by diffusion, into complicated geometries such as lumens and mated surfaces. With H2O2 (boiling point, Tb = 150 °C) condensation of the sterilant can occur prior to reaching the innermost regions of a device as the sterilant concentration approaches the saturated vapor pressure. This condensation can result in localized sub-lethal conditions leading to non-sterile devices. With NO2 (Tb = 21 °C) this is not an issue because of the high saturated vapor pressure at the sterilization temperature. Diffusion into lumens occurs without the driving force for condensation. EO sterilization relies on diffusion of the gas without the aid of vacuum to reach complicated geometries, which results in longer cycle times. EO can sterilize closed volumes within devices via diffusion through polymers given long enough exposure times.
Removal of residual sterilant is another challenge posed by gas sterilizers. Concern has been expressed over the residuals left behind by EO sterilization, which have been shown to be both cytotoxic and carcinogenic. Much of the processing time with EO sterilization is taken up by the lengthy aeration phase that is required to ensure adequate removal of residual sterilant from the devices and packaging materials. Furthermore, EO will diffuse into materials like polymers and paper over the long exposure time that is required to achieve sterility. In order to remove the residual sterilant from the devices, one must wait for the EO to diffuse back out of the materials. This aeration process is carried out over many hours or even days in order to ensure that the devices are safe.
Unlike EO, most polymers are rather impermeable to NO2, particularly over the relatively short exposure required with NO2 gas sterilant. This makes aeration a faster process. Since NO2 has a vapor pressure of 1 atm at room temperature, aeration can be carried out using either vacuum-assisted air exchanges or a steady flow of air at ambient pressure through the sterilization chamber. The aeration process with NO2 sterilization is generally about 15 minutes in duration, and this is built into an overall cycle time that usually runs about 60 to 90 minutes for the large industrial sterilizers.
NO2 sterilant is supplied as a liquid, from which vapor is dosed into the chamber during the cycle. This is a space saving alternative to large gas cylinders. NO2, while a toxic gas, is nonexplosive and non-carcinogenic. At the end of the cycle, NO2 is removed from the exhaust gas via a scrubber system that is built into Noxilizer’s industrial sterilizers, which can allow an NO2 sterilizer to be vented safely, without releasing NO2. The spent scrubber material is a non-hazardous solid waste product (considered landfill-safe in the US) that can be disposed of in accordance with local regulations. This makes NO2 sterilization a safer and more cost-effective option to bring sterilization activities inhouse and make it a real part of the manufacturing process.