The U.S. Environmental Protection Agency (EPA) finalized new regulations for ethylene oxide (EtO) in March of this year, tightening emissions controls on this commonly used sterilant for medical devices. The final rule aims to reduce emissions of the carcinogenic gas EtO from commercial sterilization facilities by more than 90%.

In response to the new regulations, industrial sterilization service providers have begun upgrading emissions control equipment and are simultaneously evaluating other chemical sterilants. The medical device industry group AdvaMed has previously warned that new restrictions on EtO emissions could reduce medical device sterilization capacity, potentially leading to supply shortages. Meanwhile, proponents of other sterilization technologies say their solutions can meet some of the industry's sterilization needs.

"In our view, the reality is that many products today can already be sterilized through other methods," said Tony Eisenhut, CEO of Novasterilis, a company that manufactures sterilization equipment based on supercritical carbon dioxide.

Experts point out that no single technology can fully replace EtO at present, but a combination of multiple alternatives will help reduce overall emission levels.

Current State of Medical Device Sterilization

After manufacturing is complete, medical devices must undergo sterilization processes to ensure they are safe for use and do not pose infection risks to patients. The U.S. Food and Drug Administration's (FDA) Center for Devices and Radiological Health (CDRH) evaluates sterilization methods for devices before they are marketed.

According to Aftin Ross, Deputy Director of the Office of Readiness and Response within CDRH's Office of Strategic Partnerships and Technological Innovation, the most common sterilization method is EtO, used for about half of medical devices; followed by gamma radiation, covering approximately 40% to 45% of devices. Both methods can handle large volumes of products, but each faces significant challenges.

EtO is a flammable gas suitable for materials that cannot withstand radiation, high temperatures, or steam sterilization. According to EPA data, inhaling EtO is carcinogenic to humans. Therefore, facilities using EtO must be equipped with emissions treatment equipment, and products must undergo an off-gassing process to ensure no residual EtO remains.

"This is one of the main challenges we currently face—there is not yet a method that can achieve the same coverage and scale as EtO."

Aftin Ross
Deputy Director, Office of Readiness and Response, Office of Strategic Partnerships and Technological Innovation, CDRH

According to the regulatory impact analysis accompanying the EPA's final rule, EtO is commonly used for polymer resin products, single-use medical devices, surgical kits, surgical trays, synthetic surgical gowns, and sealed combination drug-device products such as syringes and stents.

Gamma radiation sterilization relies on cobalt-60, a byproduct of nuclear reactors. After cobalt absorbs radiation in nuclear power plants, it is encapsulated in stainless steel "pencil" containers and transported in reinforced containers. At sterilization facilities, the radioactive material is stored in shielded bunkers, and the radiation generated is used to sterilize devices such as medical gloves, surgical gowns, syringes, and surgical staplers. Because radioactive materials are involved, the process requires careful planning: the global supply of cobalt-60 is limited, and facilities must meet strict security requirements.

"When this technology emerged in the 1950s, nuclear energy was on the rise," said Andrew Patton, CEO of Nextbeam, an electron beam sterilization company. "But the number of nuclear power plants producing radioactive cobalt-60—the key raw material for gamma facilities—has not continued to grow as expected in the 1950s and 1960s."

Nordion, a subsidiary of Sotera Health, provides cobalt-60 and gamma radiation systems for medical devices and cancer treatment. Sotera CEO Michael Petras told investors in February that the company is working with Ontario Power Generation to develop cobalt-60 supply sources to support long-term growth. According to Nordion, about half of the world's cobalt-60 is produced in Ontario, Canada.

Three people stand around a suspended metal cylinder. In 1953, workers prepare to transport radioactive cobalt-60 from Oak Ridge National Laboratory to Los Angeles for cancer patient treatment.

FDA Seeks Alternatives

The FDA has been tracking sterilization facility closures since 2019. That year, several facilities using EtO closed due to lawsuits or state government orders. In the same year, the agency launched two innovation challenges aimed at identifying new sterilization methods and technologies, and reducing EtO emissions.

