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Articles from 1998 In September

Drive System Eliminates Vibration Problem in Imaging Device

Case Histories in Medical Device Manufacture

Drive System Eliminates Vibration Problem in Imaging Device

Controlling backlash essential for accurate electrophysiology imaging.

In engineering any new product, the key to success is being able to respond quickly to design problems with innovative and efficient solutions. Such was the challenge for the engineers at Trex Medical Corp., Continental Div., (Broadview, IL), in developing the CardioArc L/C positioner for use in their new EP 2000 electrophysiology imaging system.

Electrophysiology (EP) is a diagnostic procedure that determines the nature and extent of cardiac arrhythmia. Spurred by the success of two treatment therapies using electrophysiology imaging—implantable cardioverter defibrillators and RF catheter ablation—the market for EP imaging systems is growing rapidly.

To tap into this market, Trex Medical, a developer of diagnostic imaging, created the EP 2000 to provide electrophysiologists with a wide imaging range without interference from the positioner. To accomplish this, the system features a unique floor-mounted isocentric three-axis L/C positioner called the CardioArc. Shaped like a C, the design allows for imaging from the right or left side of the table to provide unobstructed access to the patient's head. The CardioArc has two joysticks controlling three motorized motions (rotational from the center point of the C, a main rotation axis at the base, and a horizontal slide movement) to provide PA, LAO, RAO, C/C, and lateral views for catheter positioning.

The EP 2000 electrophysiology imaging system with its C-shaped CardioArc isocentric L/C positioner.

The system works by having the patient recline on the tilting/elevating table. At one end of the CardioArc is a high-frequency x-ray generator with a variable pulsed fluoroscope. At the other end is a high-resolution cardiac imaging system and a 1023 progressive-scan TV camera.

To power the movements of the CardioArc, Trex first tried using dc direct drive through a dc motor controller. However, a high degree of backlash caused the entire device to vibrate significantly. In order to provide vibration-free movement of the CardioArc and to ensure highly accurate imaging, it was essential to find a way to control the drive system backlash.

"The biggest problem we faced was that the vibration was inherent to the gear reducer we were using," says Steve Talbert, a mechanical engineer for Trex Medical. "Our only way around the problem was to find another reducer, one that would provide zero backlash and quiet operation."

The WhisperDrive zero-backlash gearhead allows the CardioArc's movements to be vibration-free.

Cone Drive (Traverse City, MI), a manufacturer of precision drive systems, offered a solution with its WhisperDrive. This quiet running, zero-backlash servo gearhead employs double-enveloping worm gearing to provide the highest possible degree of positioning accuracy and smooth operation.

Given the unique shape of the CardioArc and its relation to the other components of the EP 2000 system, there was a very limited area in which the WhisperDrive could be incorporated. Fortunately, the WhisperDrive was roughly the same size as the component that Trex had previously used. "The mounting was slightly different, but not significantly," says Talbert. "We were able to incorporate the new drive by using a different mounting bracket without having to reengineer the space."

The lesson learned from integrating the WhisperDrive into the CardioArc L/C positioner can be applied to various other devices, as more and more applications are extremely intolerant to even the lowest backlash levels. To accommodate these applications, the WhisperDrive provides a high degree of position accuracy to ensure consistent, high-quality operation.

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Products Featured on the September 1998 cover of MPMN

Products Featured on the September 1998 cover of MPMN

Machining and assembly of precision components

Equipped to machine a variety of materials—including steel, stainless steel, aluminum, brass, and copper—a company can produce parts to exact specifications. Its CNC machining centers are capable of milling up to 0.0005 in. and turning to 0.0003 in., while its precision grinders provide an accuracy of ±0.0002 in. Computer-based SPC can closely track production. Thousands of parts or just a few can be manufactured. The company also performs optical and mechanical assembly, testing, and inspections to MIL-I-45208 or MIL-Q-9858 standards. Seiler Instrument & Manufacturing Company, Inc., 170 E. Kirkham Ave., St. Louis, MO 63119.

