Artful Adaptation

Jim Carroll, a.k.a. the “Innovation Whisperer,” is a preacher of sorts. The internationally-renowned futurist and social trends expert has crisscrossed the globe, extolling the virtues of change and creative thinking to thousands of business owners searching for the secret to entrepreneurial immortality.

Carroll, however, spreads his gospel in a most paradoxical and unoriginal way—usually by repeating the same tag line in keynote speeches: “the future belongs to those who are fast.”

While it’s not the catchiest aphorism, it effectively conveys Carroll’s professional doctrine to his faithful disciples: Embracing innovation and keeping pace with a rapidly changing world will ensure future business growth and survival.

“The world is changing very fast. Things are evolving at lightning speed,” Carroll told an audience of business executives several years ago in Las Vegas, Nev. “The reality going forward at this point in time is that it isn’t necessarily the big organizations who will own, win and control the future. It will be the fast, the agile…it will be those who can keep up with very rapid change and ingest that change. The high-velocity economy demands that we do, demands that we think, demands that we collaborate, demands that we share, and demands that we innovate in different ways.”

The medtech industry—perhaps more so than other industrial sectors—has long subscribed to the Carroll Testament. Medical device manufacturers with an “adapt or die” core philosophy, for instance, have higher survival rates than those resistant to changing market forces. Medtronic Inc. is a classic example: The Minneapolis, Minn., firm ascended to Fortune 500 heaven by catering its products to physicians, once the sole agents of purchasing decisions. Now, however, innovation revolves around cost containment and clinical efficacy to satisfy penny-pinching hospital administrators and insurers.

Johnson & Johnson has had to fine-tune its focus as well. Ten years ago, the multinational firm ruled the drug-eluting stent (DES) market with a 60 percent share and hundreds of millions of dollars in sales (proceeds topped $2.62 billion during the stents’ heyday). But when the market tanked in 2010, JNJ quickly ended production of its Cypher and Cypher Select drug-coated stents and funneled its capital into diagnostic devices and non-cardiac stents.

Boston Scientific Corp., conversely, wasn’t as acclimating and thus is paying dearly for it. The Natick, Mass.-based device manufacturer has lost about seven points of DES market share to Abbott Laboratories and Medtronic over the last two years, and perpetually forfeits profits to competitors with better products.

“The world demands that we look at the future and constantly ask ourselves, ‘Given the rapid rate of change coming at us, how do we ingest that future?’ “Carroll said during one of his countless public sermons. “How do we do things differently in order to deal with the future in which the future is happening faster than ever before? We have to completely rethink what we are doing and focus on innovation. Because the same rules of the past do not apply in the future.”

Medical device packaging and sterilization providers are on the front lines of this struggle to rewrite past rules for a rapidly changing future. They’ve increasingly assumed chameleon-like qualities in recent years to contend with customer demands for safer, simpler, less costly end products. And they’ve frequently tweaked their processes to account for material advancements, new regulations and market trends.

Sterilizers, for example, are now tasked with limiting or reducing ethylene oxide (EO, or sometimes EtO) gas and complying with various, often complex instructions for use (IFUs), while packagers face the challenge of reducing package waste and protecting sensitive drug-device combination products.

“Ethylene oxide is typically mixed with HCFC (hydro chlorofluorocarbon), and there’s a U.S. ban on hydro chlorofluorocarbons that takes effect in 2023,” explained Gaet Tyranski, president of Applied Sterilization Technologies-Americas at Synergy Health plc, a Swindon, United Kingdom-based outsourcing provider of sterilization, laboratory, linen management, hospital and reusable surgical solution services. “There’s a long-term trend to move away from mixed gas. That doesn’t mean EO itself is going to be eliminated, but EO with HCFCs is going to start to be phased out and that is causing some of our customers to move away from the ethylene oxide process altogether.”

With EO waning in popularity and gamma radiation facing similar regulatory and safety threats, sterilizers—channeling Carroll, no doubt—have reworked their disinfection strategies to clean the more technologically advanced products being introduced to market.

Such a shift, however, has significantly limited the kinds of devices suitable for traditional sterilization techniques. The blistering temperatures required for steam sterilization, for instance (between 249 and 298 degrees Fahrenheit), are too damaging for  some materials: The heat can melt acrylics and styrene, distort polyvinyl chloride and corrode specific metals. Moisture from the steam can be detrimental as well, damaging electronics, clouding or staining certain materials and generating unwanted “wet packs” within disinfected loads, which in turn, compromise sterile packaging.

