Felipe Aguirre, Elda Peralta, and several of their neighbors thought they knew about all the environmental toxins endangering their city. They had, after all, spent decades lobbying against the polluters that contaminated their air, soil, and groundwater.

Thus, the group was quite surprised to learn of a new ecological hazard just a few months ago—i.e., two medical sterilization facilities bordering the Maywood, Calif., city line.

“We’re disillusioned,” Peralta told Capital & Main.

Disillusioned and deeply disturbed, actually. Peralta and her fellow environmental stewards disclosed to the online publication a pattern of illnesses amongst loved ones, including severe respiratory conditions, allergies, heart problems, and rashes. Each of them knows of neighbors battling cancer.

The latter ailment is one of the hallmarks of ethylene oxide (EtO), a colorless, odorless, combustible gas used to sterilize approximately half of all medical devices in the United States (more than 20 billion products annually). Employed as a disinfectant since the 1950s, EtO was classified as a human carcinogen by the U.S. Environmental Protection Agency (EPA) in 2006 and has been linked to brain damage, lymphoma, leukemia, stomach cancer, and breast cancer. Chronic exposure to EtO also can lead to spontaneous abortions, hematologic changes, genetic damage, and nerve damage.

EtO’s health hazards have ignited a national controversy in recent years, with grassroots community groups and lawmakers battling sterilization firms over the gas’s harmful impacts. The medtech industry, however, contends the EPA’s ethylene oxide risk value is flawed, and warns that widespread sterilization plant shutdowns will lead to future medical supply shortages.

“Ethylene oxide is suddenly getting attention because an office within the EPA changed the way it calculated the amount it considers safe to breathe,” toxicologist Gail Charnley told the press in 2019. “No new science was used, just new math.”

Nevertheless, the EPA is using that “new math” to better regulate EtO. In January, the agency required 29 medical sterilization facilities to report their emissions to a national Toxic Release Inventory. “This determination will require companies that use the largest amounts of EtO in this industry sector to report to the TRI about their releases of this chemical and shed some light on potential exposures from this use.,” Michal Freedhoff, Assistant Administrator for EPA’s Office of Chemical Safety and Pollution Control, said in releasing the new requirement. “This will help inform EPA’s future actions and empower communities to act at the local level.”

One of those future “actions” is likely new commercial sterilization rules under the Clean Air Act. Under development for several years now, the rules could be proposed in Q4 2022 (at the earliest).

In the meantime, the EPA, device manufacturers, government agencies, and sterilization experts are working to find alternative disinfectant methods. Two U.S. Food and Drug Administration Innovation Challenges have yielded 13 potential substitutes, including supercritical carbon dioxide sterilization (NovaSterilis), nitrogen dioxide sterilization (Noxilizer), accelerator-based radiation (STERIS), and vaporized hydrogen peroxide-ozone sterilization (Stryker Corp.). Additionally, some companies have developed their own alternatives: PAMA Manufacturing and Sterilization, for example, uses an ecofriendly, safe “green” method that uses 50 percent less ethylene oxide than standard industry practices and “virtually eliminates” the gas’s presence in the air, according to the Canadian firm’s website. Batch load release time is less than one day (compared to seven for most sterilization companies); PAMA uses a scrubber system to capture all EtO emissions and recycles the gas into ethylene glycol, which the company hopes to commercialize for use in windshield washer fluid and airplane de-icer.

   “…there is a solution for ethylene oxide sterilization and that solution is EtO sterilization,” a company blog states.

Maybe so, but PAMA’s resolution is likely to be just one of many alternatives resulting from the EPA’s crackdown on ethylene oxide emissions. To better gauge the potential impacts of evolving EtO emissions standards and the keys to successful packaging/sterilization processes, Medical Product Outsourcing spoke to nearly a dozen experts over the last several weeks. They included:

Seán Egan, director of global marketing and VoC Development at Nelipak Healthcare Packaging, a Cranston, R.I.-headquartered designer, developer, and manufacturer of rigid and flexible packaging for the medical device and pharmaceutical industries, with 10 facilities worldwide.