Stepper motor features round gearbox design with small footprint

By using a rounded gearbox rather than a pear-shaped one, a permanent-magnet stepper motor features a smaller footprint than standard designs. The motor measures 42 mm in diameter and is 24 mm long, while the gearbox measures 54 mm in diameter and 15 mm long. The motor/gearbox unit weighs only 11 oz. By combining this compact size with high pullout torque (5 oz-in. at 150 pps measured at the motor output shaft), designers are given a suitable choice for applications involving peristaltic pumps, valves, indexers, fluid dispensers, and syringes. Permanently lubricated, fine-pitch, sintered gearing improves gear life and contributes to the high torque rating of this round gearbox (100 oz-in. dynamic). Ball bearing versions provide added reliability based on the presence of side loads. Thomson Industries Inc., 2 Channel Dr., Port Washington, NY 11050.

RF connectors make strong terminations

RF connectors address the need to minimize assembly time while also meeting OEM requirements for strong and rugged strain relief in cable connections. The RF one-step BNC and TNC connectors terminate coaxial cables in one quick, easy step to make strong and reliable terminations. They incorporate a single-piece inner assembly that terminates the center conductor and braid of coaxial cables used in a variety of instruments. With a cable retention strength of up to 200 lb, the units create a robust soldered and insulated termination on 50- and 75- cables. The built-in strain relief that the connector provides enables the connection to stand up to rough handling or harsh conditions such as extensive vibration. Raychem Corp., 300 Constitution Dr., Menlo Park, CA 94025.

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Good News About Biomaterials, But...


Good News About Biomaterials, But...

Makers and users of implants breathed a sigh of relief recently when the House and Senate responded to a potential biomaterials shortage by signing supplier indemnification legislation in a format palatable to both sides of the political leadership.

Just before its August recess, the Senate passed the Biomaterials Access Assurance Act to protect raw materials suppliers from being included in "unwarranted" medical product liability lawsuits. Under the act, suppliers of raw materials used in medical devices can be dismissed from product liability lawsuits if the materials meet the requirements or specifications contracted with the device manufacturer. However, if the court finds evidence of negligence on the part of the material supplier, manufacturers or claimants can file post-trial motions to bring the supplier back into the liability case.

While some industry advocates attempted to expand the bill's scope beyond materials for implants to include materials for containers that collect body fluids or tissues, the final legislation appears to be well received, and offers a significant degree of protection. With the threat of product liability lawsuits removed, many of the material suppliers that withdrew from the medical market are expected to return. It's likely that small device companies without deep pockets will now be more desirable customers for material suppliers, and that their increased access to materials could result in more-sophisticated implants reaching the market.

Despite all this good news, the issue of product liability in the medical industry still looms large. While device manufacturers should be held responsible for negligent activity, the current legal system allows for extensive punitive damage rewards that can have a chilling effect on a company's business. Too many device companies have had to make business decisions to not sell a product in the United States or to discontinue development because of the liability risks.

One solution advocated by industry trade groups is to create uniform product liability standards that cap punitive damages and "pain and suffering" awards, limit attorney contingency fees, and encourage alternative dispute resolution. Such a system could protect plaintiffs with legitimate cases and also shield device companies from frivolous lawsuits or from having to pay unreasonable rewards.

Until Congress decides to face the broader product liability issue—which it clearly didn't this session—the medical device industry will continue to operate in an environment of calculated risks.

Amy Allen

Sterilization Equipment


Sterilization Equipment

Radiation technology

Working closely with its customers, a company engineers radiation sterilization facilities to meet specific requirements. The company recently installed three irradiators offering high-volume processing. Two of the irradiators are pallet facilities that process large volumes of product and provide for minimal labor requirements. They are custom designed and feature advanced automated processing as well as on-line hydraulics and stainless-steel source passes for maximum operating time and durability. The third irradiator is based on the tote irradiator design concept and is engineered for high product throughput, high cobalt efficiency, and flexible product scheduling. MDS Nordion, 447 March Rd., Kanata, Ontario K2K 1X8, Canada.

EtO gas monitoring system

An in-chamber EtO gas monitoring system is designed for the on-line measurement of the EtO concentration, relative humidity, and temperature inside the sterilization chamber during the complete conditioning and sterilization cycle. All parameters are measured by a single sensor, and a computerized evaluation of the results is provided. The intrinsically safe sensors can be placed at various desired locations within the chamber. APL Group International LLC, 862 McMeekin Pl., Lexington, KY 40502.

