Moving On From EO: Experiencing The Evolution of Today’s Sterilization Methods

As the medical device and pharmaceutical industries face pressure to phase out or move away from ethylene oxide, new sterilization trends are emerging.

Joe Darrah

Nov 25, 2024

Regardless of the sterilization method, minimizing bioburden is a significant aspect of patient safety.

Getty images, yacobchuk

When a recent rally in Memphis, TN, brought together community residents advocating for better protection of the environment, several accomplishments were celebrated. Chief among them was acknowledging the closure of a local facility that since 1976 had operated as a contracted sterilizer of medical equipment and materials. But the company has joined a growing number of plants that have shut down in response to ongoing scrutiny related to the use of ethylene oxide (EO), the colorless gas that, according to the U.S. Food and Drug Administration (FDA), is responsible for the sterilization of approximately 50% of all medical devices. A proven, effective sterilization method since the 1950s known for its ability to sterilize items that can’t withstand the heat associated with steam sterilization, EO has been linked to harmful environmental and public health effects. Although the Environmental Protection Agency (EPA) still lists nearly 90 EO-active facilities nationwide (and in Puerto Rico), the prevailing sentiment is that more appropriate alternatives for sterilization are being developed for manufacturers to pivot toward as regulations become more stringent and as more facilities close for noncompliance.

“There has been much pressure focused on ethylene oxide sterilization because some processors have not done enough to ‘scrub’ the sterilant gas when vented from the sterilization vessels at the end of a sterilization cycle,” says Len Czuba, president of Czuba Enterprises Inc., a product development organization based in Lombard, IL, that specializes in plastics and medical devices. “This has led to many facilities closing, resulting in more pressure on other facilities that are fully in compliance with eliminating toxins from effluent gas emissions. But there are other options for sterilization being offered. The product will dictate the type of sterilization that is most appropriate.”

Common Sterilization Methods Today

After steam and EO, the most common sterilization is irradiation, which is traditionally performed with gamma rays or electron beams, aka beta irradiation. A radioactive particle that kills “bugs” equivalent to what EO achieves through high-energy, high-penetrating electromagnetic rays, gamma (Cobalt-60) is challenging to contain and is not abundantly available. Still, for those who can source it, gamma provides great versatility, says Paul J. Serio, president at Accumedix Inc., a medical device contract manufacturer based in Libertyville, IL, that develops and commercializes medical, dental, and surgical products. “We have had great success with gamma,” Serio said. “We do our work in the 25-40 kilogray cycle and it is far and away our preferred method of sterilization.” While the revalidation process to ensure that items that are sterilized with EO can withstand gamma is time consuming and expensive, Serio said more manufacturers are investing in the modality because the testing for suitability is not difficult. “We’ll place a sample of the product in with a sterilization batch, and it’s quickly evident to see if there are any issues, such as discoloration or crazing in a plastic,” he said. “Anybody who’s currently using EO should be looking for alternative options. You need to weigh and consider that, increasingly, EO facilities are becoming less available. Those continuing to go with EO could very well be in a position where, without much notice, there’s no longer a place to conduct sterilization.”

After drying, items are inspected and wrapped for steam sterilization in autoclaves before drying again and cooling to room temperature for storage.Getty images, rusakWith beta irradiation, a stream of high-speed electrons sterilize products with similar sterilization effectiveness although the beta-particles have less penetration energy. Product is placed in layers on conveyor belts to pass under a curtain of particle, enabling sterilization to occur in seconds as opposed to the hours required for gamma. “With beta, the time factor is a positive over gamma since there is less time for oxygen to seep into the product, resulting in less oxidation of the polymers of construction,” Czuba said. “And when power is switched off the particle accelerator, the system has no harmful radiation, as does gamma. That’s a big advantage. I believe beta is the wave of the future.”

As methods of radiation sterilization evolve, Czuba also sees x-ray as one of the more recent developments to gain significant traction. “This is where you irradiate a specific metal target that, as with beta, you turn on the energy to the accelerator source,” he said. “The source generates a high-energy beam that energizes the target, which generates x-rays that sterilize the product to which it’s exposed. This is still in final development, but companies are investing in it and x-ray looks like it will be available commercially as the industry moves away from EO, as companies conduct proper qualification tests, and as the FDA gives its approval.” Among the benefits of x-ray is that it’s somewhat stronger and provides better penetration compared to beta, and similarly only emits rays when the power is turned on to the source, making it less dangerous than gamma. “The only drawbacks as of now would be cost related and that there would be many qualifications required to transition to it because it’s in the early stages of adoption,” said Czuba.

Additional Sterilization Alternatives: An Overview

Other trending options for sterilization include nitrogen dioxide (NO₂), chlorine dioxide (CIO₂), high-concentration carbon dioxide (CO₂), and vaporized hydrogen peroxide (VHP). At Noxilizer, an organization based in Hanover, MD, that provides sterilization services and equipment to pharmaceutical, biotech, and medical device manufacturers, a proprietary NO₂ sterilization process is helping to solve sterilization challenges throughout the process.

According to Maura O. Kahn, senior vice president of commercial products, and David Opie, PhD, senior vice president of research and development, NO₂ is best suited for drug-device combination products, including biotech drugs in pre-filled syringes, biotech and other drugs in auto-injectors, custom orthopedic medical devices, and glucose sensors. The benefits of NO₂are said to include ultra-low temperature processing that can extend the shelf life of biologics, minimal degassing required, maintaining of drug integrity, shorter processing time compared to EO, and better room air quality, as all NO₂ is captured within the scrubber.