Alan Evans, manager, Medical Package Testing; John Nino, CEO; Souk Phimphasone, sterilization validation engineer; and Michael Waldon, manager, Sterilization Validation Services at Life Science Outsourcing Inc., a Brea, Calif.-based contract manufacturer and value-added service provider to medical device and life science companies.

Melissa Green, head of global marketing at TekniPlex Healthcare, a globally integrated provider of innovative solutions through material science and manufacturing technologies.

Leonard Harris, manager, Chemistry & Container Testing; Sunny J. Modi, Ph.D., director, Package Testing; and Elizabeth Sydnor, director, Microbiology at Eurofins Medical Device Testing, a global provider of regulatory compliance expertise and GMP/GLP ISO 17025 testing services.

Matt Jordan, CEO, and Marie O’Malley, vice president of Commercial Operations, at Centerpiece, a Solana Beach, Calif.-based contract manufacturer that develops, assembles, sterilizes, and distributes medical devices.

Nicole Palluck, senior manager, Expert Advisory Services at Sterigenics, a business of Sotera Health. Sterigenics provides outsourced terminal sterilization and irradiation services for the medical device, pharmaceutical, food safety, and advanced applications markets.

Forest Rose, operations manager at Flambeau Inc., a Nordic Group company. The thermoplastics manufacturer is headquartered in Baraboo, Wis.

Benjamin White, director, Technical Services Engineering; and Tom Williams, general manager at Millstone Medical Outsourcing, a Fall River, Mass.-based provider of customized outsourcing solutions to the medical device industry.

Michael Barbella: What trends are currently impacting the packaging/sterilization sector? What factors are driving these trends?

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Seán Egan: Europe’s Medical Device Regulations (MDR) have brought additional products into the fold that require a barrier-type package that must be protective of the device, reducing the risk of contamination. Where the device is to be sterilized, the package must ensure the device remains sterile under the storage and transport conditions specified by the manufacturer until the packaging is opened at the point of use. Packaging shall ensure the integrity of the packaging is clearly evident to the final user.

Additionally, the focus on sustainability continues to increase, with more and more customers looking into sustainable packaging options and more recyclable packaging components. When considering sustainable packaging options, it’s important to make sure you’re making a choice that’s compatible with the recommended sterilization process to prevent time-consuming delays that may create a backlog. Greater sustainability and waste reduction can be best achieved by optimizing packaging design—which can reduce material usage, as well as improve packaging functionality and allow for better product protection during sterilization, shipping, transport, and storage.

Alan Evans: The packaging sector is all about performing its gap analysis for the changes made to the EU MDR. Device manufacturers have been, or are in preparation of, these re-validation activities. “Smaller is better” is another trend. A smaller footprint in regards to the amount of packaging material needed to keep devices sterile but also protects devices going through the distribution cycle. ESG [environmental, social, and governance] factors are driving this trend.

John Nino: OEMs are feverishly looking for alternative validated packaging configurations in order to mitigate pandemic-related PETG material shortages. We are helping customers to navigate this challenge by providing pre-validated pouches to replace packaging trays as a part of their material risk mitigation strategy.

Souk Phimphasone: An ongoing trend would involve the validation of backup sites due to the above factors pertaining to logistics. Also, universal cycles, which are validated for multiple product families and different product types. This would be in response to reduced EtO sustainable cycles.

Michael Waldon: Sterilization trends are material shortages, workforce challenges, sterilization capacity, volumes at large-scale sterilizers, industry initiatives (reduced EtO concentrations and alternative sterilization modalities to EtO). Factors driving the trends: regulatory pathways, supply chain optimizations, war/international conflicts, innovation over the decades with regards to combination products, and material compatibility.

Melissa Green: There are a variety of trends that medical device manufacturers need to keep pace with. COVID has created a shift toward in-home care, and many packages previously handled by a medical professional are now being opened by patients themselves. This means that considerations for human factor design are far more prevalent than in the past. Packaging must be adapted for different scenarios of in-home or other atypical clinical settings.