Sterilization system

An in-house medical device sterilization system can be integrated directly into the manufacturing process. The SureBeam system uses E-beam accelerator technology. It can sterilize individual devices at high volumes or process bulk products in their final packing cartons. The system also is small enough to fit into existing production facilities, and can be relocated to support changing production demands. Preengineered modules in the system include material-handling equipment, a self-contained shielding and safety system, and a control system. The manufacturer provides total support for the sterilizer, including installation, regulatory validation, operational procedures, and ongoing service. Titan Scan Systems, 3033 Science Park Rd., San Diego, CA 92121.

Vacuum system for autoclaves

A manufacturer has introduced a vacuum system for its autoclaves. The vacuum option provides pulsed pre- and postvacuum capabilities together with assisted drying as standard features. The system is programmed via a microprocessor following simple on-screen prompts. All eight autoclave cycles, which accommodate a variety of load types, will accept the vacuum parameters. To optimize performance, the steam generator in the electrically heated 200- and 315-L models has been upgraded to operate at 3.5 bar, and the heating power has been increased to 30 and 45 kW, respectively. LTE Scientific Ltd., Greenbridge Ln., Greenfield, Oldham OL3 7EN, England.

E-beam sterilizer

An electron-beam sterilization system is designed for in-line sterilization of medical products. The compact Minilac system occupies only 400 sq ft. In one factory application, the elapsed time between packaging the product, E-beam sterilization, and loading the product into shipping cartons was less than five minutes. The system may reduce costs by eliminating product handling between the production line and sterilizer, as well as eliminating added inventory expenses and transportation expenses associated with off-site sterilization. RPC Technologies, 21325 Cabot Blvd., Hayward, CA 94545.

EtO systems

A company offers 100% EtO sterilization systems that employ gas-diffusion technology. This technique matches the unit dose of gas exactly to load size, maximizing validation accuracy and minimizing regulatory compliance costs. Available accessories to the Sterijet and EtOGas systems include monitors, gas-disposal systems, packaging and pouches, indicators, and instrument cleaners and lubricants. H.W. Andersen Products Inc., Health Science Park, 3202 Carolina Dr., Haw River, NC 27258.

EtO sterilizers

A company designs and manufactures industrial-size, 100% EtO sterilizers. In-house welding, engineering, fabrication, and testing allow the company to maintain total quality control of its custom chambers from start to finish. Features such as its air-jacket heating system and Pro-Genesis 300 control system enhance performance and safety. In addition, the company offers a wide range of accessory equipment, feasibility studies and engineering services, postpurchase maintenance contracts, and system upgrades. Environmental Tectonics Corp., 125 James Way, Southampton, PA 18966.

PLC-controlled sterilizers

Automatic, PLC-controlled 100% EtO sterilizers are designed for the low-volume medical device manufacturer. The Magnaflux sterilizers are available with chamber capacities of 200, 500, and 1000 L. The systems are designed in accordance with AAMI ST24, NFPA 560, and ISO 11135 standards. Gas supply inlets can be configured for use with disposable cartridges or stand-alone cylinders. Each sterilizer is equipped with a built-in steam generator that is used for dynamic steam conditioning of the product. Quetzal International Inc., Luxembourg Corporate Center, 414 Executive Dr., Langhorne, PA 19047.

E-beam sterilization systems

Designed for in-house sterilization of medical products, an E-beam sterilizer is rated at 10 MeV and can be configured for maximum power between 15 and 35 kW. The compact Rhodotron TT100 is the smallest member of the Rhodotron family of E-beam accelerators. According to its manufacturer, a recent installation of the system for a medical device manufacturer demonstrated its advantages, particularly in ease of product handling and tracking combined with rapid processing. Ion Beam Applications, Chemin du Cyclotron 3, B-1348 Louvain-la-Neuv, Belgium.

Laser Scanning Detects Microbial Contamination

Sterilization Testing

Laser Scanning Detects Microbial Contamination

Faster results mean quicker product release to market

TESTING THE EFFECTIVENESS of a sterilization process can often take longer than desired. Traditional testing for microbial contamination in sterilized products or packaging involves growth-based methods that can take up to two days.

