New technologies, systems that are smaller and less expensive, and manufacturers' changing requirements are changing the sterilization equipment market.
by Jenevieve Blair Polin, Contributing Editor
The contract sterilization industry has enjoyed phenomenal growth over the past two decades because it makes sterilization cost-effective for everyone from the small manufacturer launching a new product to the large manufacturer sterilizing huge lots of commodity items. Statistics compiled by MDS Nordion (Kanata, ON, Canada) indicate that 87% of medical device manufacturers use contract sterilization, although some of those also do in-house sterilization. Nevertheless, manufacturers whose needs are changing should take a hard look at contract sterilization costs and shipping times to determine whether in-house sterilization is a cost-effective alternative.
The old rule of thumb holds that in-house sterilization is worth considering only for the device manufacturer who annually processes a million cubic feet of product or spends $1 million on contract services. These figures need updating. With new technologies, new systems designed to be cost-effective for smaller volumes, and the changing requirements of medical device manufacturers, the equations determining the choice between contract and in-house sterilization are changing.
ADVANTAGES OF IN-HOUSE STERILIZATION
Most of the advantages of in-house sterilization derive from control over a key manufacturing process. Many companies bring sterilization in-house because "quality is so key to their success and their strategic direction, and sterilization is a very highly value-added part of production," says Wayne Gibson, manager, new products development, at the industrial irradiation division of MDS Nordion.
When determining how to achieve regulatory compliance, "contract sterilizers are businesses, and they have their own business plans and their own agendas that might not concur with ours," points out Jon Seulean, manager of Cobe Sterilization Services (Denver). Cobe Sterilization Services is a division of Gambro, a healthcare provider with more than 17,000 employees serving the transfusion medicine, therapeutic apheresis, stem cell therapy, renal care products and services, and cardiopulmonary care markets. "Regulations often contain a fair amount of ambiguity because of their nature of having to be applied to differently designed facilities. The means of compliance can therefore be subject to interpretation," Seulean says. "There's a potential that the contract sterilizer didn't do things as I would have, and now there's a problem."
If there's a need to expedite product or address a manufacturing problem that entails rework or repackaging, the job is more easily accomplished if the sterilization process is in-house. Moving quality assurance personnel from one part of the facility to another is simpler than putting them on a plane.
1996 sterilization market volume of single-use medical devices, distinguished by contract or in-house sterilization location.
Cost control is another incentive. "You're basically at the mercy of the market if someone else is costing the service to you," says Seulean. Although in a favorable market contract service providers may offer a very low rate, the market may change. Transportation costs also contribute significantly to the cost of contract services. "You have to add $1 a mile per cubic foot for trucking, usually," says Gibson.
The primary advantage of in-house sterilization for many manufacturers, though, is time, and in manufacturing, time is definitely money. Depending on the technology the manufacturer chooses, an in-house operation may allow just-in-time sterilization, which translates into a significant inventory reduction. If a company's contract EtO sterilization turnaround time is 10 days, for instance, it must maintain double that, or 20 days' worth of inventory, explains Byron Lambert, manager of quality services for Guidant Corp. (Temecula, CA). "If an in-house system allows you to reduce your inventory levels by 7 days, it is like putting the value of the reduced inventory in the bank instead of down the drain," Lambert adds.
Ethylene oxide (EtO) is the workhorse of medical device sterilization, sterilizing the majority of packaged medical products. There once was a time when a manufacturer could install one EtO chamber and have inexpensive on-site sterilization.
But EtO's situation has changed drastically in the past few decades. The discovery in the 1970s that the gas is carcinogenic prompted restrictions on emissions to the atmosphere and on worker-exposure levels. The discovery in the 1980s that fluorocarbons were depleting the planet's ozone layer prompted a restriction on the use of freon, which had until then been mixed with EtO in an 80:20 ratio to change the gas from extremely volatile to relatively inert. As EtO users switched to 100% EtO, EPA mandated further reductions in the concentration of emissions into the atmosphere through the National Emissions Standard for Hazardous Air Pollutants (NESHAP), with tragic consequences. Explosions at four EtO sterilization facilities around the country in 1997 followed the implementation of thermal oxidizers to heat and destroy EtO fumes. In one of these explosions, one person was killed and 69 were injured. EPA has consequently extended the grace period for compliance with NESHAP while investigating these explosions. Clearly, the decision to have an on-site EtO facility is not one to be taken lightly.
"In my opinion, human error was the cause of those explosions," says Cobe's Seulean. "It appears that in some cases, people were attempting to control 100% EtO in a manner with which they had insufficient familiarity. With meticulous validation of process control equipment, none of these explosions should have happened."
