If we know that commonly used sterile barrier systems are inherently stable after years of aging studies, why is the burden of stability testing still so great? Wicked Stability, an ongoing project under the “Let’s Speed Things Up” focus area for volunteer-based Kilmer Innovations in Packaging (KiiP) is taking aim at the topic.
Editor’s Note: If you’re not familiar with KiiP, check out our primer here.
Approximately two years ago, KiiP group members from Medtronic, J&J, and Boston Scientific discussed common challenges over coffee and looked for opportunities to focus their time and energy. One sticking point: regulators’ expectations for repetitive stability testing activities on the same materials of construction (MOCs) over and over, particularly in the face of changes in sealing equipment, minor changes to sterilization processes, or laminate layer material changes for equivalent polymers.
The team noted they were never failing aging studies when conducted, and as Jordan Montgomery, distinguished packaging engineer at Medtronic, explains, they wondered why it’s beneficial to spend so much time, resources, effort, money, etc. repeating these studies as a simple compliance activity, when the materials themselves have a proven track record of stability in actual use conditions.
“We all have these redundant stability test activities, and we could focus our resources on more significant challenges that are actually going to provide value to patients and users of the products,” says Montgomery.
They asked themselves what they could do to offer the industry better access to known material stability information and began bringing in materials experts to think about mechanisms of degradation, and the major factors that drive aging from a material perspective. It’s now blossomed into a white paper effort, as part of Wicked Stability, says Rod Patch, sr. director, package engineering & product labeling at Johnson & Johnson. Over time, the paper evolved through a few different titles into its current focus about modeling the material aging mechanism for the purpose of stability testing of common sterile barrier packaging systems.
In the big picture, Patch explains, “this is about how to think about the predictive nature of these common sterile barrier systems and the ability to model and predict how effective they would be from an aging perspective following exposure to expected hazards.”
Oxidative induction time
When PAXXUS’ Henk Blom arrived, the big challenge was how they would demonstrate the materials’ stability. “They're not going anywhere in the five-year shelf life. I had the idea of using the technique called OIT, short for oxidative induction time,” he says.
OIT is a relative measure of the resistance of a stabilized material—in this case, packaging material—to oxidative decomposition, which can be measured by using analytical techniques such as differential scanning calorimeter (DSC) or thermal gravimetric analysis (TGA). Stabilizers are intentional additives that provide resistance to mechanisms of degradation present in the environment. These include ultraviolet light (UV), heat, humidity, etc.
“The basic theory is that the materials we use are purposely stabilized by the resin manufacturer. So, whoever's making a particular resin, say polyethylene for instance, puts additives into the resin that help stabilize the material after conversion. OIT is a way of measuring how much of that stabilizer is still there or how much of it is left after it's been sitting for a while. So that's what we've been exploring with the Wicked Stability team,” Blom says.
At a high level the team wants to demonstrate the correlation between OIT measurement and functional mechanical stability over time for well-established materials.
This work may lead to a new minimum floor of stability for a given material, enabling a company and regulatory bodies to have consensus that a film material is good for at least two or three years under a given set of assumptions.
Montgomery says, “We haven't had the ability or the know-how to take credit for a lot of that stability that's pre-engineered into these types of plastics by polymer suppliers. The other elephant in the room is a lot of these materials are so stable that they won't go away. If you look for literature on how to get them to go away, you're reading about landfill technologies and how to force degradation onto materials… these systems just aren't degrading, and I think there's common knowledge to that, but we really haven't had an avenue to take credit for a lot of that inherent material science built into the stability of the materials.”
Often in life sciences, companies will shy away from making technological or efficiency changes because it would require rigorous testing post-change. This method may one day preclude the need for stability testing of small changes such as adding new heat-sealing equipment. As Blom explains, “Some of the regulatory agencies say you have to start the aging process all over again for this new heat sealer. One of the things we hope to be able to demonstrate with this project that is that, from a scientific perspective, we can measure the OIT at the heat seal and somewhere toward the middle of the pouch where it wasn't heat sealed, and there is no difference between the OIT in those places.”
Based on the data, they hope to approach regulators to explain that redoing stability tests for every change on the heat seal may not be necessary in favor of demonstrating a few key points of data. This would allow companies to make material process upgrades more easily, provided the data supports claims.
Conserving time and money
The packaging community tends not to talk in absolutes, but the potential savings in time and money are substantial. As Jennifer Benolken, MDM & regulatory specialist, packaging engineering at DuPont, explains, the rule of thumb is about a month – six weeks of accelerated aging testing per year of shelf life (but it really depends on how you’ve set the conditions around accelerated aging); you also have to factor in sample procurement and preparation. It can also take several months to synthesize data and generate a report post-testing. “It's not just the oven time for acceleration. People like to think it's five months for five years’ shelf life, but you have a few months ahead of that and a few months afterwards,” she says. “When you put that all together, it can get you close to a year. That's really tight when you're working with new product development, and you can't even get the representative samples until close to the end of the design of the project. The last thing that the company wants to do is wait for that oven time to finish.”