The Scan RDI system from Chemunex S.A. (Maisons-Alfort, France) is designed to detect and identify microorganisms in less than 90 minutes. Used in a laboratory or production environment, the system provides quantitative real-time in-process bioburden results down to a single cell, ensuring that sterilization systems and procedures have effectively destroyed any microbial contamination.

Scan RDI uses a simple three-step protocol that includes membrane filtration, cell labeling, and laser scanning. After filtration, cells are labeled with Fluoroassure reagents, a sophisticated technique that works with fungi, bacteria, spores, and stressed and fastidious cells. Then, the in-process bioburden level can be checked in less than 90 minutes using the system's high-speed laser scanner—considerably less time than the two-day average to complete such testing with growth-based methods.

With high-speed laser scanning, samples can be loaded every three minutes. Direct cell detection means there is no need for complex statistical interpretation of the data.

For more information, contact Chemunex S.A. (France) at +33 143 96 9200.

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Styrenic Compounds Introduced to North American Market

Materials are flexible, recyclable, and easy to process

A LINE OF STYRENIC block copolymer compounds that have been widely used in Europe is now being offered to the North American market. Manufactured by AlphaGary Corp. (Leominster, MA), Evoprene thermoplastic compounds exhibit high elongation and good recovery, making them a viable substitute for latex and silicone in medical applications.

According to global business manager Derek Fraser, the Evoprene compounds have a proven track record overseas, and offer significant advantages to both processors and end-users. Available in five different grades, Evoprene can be processed using standard thermoplastic machinery, usually without predrying. All grades are fully recyclable and compatible for bonding with polystyrene or polypropylene.

The compounds' high elongation makes them appropriate for caps of drug-delivery ports, providing a closure that won't tear or damage upon removal. In addition, the compounds' good recovery after compression makes them suitable replacements for silicone in peristaltic pumps. According to the manufacturer, Evoprene is also less costly than silicone and easier to fabricate. As Fraser says, Evoprene provides "a cost-effective alternative to rubber, and, with the exception of flame-retardant grades, is halogen free."

Designed for high-temperature and high-performance applications, the Evoprene Super G–grade compounds are available from 30 to 80 durometer Shore A. Compared with other TPEs of similar durometer, the low-compression Evoprene Super G compounds have less tendency to "neck" when stretched over rigid parts. This grade is also capable of being used in service temperatures as high as 285°F and as low as –40°C.

For more information, contact AlphaGary Corp. at 978/537-8071.

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New Equipment

Pump Offers Accurate Metering without Leakage

Digital control increases ease of use

COMBINING THE ACCURACY of a syringe pump with the continuous flow and low pulsation of a piston pump, the Travcyl system from Encynova International Inc. (Broomfield, CO) offers precision fluid dispensing and metering without leakage.

Incorporating ceramics and other inert wetted parts, the Travcyl pump can be used in a number of medical applications, including kidney dialysis, chromatography, titration, and preparation of IV solutions.

The pump uses alternating pistons to draw and expel liquid from openings within sliding port plates. While sliding, the ceramic port plates form a hermetic seal that does not allow for fluid leakage. These port plates offer a recessed area that matches the tip of the piston, forming a tight seal without dead volume. Because there is no clearance between the sliding surfaces of the pumping elements, fluid is never squeezed between parts—an advantage for medical processes involving the pumping of cells or proteins. Using the Travcyl, cells and proteins will never be crushed or squeezed during pumping.

Designed for easy use, the Travcyl features digital control for increased precision. Digital control also offers variable programming without the need for calibration at start-up. As a result, the pump requires only the push of a button to begin working.

The pump requires no lubrication, and offers a valveless design with short fluid paths, making the system easy to clean for medical applications. In addition to keeping pulsation low during operation, the pump's four manifolds can also be removed for easy cleaning of the fluid paths.

For more information, contact Encynova International Inc. at 303/404-3583

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Advances in Materials and Manufacturing Technologies Highlighted at MD&M East

Advances in Materials and Manufacturing Technologies Highlighted at MD&M East

New developments in adhesives, laser marking, and extrusion explored

According to experts speaking at a seminar presented at the Medical Design & Manufacturing (MD&M) East Conference and Exposition in New York City held June 2–4, medical device manufacturers can use a variety of new adhesives to improve product performance. Patrick J. Courtney, senior application engineer for Loctite Corp. (Rocky Hill, CT), discussed how recent developments in cyanoacrylates—one-part adhesives curable at room temperature—are worth considering. Courtney said, "Performance limitations of early generations of cyanoacrylates, such as poor thermal resistance and peel strength, have led to various product improvements that include fixture in seconds, room-temperature cure, and excellent adhesion to substrates."

