In 2014, EPA announced a change to the longstanding calculations of how Ethylene Oxide (EtO) monitoring was presented for public safety, reducing what the agency considered to be a safe level for human exposure. Since EPA’s 2018 release of data from the 2014 National Air Toxics Assessment, a spotlight has been focused on EtO sterilization.
Industry professionals, toxicologists and scientists are concerned that the new calculation is misleading the public on the realistic dangers of EtO sterilization processes.
“When this issue first came to light in the beginning of 2019, all the media attention was on, ‘How do we eliminate EtO from medical device sterilization?’” said Gary Socola, President of HIGHPOWER Validation Testing & Lab Services. “It wasn’t, ‘Let’s get the facts and see if that’s really necessary.’”
Results from EPA’s National Air Toxics Assessment estimated that there is a health concern for cancer in 30 out of every 1 million people in the U.S. associated with breathing toxic chemicals. This estimate is based on someone living in the exact same location for 70 years and breathing contaminated air 24 hours a day. That means all toxic chemicals, not just EtO, which is a naturally occurring substance as well as a chemical emitted from everyday items such as SUVs, lawnmowers, charcoal fire grills and even sauerkraut.
“When these EtO emissions are being studied outside of one of these processing plants, there’s no technology to discern what’s coming out of the EtO exhaust stack, and what’s coming out from the diesel buses sitting down on the corner that’s letting people off for work,” Socola said.
For perspective, the American Chemistry Council released a report showing that the typical concentration of naturally occurring EtO in the human body of a nonsmoker is 19,000 times greater than the new level EPA deemed to be an unsafe level of continued human exposure. According to an article written by Gail Charnley, Ph.D., a toxicologist and principal at HealthRisk Strategies LLC, the number that EPA now considers to be a safe level of EtO for humans to be near is over five million times more stringent than any scientific judgment underlying all other regulatory limits on EtO in the U.S. and worldwide.
Socola acknowledges the importance of the government trying to keep public safety at the forefront and leaning to the conservative side of estimating safety standards. However, he questions whether there are limits to how far they can go before impeding properly functioning systems and potentially putting more people at risk.
Since EPA’s release of that 2014 data, multiple EtO facilities serving medical device companies have closed; the public who live near sterilization facilities have grown increasingly concerned that they may be breathing toxic air, and FDA, showing concern for medical device shortages, has held advisory committee meetings and pushed industry for new sterilization technologies.
As the orthopedic industry examines alternative sterilization methods, there are numerous questions to answer. In our regular series asking suppliers and service providers for their perspectives, we examine the sterilization issue through their lens.
Challenges with Replacing EtO
As the conversation surrounding the new calculations for safe EtO levels intensifies, discussions about shifting to different—or even new—sterilization technologies have taken shape. The question of whether there will be regulations that further limit the use of EtO is still up in the air (so to speak), but several sterilization companies are moving forward with innovative techniques all the same.
“The biggest two alternatives that are being discussed are hydrogen peroxide and nitrogen dioxide, H2O2 and NO2,” Socola said. “But the thing about it is, those two types of sterilization processes don’t have the infrastructure for processing the large volumes that are required to replace EtO.”
The capacity is not available for orthopedic device companies to simply move to a new sterilization process. Even if it was, adoption of a new sterilization technology takes time. There are validation, regulatory and infrastructure considerations, to just name a few.
EtO has been used for decades, and because of that, there are international standards for industrial processing of medical devices, including standards on the packaging systems to use in EtO and the biological indicators (BI) and chemical indicators that are used to monitor EtO processes, Socola said. Standards haven’t been created for medical device use of NO2 and H2O2.
The Association for the Advancement of Medical Instrumentation (AAMI) and the International Organization for Standardization (ISO) have designated committees working on standards for alternative sterilization processes, but the development of those standards takes years.
“We’ve been working on a biological indicator standard for hydrogen peroxide sterilization for about a decade now, and we still haven’t been able to come up with reproducible results that allow us to have a standard that can be followed by anyone anywhere in the world. Not like we can with steam and EtO,” Socola said.
Historically, nitrogen oxide and hydrogen peroxide are used for sterilization of specialty items, like bovine ligaments and tendons that can’t be sterilized using EtO or steam. But it’s a niche market.
