Justice seldom forges a swift path.

It can take years for civil lawsuits and criminal cases to make their way to a jury, and even longer for wrongful convictions to be dismissed. A Boston man, for example, spent more than 47 years in prison before Massachusetts’ highest court vacated his sentence, while a Michigan father of two waited 45 years for his innocence to be revealed.

Environmental justice can be equally as sluggish. In 1992, the U.S. Environmental Protection Agency (EPA) officially defined “environmental justice” and established an office devoted to the cause. Two years later, President Bill Clinton issued an executive order imploring all government agencies to consider environmental justice in their decisions.

Despite such actions, however, environmental justice remains more of a pipe dream than an achievable goal. Some of the worst cases of ecological abuse and neglect continues to impact communities throughout America, with corroded pipes leaking lead into drinking water sources, and natural gas burn-offs at fracking sites spewing pollutants like polycyclic aromatic hydrocarbons, carbon monoxide, nitrogen oxide, and black carbon into the air.

Ethylene oxide (EtO) has joined that poisonous potpourri in recent years via medical device sterilization facilities. The colorless, odorless gas is used to sanitize roughly half of all medical products sold in the United States requiring sterilization—more than 20 billion devices annually, according to the U.S. Food and Drug Administration.

Deemed a human carcinogen in 2016, EtO has been the subject of numerous lawsuits by residents living or working near medtech sterilization plants. Studies have shown that breathing air containing elevated EtO levels over many years increases lymphoid cancer risk in males and breast cancer risk in females.

As part of its pursuit of environmental justice, the EPA is planning to broaden its oversight of EtO-emitting sources. Last fall, the agency alerted 31 facilities nationwide of new reporting requirements under Toxic Release Inventory rules. New regulations for EtO emissions are now expected in Q4 2022 (at the earliest)—three years after the EPA’s initial notice of proposed new regulations.

Before the new regulations are released, though, the EPA’s inspector general requested the agency conduct a new residual risk and technology review (RTR) for commercial and industrial sites that use or produce ethylene oxide. “Information generated by the EPA indicates elevated cancer risks from chloroprene and ethylene oxide emissions,” states a report released last May. “The Agency has not incorporated new risk values for these pollutants into residual risk reviews for most source categories. Therefore, the EPA cannot assure that current emission standards are protective of human health. Without new RTRs or emission standards, the EPA may not be able to achieve environmental justice to protect the health of overburdened minority and low-income communities.”

Environmental justice and proposed new ethylene oxide emission standards are just a few of the major challenges currently facing medical device packaging and sterilization providers. To gauge the other hurdles and opportunities these companies face—as well as their future prospects—Orthopedic Design & Technology solicited input from a half-dozen experts over the last few weeks. Those interviewed included:

• Jennifer Gygi, B.S., expert technical consultant at Nelson Labs LLC, a Sotera Health company. The firm is a global provider of laboratory testing and expert advisory services, performing more than 800 microbiological and analytical lab tests across the medical device, pharmaceutical, and tissue industries. 
• Robert Hegedus, senior quality assurance manager at contract manufacturer Cadence Inc.
• John Nino, CEO of Life Science Outsourcing Inc., a Brea, Calif.-based contract manufacturer and value-added service provider to medical device and life science companies.
• Elizabeth Sydnor, director of microbiology at Eurofins Medical Device Testing, a global provider of regulatory compliance expertise and GMP/GLP ISO 17025 testing services.
• Don Tumminelli, senior technical manager, Client Services, at HIGHPOWER Validation Testing & Lab Services, a Rochester, N.Y.-based validation and testing laboratory that focuses primarily on reusable medical devices requiring cleaning, packaging, and sterilization.
• Tom Williams, general manager at Millstone Medical Outsourcing, a provider of customized outsourcing solutions to the medical device industry.

Michael Barbella: What critical sterilization parameters impact packaging material selection and packaging design?

Jennifer Gygi: First, materials need to be compatible with the sterilization modality, meaning they will not severely degrade or lose strength after exposure to the sterilant. Next, the material needs sufficient breathability (for gas-based sterilization) to allow penetration of the sterilant and to equilibrate during sharp changes in pressure that occur within sterilization chambers. Many cycles include pulses, where a substantial vacuum is drawn and then released, which can stress packaging seals if the material is not sufficiently breathable. Finally, the materials should be sufficiently durable to maintain the sterile barrier for the expected shelf life regardless of the sterilization modality used.