According to Stephen Cantor of Dymax (Torrington, CT), advances in UV/visible-light curing adhesives also provide a range of benefits including faster cures, safe visible (blue) light, and bonding of UV-blocked or tinted plastics.

Stephen Cantor of Dymax described recent developments in UV adhesives and Patrick Courtney of Loctite discussed advances in cyanoacrylates during MD&M East.

At another seminar, "The Basics and Beyond: A Practical Guide to Better Injection Molding," the theory and practice of this increasingly important technology was discussed. The seminar's instructor, Robert Beard of Robert A. Beard & Associates (Kenosha, WI), provided updates on materials, mold and part design, equipment, and troubleshooting. The importance of employing the correct mold was emphasized in an overview of mold design that highlighted the different types of injection molds. The seminar's participants were also updated on injection molding software that can help to prevent mistakes and achieve satisfactory outcomes.

New laser marking technologies were discussed in the seminar, "Laser Marking of Medical Devices: Advances and Applications." Traditional marking methods such as direct printing and labeling have many disadvantages that can be overcome with laser marking, according to Alan Burgess of M.A. Hanna Color (Suwanee, GA) and Ronald Shaeffer of PhotoMachining (Pelham, NH). The most serious problem is that traditional printing methods do not make permanent marks. Sterilization, contact with chemicals and body fluids, or simply wear over time can render a mark or label unreadable. To have this happen to warning labels or marks is simply unacceptable in the medical industry, the speakers agreed. Laser marking eliminates this problem by making permanent marks. A further advantage of laser marking is that the mark can be applied at high speed and in-line, whereas direct printing and labeling must often be accomplished in secondary operations. "Typically, marking a plastic part costs four or five times the cost of the part itself," Burgess explained. "With laser marking, you can typically cut that cost in half."

MD&M East featured products and services from more than 700 companies.

The increasing popularity of bar coding has fostered different forms of the technology—and medical device manufacturers and packagers must make sure they are using the kinds of bar codes that their customers want. That was the consensus at one of the seminars given at the third annual Medical Packaging Symposium, held in conjunction with MD&M East. According to Bonney Stamper Shuman, CEO of Stratix Corp. (Norcross, GA), many companies will not do business with those who do not use bar codes or some sort of identification technology. "You should look at your customers' needs, because doing so can bring you all sorts of benefits," Shuman said. "Find out what they use today and what they might be ready for in the future. Figure out their item-level and carton-level requirements."

At another Medical Packaging Symposium seminar, Cathy Nutter, senior scientific reviewer at FDA's Center for Devices and Radiological Health (CDRH), said that medical device packagers may not need to present as much data to FDA as they used to before the FDA Modernization Act of 1997, but they will have to make sure they have thorough documentation in their own files.

Nutter said that the agency is in the process of implementing the new regulations with the goal of forming consistent standards from guidance to enforcement. Though it is too early to tell what all the end results will be, she said that there are several things that those in the medical device industry should keep in mind. "First, know your standards well and which ones apply to your device. Second, just as location is important in real estate, documentation is important in regulation. Third, stay tuned to the CDRH Web site for guidance updates."

Some of the MD&M East show's attendees actually spent the first day of the show in Connecticut, where they toured Harrel Inc. to learn about medical tubing extrusion systems. The company's focus is on complete automation of each step in the extrusion process. Benefits of this automated system are multifold. A process engineer can determine and enter specific parameters for any given day, at which point a floor operator need only open a computer file and run it. System software runs continuous surveillance of all process parameters and makes any necessary adjustments to keep production running smoothly. This capability greatly reduces operator labor and virtually eliminates human error.

The MD&M East Conference and Exposition and the Medical Packaging Symposium were attended by nearly 6000 people. More than 700 companies exhibited their products and services.

The next MD&M Conference and Exposition will be held in Minnesota, November 2–4. For information, call the trade show department at Canon Communications LLC, 310/392-5509.

