Ethylene Oxide: A Widely Used but Controversial Sterilizing Agent
30/01/2025

Ethylene oxide (EO) sterilization is one of the most widely used methods for sterilizing medical devices worldwide. In the United States (US), less than 5-10% of medical devices are sterilized using methods other than EO or radiation (source: FDA). EO is primarily used to sterilize medical devices that are sensitive to heat, radiation, and moisture. It is particularly suitable for materials like plastics, polymers, and devices combining multiple materials. Common devices sterilized with EO include catheters, medical implants (stents, prostheses), electro-medical devices (pacemakers, insulin pumps), and single-use products (gloves, masks). In the pharmaceutical sector, EO can be used to sterilize the surfaces of containers and/or packaging systems for active pharmaceutical ingredients or powdered formulations.
Although widely used due to its recognized effectiveness, EO raises significant concerns, particularly regarding the risks associated with its use during the sterilization process and the presence of residues that may remain on the surface of medical devices.
A Harmful Effect
Despite its widespread use, EO remains a Carcinogenic, Mutagenic, and Reprotoxic (CMR) gas that is colorless and explosive. Despite degassing and treatment of EO in the sterilization chamber by the sterilizer, some of the EO used during the sterilization of healthcare products can remain on the products afterwards. A portion of this residual EO transforms into ethylene chlorohydrin (ECH) and ethylene glycol (EG), leaving three types of residues on the products. EC) forms when EO comes into contact with free chloride ions, while EG forms when EO comes into contact with water. Chemistry is thus a critical point of attention, and environmental conditions can greatly influence the amount of residual quantities.
On April 9, 2024, the US Environmental Protection Agency (EPA) announced a set of final rules aimed at significantly reducing toxic air pollutant emissions from chemical plants, including potent pollutants like EO. These rules aim to significantly reduce the number of people exposed to heightened cancer risks associated with this pollutant in communities near facilities using EO. Many sterilization units using EO have implemented technical upgrades to their infrastructure to comply with the new regulations. In addition to emission reduction methods, some manufacturers are also adopting EO cycles with lower concentrations to help reduce emissions. In this context, and to avoid potential disruptions in the supply chain or shortages of sterile medical devices, the FDA also issued guidance in November 2024 to facilitate understanding of the data required to change sterilization sites for Class III medical devices.
EO is classified as a CMR substance under the REACH/CLP regulations, and its use is strictly controlled under several European Union regulatory frameworks, including the European regulations on food safety (Regulation (EC) No 396/2005), the European directive on health and safety at work (Directive 2004/37/EC), and the Medical Device Regulation (2017/745).
In 2021, the European Commission proposed new restrictions on EO under REACH, focusing on its use in industrial applications and sterilization processes. In 2023, the European Union launched consultations to evaluate safer alternatives to EO for sterilization, reflecting a growing desire to reduce its use due to health and environmental concerns. These measures are part of a broader strategy to phase out hazardous chemicals and promote safer alternatives.
Aeration of EO-Sterilized Products
The residual presence of EO, ECH, and EG requires finished products to undergo aeration. This aeration process reduces their concentrations. The aforementioned three types of substances can be hazardous depending on their concentrations, making it imperative for manufacturers to ensure that their concentrations are well below allowable limits before releasing the products on the market. The allowable limit is established in theISO 10993-7 standard and depends on several factors, including the population in contact with the device, the type of device-patient contact, and the number of devices in contact.
To achieve the allowable limit, products are aerated. Aeration, as defined in the ISO 11135 standard, is the phase of the sterilization process during which EO and/or its reaction by-products are desorbed from the medical device until predetermined levels are reached.
During this aeration phase, products are placed in an aeration chamber with controlled parameters. The EO residue levels in medical devices depend on the aeration temperature, the density and configuration of the load (e.g., chimney in the center of pallets, palette wrapping, etc.), airflow, type of load, the extent of ventilated product surfaces, and aeration times.
Validation and Control of Aeration
The aeration phase can be validated, which eliminates the need for manufacturers to conduct systematic testing to release sterilized batches. In this case, manufacturers are expected to evaluate the repeatability of the aeration period during validation and to consider worst-case conditions for routine loads.