Robert Hegedus: It is critical when evaluating packaging materials that the risks from sterilization methods are assessed. Different types of sterilization methods impact materials and products in different ways.

For example, Gamma sterilization is a method of sterilization that utilizes high-energy gamma rays to emit radiation to kill microorganisms. It is crucial that manufacturers of devices understand the impacts of gamma rays on their material selection. This method is compatible with most plastics and other packaging materials, but under some circumstances can impact the stability of materials, making them brittle and more susceptible to exposure.

EtO is another highly used sterilization method in the medical device industry that exposes products to EtO gases. As a result, packaging materials must be breathable to allow for exposure to these gases.

John Nino: Packaging material must be compatible with exposure time, temperature (steam is 121 degrees Celsius vs. EtO, 55 degrees Celsius), and relative humidity.

Volume will impact design. Packaging designs differ from small lot cycle vs. a multi-pallet system. Early development products will benefit from using an existing validated product pouch/tray and expedite time to market versus custom designed/higher-volume configurations.

Don Tumminelli: All sterilization packaging systems must undergo multiple testing to demonstrate the material to withstand the sterilization parameters maintains sterility post processing and also allows for the sterilant to penetrate and achieve the required sterility assurance level (SAL). When it comes to critical parameters, each modality has its limitations so each modality should be validated separately. To put this in perspective, the more aggressive or stringent the parameters, the more vulnerable the packaging material is to breakdown and therefore, will not be able to pass these tests. For instance, hydrogen peroxide is becoming more popular in hospitals. These systems vary in parameters and concentration or peroxide, so the higher the concentration, the more aggressive the cycle can be, while a higher concentration may increase the probability of SAL, it can also decrease the ability of the material from maintaining sterility post processing of the material degrade.

Tom Williams: Selection of sterilization method starts with the product’s materials and properties. For instance, gamma cannot be used on products with electronic components, so these must be sterilized with hydrogen peroxide or EtO. Moreover, it’s not just how materials are affected at the time of sterilization, but also how they behave post-sterilization: plastics or polymers can become brittle and degrade over time if sterilized with gamma, or cross-linking can occur. For package design, a key consideration is whether the sterile barrier is porous or non-porous, and/or if there is an oxygen content requirement.

Barbella: How can supply chain-related packaging material shortages best be managed? What options are available to packaging/sterilization providers?

Gygi: As the pandemic drags on and supply shortages increase, many companies are moving from a just-in-time approach to holding a larger inventory of critical supplies, like packaging. If you need to make a packaging change, either to a different vendor for the same supply or to a different packaging component, these changes need to be carefully considered. Any packaging change must be analyzed against the packaging validation, and while some changes can be more easily justified using a paper rationale, most changes will require additional validation testing to properly assess the impact of the change. As testing requires time and money, these should also be considered when looking for alternate packaging options.

Hegedus: COVID-related supply chain challenges are having an impact on packaging materials used in medical products. Cadence Inc. is not immune to these issues and has been working with OEMs to assess equivalent materials that can be used to reduce dependency and materials with extended lead times. These changes are not easy and require extensive testing and qualification to ensure adequacy of the materials.

Nino: Utilization of pre-validated packages and trays can help manage reduced lead times and ensure continuity of supplies and maintain time to market. Utilization of common lids for multiple tray configurations may also alleviate supply chain issues and use costs. Maintain stock levels.

Tumminelli: This is happening as we speak with sterilization wrap. The best way to manage is not to have a single source of packing but rather validate and/or qualify a secondary source so you are not caught off guard if/when this happens. As mentioned, there are many options to packaging including, pouches, wrap, containers, and Tyvek lidded trays.

Williams: Material shortages have been a persistent supply chain challenge for 2020 and 2021. We all remember the early-pandemic toilet paper shortages, and how they made people behave. Shortages can compel people—and firms and suppliers—to hoard in an effect to stay ahead. This hoarding can compound the difficulties of sourcing.