“They’ve just never been scaled up,” Socola said. “The marketplace is a smaller volume right now. So that’s why the infrastructure to build these big machines and these big chambers with these new technologies and the standards on how to do that and how to monitor that are decades away from being in place.”
Sterilization Technologies on the Horizon
The series of EtO events have pushed government and industry to consider alternative sterilization methods and improve upon those already in use.
In December 2019, FDA announced participants in two innovation challenges. The first challenge focuses on identifying safe and effective sterilization methods or technologies that do not rely on EtO. FDA selected the following companies and technologies to examine further:
- NovaSterilis (Supercritical Carbon Dioxide)
- Noxilizer (NO2)
- STERIS (Accelerated-Based Radiation, Vaporized Hydrogen Peroxide)
- TSO3 (Vaporized Hydrogen Peroxide-Ozone).
The second challenge is intended to develop strategies or technologies to reduce emissions to as close to zero as possible from the EtO sterilization process. Companies chosen include:
- Anderson Scientific
- Becton Dickinson and Company
- DMB Apparatebau
- Sterigenics U.S.
- Taiwan Advanced Sterilization Technologies
We reached out to companies in the first challenge to find out more about their technologies and how they could benefit the orthopedic industry. NovaSterilis and Noxilizer responded.
NovaSterilis: Supercritical Carbon Dioxide Sterilization
Tony Eisenhut, CEO and Co-Founder of NovaSterilis, talked us through the company’s sterilization technique. The process is based on the use of supercritical CO2 along with a sterilant, an additive they refer to as NovaKill. Through this process, they have achieved FDA sterility level assurance 6 across a broad spectrum of products. NovaKill is a terminal sterilization process that can be applied when products are in their final packaging.
Development of the process and how it works: “We picked it up from the university lab setting and ultimately had to make a significant number of changes. Originally their goal was not to have any additive, just do it with supercritical CO2 alone, but to achieve FDA levels of sterility, it’s not possible to do it with supercritical CO2 alone. We iterated and modified significantly the use of supercritical carbon dioxide and tested a number of additives and ultimately came up with the formulation that we use today," Eisenhut said. “It’s a peracetic acid-based additive, which is a chemical commonly used in the healthcare and medical device industry. But the unique thing about our process is that we are able to use several orders of magnitude less peracetic acid in their formulation, and because of the synergistic effect between carbon dioxide and the peracetic acid, there are high levels of microbial inactivation, and ultimately full sterilization.”
How it’s applied: “Supercritical CO2 isn’t a gas phase, but similar in that it utilizes a chamber that can be of varying sizes. Our smallest chambers are in the order of 600 milliliters and are sold into the research R&D market. We sell 100-liter vessels into the medical device manufacturing market," Eisenhut said. “When we originally decided to look at supercritical CO2, we considered it because there is an industrial infrastructure that was already established. For example, decaffeinated coffee is often processed through supercritical CO2. Millions of pounds of coffee per year are decaffeinated this way.
“In our mind, there was an industrial use that said operationally, equipment and knowhow existed that we could leverage. Number two, humans have been exposed to supercritical CO2-processed products on an ongoing and regular basis, and it’s safe. Those variables gave us a comfort level that, if we could develop a sterilization process, would be scalable and it would be safe.”
How CO2 is used in orthopedics: “Our first units were sold in late 2008, early 2009 to a handful of customers. From 2009 through today, there are a number of tissue banks, the majority outside of the U.S., that have utilized our sterilization modality on bone, bone crunch, tendons, soft tissue tendons, ligament, dermis, amnion, BTBs (bone tendon bones) and orthopedic sports applications. There’s probably north of 200,000 surgeries that have been done using supercritical carbon dioxide processed tissue," Eisenhut said.
What sets CO2 apart from other sterilization technologies: “The unique value proposition of our supercritical CO2 sterilization process is that it is low temperature, it is minimally reactive as far as the additive goes, and it is deep penetrating," Eisenhut said. “We can penetrate the entirety of a bone or a ligament and ensure terminal sterilization for, again, the entirety of the product being processed. In the tissue banking world, it’s used for both cleaning and for terminal sterilization, two different steps in the manufacturing process, but supercritical CO2 is a great solvent and it extracts lipids extremely well. We have a number of our customers who clean with our process first and then turn around and do sterilization at the end.