Lack of compatibility with NO₂ is seen with cellulosic materials. As such, high-volume, pre-packed surgical kits are not candidates. For those seeking a potential transition to NO₂, Kahn and Opie suggest evaluating options as early in product development as possible. Currently marketed products also have options for testing material compatibility, sterilization feasibility, and validation studies.

Although CIO₂can also be hazardous, its ability to achieve high levels of sterilization at lower temperatures and shorter exposure times compared to other traditional methods makes it another viable option. Other benefits of CIO₂are that, as compared to EO, it is non-flammable, non-explosive at use concentrations, and can be exhausted in almost all locations, says Czuba. “I think we have better ability to scrub this away today [compared to previously],” he said.

High-concentration CO₂ (or supercritical CO₂) sterilization has also gained notoriety as a safe and efficient modality with multiple applications for both synthetic and biologic devices and drugs. An inert, non-reactive molecule, it sterilizes at low temperatures, as with NO₂, and does not require outgassing.

VHP, an antimicrobial sterilization “cocktail” that works via a combination of hydrogen peroxide vapor and water vapor for devices and other items including implants, pharmaceutical containers, parenteral drug delivery systems, and other products that are sensitive to high temperatures, could be an especially attractive option for small-to-mid-size manufacturers due to available lower-cost options, says Brian McCollum, principal consultant at GSD Medical Device Consulting, Redwood City, CA. However, while McCollum sees some promise regarding alternatives, he said a lack of infrastructure for industry is concerning. “The most important thing is that the industry as a whole – the sterilizers and the regulators – need to be completely transparent with regards to the direction that things are going,” he said. “If I’m going to have billions of dollars worth of product that must now be revalidated in a few years, then I’m going to have to start that process as of yesterday. For any dramatic change that’s headed our way, we need to have visibility on where the direction is going.”

That said, not all sterilization methods are created equally or are appropriate universally, especially considering liquids, which cannot be sterilized with gas or radiation. “Gas cannot penetrate liquid to kill microorganisms, and the energy of radiation affects the chemical components of the liquid, causing them to degrade, whether it’s gamma, beta, or x-ray,” explains Czuba. “This would lead to byproducts in the solutions that are not intended. Virtually all liquids, including IV bags, blood bags, surgical lubricants, and wound rinses must be sterilized with steam through an autoclave.” The exception to using something other than steam to sterilize liquids is for those products that are aseptically made, a process in which products are made sterile before being packaged in a sterile environment – suitable for materials that do not require refrigeration.

Minimizing Bioburden Along the Pathway

Regardless of the sterilization method, minimizing bioburden is a significant aspect of patient safety, says Steve Laninga, managing director of devices, at Ascential Medical & Life Sciences, a design, development, and manufacturing solutions company based in Minnesota.

“An often-underappreciated step in the process is the upstream activity that occurs ahead of the actual sterilization,” Laninga said. “This is critical to the effectiveness and efficiency of the sterilization – the minimization of pathogens that would be a result of sterilizing a higher bioburden load. Our focus is on how to improve and maintain the most sterile environment upstream to minimize the generation of any bioburden to begin with.”

Best practices for reducing bioburden include cleanroom manufacturing, strict gowning procedures for staff members, aseptic technique, and monitoring of the environment, as well as performance of personnel. With contamination through human contact being a common cause of bioburden, identifying ways to automate cleanroom processes upstream is a trending aspect for reducing risk. “Robotic material handling reduces the need for human contact in advancing material to the next unit operation within a clean room,” Laninga said. “Automated inspection eliminates the need for human contact at inspection points.”

Laninga said cleanroom design is also critical. “That starts with the initial concept of the suite,” he said. “Making sure that you have the right material flow. The suite should be designed so that air flow is appropriate to create a sterile environment. And with the way that the materials and the people are moving throughout the cleanroom, the product should be isolated from any people or other contaminants.” Training operators on the reasoning behind certain procedures is also essential, according to Laninga. Garrett Mitchell, MSN, RN, CMSRN, CNOR, an operating room (OR) nurse based in Arizona, also assists sterilization processes upstream. “We follow Joint Commission standards for onsite sterilization, as well as protocols defined by manufacturers,” he said. Sterilization for Mitchell’s OR follows a detailed process in which items are handwashed with bactericidal chemical non-foaming soap and placed on trays in washers that run higher than 180 degrees. After drying, items are inspected and wrapped for steam sterilization in autoclaves before drying again and cooling to room temperature for storage.

Indicators are placed onto wrapped products that change colors if contamination occurs.

Moving Forward With EPA & FDA Regulations

While EPA and FDA officials acknowledge that EO remains the only method to sterilize certain devices, the EPA has finalized a rule to reduce its emissions. By installing proven and achievable air pollution controls that many facilities have implemented, commercial sterilizers will reduce emissions by more than 90%. EPA officials said the ruling considers the latest data and science. “And it cannot be overstated: The science behind sterilization is exponentially more complicated than virtually anything else that we do in the med-device industry,” said McCollum. “So the expectations are very high. To come up with something novel, that can be utilized, will mean the method will have to be as good or better than something that’s been studied for decades. That’s a big ask, even for modern technology.”