Background
After decades of very few changes in the sterilization world, sterilization is now a hot topic. This includes the medical packaging industry. With uncertainty over the impact of strict EPA regulations imposed on ethylene oxide emissions from commercial sterilizers, as well as issues with gamma sterilization, companies are looking at alternative methods. While the prospect of alternative methods may be exciting, from my perspective, it’s also important to be realistic. There are significant hurdles to overcome—there is not one perfect solution that can be a drop-in place replacement.
Today, 50% of the industrial market is sterilized by ethylene oxide (EO) and 40% of the market is sterilized with gamma radiation. To put it into perspective, that means 90% of the products currently in the healthcare market are sterilized with either of these two methods. This equates to billions of devices annually just in the U.S. alone. There are now significant concerns with both, which is quite a scary situation.
Concerns around Gamma: ~ 40% of the Market
Gamma sterilization uses the radioactive isotope, cobalt-60, which is produced by bombarding naturally occurring cobalt-59 with neutrons in a nuclear reactor until it becomes radioactive. It is then used by contract irradiators to sterilize medical devices or by hospitals for cancer treatments with the gamma rays that are emitted. The security of these facilities and of the material has come under more scrutiny as they are often less secured facilities than a nuclear reactor, for example. In 2013, a truck carrying radioactive cobalt-60 was stolen from a gas station in Mexico. This prompted fears of terrorists obtaining this radioactive material and potentially constructing a “dirty bomb”. There are also environmental concerns regarding the disposal of radioactive waste. Many governments have called for a switch to an accelerator-based irradiation process like e-beam or x-ray that do not utilize radioactive material. Another potential concern around gamma sterilization is the supply of cobalt. Cobalt is used in the production of batteries for electric vehicles, and a large percentage of cobalt comes from the politically unstable country of Congo so the ability to adequately supply the market and avoid device shortages is a concern. The future demand is expected to outpace the supply.
E-beam has been used for years but only around 5% of all industrial sterilized devices utilize this method. The reason is that e-beam does not penetrate as well as gamma. Electrons have mass and this limits their ability to penetrate the product. Gamma and X-ray use photons which do not have mass and thus penetrate much better in denser products and sterilization loads. X-ray is not new to industry but was not used to the same degree because it is a relatively inefficient process. You convert electrons to X-rays using an “X-ray target”. This is a very dense metal like tantalum or tungsten that quickly decelerates the electrons. As the electrons decelerate, X-rays are generated but the conversion is quite low. With the concerns around gamma, the need for an accelerator- based method that can penetrate as well as gamma was needed and as a result X-ray facilities are quickly being built in locations all over the world, with it quickly becoming a more mainstream option for sterilization. In most cases, it can be a simple conversion from gamma to X-ray as they have very similar material compatibility, you can use the existing radiation standards, and the validation process is the same. It can also handle large volumes like gamma and e-beam. We may see a migration from gamma to X-ray sterilization but it is unlikely that you will see a significant portion of currently EO sterilized product move to X-ray due to the material compatibility issues.
Concerns around EO: ~50% of the Market
Ethylene oxide is a tremendously effective sterilization method and is used to sterilize billions of devices in the U.S. every year. It has been used to sterilize medical products since the 1940’s. However, this is the method that is facing the most scrutiny. In 2016 the EPA reclassified EO as a human carcinogen using their Integrated Risk Information System (IRIS) tool. This program identifies and characterizes health hazards of chemicals. There is significant controversy in the industry regarding the science behind the model that made this determination, yet the agency did not budge. Once this classification was made, it became harder to convince the public that it can be dealt with safely. While the technology is there to safely work with ethylene oxide, political and public pressure persist. There are fears of device shortages if even one of these facilities were to shut down due to the lack of capacity at other facilities. This would be a major supply chain crisis for the healthcare industry. Companies know and recognize this—many are starting to hedge their bets and move some, or all, of their sterilization needs offshore to other countries such as Mexico, Costa Rica, and the Dominican Republic among others.
Finding alternatives to EO is not a simple task. There are three major challenges when looking for an effective substitute to EO: scalability, material compatibility, and the ability of the sterilant to penetrate the hardest to sterilize locations on the device. When it comes to scalability, many people don’t realize the sheer volume of product that is sterilized with EO. In the United States alone, 20 billion devices are processed with EO every year. The alternative modalities such as vaporized hydrogen peroxide (VH2O2), chlorine dioxide, nitrogen dioxide, etc. do not currently have the numbers or chambers as large as EO. Many large industrial EO chambers can fit 20-30 pallets of product per sterilization load. Some of the companies of these alternative modalities are talking of scaling up to larger sterilizers that can accommodate multiple pallets, but significant quantities and sizes of chambers do not exist now. It will take years to get the needed infrastructure and enough facilities up and running to handle this volume. The second challenge, material compatibility, is significant. While irradiation facilities can handle large volumes of product, a significant percentage of EO sterilized products are not compatible with radiation. Radiation can cause crosslinking or chain scission in many polymers which can adversely affect the functionality of the device. Lastly, the ability for the sterilant to penetrate the hard to sterilize locations of the device to achieve the desired sterility assurance level (SAL) is the third challenge. These locations include long narrow lumens, mated surfaces, closures, and stopcocks. The packaging itself can present an additional challenge to sterilization as well. The sterilant must penetrate through multiple packaging layers. This could include corrugate shippers (and in some cases shrink wrap is still used), shelf cartons, and potentially multiple sterile barrier systems (SBS). As a gas, EO is unmatched in its ability to get through the packaging and into the device locations that other gaseous sterilants can’t. If you look at EO objectively, yes, it has its disadvantages around toxicity, but it has many advantages as well including its ability to penetrate, material compatibility, long regulatory history, and availability.