“Steam sterilization still remains a preferred method of the FDA and is more commonly used but as medical devices become more complex (internal electronics, heat-sensitive materials), device manufacturers will be forced to move away from heat sterilization,” said Aaron Burke, director of business development for Pacific BioLabs, a contract research organization in Hercules, Calif., that provides testing and research support services to the medical device, biotechnology and pharmaceutical industries. “Hydrogen peroxide sterilization is becoming more commonplace for devices that will be repeatedly sterilized such as in a hospital setting.”

Hydrogen peroxide has its limits too, though. Neither the vaporized nor plasma methods are suitable for devices with embedded batteries or electronics, and both techniques require longer cycle times (between 90 minutes and three hours), which can increase costs and slow product commercialization. In addition, hydrogen peroxide cannot penetrate certain types of long, narrow lumens and the process—like steam—is incompatible with various materials.

X-ray sterilization has become a viable alternative to hydrogen peroxide, steam and other traditional cleaning methods over the last several years due to advancements in high-energy, high-power electron accelerators. Belgian firm Ion Beam Applications S.A. (IBA) is a pioneer in the field, having developed a particle accelerator in 1992 from a patented concept of the French Atomic Energy Commission. The company offers customers an X-ray sterilization solution called eXelis based on its high-power, high-energy Rhodotron accelerator, which provides one or several beam outputs from 2 to 10 MeV with power ranging from 35 to 700 kW. IBA says eXelis helps improve the cost competitiveness of X-ray sterilization by reducing dose uniformity ratio (DUR) levels (the ratio between the maximal and minimal dose required to effectively process a product). Data supplied by IBA claim X-radiation can achieve a DUR of 1.25 for pallet loads of low-density materials compared with a DUR of 1.45 for the same low-density loads in a cobalt-60 gamma radiation facility.

“The DUR of the X-ray process permits pallet-based sterilization of medical devices, which could only be processed previously by means of gamma-based tote sterilization,” states an IBA white paper on X-ray sterilization of medical devices. “The simulated cost per volume of sterilized medical devices (cost per m3 of sterilized products, for example) shows that compared with gamma sterilization, the economic advantages of X-ray sterilization increase in relation to the production volume of the facility.”

From a practical standpoint, X-ray sterilization systems offer several advantages over gamma radiation. For starters, X-ray photons are more concentrated and directed than the widely scattered cobalt-60 gamma rays. X-ray systems also penetrate full pallets of product better than gamma and electron beam methods, hence their lower DURs. Pallets in X-ray facilities typically are irradiated from one side as they pass in front of a long, vertically-oriented target and irradiated on the opposite side to obtain a nearly uniform dose in the vertical direction.

The concentration of X-ray photons significantly reduces product exposure times, thereby minimizing or altogether eliminating damage to certain medical device materials. X-ray processing, in fact, can be used to chemically bond (cross-link) polymer chains together, effectually making plastics more resistant to stress and extreme conditions.  

And because it is a relatively quick process, X-ray sterilization can reduce supply chain turnaround times by days compared with traditional ethylene oxide and gamma cycles. Experts note the technology also can process multiple products with different dose requirements within the same irradiation cycle, offering faster turnaround times than both gamma and e-beam methods.

While they are not as commonplace as other disinfection facilities, X-ray plants nevertheless are designed to fulfill international standards, including ISO 13485:2003, ISO 9001:2008 and ISO 11137 quality management system regulations for medical devices; Sterilization of Healthcare Products—Radiation, Parts 1–3 (ISO 11137); cGMP (Current Good Manufacturing Standards); and U.S. Food and Drug Administration (FDA) guidelines. ISO 11137 accepts X-ray technology as an alternative to gamma and E-beam methods. Furthermore, research has shown that D-10 values of microorganisms are not significantly different when treated by either gamma rays or X-rays in both wet and dry conditions.

In addition to its faster turnaround times, minimal impact on materials and lower DURs, X-ray sterilization offers users more design options, experts claim. For example, a nonstop sterilization facility operates more than 8,000 hours annually. With this configuration, initial investments are reduced since the required power is optimized for nonstop production. When more capacity is needed, X-ray generator power can be increased with minimal downtime.

