Last But Not Least

Packaging and sterilization are critical for compliance and speed to market.

Mark Crawford, Contributing Writer

Packaging and sterilization may be the last steps in preparing medical devices for delivery—but they are two of the most important. In fact, medical device manufacturers (MDMs) sometimes get so consumed with R&D and market windows during the design process that packaging and sterilization becomes an afterthought, which then—typically—backfires. Launch dates can be delayed—leaving expectant customers fuming—when the medical device manufacturer fails to incorporate packaging and sterilization in the earliest product-design brainstorming sessions.

As industry experts told Medical Product Outsourcing, there are seemingly infinite variables that must be considered early in the process before a medical device or component can be packaged and sterilized optimally.

“Suppose an MDM incorporates polyvinyl chloride (PVC) into a medical device and plans to use irradiation as the sterilization technique—this won’t work because irradiation makes PVC brittle, which means the manufacturer will have to switch to ethylene oxide, throwing off the production schedule,” explained Brandon Tillman, sales manager for Nelson Laboratories in Salt Lake City, Utah. “Another common problem is that devices with sharp edges often puncture standard packaging. It’s highly important to evaluate early on the materials being used and how they react to different sterilization techniques, in order to map out the most effective packaging and sterilization techniques for that particular product.”

OEMs expect their contract packagers and sterilizers to respond quickly to their seemingly ever-evolving needs. Increasingly complex devices with more polymer combinations and intricate parts, combination products that incorporate biological or chemical entities with medical devices and the constant push for speed to market (all while reducing costs and maintaining quality and compliance with FDA regulations), create big packaging and sterilization challenges.

“Due to sophisticated product design and/or the specialized and lengthy manufacturing process of many products, more device companies are seeking extremely rapid sterilization processing,” said Susie Perlman, director of customer relations for BeamOne LLC in San Diego, Calif.

Using increasingly delicate materials with biological coatings or incorporated therapeutic agents in the manufacture of many new medical devices also has created the need for such special handling requirements as refrigeration, freezing or even “per-unit” (as opposed to “boxed”) sterilization processing of some products.

“Many of these devices must be shipped to the sterilizer, stored and repacked for outbound shipping after processing in temperature-controlled containers to protect product viability,” continued Perlman. “These requirements have made it necessary for contract sterilizers to have available and maintain appropriate temperature control devices in their service centers. The use of biological materials in medical devices that can support microbial growth dictates rapid sterilization to avoid increases in bioburden that could risk invalidating the required sterility assurance level.”

New medical device materials also have created the need for tightly controlled doses of radiation. Bio-absorbable products, implantables such as tissue and demineralized bone and other highly specialized pharmaceutical or biologic-based products are in growing demand. The inherent bioburden on the product and its handling during the manufacturing process will determine the minimum dose of radiation required to render the product sterile; the maximum dose allowable is driven by the type of raw material in the product and its ability to withstand radiation processing. For radiation sensitive materials, wide dose distribution can translate to variability in product performance.

“This range between minimum and maximum dose is frequently extremely narrow in specialty products,” said Perlman. “The processing methodologies utilized to accomplish such tight dose ranges are both labor intensive and frequently lengthy.”

Packaging Challenges

A study director at Nelson Labs loading samples to be sterilized. Photo courtesy of Nelson Laboratories.

Contract packagers must be prepared to meet a wide range of needs to satisfy their diverse customer base.

“We have customers who want us to provide carton pack out with no plastic and those who are asking us to thermoform a PETG (polyethylene terephthalate) tray, put their product in the tray, and then Tyvek lid the kit, and everything in between,” said Michael Anderson, manager of contract manufacturing for OraTech in Riverton, Utah. “Every medical company is so unique that what they ask for comes down to its device, disbursement method and personal beliefs of what they think will generate the best results. We work with our customers and allow them to provide direction and then we insert our expertise to ensure they are getting the best of whatever it is they want.”

More hospitals and physicians have been requesting high-performance, sterile barrier systems for implantable devices and other Class II and Class III medical devices. High-barrier (foil and clear) pouches and lids for oxygen, moisture and UV protection for the drug/device combination product market also are in demand, creating new challenges for ethylene oxide (EtO) sterilizable barrier packaging. Companies also have had requests for puncture- and abrasion-resistant pouches.

“Many MDMs using standard pouch designs say they experience package failures as a result of distribution testing when the pouch contains a medical device in a tray,” said Teri Meadow, director of marketing and strategic development for Oliver-Tolas Healthcare Packaging in Grand Rapids, Mich. “The pouch design, material selection, proper fit with the tray and manufacturing process are all critical to the significantly higher performance of the reinforced pouch as compared to a standard nylon pouch.”

Tapemark, a contract manufacturer in West St. Paul, Minn., works with several customers that require a custom atmosphere in the pouching of their device for keeping their product activated (with oxygen, for example) or dormant (with nitrogen).