“Because of that ability to penetrate and penetrate deeply, the process can be used to incorporate bioactives into the product. Epidermal growth factor is something that will maintain its activity post-sterilization with the supercritical CO2 process, unlike EtO and gamma processes.
“There’s a whole body of work out there about how the supercritical CO2 processed material is actually enhancing and aiding in the healing process. The unique value proposition, with the deep penetrating, the low temperature, but also the minimally or nonreactive component allows for the biologics—whether they be proteins or various growth factors—for their activity level to be maintained and preserved through the terminal sterilization process. It’s a clear differentiator for us.”
Noxilizer: Nitrogen Dioxide Sterilization
Maura Kahn, Senior Vice President of Business Development and Marketing for Noxilizer, describes their nitrogen dioxide sterilization technique as a gas-based surface sterilization method capable of handling complex geometries. It is an ultra-low temperature process where several of the cycle perimeters are flexible, including things like the use of humidity.
How the NO2 process works: “Sterilization takes place in Noxilizer sterilizers. Our smallest production sterilizer is a 400-liter chamber, and our largest is 16,000 liters. The chamber is vacuumed down, the NO2 is introduced to the chamber, followed by humidity, to reach a certain level. And then, we dwell for five or 10 minutes and then evacuate the chamber again and repeat. Each cycle is designed for a customer, but let’s say a typical cycle is four pulses of NO2 at 10 milligrams per liter at a 10-minute dwell," Kahn said. “To follow ISO 14937, which is the validation guideline that we follow for NO2, that is just the half cycle. You have to demonstrate a quality assurance level of 10-6 in order to prove sterility. So, you repeat that half cycle a second time, and that’s considered the overkill method for sterilization validation, and that’s what you submit to FDA along with the rest of your regulatory submission.”
How NO2 is used in orthopedics: “It’s a gas surface sterilant that can sterilize complex geometries as long as there’s gas access with variable parameters like temperature and humidity. Today, it is used and sought after for drug device combination products, temperature and humidity sensitive medical devices and companies that want to bring sterilization back in-house," Kahn said. “The advantage is twofold as it relates to drug device combination products, which do exist in orthopedics, or medical devices that are administered in a sterile field. The contents of those drug delivery systems are often temperature sensitive. Sterilizing them with steam or ethylene oxide, or even hydrogen peroxide, may change the shelf life or even the product integrity. Our role relates to temperature. NO2 can sterilize between 10° to30℃, where you’re seeing other methods are oftentimes 40℃ and higher. In steam, obviously, much higher.
“We’re finding in the biomaterials space that new innovative devices often include materials that are moisture sensitive. Having a lower humidity sterilization process is more advantageous to maintaining the integrity of these materials.”
How NO2 fits in orthopedics: “We are doing quite a bit of work in the area of orthopedics. We focus on single-use medical devices like semi-custom and custom implants. That will broaden over time, but that seems to be the area where there’s the most interest today. Companies are very interested in exploring additional sterilization options, and they’re also very open to bringing sterilization in-house. Noxilizer sells sterilizers and installs them in a customer’s facility, but we also offer contract sterilization through our exclusive agreement with Sterigenics. The majority of orthopedic customers are looking to improve their supply chain, therefore bringing sterilization in-house," Kahn said.
Where Do We Go From Here?
Undoubtedly, sterilization will be one of the major conversations for the entire medical device industry in 2020 and likely beyond. It’s clear that as orthopedic manufacturers await future EtO actions by EPA and FDA, they’re weighing compatibility and capacity options for alternative sterilization methods, as they should.
As Kahn noted, orthopedic manufacturers may seek to bring sterilization in house. The EoT disruption and the uptick in just-in-time manufacturing may push companies to consider technologies—and the investment—that allow them to control their sterilization.
New standards and infrastructure are also expected to be high areas of focus for new sterilization technologies.
“What FDA is looking at primarily in that challenge is, how do we expand capacity?” Kahn said, noting that FDA is familiar with NO2. “We recognize that this is considered a relatively new sterilization method, and it’s important to have an open dialogue with regulators, and that’s been our approach.”
While the conversation around new technologies is progressing, industry is in a wait-and-see period with EtO.
EPA is expected to provide an update on the status of the agency’s reviews of two National Emissions Standards for Hazardous Air Pollutants (NESHAP) and FDA is expected to announce findings of its sterilization challenges and pilot program.
Heather Tunstall is an ORTHOWORLD Contributing Editor.