Also, with this shift toward in-home care, sustainability is becoming more critical. Patients handling waste are looking for specific instructions for recyclability, reusability, and/or disposal, and are voicing their frustrations to suppliers concerning a lack of options. Sustainability is no longer a nice value-add; it’s becoming a must-do.

Sterilization technologies are being criticized as well, as there are known issues with EtO releases and gamma exposure.  The pressure is mounting for alternate, safer technologies.

Requests for functional packaging also are rising. This comprises packaging that enables proper use of the device, serves a dual purpose, or helps to position the device more precisely.

Sunny J. Modi: There are multiple trends in the packaging sector ranging from extending/longer shelf-life of medical devices, recent changes to governmental and regulatory guidelines, or the use of sustainable packaging material to reduce the carbon footprint. Specifically, medical device packaging is following the global trend in packaging for more environmentally friendly material that can be recyclable to help reduce waste and potentially improve cost efficiency. One example is the use of certified circular polyethylene (PE) materials, which allows for plastic waste to be converted into new product that meets the quality and performance of products made with virgin raw material.

Elizabeth Sydnor: Some manufacturers are considering alternative sterilization modalities if they are using EtO or gamma to terminally sterilize their product. Due to the environmental concerns of EtO and the potential shortage of cobalt 60, some manufacturers are exploring the impact of revalidating with a comparable method.

Matt Jordan and Marie O’Malley: The medical device and pharmaceutical markets continue to expand and so does the need for innovative packaging solutions and sterilization processing services. First, medical device companies are requiring suppliers to offer more “value-added” services as they look to streamline supply chains and reduce the number of suppliers. These additional services—now required to compliment standard packaging processes—include device assembly, cleaning, inspection, and/or testing. Pertaining to trends within the sterilization sector, capacity constraints continue to threaten supply lines across North America. Lead times are getting longer, which leads to increased safety-stock inventory levels.

Centerpiece is positioned to support customers with contract manufacturing, packaging, and in-house EtO sterilization processing.  The company has plans to increase its sterilization capacity by 3x later this year, while its contract manufacturing business continues to develop and add new capabilities to offer customers.

Nicole Palluck: Due to sterilization capacity constraints across the medical industry, there is a desire to make the most efficient use of the various sterilization modalities as possible. Whether it is using lower gas concentrations or expanding dose ranges to encompass the actual minimum sterilization dose possible for a product, both manufacturers and sterilization providers are working together to address the capacity concerns.

In addition, work on alternative sterilization modalities such as X-ray, nitrogen dioxide, or vaporized hydrogen peroxide will allow for some applicable products to be processed in ways that have not been traditionally used in the past.

Forest Rose: Tyved has 10 week lead-times, and the lead time for a quarterly dose audit is longer than three months.

Benjamin White: Certainly, supply chain pressure is the headline story, but it’s not the only one. For the past five years, many OEMs have been preparing for EU MDR enforcement, and now we’re seeing the majority go live with multiple aspects of its implementation. This adds complexity, and one example is how different OEMs are approaching serialization of components. Some are assigning a serial number at inception, which we then must track all the way to finished goods. Others are applying serialization strictly to labeled finished goods, not the upfront manufacturing, so outsourcing partners must focus on this new aspect.

Tom Williams: No one will be surprised by the high-level answer here: supply chain pressure is still the biggest trend affecting most industries and functions, including packaging and sterilization. I think of the state of supply chains right now as “hand to mouth” on everything. Customers are trying to ramp up post-COVID, and material availability continues to be a major challenge—it’s hard to get ahead of materials. OEMs and their partners must be tighter with forecasting and planning than ever before to stay on top of supply chains.

Barbella: At what point in the product development process should packaging/sterilization services be considered?