“This may require dedicated chambers in the converting equipment to eliminate exposures and purge the ambient atmosphere,” said Tom Yetter, vice president of research and development for Tapemark. “In these situations, care needs to be directed to the gas transmission rates of the packaging films. There are degrees of sensitivity to oxygen and moisture. Purging the pouch in a formulation that is marginally reactive can make the difference between 18-month and two-year stability—that has huge value.”

To meet customer demand for higher-performing packaging for the combination drug/device and other growing market segments, Oliver-Tolas has enhanced standard pouch and lid designs and added new technologies to meet these needs. For example, its Osurance zone-coated lids prevent the devices from coming in contact with the adhesive, applying the adhesive only in the seal area of the lid. This eliminates the risk of product contamination and maximizes porosity of the lid, allowing for more cost-effective sterilization cycles.

If not proactively managed, package design and validation can be a gating, critical-path barrier to market release. This does, unfortunately, happen frequently in the industry and requires packagers and their sub-tier suppliers to scramble to find the right solution quickly, with no negative impacts to quality and delivery.

“Packaging engineers are usually brought into a project late and the timeline is already behind schedule before the project gets to the packaging issues,” said John A. Abraham, president of Atlas Vac Machine in Cincinnati, Ohio. “Enabling them to validate new package designs or processes with certainty and full resources is critical for meeting project launch dates.”

Packagers typically create ongoing databases of successful packaging solutions based on parameters from previous projects, including the type of medical device, its composite materials, type of packaging material and the sterilization methods used.

“If we have a successful packaging project where we know the total tray sealing flange area and down force used, we can then easily predict the most likely nominal down-force value for the next project, which may be a tray of total different size and therefore flange area,” said Abraham. “This assumes you start with the same temperature and dwell times while using the same Tyvek material. Traditionally a packager will experiment with a wide range of values for dwell time, temperature and psi to map out results statistically and identify the best operational setting points. Knowing in advance the required down force per square unit surface area enables the next project to start quickly at a high probability set point with far less experimentation. You then can open the parameters from there to develop a robust and workable set of production parameters to fully validate, which means quicker time to market.”

An increasing number of OEM clients also are asking packagers for “sustainable” or “green” packaging practices, which is basically a call for less packaging material to save natural resources and reduce the amount of waste going to landfills (usually requested by the end user).

“We have certain customers who want to avoid rigid packaging if possible and use flexible barrier systems,” said Bob Lord, director of sales and marketing for Quality Tech Services in Bloomington Minn. “Designing a flexible barrier system that fully protects the device, survives distribution and provides clear direction to the end user can be a challenge, especially for complex devices. Less waste in packaging can result in less protection for the device, which would then require unique protective packaging elements—complicating the packaging process.”

Sterilization Challenges

As the medical device manufacturing industry continues to innovate with new designs and raw materials (which results in more creative packaging to control costs and improved product performance), contract sterilizers must be on top of their game to meet the ever-changing sterilization needs of their OEMs. For example, there currently is a demand for lower-cost polymers or co-polymer mixtures in medical devices—but how will these less-tested polymers stand up to sterilization techniques?

“The challenge is finding a sterilization method that gives the sterility assurance level required or desired while still maintaining all of the desirable functional and appearance properties of the device,” said Betty Howard, radiation tech team manager for STERIS Isomedix Services in Libertyville, Ill.

One of the biggest challenges contract sterilizers face is the increasing popularity of combination devices, bio-absorbables and drug-covered stents.

“For these products, it is critical the sterilization technique does not negatively impact the biologic agent, or create free radicals,” Tillman said. “Traditionally, the higher the temperature, the higher the kill; if lower temperatures were used, the cycles had to be much longer. Now we can use lower-temperature and lower humidity EtO sterilization cycles over shorter cycles, as well as lower irradiation levels and tighter dose ranges.”

Faster turn times are expected by OEMs, especially for temperature-sensitive products. Some devices have very narrow ranges of tolerance; others have wider dose ranges that provide more flexibility in scheduling and allow more product to be added to each carrier per run, which saves costs. Of course, documentation of delivered dose or sterilization conditions also is expected by OEMs and the U.S. Food and Drug Administration (FDA).

“All of this can be accomplished,” added Howard. “The details and limits must be worked out carefully between the customer and the specific processing plant.”

E-beam sterilization, a technology that has cycled in popularity over the past few decades, now is recapturing interest because of its speed and effectiveness.

“There is a notable increase in using electron-beam sterilization as medical device and pharmaceutical manufacturers understand and value the flexibility, precision and speed of this sterilization modality,” said Perlman. “Due to its polymer-friendly processing and ability to sterilize products rapidly, the 12 to 15 percent market share in North America for this technology is anticipated to rise significantly in the next five years.”

About 80 to 90 percent of all disposable medical plastic products currently manufactured are compatible with electron beam processing. Compared with ethylene oxide, electron-beam processing is faster (hours versus days) and simpler (no need for pre-humidification, post-sterilization aeration, sterility testing, or gas concentration, vacuum or pressure monitoring). Electron beam also does not require the special “breathable” packaging necessary for EtO aeration. In addition, non-permeable plastic packaging is less expensive and easily can be penetrated with an electron beam. Compared with gamma irradiation, sterilization via electron beam takes a matter of seconds instead of minutes or hours. Because of the shorter exposure time to the irradiation source, electron beam processing also reduces the oxidation effects on products and reduces material degradation.