Each new restriction on the use of EtO has forced manufacturers to reconsider in-house EtO sterilization and to look instead to converting to another sterilization technology or shutting down in-house EtO facilities and switching over to a contract EtO sterilizer. For selected companies, however, in-house EtO still makes sense, and some are willing to make a major investment in it.
Cobe recently completed construction of a new 60,000-sq-ft EtO sterilization facility. Cobe is at maximum capacity at its existing EtO facility, which it will be closing in the next few months after transferring its process to the new plant. Cobe also has an in-house gamma facility, which is running at only half capacity.
At one time the company considered converting some product to gamma sterilization, which would have allowed them to delay the investment in a new EtO facility for a few years. They determined that conversion was not economically feasible, even in light of the considerable expense of a new facility. "For products in the mature part of the product life cycle, what you're dealing with in the marketplace is price competitiveness," Seulean explains. "If you're not able to pass conversion costs on to the final customer, then it's an investment you don't recover, which just affects your bottom line."
Gamma irradiation, as already mentioned, is an attractive alternative to EtO sterilization for many products. Because product can be released for shipment the same day it is sterilized, unlike traditional EtO sterilization that requires a period of at least days and in some cases weeks for outgassing, manufacturers can keep less inventory on hand. Also, validation of a radiation process is transferable and takes less time than validation of EtO sterilization; validation of a gamma process is simpler and requires less dosimetry than validation of an E-beam process.
Because gamma rays penetrate anything, including steel, gamma can be used to sterilize products with complex geometries and varying densities. Material compatibility is perhaps the greatest limitation of the use of gamma rays. During the 2–4 hours that the product is exposed to gamma radiation, oxygen interacts with the surface, free radicals are generated, and cross-linking and chain fission occur on the molecular surface. Furthermore, the temperature within the chamber increases by up to 20°C. These conditions may detrimentally affect product performance. Common complaints are embrittlement, discoloration, and noxious odor. The availability of more radiation-stable materials and the reduction of the required radiation dose for some products are, however, some solutions to radiation incompatibility issues.
Cobe's EtO sterilization plant, which is being commissioned this spring, will initially feature five oversized EtO chambers built by ETC (Southampton, PA).
Manufacturers who decide gamma sterilization is right for their products must still determine whether an in-house installation is justified. The bulk of gamma sterilization is done at contract sterilizers. The project cost for a standard gamma installation is a few million dollars, and the cobalt 60 decays and is expensive to replace. Therefore people traditionally have estimated that an in-house system would be a consideration only for manufacturers spending $1 million or more a year on contract sterilization, or those processing a million or more cubic feet of product a year.
MDS Nordion, however, is aiming to design irradiators that are economically attractive to manufacturers with volumes as low as 500,000 cu ft a year, according to Gibson. "The volume is important, but you have to put it together with density and dose," he adds.
SteriGenics, a contract sterilization services provider headquartered in Fremont, CA, also has a concept for a small gamma system. According to Pamela Wilkerson, director of corporate communications for SteriGenics, its MiniCell can be installed in an existing warehouse and processes product in batch sizes of approximately 300 cu ft. SteriGenics asserts that the MiniCell may be cost-effective for manufacturers with volumes between 500,000 and 2 million cu ft a year. SteriGenics proposes to lease and install the equipment and service it with its experts. "You can think of it as an in-house outsourcing capability," Wilkerson explains. To date, however, no firm has leased one. The only MiniCells installed are in SteriGenics's own contract sterilization facilities. Medical Action Industries was considering the MiniCell as a replacement to its in-house EtO chambers. But after an in-depth assessment of its operation and an analysis of its sterilization requirements, both immediate and future, it was determined to be more advantageous to use SteriGenics's contract services in Charlotte, NC.
Only a small portion of medical devices in the United States, perhaps less than 10% according to MDS Nordion's statistics, are sterilized by electron beam. The major limitation of E-beam is product density. Because the electrons in the beam have mass, unlike the photons in gamma irradiation, they slow down when they encounter the product. Penetration is therefore limited, but, says Pauline Pastore, U.S. agent for Ion Beam Applications (IBA; Louvain-la-Neuve, Belgium), the limitation has been exaggerated.
The highest voltage available in the early E-beam systems marketed in the early 1980s was 4.5 or 5 MeV, and at that voltage they could sterilize only low- and low-medium–density products. Many accelerators now in use for medical device sterilization, however, are operating at 10 MeV. "Today, 95% of all medical devices that are suitable for radiation sterilization can be sterilized by E-beam," Pastore says.