Egan: OEMs and packaging vendors should be working together as early in the design process as possible to achieve the best outcomes. The efficacy of packaging for medical devices and pharmaceuticals is shaped long before the manufacturing process—just like medical device innovation, medical packaging is innovating. Starting the conversation early on with the packaging supplier can help ensure the right package for the right application. Understanding the product to be packed, how it will be packed, choice of sterilization process, and importantly, the end-user experience, will result in sustainable packaging performance lowering total cost of ownership and impact to the environment. Early understanding of the sterilization process to be used ensures both material selection and packaging design leverages what packaging can offer to complement the device and patient safety.

Evans: Sterilization and packaging go hand in hand, so these two activities should be considered very early in the development of the device itself. The device engineer will have the knowledge of how their device’s materials will act and react to different types of sterilization. If the engineer has a question how their device will perform after sterilization, feasibility studies might need to be obtained. Once that is determined, the packaging engineer will have the knowledge of choosing the correct packaging materials that are compatible with the chosen type of sterilization.

Nino: Packaging configuration and sterilization services should be considered as early as possible. Ideally, this effort takes place soon after functional prototyping is completed and prior to pilot production runs. Prioritizing packaging and sterilization in this manner facilitates commercialization and helps to accelerate time to market.

Phimphasone: On the backend, there should be a consideration of backup sites due to unexpected delays or facility shutdowns/maintenance.

Waldon: End to end (E2E) considerations. Bioburden consideration (cleanliness and contamination control), supply chain (business continuity, avoid single source sterilization contractors, and consider 2X capability for reprocessing), material compatibility to the sterilant and packaging, etc. Primarily you need to look at all the benefits and risk factors.

Green: Medical device manufacturers are, of course, focused on device design, and do not generally consider packaging or sterilization until the very end of the process. Given that the device typically determines the sterilization method, and the sterilization method dictates the packaging, package design must start as soon as the sterilization method is known.

Importantly, not all packaging is compatible with every sterilization method, so consideration must be taken to ensure the materials will withstand the demands of the sterilization cycle. Factors that must be considered are thermal stability, porosity, microbial and environmental barrier requirements, shelf-life, and seal strength.

Leonard Harris: The packaging/sterilization services should be considered at the very beginning of the development process. This needs to be done in order to avoid unnecessary delays and costs later in the project. Sterilization of the product is a critical step and there are many factors that need to be considered in determining the path of sterilization, such as whether the product is compatible with specific sterilization processes, what packaging is compatible with the sterilization process, and what will be necessary following sterilization to release the product.

Modi: Traditionally packaging design and development takes place at the last few stages of a medical device development process. However, designing the packaging system and selecting the appropriate materials during the early development process of the device will alleviate the stress during market launch. By getting the packaging design process started early will not only create a more effective product, but reduce any timeline risks or eliminate cost surprise of the packaging material.

Sydnor: Once the manufacturer has identified their product will need sterilization, they should immediately establish a relationship with the sterilizer/test laboratory. There are a number of feasibility tests that can be done in the beginning phases of development.

Jordan and O’Malley: Packaging is often an afterthought in the product development process. Consideration for packaging materials must be part of the initial design stage. This allows for a thorough analysis of available sterilization methods and provides ample time to “stress test” the product and packaging material combination. In many cases, adverse effects such as product and package degassing may be overlooked until it’s too late. The result can be very inefficient in terms of lead time and cost.

Palluck: The sterilization method should be considered when product and packaging designs are being developed. The material used for the product and how the product is configured impacts what sterilization methods can be used. If the sterilization method is chosen early in product development, before the design is finalized, changes to product design can be made to better allow the sterilant to interact with the product. By taking potential implications into consideration during the product and packaging design phase product designers and manufacturers may avoid costly and time-consuming changes down the road when the validation starts.

Rose: Because the automation of packaging is so important to labor and cost reduction, this must be considered early on the NPI process.

White: For years, I’ve been emphasizing that the most successful product development considers product and package design holistically and anticipates sterilization requirements early in the process. But it hasn’t always been this way. Happily, we’re seeing this holistic approach happening more frequently now. It’s essential, because this end-to-end approach boosts the likelihood of success, from meeting launch timelines and targets to reaping first-mover advantage and even driving higher ROI. And so, in the interest of continued progress, I’ll say it again: manufacturers should begin thinking about product packaging and sterilization at the beginning of the product design process to set everything downstream up for success.