Because of this, a continued focus on supplier management is essential. At present, this entails having a risk-based supplier management program to establish redundant suppliers and managing the supply chain in a more strategic and less tactical way. This is about getting more granular in forecasting, lead times, coordination, and integrating much more communication up and down the supply chain. This granularity must extend to more foresight and redundancy, too, for things that are scarcer—think about pouches, for example, which have been in short supply.

Barbella: What kinds of alternative sterilization methods are companies embracing to reduce their dependency on EtO, given the technology’s much-publicized health/environmental risk factors?

Hegedus: Since 2019, the FDA and regulators have been evaluating alternative sterilization services to reduce dependence on EtO sterilization, which has been the primary method used in the medical device industry. Based on some quick research, a few alternative methods include NovaSterillis – Supercritical Carbon Dioxide Sterilization; Vaporized Hydrogen peroxide (Steris); and X-ray.

Nino: Life Science Outsourcing has not seen a decrease in EtO use. If there are concerns, consider the use of E-beam. Life Science Outsourcing systems utilize small, single-use canisters that pose the same environmental concerns that large-scale, high-volume plum systems pose.

Elizabeth Sydnor: Depending on product and packaging material, gamma irradiation, eBeam, and VHP can be considered as an alternative sterilization method. However, a validation of this alternative method would need to completed.

Tumminelli: As we know, the EtO concerns are still active; however, the topic has slowed a bit in light of medical device shortages due to COVID-19, and it seems that many of the devices still require EtO and the risk to processing is not greater than the risk of COVID-19. There are companies working on alternative methods as we speak such as chlorine dioxide, hydrogen peroxide, and paramedic acid along with newer Gamma technology. I would suspect that within the next decade we will have alternatives in place for EtO for single-use devices. I believe EtO will continue to be used in healthcare for reusable devices for quite some time to come.

Williams: The introduction of X-ray sterilization to the U.S. market is a game-changer for orthopedics for several reasons. It’s a more stable method. And it doesn’t have the capacity constraints of gamma sterilization. It’s also not encumbered by the health and environmental risk factors of EtO. There’s another advantage, too—X-ray sterilization can be used on larger components and even pallets, which means devices and products can be sterilized more efficiently.

Barbella: How have packaging and sterilization providers learned to better manage supply chain risk in the wake of COVID-19?

Gygi: Given the challenges with packaging changes from a validation perspective, the best short-term approach may be to increase the inventory of packaging materials to buffer the impact of a delayed supplies.

However, stockpiling materials can increase the severity of shortages for the industry as a whole. A long-term solution would be to validate additional options now to increase flexibility for the future. This applies to both packaging and sterilization. We have seen companies qualifying different sterilization sites as well as different sterilization modalities in some cases to allow for more options when a specific site gets backlogged (or closed). For packaging, having multiple sterile barrier or shipping configurations validated would provide more flexibility, should a particular item become difficult to stock.

Hegedus: Manufacturers have been evaluating alternative methods as outlined previously. In addition to packaging materials, sterilization methods are also a risk. As a result, alternative sterilization methods are being evaluated to ensure minimal impacts. Some alternative methods that have been implemented in recent years are nitrogen oxide and X-ray sterilization. Cadence has also looked to diversify by identifying and qualifying additional sterilization providers and testing labs in order to reduce dependency upon one third-party sterilizer.

Nino: Look into alternatives. Be open-minded to configurations (outer geometry). Be flexible with configurations. Utilization of pre-validated packages and trays can help manage reduced lead times and ensure continuity of supplies and maintain time to market.

Tumminelli: As much as they can regarding resources. Of course, the biggest concern at this time is the raw material as supply chain interruptions are still very well alive.

Williams: Supply chain has really been the number one story of the last two years. And the pressure has come not only from supply chains built for efficiency and not resilience, but also from material shortages resulting from new needs like PPE and shipping delays around the world. These challenges demand that OEMs move away from tactical management and embrace a strategic approach to supply chain management that focuses on integration, emphasizes resilience over efficiency, and injects more communication touchpoints into the supply chain. These can help you understand the challenges your Tier 2 and 3 vendors are facing much earlier, enabling you to be proactive in addressing them before they derail lead times and coordination.