Under some circumstances though, it may be more feasible to operate an X-ray sterilization facility only during off-peak hours (to reduce costs). Such a prospect is possible by installing an accelerator with more power than is required, allowing the manufacturer to treat the same volume in less time. This extra power also is available and useful for production volume surges.

Temporary power licenses are possible with X-ray sterilization systems as well. Depending on the facility and system installation, these licenses can be purchased to manage a sudden temporary peak in production due to an unanticipated customer request or to compensate for a production delay. The cost of temporary licenses, naturally, varies depending on specific power needs and duration.

Despite its litany of benefits, however, X-ray sterilization is decidedly under-used due largely to a lack of capacity. The industry’s only large-scale medical device X-ray sterilization facility is owned by Synergy Health and located in Däniken, Switzerland. The company inherited the plant with its 2012 purchase of Leoni Studer Hard AG for 47.6 million euros ($63.4 million). Featuring a 700kW Rhodotron electron beam accelerator, the facility can process up to 80,000 pallets annually.

“We bought the Däniken facility for its technology—to learn it, stabilize it, get acceptance and then adapt that and proliferate the technology,” Tyranski told Medical Product Outsourcing. “X-ray as a sterilization method has been around for a couple of decades.
It’s a high-volume irradiation method…the physics behind it are very similar to e-beam. You accelerate an electron and it penetrates the product. The advantage of using X-ray in the sterilization of medical devices is that it’s comparable to gamma, so products that are gamma irradiated can also be X-ray irradiated. The down side is current availability. Most medical devices that are gamma irradiated are registered with the FDA as gamma irradiated and would require a conversion to X-ray which may not require a new 510(k) submission if equivalence can be proved. The advantages are that it’s not radioactive material with associated disposal, and there’s a lower maximum dose for sensitive products. It’s better for products that are sensitive to high doses. X-ray is starting to become more popular but there’s not a lot of capacity out there. We have an X-ray facility in Switzerland, there are X-ray facilities in the U.S. irradiating mail, but it’s not as widespread as other technologies.”

That could soon change, though. Several major medical device manufacturers currently are in post experimental production with X-ray sterilization systems, having been drawn to the technology by its clean environmental footprint and relatively low cost.

The cost of an X-ray generator in a sterilization facility is comparable to the initial cobalt-60 loading of a gamma facility, according to industry data. In general, X-ray generators are more economical from 1.5 MCi to 2 MCi, depending on local electricity costs.

Converting from e-beam to X-ray isn’t that difficult or expensive, either. Tyranski notes that e-beam providers can easily (and rather cheaply) modify their equipment to add X-ray capabilities to their offerings. IBA even developed a configuration combining 10 MeV e-beam and 7MeV X-ray technology on one accelerator. The configuration uses a single conveyor for both technologies, keeping costs to a minimum.

As the industry works to mainstream X-ray sterilization technology, Sterigenics International LLC is shaping its future (a la Carroll) with existing systems, by introducing computer software innovation that enhances customer service. Sterigenics Global Processing Status platform—launched early last year—allows real-time order tracking and just-in-time supply chain operation, enabling customers to monitor the status of their product from their computers, smartphones or tablet devices. Sterigenics GPS, with one platform of data, offers a window into the company’s global processing facilities to deliver real-time visibility for every work order and sterilization technology on a 24/7 basis.

Its VeriCycle Automated Process Verification solution, meanwhile, is an automated batch record review system designed to validate EO equipment sterilization prior to shipment. An industry first, the solution is offered in all of the company’s 18 global EO processing centers to help customers improve speed to market.

“VeriCycle Automated Process Verification automates the manual and laborious process of verifying the various sterilization batch records line by line. Now, this automated process allows the product to be released once it comes out of chambers. There’s hundreds of steps that happen inside the chamber for ethylene oxide sterilization,” explained Patrick Hughes, senior vice president of global sales and marketing for the Deerfield, Ill.-based provider of contract EO, gamma and e-beam sterilization services for the medical device and pharmaceutical industries.