For repeatability, data from at least three complete exposure cycles must be analyzed. Depending on the routine loads to be aerated, the number of cycles required for validation may be higher, especially if density-based control is performed using maximum and minimum density loads or if the number of pallets/cartons varies. For instance, it is challenging to determine whether aeration of a minimum density load will be faster than a maximal density load. A minimum density load represents a lesser constraint on EO diffusion.
To obtain EO residue dissipation curves, a kinetic study with three successive time points must be conducted for each cycle. This involves sampling during aeration and measuring residue levels. Testing methods must be validated and must demonstrate sufficient accuracy, precision, selectivity, linearity, robustness, and sensitivity.
The time interval between removing samples from a controlled aeration zone and beginning laboratory extraction should be minimized. When analysis is delayed, samples should be sealed, shipped, and stored frozen to halt residue dissipation.
To define the samples to be tested, itis necessary to identify the most unfavorable products for the aeration phase and to determine the most appropriate location for placing product samples.
Defining Worst-Case Scenarios and Aeration Duration
A comparative study selecting several products identified as worst-case scenarios can be conducted to determine the product most resistant to residue dissipation. During this phase, factors such as configuration, exchange surface, packaging, and materials help define the product most challenging for residue dissipation. It is important to consider the materials used as they absorb/adsorb EO at varying rates. For example, PVC tends to absorb EO quickly but also desorb it rapidly.
Special attention should also be given to incoming and outgoing products in the aeration chamber during the aeration phase. A load/pallet exiting sterilization placed near a load/pallet at the end of desorption can contaminate the latter. EO concentrations in the aeration zone can delay degassing, particularly when low allowable limits are required for certain subpopulations (e.g., pediatric, neonatal). The aeration chamber’s occupancy rate and incoming/outgoing flows (in the case of non-dedicated aeration chambers) are additional parameters to consider.
The time required for all measurements to comply with predefined limits will determine the validated aeration duration used routinely to release products. This duration can vary significantly, from a few hours to several days, depending on the loads, the aeration chamber’s capacity, and the sterilization cycle used. Naturally, longer aeration increases routine treatment costs.
Future Directions
EO remains an essential method for sterilizing medical devices, especially for heat- or moisture-sensitive products. However, its use requires rigorous process control and strict compliance with applicable standards.
The ISO 10993-7 standard is undergoing revision, with proposed key changes including:
- Manufacturer to define allowable limits and extraction conditions, based on the patient population and the duration of use; aligning with the method with the new ISO 10993-17 standard.
- Allow for the use of a risk assessment to establish allowable limits;
- Provide additional guidance on product release;
- Provide additional guidance on determining residuals and the factors that affect residual.
Although the Points of Departure (PODs) for determining allowable limits are not being re-evaluated in this draft standard, it is expected that the limits will become more restrictive. Manufacturers may need to conduct new studies to validate revised aeration durations. For instance, the simple adjustment of the adult patient weight from 70 kg to 60 kg will lower allowable limits for manufacturers who previously considered a 70 kg weight.
Conclusion
EO remains indispensable for sterilizing medical devices, particularly those sensitive to heat or moisture. However, the health and environmental risks associated with its use necessitate rigorous process management and strict compliance with standards like the ISO 10993-7, currently under revision. These regulatory developments aim to enhance patient safety and reduce EO residues while requiring manufacturers to validate more precise aeration durations and adopt risk-based approaches.
In response to growing concerns, international initiatives, such as those by the EPA and the European Union, seek to limit EO emissions and explore safer alternatives. The future of this sterilization method depends on better process control, adaptation to stricter requirements, and effective management of environmental emissions. These efforts will preserve sterilization efficacy while protecting public health and the environment, balancing medical and ecological imperatives.
Need help?
Contact our Bio-Tox team for support with the following:
- Drafting sterilization validation protocols/reports for EO.
- Instructions/procedures/expert reports
- Training sessions on ethylene oxide sterilization, radiation sterilization (according to ISO 11137) and moist heat sterilization (according to ISO 11135)
Contact us at: onedt@efor-group.com
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