The urgency to make this shift is real. Over the last two years, we’ve worked with an increasing number of OEMs in our Tier 1 services. In this approach to expert sourcing, we coordinate with the OEM’s chosen contract manufacturer to receive products, perform quality critical inspection, and provide best-in-class cleaning, packaging, and sterilization. This kind of expert and comprehensive approach can help OEMs weather the next storms in supply chain management.

Barbella: What challenges, if any, do 3D-printed orthopedic devices introduce into the sterilization and packaging process?

Hegedus: Cadence Inc. does not currently sterilize any 3D-printed devices, but some of the perceived challenges when selecting an adequate sterilization method are understanding the impacts to not only the packaging but to the device itself. For instance, the radiation from gamma sterilization may impact the plastics making them brittle. Under this circumstance, a manufacturer may be more inclined to utilize alternative methods such as EtO.

Nino: Life Science Outsourcing has not seen any challenges related to this type of medical device. Clients are beginning to use 3D-printed parts as dunnage for package testing rather than using actual parts, which are expensive. The ability to 3D print complex medical devices may lead to the use of EtO rather than steam. 3D allows for the use of complex geometry with internal crevices, which steam may not be able to penetrate. EtO may be better suited.

3D parts may lend themselves to EtO due to temperature tolerances. Rough surface finishes with 3D-printed parts vs. machined parts may require extra attention to validation protocol.

Tumminelli: From my perspective I do not see why a 3D-printed device would be treated any differently than other methods of manufacturing when it comes to sterilization and packaging. I would think all the current validation methods would also apply. Maybe the bigger challenge is integrating the 3D printing into a manufacturing line, especially if manufacturing is occurring in an aseptically classified facility.

Williams: Material is a critical factor. Many 3D-printed devices have surfaces intended to promote tissue growth. This adds complexity to how we sterilize and safely package the device. To illustrate this from a geometry standpoint, these tissue-promotion surfaces have a rougher surface, so we must address the question of whether gamma can penetrate, or a gas is needed. If we’re sending it through gamma or e-beam, we also need to consider the potential for polymer cross-linking, which can happen during these sterilization methods.

Barbella: How can packaging material changes affect the packaging and/or sterilization process? What is required from a validation standpoint?

Gygi: Changes to the packaging (sterile barrier packaging or protective packaging) may make a device harder or easier to sterilize, which is why both the sterilization validation and packaging validation should be reviewed as part of a packaging change. The validation requirements will vary, depending on the estimated impact of the change and could be as simple as a paper justification or as complicated as repeating the entire validation. In most cases, some testing is required to show equivalence from the original to the proposed change or to confirm the estimated impact of the packaging change.

Hegedus: Packaging changes can be very impactful if all risks are not fully assessed to ensure the new material is adequate in preventing contamination or even damage. Packaging materials must be assessed and validated to the following, but not limited to:

• Transit Testing
• Stability Testing
• Peal Strength
• Burst Testing
• Sealing equipment validation

Nino: Packaging: When making a material change, a risk analysis would be helpful in determining if a re-validation is needed. (i.e., size of pouch/tray). If a material change is significant, then re-validation is needed—i.e., pouch to tray, Tyvek to Poly.

Sterilization: A material change may not automatically trigger a re-validation, instead, a risk analysis should be performed. Per ISO standards, packaging changes can be justified by a written adoption.

Tumminelli: Any time there is a change in packaging, an assessment must be made looking at various aspects such as regulatory and validation. The assessment should look at the changes and determine if the change affects any specifications, claims, etc. If the changes are justified and do not significantly affect the regulatory claims and/or performance of the device, then it may be possible to move forward with a letter to file. Anything else would require revalidation activities and possibly refiling.

Williams: Even minor changes like a different adhesive can have major impacts in sterile integrity and seal strength. The material we use is a key point for validation to align with ISO requirements, and changes can require revalidation. Because of ongoing supply chain problems, OEMs have considered substitutions that could be available with much shorter lead times. What they don’t always realize is that shortening a lead time might seem to be a solution, but it introduces three months or more of validation work.