When it comes to decontamination and sterilization techniques, there are several methods by which the medical industry can choose. These include gamma radiation, hydrogen dioxide (peroxide), nitrogen dioxide, ethylene oxide, and the oldest method, steam. However, most of these procedures have disadvantages that far outweigh their satisfactory qualities, making them risky avenues for sterilization.
Pharmaceutical companies and the medical field alike have a constant need for decontamination of devices and equipment. They differ in the specific equipment to be sterilized. Surgical tools, needles, and implants, for example, are some of the everyday items used in the medical field that must be stripped of harmful microbes before use. Other materials that must also be sterilized are ‘biologics’ such as prefilled syringes containing drugs and sometimes bio-molecules such as proteins.
For years, the preferred, and therefore most popular, technique for sterilization has been ethylene oxide. It is compatible with a wide variety of materials and is great at ridding substances of harmful microorganisms. However, it is not capable of safely decontaminating biologics. In fact, while ethylene oxide, gamma radiation, and steam have all been used to sterilize biologic equipment, the best sterilant that can do so safely and effectively without altering the composition of the drug is nitrogen dioxide.
This is even more important today since the expansion of biological drug companies in the last few years. Biotherapeutics, such as protein treatments, account for more than 60% of novel pharmacological products now under development, which puts sterilization techniques like nitrogen dioxide ahead of the game!
Ethylene oxide (EO) has been the primary choice of sterilant since it can effectively sterilize most substances. It was previously used as an insecticide due to its lysing capabilities. As a sterilant, it functions similarly, breaking down the outer membrane of cells to kill harmful microorganisms. However, it can also kill good microorganisms contained in some prefilled syringes.
The EO method requires high temperatures anywhere from 122 – 140℉ which makes it almost impossible for any living organism to survive. The extreme heat and pressure cause unwanted chemical alterations such as the breaking down of genetic material in the biological therapeutic. Additionally, EO has been known to penetrate the substance completely, making it unsuitable for biological drugs.
Nitrogen dioxide (NO₂) is a powerful oxidant that quickly and effectively kills all surface bacteria (both dormant and active). The gas behaves similarly to our own immune cells by destroying or breaking down the genetic structures of microbes. It does not permeate the devices or seals, therefore, it does not alter the living component of biologically active drugs. Moreover, NO₂ is a safe sterilization method for injectable solutions that are easily affected by high temperatures and pressures. It remains a gas at room temperatures (50 – 86℉), so is not necessary to increase the temperature of the gas in order for it to successfully work.
|Noxilizer RTS 360TM||Typical EO System|
|Estimated Average Cycle Time||2 hours||12-18 hours|
|Capacity||360 Liters||2200 Liters|
|Estimated Aeration Time||60 minutes||9 days|
|Relative Humidity||Low to High (30%-80%)||High (70%)|
|Room Temperature (50°F – 86°F)|
High(122°F – 140°F)
|Pre-filled Syringes & Biologics (PFS) Material Compatibility||Yes||Yes|
|Sterilant Ingress||Below WFI limit||Common Issue|
|Low non-cytotoxic non-carcinogenic||Low cytotoxic carcinogenic|
|Operator & Environmentally Friendly||Yes||No|
|Manufacturing to Release Time||On-site, immediate release||Off-site, 7-24 day turnaround|
Both EO and NO₂ have a toxicity rating of 3 out of 4, meaning they pose an “extreme danger” in terms of overall health. Permissible Exposure Limit (PEL) is the highest quantity or concentration of a toxin that OSHA rules allow a person to be subjected to. The PEL of EO is 1 part per million (ppm) over an 8 hour time weighted average (TWA). This means, according to OSHA, the average EO concentration should not exceed 5 ppm throughout any 15 minute working period. For comparison, the PEL of NO₂ is 5ppm for the same 8 hour TWA.
This information is especially crucial when considering the amounts of sterilant needed to complete one round of sterilization. EO requires 450 – 1200mg/L, while NO₂ only requires 1 – 20mg/L, less than 1% of the total volume of solution. This small concentration still provides a lethal dose potent enough to achieve a sterility assurance level (SAL) of 10-6 in a process with a total (normal) duration of 60 – 120 minutes, hence reducing the amount of time that the medicinal product is exposed to ambient temperature throughout the cycle.
EO is also toxic to the environment which causes concern for disposal of any waste products after sterilization. However, the NO₂ sterilization chamber can be quickly neutralized of any remnants via a specialized scrubber to prevent toxic fumes from being released after sterilization. Furthermore, the scrubber is completely biodegradable and safe for the environment.
|Safety-Related Property||Nitrogen Dioxide||Ethylene Oxide|
|Odor Threshold||0.1 ppm||200-400 ppm|
|OSHA PEL||5 ppm||1 ppm|
Other health hazards such as extreme flammability and explosion potential make EO an unsafe sterilant. EO is extremely unstable with a fire hazard rating of “4”, which means it is capable of combustion at temperatures below 73℉. NO₂ is non-flammable (fire hazard rating of “0”) and virtually non-reactive, making it safer for use.
Another major drawback of the EO method is the total time it takes to sterilize substances. Aeration alone, which is the stripping away of the sterilant after decontamination, can take upwards of 17 days for EO, with the total turnaround time taking as long as 25 days depending on the substances being decontaminated.
The NO₂ treatment lasts anywhere from 2 – 4 hours including aeration times. With the in-house NO₂ sterilization system, RTS 360 Industrial NO₂ Sterilizer, substances can be microbe-free within 2 hours! Additionally, in-house sterilizing saves 40-60% compared to contract sterilization in regards to both transit and inventory related expenses.
NO₂ has some limitations, as it is not compatible with substances containing cellulose, such as cotton and paper, polyamides like nylon, and polyurethanes. However, there is evidence of its compatibility with stainless steel equipment used in sterile settings, screening devices that directly touch the mucosa, bioabsorbable implants as well as containers for biologics, lumens, and needles. Additionally, it is compatible with materials such as polypropylene and silicone, the primary constituents of stoppers and other equipment in the medical field. Comparing the advantages and disadvantages of both EO and NO₂, nitrogen dioxide is clearly the way to go!
Additional source: Nitrogen Dioxide Sterilization Supports Innovation in Medical Device Market
|Ethylene oxide||Nitrogen dioxide|
|• Reliable and effective • Long history of use with medical devices • Compatible materials are built into current medical devices • Flexible load capacity • Penetrates packing materials, device lumens • Ability to process in large volume quantities (pallets)||• Low sterility concentration • Ultra low or room temperature process • Short exposure • Aeration occurs during the cycle • Low sterilant residuals • Not requiring vacuum • Ability to tune process parameters to optimize compatibility to each use case • Ability to process in large volume quantities (pallets) • In house opportunity option|
|• Toxic, carcinogenic • Explosive • Environmental pollutant • Physical & health hazards • Long aeration period • Necessary infrastructure is expensive • Load composition limitations • High process temperatures degrade biomolecules • Diffuses past plungers, contaminating vial and syringe contents||• Compatibility issues with nylon, cellulose, linens, cottons, liquid, and paper (Less problematic with single use devices compared with reusable devices)* |
*Source: AAMI TIR 17