Ray Calhoun, director of business development for Titan Scan Corp. (San Diego), concurs, adding that the upper limit of density at which E-beam sterilization is practical is around 0.2 to 0.25 g/cm3, about the density of surgical gloves. The density of a very high percentage of medical devices, Calhoun states, is between 0.075 and 0.15 g/cm3—petri dishes, specimen cups, infusion sets, tubing. "They are basically some plastic and air and mostly packaging, and that is absolutely ideal for E-beam," he adds.
The majority of the manufacturers now converting to E-beam sterilization, Calhoun says, are those who tried converting product from EtO to gamma sterilization several years ago without success. With E-beam, the product is irradiated for only a few seconds and therefore may not be subject to the radiation incompatibility sometimes seen with gamma irradiation.
According to Pastore, for significant volumes the minimum cost of an electron accelerator for medical device sterilization is between $1 million and $2 million, and the total cost of the project is at least double the cost of the equipment. Calhoun says that smaller-volume systems usually run about a third of the total cost of the project. Large-scale installations are ideal for the types of high-volume commodity products already mentioned, but both Titan Scan and IBA have small-scale systems designed for makers of low-volume, high-value products. Calhoun says Titan Scan has a system that may be cost-effective for as little as 100,000 to 200,000 cu ft a year of a high-value item.
Guidant Corp. uses a 10-MeV, 4-kW Titan Scan system with a yearly capacity of 400,000 cu ft to sterilize its vascular intervention products, including balloon catheters and stents. According to Guidant's Lambert, this system offers three major advantages: improved operational logistics and inventory control, faster speed to market, and better customer responsiveness.
The typical market life span of most Guidant products is 9 to 15 months. A new product, such as the stent it introduced a year and a half ago, represents hundreds of millions of dollars in revenue to Guidant and billions of dollars in healthcare cost savings over the course of a year. Each successive new product brings additional benefit to the patient with corresponding Guidant revenue and overall reduced healthcare costs, Lambert says. For instance, when the rate of reclogged arteries is reduced with new technology, fewer procedures are required. "It is critical, therefore, that you keep bringing innovative new products out."
Current market volume of single-use medical devices, by sterilization method.
An in-house E-beam system lets Guidant's research and development team build a new prototype, sterilize it the same day, and start testing it the next, rather than waiting a week for contract sterilization. "You can get five times as many iterations done in the same amount of time and shave months off the development cycle," Lambert says.
The in-house system improves customer responsiveness as well. At Guidant, 20% of the product catalog represents 80% of sales. They may get an order for an odd size of balloon catheter or stent only once or twice a year, for instance, when a young child needs a procedure. Then response time is of the essence. "If we get an order in the morning and we're out of stock," says Lambert, "we can manufacture, sterilize, and ship the item the same day."
HYDROGEN PEROXIDE GAS PLASMA
While EtO, gamma, and E-beam sterilize the vast majority of medical devices, Advanced Sterilization Products (ASP; Irvine, CA) offers a new alternative, the Sterrad 100 SI GMP hydrogen peroxide gas plasma system, available since 1997. Like the small E-beam system used by Guidant, the Sterrad 100 is designed for small-volume, high-value medical devices, but not long-lumened ones like Guidant's catheters and stents. The process is strictly for surface sterilization, not sterilization of products with any convoluted geometry that requires a technology to penetrate the product material to reach hidden surfaces.
The products ideally suited to hydrogen peroxide gas plasma sterilization are implantable devices, including pacemakers and orthopedic implantables.
The system injects and vaporizes a solution of 59% hydrogen peroxide into the chamber, sterilizing any package and product surfaces the vapor can reach. An electromagnetic field then creates a plasma cloud that generates free radicals that kill any remaining bacteria.
The Sterrad 100 SI GMP incorporates variable-cycle software and monitors key parameters, including hydrogen peroxide concentration, in real time. The latter feature allows manufacturers to validate for parametric release, making just-in-time sterilization possible.
Because hydrogen peroxide gas plasma sterilization is a batch process, it will not likely be suitable for high-volume commodity-type products. The production equipment costs $150,000 to $400,000, depending upon model. The largest unit, the Sterrad 800, may be cost-effective for manufacturers sterilizing as little as 30,000 cu ft per shift per year of a high-value product, says John Simmons, business director for ASP's scientific and industrial group. It will be available this fall.
Contract sterilization is still probably the best choice for most medical device manufacturers because of its suitability for both large and small companies. It also allows these companies to focus on their core competencies—R&D, design, manufacturing, and marketing.
Nevertheless, device manufacturers shouldn't rule out an in-house system just because the majority of the industry has. Cost and time savings can be realized for some companies whose needs clearly dictate bringing such a system in-house. Talking to both equipment and service suppliers can help a company determine how to best meet its needs.