Regulatory
When it comes to regulations and standards around sterilization methods, not all modalities have their own dedicated validation and regulatory standards. The FDA categorizes sterilants into Established Category A (methods with a long history of safe use where approved consensus standards exist) these are methods such as EO, radiation, moist heat, dry heat, and as of January of 2024, VH2O2 was added to this category. This was due, in part, to FDA recently recognizing ISO 22441 as a consensus standard. Established category B methods would be methods where there are no FDA-recognized consensus standards, but plenty of available published information on the development, validation, and routine control of the method. Examples of Established Category B would be ozone and flexible bag systems utilizing EO. The third category would be the Novel Sterilization Methods category. These methods would receive the most regulatory scrutiny and most of the alternative modalities would fall into this category. Now that a standard exists for VH2O2, the framework is in place to potentially use this as a template for development of specific standards on chlorine dioxide, nitrogen dioxide and other methods as more data and history of use becomes available. In the absence of a specific standard, these novel methods must validate their processes using ISO 14937, a broad general standard outlining requirements on characterizing a sterilization agent, and developing, validating and the routine control of a sterilization process. Generally, whenever there is a standard associated with a sterilization method, it makes an easier path to obtain FDA clearance. These newer methods will likely face additional regulatory scrutiny and create more questions from regulators that will have to be addressed in regulatory submissions. The reason is just they are new, and regulators don’t know what they don’t know. They tend to err on the side of caution.
An Opportunity for the Industry to Work Together
I recently attended an Industry Scientific Exchange in Munich, Germany in March 2024 put on by J&J, Medtronic, and TÜV SÜD. The exchange included stakeholders from medical device companies, packaging companies, sterilization providers, contract laboratories, regulatory agencies - including the U.S. FDA and the notified body TÜV SÜD. The goal of the Scientific Exchange was to accelerate the adoption of these alternative methods, some which have been around for decades, but have never been widely adopted. The challenge was to collaborate as an industry to generate data and find pathways to make adoption of these alternative methods easier. The conference highlighted two case studies where different stakeholders came together to collaborate to solve an issue. One of these case studies was the DuPont MPTP project where a materials science company made a manufacturing change, impacting a critical material used in a highly regulated industry. DuPont found a way to validate Tyvek® made on updated assets without causing their end user customers to have to individually validate all their products. They involved the entire value chain, sought early buy-in from FDA and notified bodies, and included participation from sterile packaging manufacturers and medical device manufacturers. The second case study was on the NASA and Jet Propulsion Laboratory (JPL) project to bring samples back from Mars. They collaborated with medical device sterilization experts and other stakeholders to find ways to ensure the sample return canisters could be adequately sterilized and safely returned to earth. Their planetary protection officer stated they felt a profound responsibility to define a safe return to earth of a Mars sample potentially carrying a life form or complex molecule that is capable with interacting with biological processes on earth. These two case studies were examples that we could draw from to collaborate on producing data to accelerate adoption of these alternative sterilization methods. Future follow up sessions are planned.
Where Does This Leave the Medical Packaging Industry?
These newer methods work for a lot of products but not for all products. Therefore, industry needs to stay focused on working together to better understand these alternative methods, as well as generate safety and material compatibility data to accelerate adoption.
Packaging may need to change. We may have to present the products differently to the sterilization process than we do today. In addition to the challenges with penetration through the packaging and product, there is an additional concern. Many of the gaseous methods are either incompatible with cellulose or do not recommend it as it absorbs the sterilant. This would mean no corrugate shipper boxes, paper labels, paper packaging, or IFUs. We may have to perform packaging postponement and sterilize product in primary packaging only and then add the labels, IFUs, and box up the product into shelf cartons and corrugate shippers after sterilization. This is easier if you can sterilize in house but very challenging if you have to ship hundreds of miles away to a contract sterilizer and still protect the product and SBS from damage. This logistical challenge will have to be solved if the methods are able to scale up to handle the enormous volumes currently performed with ethylene oxide and gamma.
In summary, we just don’t have the same data and experience with these newer methods and until we can find an answer to some of the concerns identified, both EO and gamma are going to have to be around for quite some time, and we must continue to find ways to work with them even more safely.