“In many cases, manufacturers deliver their products to an e-beam service center and wait for the products to be processed and released back to the manufacturer as sterile—this takes as little as an hour from start to finish, depending upon the size of the shipment,” said Perlman.

Validation and Compliance

Just like medical device manufacturers themselves, contract packagers and sterilizers also must face the challenge of dealing with the new and revised standards that govern the industry (and often are expected by their OEMs to be experts and consultants). The 510(k) process is under stricter scrutiny by the FDA, resulting in more comprehensive validation testing and documentation by the device manufacturers and their supply chains. As a result, MDMs are pushing their outsource suppliers to conduct their own qualifications/vendor management.

Packaging and sterilization play key roles in getting products approved quickly by the FDA and must be documented through proper validation.

“Validation is the only thing that changes from package to package,” said Anderson. “Quality and compliance have to be constants. However, the validation level to which the product and corresponding packaging will be held will definitely impact the package design and direction.”

In the area of drug/device combination products such as transdermal patches, Tapemark’s Yetter said his firm defers to the stronger drug regulatory requirements.

“The concern is more about stability of the drug than simply protection of the device and appropriate barrier properties of the packaging are critical, such as moisture vapor transmission rate and oxygen transmission. Product development timelines also need to allow for stability testing. Some of the materials that provide the highest barrier, such as various foil constructions, have longer lead times that require even more advanced planning.”

The recent ISO 10993-7:2008 revised standard implemented some significant changes to the ethylene oxide (EtO) residual requirements. Not only do sterilizers need to concern themselves with residual indirect contact doses of EtO, but also the portions of the device that come in contact with the patient directly via skin or body. Manufacturers need to be sure their manufacturing, sterilization and aeration processes will enable them to meet these new limits.

“For our company, which has several thousand catalog items, this presents quite a challenge,” said Bill Rowlands, quality assurance sterilization specialist for B. Braun Medical in Bethlehem, Pa. “At the same time it also provides an opportunity, as we are evaluating devices to see which products and materials may require more aeration time for EtO dissipation. For most disposable medical devices, EtO is still the most material-compatible sterilization technique. It can be done at low temperature and typically does not alter a material’s physical properties as other sterilization processes may. We will come out of this evaluation with an excellent body of expertise that we can share with our customers in terms of designing a device that will meet the revised ISO standard while optimizing aeration time. With our understanding of the specifics of materials and dissipation rates, we can help customers determine which materials best meet their needs both in design and ease of sterilization.”

With the FDA taking longer with pre-market approvals and 510(k) applications, “our clients just want to know what they have to do to get their products through the FDA as quickly as possible,” said Tillman. “Using a tried-and-true sterilization method is probably the best choice. If a different process is used, however, be certain it is highly documented so a lot of questions don’t arise during the review.”

Working Together

Sterilization is a key factor in determining what sort of packaging will work best for a medical device. Increased challenges come from extreme cycles and conditions, new processes and sterilization-sensitive devices such as drug/device combinations.

“The package is part of the device,” said Howard. “It is placed on the product as a last step in the manufacturing process before sterilization and marks the barrier between the outside, contaminated world and the sealed sterile environment inside the package.”

Packaging must protect the sterilized status of product throughout shipment and storage until the moment it is opened. Materials must be selected or tested to assure they provide the proper barrier through the product’s post-production life cycle. If the sterilization method requires a breathable package, it must be designed to allow the sterilant to pass through the material as well as handle the conditions of the sterilization process (such as temperature moisture and vacuum pressure with EtO sterilization). If irradiation is used, the package materials must not become brittle and adhesives must remain intact.

Overall, the greatest challenge in accomplishing a smooth sterilization/packaging success is getting all the required information about the method of sterilization to be used, followed by the level that will be reached within that specific type of sterilization, early in the design/production process.

“Once we know the parameters, the packaging is a breeze,” said Anderson. “We work with our customers down the sterilization pathway if they don’t already know the direction they want to take when they come to us. At the end of the day their knowledge about how their product is sterilized is more important than ours.”

Contract sterilizers and contract packagers or the manufacturer’s own packaging engineers often work very closely together in the development of packaging for a new product or re-packaging of an existing product, experts said.

“Both packaging materials and final package configuration must be taken into account; utilization of materials which may be adversely affected by the sterilization method or the creation of a package which is inappropriate in either size or bulk may delay final validation of the product,” said Perlman. “Any collaborative effort between sterilizers and packaging experts will provide smoother validation and elimination of failures. In fact, the importance of involving the packager and sterilizer in the major development stages of product design cannot be emphasized highly enough.”

Mark Crawford is a full-time freelance business and marketing/communications writer based in Madison, Wis. His clients range from startups to global manufacturing leaders such as Kohler. He also writes a variety of feature articles for regional and national publications and is the author of five books. Contact him at mark.crawford@charter.net.