"Our biggest takeaway is that there is no one-size-fits-all solution," Ross said. "We will continue to take a multi-pronged approach to reduce EtO emissions."

Alternatives explored by challenge participants include vaporized hydrogen peroxide, nitrogen dioxide, and supercritical carbon dioxide. Ross said the FDA has noticed that device manufacturers are beginning to collaborate with sterilization service providers to validate new or different sterilization methods and assess the feasibility of scaling these methods.

"This is one of the challenges we currently face," she said. "There is not yet a method that has the coverage and scale of EtO."

When adopting new sterilization methods, manufacturers need to consider compatibility with device design. For example, EtO is widely used because it is suitable for a variety of materials and designs with complex geometries, and is also commonly used for surgical kits containing multiple material components.

Packaging is also critical. With EtO, for example, devices must be sealed in breathable packaging. Vaporized hydrogen peroxide is incompatible with cellulose-based materials such as cardboard, meaning companies may not be able to sterilize in final packaging, Ross added.

Manufacturing processes also need to be considered. With EtO, devices are typically transported to separate facilities for sterilization; some other methods, however, allow sterilization to be completed within the production line.

Ross said the FDA is considering multiple pathways "because even if we can shift a small number of products to a particular method—maybe one product fits here, another fits there—cumulatively, it can have a greater impact."

A syringe and separate needle placed in plastic packaging. Medical devices such as syringes must be sterilized before use in hospitals.

Vaporized Hydrogen Peroxide

One alternative being considered by medical device companies is vaporized hydrogen peroxide (VHP). This technology has long been used for cleaning and disinfecting reusable devices in hospitals. The FDA recently classified vaporized hydrogen peroxide as a Category A sterilization method, making it easier for device companies to use it as a sterilant in manufacturing environments.

Steris and a subsidiary of Stryker are two companies that participated in the innovation challenge to study this technology.

The method works by diffusing hydrogen peroxide vapor in a vacuum chamber. After sterilization is complete, the vapor breaks down into oxygen and water, making it non-hazardous, explained Maryam Tabrizian, a professor of biomedical engineering at McGill University.

According to Steris, this method is suitable for temperature-sensitive devices, pre-filled syringes, implants, and devices containing electronic components. However, the method is incompatible with cellulose-based materials and other highly hygroscopic materials, which is a major challenge.

Nitrogen Dioxide

Another sterilization gas involved in the challenge is nitrogen dioxide, a technology specialized by Noxilizer. David Opie, Senior Vice President of R&D at Noxilizer, explained that nitrogen dioxide gas is pumped into a sterilization chamber under humidity and air, and pressurized. A chemical reaction generates nitric oxide, which kills microorganisms by degrading their DNA.

Opie said one of the earliest commercial applications of nitrogen dioxide was in combination drug-device products such as pre-filled syringes and auto-injectors. Noxilizer's sterilization process operates at low temperatures, making it suitable for such products; additionally, its minimum working pressure is higher than some alternatives, meaning it is less likely to push syringe plunger components when removing gas from the vacuum chamber. Opie also believes customized 3D-printed orthopedic devices are a good application scenario because their off-gassing time is shorter than with EtO.

"Looking for a solution that can directly replace ethylene oxide sterilization is like looking for a unicorn. The future is likely to be a combination of alternative technologies."

David Opie
Senior Vice President of R&D, Noxilizer

Despite these advantages, Opie still does not believe nitrogen dioxide will replace EtO. "My view is that medical device manufacturers may adopt alternative sterilization methods—chlorine dioxide, hydrogen peroxide, and nitrogen dioxide—for new products in the future," he said. "But from an economic standpoint, it seems difficult to shift existing products currently sterilized with ethylene oxide."

The biggest concern with switching to new methods is capacity. Currently, Noxilizer has five sterilization chambers, each capable of handling one pallet at a time; however, the company can also manufacture chambers for two to three pallets or larger. "We are ramping up production now, but capacity growth takes years," Opie said. "One of the challenges of alternative sterilization is whether capacity can come online fast enough to make a substantial impact."