“Previously, that release process could take an employee up to 30 minutes to complete. Automating the process eliminates the potential for human error and substantially reduces the time per review. Using manual processes, customers may have required up to 20 people reviewing various records in the QA department,” Hughes said. “With VeriCycle Automated Process Verification, customers can better utilize resources in their organization. Large customers are providing favorable feedback and praising the benefits and cost savings. As Sterigenics is part of its customers’ supply chains, VeriCycle Automated Process Verification becomes an indispensable asset, in turn increasing customer loyalty.”

Noxilizer Inc. is winning over customers as well with its room-temperature sterilization technology based on nitrogen dioxide (NO2) gas. Effective against both vegetative and spore forms of bacteria, NO2 sterilization provides medical device manufacturers with an
effective alternative to many of the challenges posed by other techniques, including the use of X-ray.

One of the main advantages of NO2 technology is its compatibility with temperature-sensitive materials like bioresorbable polymers and drug-device combination products such as pre-filled syringes. The low permeability of most polymers to NO2 prevents the sterilant from interacting with or contaminating the drug within the syringes. Plus, the gas is well-suited to common syringe materials including glass, cyclic olefin copolymers, polypropylene, silicone, most rubbers and thermoplastic elastomers. In fact, NO2 can be used to disinfect syringe parts after manufacturing, as well as decontaminate syringe tubs prior to entering the filling line.

Another major benefit of NO2 sterilization is its short aeration and cycle times. A routine cycle lasts 60-90 minutes (including 15 minutes for aeration), thus enabling a small sterilizer (about 360 liters of usable volume) to disinfect an entire pallet of product in an eight-hour shift and return it immediately to inventory.

Perhaps the greatest advantage of NO2 technology, though, is the potential for in-house processing, which can eliminate the transportation and inventory carrying costs typically incurred by higher volume manufacturers.

“Noxilizer’s process, being a user-friendly process that is non-carcinogenic and relatively fast, can be easily installed in any location without a hazard of exposing operators to a carcinogen or without adding a lot of radiation-absorbing materials like you would if you installed a gamma system,” said David Opie, senior vice president of research and development at Noxilizer, a Baltimore, Md.-headquartered seller of sterilization equipment and a contract NO2 sterilization provider to the medical device, biotechnology and pharmaceutical industries.

“Bringing sterilization in-house by using NO2 sterilization is the only viable option for most companies. Only the largest companies can consider in-house EO, companies like Abbott, Johnson & Johnson, Cook Medical and several others,” he continued.

“Outsourced sterilization has been the trend for the last 20 years and it’s not getting any easier to put these systems in-house. The EO concerns with operator safety and the cost to put in a gamma system is just enormous. To reduce processing time, the options people have is to use an NO2  system. Next up in scale is putting in an e-beam system, but that will be far more expensive than using NO2. If you put in an NO2 system, you can pay it off in about eight to 10 months depending on the volume you put through. And that’s very cost effective.”

Innovations in Packaging
All companies innovate but few, if any, live up to Jim Carroll’s definition of the word. In his eyes, innovators are not the quintessential “cool” people developing “cool” products but rather the ordinary minions who have learned how to grow and transform their business.

“Innovation is a funny word. We hear the word  ‘innovation’ and who do we think of? We think of Steve Jobs,” Carroll once mused to CEOs and senior executives. “But innovation is about much more than people who innovate new products. To a degree the ability to innovate hinges on how quickly you can ingest all of the new ideas, capabilities and methodologies that are emerging. We’re in a world in which it can no longer take five years to plan and release something new. Innovative organizations know we’re in a world where volatility is the new normal. Everything is changing faster than ever before. Innovative organizations concentrate on how to build global scale. Innovative organizations know that things are going to evolve and change and twist and turn, particularly with the global economy.”

The most innovative organizations perfectly fit all those curves and evolve just as quickly as the hypercompetitive world in which they exist. They are the ones to first invest in emerging markets, or support new, unproven yet potentially disruptive technologies. Innovative organizations can anticipate trends before they happen, enabling them to avoid the “tyranny of success” trap that has led to the demise of countless corporations. 