While much focus is placed on what it takes to get to market launch with accelerated testing, MDMs also have to back up claims with real-time studies. “We should not forget that whatever we put on the label for a claim of stability, it's a combination of the device and its stability, as well as the stability of the packaging system. Whichever one of those is the least resistant to aging is the maximum you can label your product at,” Patch notes. “Whenever we put a duration out there—some products are three years, a lot of products are five, orthopedics you can find 10 years—there is an ongoing, active, real-time study. That's taking resources, costing money to support that real-time claim. If I have 10 years on the label, I probably have product waiting 11 years in some type of stability program.”
Holding product for numerous years for real-time study requires physical space and personnel to manage it. Benolken notes that with company turnover, mergers, and limited guidelines on how to manage these product/packaging systems, companies must be vigilant about sample management which expends resources.
Attend any life sciences conference with regulatory speakers, and they’ll tell you that they want to work with companies to modernize the industry. Beginning with the end in mind, the team talked early on with some subject matter experts about whether the concept and approach had merit before getting too far in testing and feasibility assessments. The pursuit has been well-supported by packaging, chemical, and OIT experts. Says Patch. “Once OIT was identified as a proven method for measuring thermodynamic material degradation factor—and that being the degradation factor of greatest concern—we started exploring with some SMEs, including regulatory agencies, their thoughts and their feedback on that approach and that has kept us guided.”
They’ve received early feedback from FDA, as well as notified body representation the EU market. From early talks, regulators have been receptive of the approach to answering the stability question. Montgomery notes, “They understood our perspective as material manufacturers and device manufacturers on just how redundant this space is becoming, and it only looks like it's getting worse. We had good dialogue with them on what we've been proposing, and I think there was some optimism from them in terms of potential data we'd be able to offer. There are remaining hurdles in terms of how we translate an OIT result into something tangible that a packaging engineer or a regulator can take away with a meaningful interpretation as to the stability of the packaging system. So, there's a lot of work to do there, but I think they were aligned that the time is right and It's appropriate to be looking at more advanced and better ways of doing the work.”
COVID-19 has also brought, as a byproduct, potential for openness. Chris Sarantos says, “Perhaps people are more receptive from a regulatory perspective to consider these things because of all the EUAs. One of the cool things about this method is that OIT is not a new technique. It’s an established science with a lot of history being applied in a new way to enhance packaging science. The environment is more receptive from a regulatory perspective to consider breaking the norm and moving faster.”
The team is taking a “usual suspects” approach, studying a few common MOCs first that are widely used across the device packaging community, both rigid and flexible. While there are any number of combinations of materials—multi-layer or coated structures—for performance, the goal is to focus resources and keep things as foundational as possible to start. Blom adds, “What we're trying to do here is outline an approach and demonstrate its appropriateness and then really encourage others to apply it to other MOCs.”
Currently, the team is designing the protocol, fine tuning the test method and parameters—including conditions such as temperature—for what is most repeatable and reproducible across sites for the two different methods of measuring OIT. Different materials will need slightly different conditions in order to achieve the most accurate result.
The timing is right, with the industry having recently undergone the intensive functional equivalence assessment (which includes material stability testing) known as the Medical Packaging Transition Protocol (MPTP) that DuPont led for the transition to the new Tyvek®.
“The amount of data points that went into that study, the number of samples, different structures, sealing processes, sterilization, and modalities… all of that, and at the end of the day, how many of those failed stability? Zero, not one. And what was their common denominator? They all had Tyvek® ,” says Patch. “So that was a founding genesis conversation to ‘Are we really adding value repeating this testing over and over again?’ The project demonstrated wholeheartedly and effectively that these materials are extremely stable. This is not the challenge we have in a sterile barrier packaging system, so how can we show and prove that? And where else can we focus our efforts?”
|Read this story on safety factors for ethylene oxide (EtO) sterilization.
What could be possible with time and resources freed up from eliminating redundant stability testing will be different for each organization. Montgomery and Patch note that time could be devoted to packaging sustainability projects, or tackling issues related to supply chain disruptions and material shortages in the marketplace, among other things.
Through experiments at both Medtronic and Boston Scientific, initial data has looked promising in being able to demonstrate significant residual stability in the material after a five-year shelf life. “If the data continues to say what we think it will say, ultimately what we hope to do is not get rid of aging studies, but as Jordan likes to say, right-size the aging studies,” explains Blom.
Montgomery adds, “It’s the Goldilocks approach. We're doing way too many tests. We want to find the right amount of shelf-life testing for MDMs and suppliers, and we don't think the industry knows that today.”
If all goes according to plan, the project will deliver some needed evidence-based practicality to med device package testing. “To apply a bit of logic and common sense—packaging engineers are notorious for having packages sitting in our offices or spaces for a long time. They don’t spontaneously disintegrate. It’s inherent that there's a lot of stability in these materials,” Patch says. “From a regulatory market access perspective, we treat packages as if they're very fragile and anything can break them, and you have to prove their performance over and over again. That just doesn't match up to the practicality of the materials themselves. If anything, this method has an opportunity to show how over-engineered the materials are for their stability performance, and with a good method, potentially in the future state, you could design the material to degrade at the rate that you want to degrade. If you only need to have a certain level of performance characteristics and stabilization, then it may be okay for it to end its useful, functional life sooner.”