Supercritical Carbon Dioxide

Novasterilis, which provides supercritical carbon dioxide sterilization technology, also participated in the FDA's innovation challenge. Eisenhut said the company was founded in 2000, with technology originating from MIT.

The technology pressurizes carbon dioxide into a supercritical fluid, allowing it to penetrate porous materials, while adding a peracetic acid-based solution as a sterilant. Eisenhut said that at the end of the sterilization cycle, residues are minimal or undetectable, and products can be used directly.

A metal cart with screens and metal cylinders. Novasterilis's Nova2210 equipment uses supercritical carbon dioxide to sterilize medical devices for manufacturers and contract sterilizers.

Products made from multiple materials, such as pre-packaged surgical kits, are a "signature" application for the company. However, because Novasterilis's system is pressure-based, its single-batch capacity is not as large as EtO. "When it comes to high-volume scenarios of hundreds of thousands of units per day, our method is not suitable," Eisenhut said.

Novasterilis sells systems to manufacturers for in-house sterilization. Eisenhut said participating in the FDA's innovation challenge was "transformative" for the company, helping it become more involved in regulated medical product areas. The first medical device using Novasterilis's process was a hernia repair product approved in 2014; since 2020, five products have been cleared using supercritical carbon dioxide sterilization.

Eisenhut does not believe EtO will completely disappear, but he said that as medical devices become increasingly sophisticated, the demand for alternatives will continue to rise. "Adoption cycles are slow," he said. "This is largely because the industry tends to be risk-averse, and any change means introducing a certain level of risk."

Other Radiation Technologies

Medical device companies are also exploring other radiation sterilization methods, such as electron beam (e-beam) and X-rays.

Nextbeam's Patton said electron beam radiation has existed since the 1950s and currently accounts for only 5% of the sterilization market. He founded the company in 2020 and invested $20 million to build a sterilization facility in North Sioux City, South Dakota.

The technology uses linear particle accelerators, where devices pass through a "high-speed electron curtain" and radiation penetrates the product. Patton added that over the past decade, electron beam technology has become more reliable and processing capacity has increased.

"For a long time, EtO and gamma were so cheap that it was hard to compete," he said. "When EtO is cheap and there is no perception of environmental risk, and gamma is cheap and there is no perception of supply shortages, there really is no reason to compete."

Patton said that as prices for other sterilization methods rise and availability declines, people are beginning to invest more in electron beam. Some products currently sterilized with EtO can switch to electron beam, but challenges remain. For example, radiation degrades polytetrafluoroethylene (Teflon), a material often used in device components that need smooth sliding.

Packaging is also an issue—because electron beam uses large particles, its penetration depth is not as great as other methods. Patton used a steak-cooking analogy: if the steak is too thick, the center may not be fully cooked. X-rays can sterilize an entire pallet of devices at once, while electron beam can only penetrate to a depth of about one or two boxes.

More commercial sterilizers are also looking at X-ray technology. Steris CEO Dan Carestio told investors in February that the company plans to add two X-ray processing sites this year in Chicago and Ontario, California. Patton said there is strong industry interest in X-ray sterilization, but the technology is less efficient, requires more electricity and larger facilities than electron beam, and is less mature. Nevertheless, Patton said he hopes to open an X-ray facility in the future.

The Future of Sterilization

Some companies are using FDA-launched programs to switch to other sterilization methods. CDRH's Ross said the FDA has noticed that some innovation challenge participants are also joining the agency's master file pilot programs, which are designed to streamline the process of switching sterilization methods. Currently, three master file programs related to sterilization are open to participants.

Steris's Carestio told investors in November last year that the company is participating in a master file pilot program that allows its customers to switch between different sterilization modalities, "whether it's from EtO to X-ray, gamma to X-ray, or e-beam to gamma," without needing to resubmit a 510(k) application. "I think this lowers a significant regulatory barrier, enabling customers to build greater resilience and switch flexibly between different technologies," he said.

Looking ahead, proponents of EtO alternatives see a promising future, albeit slow-moving. "Looking for a solution that can directly replace ethylene oxide sterilization is like looking for a unicorn," said Noxilizer's Opie. "The future is likely to be a combination of multiple alternative technologies."