For packaging firms, the twists and turns have assumed many forms, from European waste reduction requirements and 3-D printing to material changes and product customization. Another major hairpin is looming with the Sept. 24 implementation of the FDA’s unique device identification (UDI) rule, which requires most medical devices to contain a UDI to help regulators better track products, monitor their safety and expedite recalls. Packaging is particularly impacted, as the directive calls for most parcels to include both a device identifier, a mandatory, fixed portion of a UDI naming the labeler and specific version or model of the packaged device; and a production identifier—a conditional, variable portion of a UDI that includes one or more of the following on the device label:

• The lot or batch number within which a device was manufactured;
• The device serial number and expiration date;
• The device manufacturing date; or
• The distinct identification code required by 1271.290(c) for a human cell, tissue or cellular and tissue-based product regulated as a device.

“A big area of focus for us right now is the release of the UDI guidelines from the FDA,” said John Martyn, quality assurance manager at Advant Medical Ltd., a Galway, Ireland-based developer of contract medical manufacturing and packaging solutions for Class I, II and III implantable devices. “That will have significant impacts in terms of the device labeling process. We are ready for this and are already working with relevant customers to prepare for the changes.”

Most mandated changes generate untold volumes of discontent and frustration among business executives. But regulations are not always an enemy of state; they also can inspire some truly remarkable innovation.

In truth, innovation is not only about unique inventions like drug-eluting stents or 3-D-printed body parts, but enabling the adoption of better ideas that ensure progress toward improved patient care. Simply stated, regulations increase the supply and demand for safer, more cost-effective alternatives.

“Validation has a big impact on what kinds of materials are used,” explained Lorraine Eagleton, sales and marketing manager at Advant. “Through our sourcing management and packaging design, we’ve provided many of our customers alternative cost-effective and environmentally friendly packaging solutions for their devices.”

Solutions like blister packs from recycled PETG (polyethylene terephthalate glycol-modified) are an effective alternative as well. The material—a clear amorphous thermoplastic that can be injection molded or sheet extruded—is well-suited for medical device packaging because it is recyclable, strong, impact-resistant, and makes for a good barrier to gas, moisture, alcohol and solvents.  
“For packaging parts with reduced requirements, it’s an attractive alternative,” said Bernhard Gygax, project manager at Cendres+Métaux S.A., a Swiss company that produces implantable, micromechanical components and systems with complex geometries made from precious metal or titanium alloys.

Some packaging companies have managed to stay ahead of the innovation curve by setting (unofficial) industry standards themselves. J-Pac Medical LLC is attempting to do so in 3-D device packaging and overall container versatility. The Somersworth, N.H.-based provider of contract manufacturing solutions for the medical device and diagnostic industries works with customers to develop a methodology that would enable them either to downgauge or move from rigid trays to flexible put-ups.

Such a transition—while beneficial for the environment—is fraught with challenges, though. For starters, companies must ensure their flexible package design will maintain the device in an operational manner, can physically support the product (heavy or 3-D objects might be better off in a rigid container, for example), will provide a sterile barrier and be sterilizable as well.

“It’s better for the environment to be smaller and to use less materials. These transitions will do that,” said Rick Crane, vice president of J-Pac Medical’s Innovation Services Group. “Lower profiles are easier. That’s not to say you can’t put a 3-D or heavy object in a flexible put-up, but you have to put in an internal component that protects the flexible sterile barrier from being penetrated by what is being packaged. That becomes the challenge of transitioning from rigid to flexible.”

Beacon Converters Inc. resolved a similar challenge several years ago by designing a 3-D functionally rigid tray for the HeartLight Cardiac Ablation System Balloon catheter from CardioFocus, a product with a heavy, bulky handle, a large fluid reservoir, bending-sensitive fiber-optics and tubing. Typically, a heavy-gauge thermoformed tray would be used for a system like this but Beacon developed a high-density polyethylene die-cut flexible sheet that is folded and fastened to form a functionally rigid tray. Featuring five different die-cut holds (finger tabs, carabineer closures, belt style tabs, U-shaped pop ups, and semi-circle end flaps), the recyclable tray uses 32 percent less packaging material and 50 percent less weight than a thermoformed tray. The product garnered Beacon the Flexible Packaging Association’s Gold Award for Environmental and Sustainability Achievement and its Gold Award for Technical Innovation in 2013.