Barbella: How can medical device packaging be adapted to support the market as the medtech industry searches for new and better sterilization methodologies?

Egan: EtO remains the main method of sterilization in the market, recent developments have seen providers work to improve the efficiency of the process with a focus on safety. Shorter cycle times place new demands on the packaging, which both OEMs and packaging suppliers need to understand to ensure packaging meet these demands to prevent failure of the package integrity. Additionally, new sterilization methodologies are growing in popularity, which medical packaging suppliers need to understand and be prepared for. You need to balance the desire for increased recyclability and sustainability with the best material choice to undergo the necessary processes.  Be aware of the type of sterilization that will be used and how the package needs to perform during the process to be fit for purpose.

Evans: Packaging materials and packaging methods can be integral to new sterilization methods that are emerging. Feasibility studies should show packaging materials will perform during X-ray, Noxilizer, or hydrogen peroxide modalities. Will foam inserts in certain packaging applications break down after these newer sterilization services? Will the heat seals on trays and pouches still hold up after the shelf-life of the device? These new sterilization methods should not have to wait for the packaging industry to determine if they have a system or material that is compatible.

Green: The adaptation of the packaging will depend on the sterilization methodologies developed. Once the specifications are understood, the packaging suppliers will play catch up to meet the needs of the industry. For innovations in both sterilization methodology and packaging to occur efficiently, effectively, and in unison, partnerships must form between sterilization companies and packaging suppliers. With this approach, an answer to a key industry problem will be found in a far more timely manner.

White: Embracing change is really the name of the game. It’s natural to be resistant to change, especially in an industry as heavily regulated as medical device manufacturing. When considering change, you’re not sure at the outset how it will be viewed by a regulatory body. But communication and collaboration from both sides on the end goal—a successful product launch with a relentless focus on patient safety—can help packaging and sterilization innovate and meet the complexities and challenges of the present and future.

Barbella: How is sustainability impacting sterilization methods and packaging?

Egan: As customers look to reduce package size and material waste, they still need to ensure the package is compatible with the method of sterilization (for example, with EtO sterilization). If the packaging is not designed to meet that process, it can result in damage to the packaging, such as popped seals and possible damage to the package itself. For example, Tyvek is breathable and often used in EtO. But if you do the process too fast, the gas can’t get in or out fast enough, causing the pressure to increase and the package can be physically damaged.

Nino: These changes are having more of an impact on EtO cycles by reducing gas concentration, but it is also driving OEMs to consider alternative methods to EtO.

Waldon: If we look at sustainability in economic, societal, and environmental terms without compromising future generations to meet these needs, there needs to be a continuation in industry initiatives (in the form of global trade associations and conference consultations and communities) that will help drive change.

Green: The honest assessment is that, to date, sustainability has had little to no impact on overall decision-making when it comes to medical device packaging and sterilization. The medical device industry has been talking about sustainability, but patient safety continues to win out. The industry rarely deviates into using alternative materials when sustainability is the only advantage. Cost, limited resources, and a dearth of experience typically force MDMs to default to standard materials.  While always enticing, sustainability and using materials with recycled content is rarely considered due to not knowing where the recycled content comes from, and the inherent risk that comes along with that.

However, there are promising signs that the tides are beginning to turn. New regulations and plastic taxes are looming in some geographies, and medical device packaging is not exempt. This non-exemption should prompt action quite quickly and, from there, we’ll start seeing materials typically found in consumer applications be utilized for some lower-risk medical packaging applications.

Modi: Many medical device companies and suppliers of packaging systems are looking at sustainability of packaging material more closely. These companies see value in incorporating sustainability initiatives to help reduce waste and improve cost efficiency.

White: We’re commonly hearing two types of questions from customers. The first type concerns waste associated with packaging materials when used by the end-user. The second, particular to sterilization, is about the environmental impact—and much of this is driven by EtO.