Ethylene Oxide Sterilization for Medical Devices,Why use ethylene oxide (EO) for sterilizing medical devices?

Ethylene oxide (EO) sterilization is the most common industrial sterilization technique for medical devices. It is a relatively ‘cold’ sterilization technique and offers high compatibility with most materials used in the manufacture of medical devices, such as plastics, polymers, metals and glass. Its lethality is driven by a chemical reaction (alkylation) with the DNA of bacteria, viruses, molds, yeasts and even insects. Care is required when designing a cycle to ensure thorough consideration of any potential limitations in products, materials, coatings, bonds or packaging.

Temperature is one of the key considerations in cycle design and it’s important to select the highest temperature that can be tolerated by product in order to provide the most efficient and cost-effective process design. However, a higher temperature set point might impact the product material or packaging, so this should be evaluated and some conservatism is advised. EO sterilization typically operates within the range of 90°F to 135°F. Generally, the rate of the lethality of the process is doubled with every increase of 18°F. So elevating temperature can provide benefits such as reduced product contact time with ethylene oxide, which may result in lower EO residue levels and hence shorter aeration times. Cold temperature may also provide sufficient lethality, but will require a longer EO exposure time. It’s this flexibility in operating temperature that makes EO sterilization a viable option for products with multiple devices, components and materials.

Water vapor is also an essential element in enhancing the deactivation of bacteria. It can both increase material porosity, hence improving EO penetration, and also drive the alkylation reaction within the DNA of the bacteria to provide greater lethality. It’s important to limit exposure to steam, particularly for some moisture-sensitive materials (e.g. bioresorbable polymers such as PLA, PGLA, etc.). In summary, relative humidity levels of above 30% are advised in order to provide repeatable process lethality. The maximum specification for steam addition/RH should be assessed and determined based on any limitations in product and/or packaging.

Depth of vacuum is another important factor and physical limitations in product and packaging design may dictate the cycle pressure profile. For effective EO sterilization, it’s important to displace air and replace with EO, so deep vacuum cycles tend to be more efficient in providing optimal EO penetration into product and packaging, particularly when product design includes a long lumen. There are conditions that will limit the vacuum depth that can be applied:

*Sealed aluminum pouches containing sterile product that cannot be exposed to EO will not withstand deep vacuum (burst risk).

*Plungers from prefilled syringes might be moved when applying deep vacuum.

*Plastic containers may be deformed at low pressures.

*Bags which are poorly vented and may inflate.

In these cases, the vacuum depths of the cycle can be reduced to compensate, but this change will impact EO gas penetration and removal, typically resulting in longer cycle times and increased aeration time.

The final critical element is the concentration of ethylene oxide. Typically, the operating range varies from 400 mg/l to 800 mg/l. For higher concentrations, the lethality no longer follows a linear behavior and brings only adverse effects, e.g. flammable cycles, higher residual content and limited improvement on lethality. Therefore the selection of EO concentration must be based on the compromise between attainment of the required conservative sterility assurance level and minimized EO residual levels in the product.

After a potential cycle design has been identified, and before launching a formal validation of product sterility assurance, it’s important to verify that there is no significant adverse impact on final product and packaging design. In order to mitigate risk, it is strongly recommended to perform stability and functionality studies on samples that have been exposed to two or three test cycles using a ‘worst-case’ version of the proposed cycle design. By verifying product can withstand multiple sterilization processes, products can be re-processed in case of any deviation.

Once the cycle design has been established, and verified to be appropriate for product and packaging, validation of the sterility of the medical device(s) should be performed in accordance with ISO 11135:2014. In addition, safe levels of EO in product should be verified in accordance with ISO10993/7:2008.

In conclusion, the ability to vary, by design, combinations of process parameters results in ethylene oxide providing flexible solutions to sterilize a wide variety of medical devices and materials which has driven its continued growth as a major sterilization technology.