“We have seen shifts to flexible from rigid for sustainability reasons as well as hospital utilization of space. Hospitals want packages to take up less space, and they want less waste so there’s less to dispose of,” noted Kathleen Daly Mascolo, vice president, sales, and marketing director at Beacon Converters, a Saddle Brook, N.J.-based sterilization packaging manufacturer for the medical device and pharmaceutical industry. “Hospitals have their own issues with waste disposal. Rigid packaging is bigger and heavier, and therefore it’s more costly to dispose of. Flexible packaging is a less expensive alternative and it’s easier to dispose of. This flexible high-density, die-cut insert card can be rolled up like a camping mat and thrown out. There’s really nothing you can do to make a huge, rigid tray much smaller, so the flexible packaging is desired by hospitals.”

Besides its award-winning flexible tray, Beacon also has developed packaging that can withstand sterilization and maintain sterility as well as protect the device from the environment. The company’s insert cards sometimes are used to protect the device from the package—by suspending the device, for example, so it does not touch the package. Beacon also offers blue films that provide a visual indication of seal locations, which helps in quick visual inspections during packaging. Package contents frequently need specific protection from moisture, light and other environmental conditions, yet users still desire to be able to see the product inside.

To meet this challenge, Beacon has developed a variety of transparent barrier packaging materials as well as the traditional opaque styles.

Rather than pioneer new standards, some companies choose to follow Steve Jobs’ approach to innovation, inventing “cool” products based on market need. Barger, the medical division of packaging designer and manufacturer Placon Corporation, developed special packaging for Millstone Medical Outsourcing that fits roughly 80 percent of spinal and extremities implants and can be sterilized by Gamma irradiation, EtO or e-beam. Together, the companies created a double-sterile barrier thermoform tray with two polyurethane liners for protection, inner and outer lids made from Tyvek and a shelf carton.

“With regulatory implications around cleaning, increased infection rates at hospitals, and the way European models have been driving toward a sterile packaged implant, a lot of companies are coming to Millstone with a need for sterile packaging,” said Tom Williams, president of Millstone Medical’s Fall River, Mass., facility. The outsourced medical packaging solutions provider also operates three facilities in Massachusetts and Olive Branch, Miss. 

“It’s a very flexible design that cuts down on validation costs as well as the validation timeline to release sterile packaged products to market. Rather than trying to reinvent the wheel with every packaging request, we worked with Barger to come up with an efficient design that fits the vast majority of spinal and extremities implants into a pretty small footprint.”

Similarly, SteriPack developed and introduced a line of linear tear and peelable vent pouches earlier this year that replace its traditional predecessors with film to film and breathable vents that provide airflow for EO sterilization and outgassing.

Various sized vents in the new PeelVent and TearVent packaging can be positioned at optimum locations to ensure proper airflow during EO gassing. The products also are amenable to irradiation sterilization. A further benefit to the vented pouch is that it eliminates the requirement for altitude package testing and mitigates the associated issues typically caused by vacuum packaging regular film to film pouches, the company claims.

“These pouches replace a full face of Tyvek with a small circular vent or combination of vents to ensure an OEM’s existing EO cycle can still be used despite making the switch from a traditional Tyvek to Film pouch,” said David Moore, business development manager at SteriPack USA, a provider of sterile packaging solutions and contract manufacturing services to the medical device and pharmaceutical industries. “With a more economical use of Tyvek, these pouches can substantially lower the cost of packaging while still maintaining a sterile barrier and providing an aesthetically appealing package to the end user.”

Quality Tech Services lowers packaging costs through its QSeal line of pre-validated medical device packaging trays and pouches. The company claims QSeal can lower packaging development costs by more than 30 and reduce development time by as much as 60 percent, depending on the device and customer specifications. 

QSeal trays, lids and pouches cover a range of sizes. Trays can be customized within the seal flange of the stock trays to accommodate various devices and retention features that ensure the contents are protected. Pouches also can be made to fit specific products by adjusting the length and width.

“Most of our customers are under great pressure to shorten time to market and reduce packaging costs,” said Brian Nissen, project engineer at the Minneapolis, Minn.-based provider of contract outsourcing solutions for medical device assembly, packaging and sterilization. “This pressure has been increasing in recent years due to fears and concerns regarding U.S. and world legislation regarding medical device reimbursement and regulation. As governments pressure device makers to reduce sales prices, device manufacturers become more conscious of cash outlay on projects in relation to when the product can be marketed, while being mindful of the shelf life once the product is launched.”