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New on the Industry Landscape

Norton Performance Plastics (Wayne, NJ) established a 22,000-sq-ft polymer technology center at its corporate headquarters. The center was created to provide multidisciplinary support for the firm's 11 decentralized R&D teams, undertake long-term development projects, and conduct research on glass and plastic composites for Norton's parent company, Saint-Gobain. Product testing firm Intertek Testing Services (Boxborough, MA) opened a 44,700-sq-ft testing campus to incorporate its global product testing and certification services. The thermoplastic elastomers division of GLS Corp. (Cary, IL) is establishing a new facility in McHenry, IL, with a completion date scheduled for mid-December. Construction for Dow Chemical's Freeport, TX, Inspire polypropylene production facility is expected to be completed in 2000. According to Dow, the facility will use Spheripol technology and will produce more than 500 million lb of polypropylene per year. Laser micromachining company Resonetics Inc. (Nashua, NH) added a 2000-sq-ft environment-controlled cleanroom to its facility. AlphaGary Corp. (Leominster, MA) is enlarging AW Compounders, its manufacturing company in Stoney Creek, Ontario, Canada. The 25,000-sq-ft expansion will include a new twin-screw compounding line, which will increase capacity by 10 million lb per year. Fractional and subfractional dc motor maker Maxon Precision Motors (Burlingame, CA) opened a facility in Fall River, MA, to house administrative, sales, and marketing offices, as well as a model shop and warehouse. Adhesives Research (Glen Rock, PA) is constructing a 24,000-sq-ft manufacturing facility in Limerick, Ireland, that is expected to be completed by the year's end. Miniature air pump manufacturer Sensidyne Inc. has completed construction of its dust-free manufacturing room within its Clearwater, FL, facility.

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Acquisitions and Business Action

Cincinnati Milacron's Plastics Technology Group (Batavia, OH) expanded its presence in the vertical insert injection molding machinery market with its purchase of Autojectors Inc. (Avilla, IN). Autojectors will maintain its company name, operations, and separate distribution channels. MetroLine Industries (Corona, CA) has acquired the Branson/IPC line of batch plasma systems from GaSonics (San Jose), adding plasma equipment to MetroLine's plasma surface-treatment operations. Testing systems maker MTS Systems Corp. (Eden Prairie, MN) reached an agreement to acquire Nano Instruments Inc. (Oak Ridge, TN), a manufacturer of instrumented indentation systems for ultra-low-force nanoindentation testing of surfaces and thin films. Nano Instruments markets three mechanical properties microprobe systems for low- and ultra-low-load indentation testing, including a dynamic contact module for the biomedical industry. Tektagen Inc. (Malvern, PA), a biosafety and bioanalytical testing service firm, was acquired by Charles River Laboratories (Wilmington, MA). Davis-Standard Corp. (Pawcatuck, CT) acquired the complete extrusion machinery business of Betol Machinery (Luton, UK). Assembly and packaging services provider GDM Electronic & Medical (Milpitas, CA) is teaming up with contract sterilization and irradiation services provider Nutek Corp. (Hayward, CA) to offer combined services as one vendor. Dispensing equipment manufacturer Liquid Control Corp. (North Canton, OH), through its acquisition of Florida-based Decker Industries Inc., expanded its offerings to include two-component polyurethane processing equipment. Molded Rubber & Plastics Corp. (Butler, WI) completed its purchase of Beere Precision Silicone Rubber Products (Racine, WI). Beere, an extruder of precision silicone tubing, will operate as the extrusion division of Molded Rubber & Plastic Corp. Full-service plastic thermoformer and fabricator Specialty Manufacturing Inc. (San Diego) acquired Protogenesis, a 3-D CAD/CAM company specializing in mechanical design, prototyping, modeling, and CNC-machined tooling. Protogenesis has moved to SMI's manufacturing facility. Anorad Corp. (Hauppauge, NY) was honored with the Hauppauge Industrial Association 1998 Business Achievement Award for large firms.

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Refractive Surgical Device Benefits from Plastic Construction

Refractive Surgical Device Benefits from Plastic Construction

Because of their wide range of properties, ability to be sterilized, and economical benefits, plastics are being used in place of metals in a number of medical devices. For Refractive Technologies Inc. (Cleveland), selecting the appropriate material was key to the viability of developing the first predominantly plastic microkeratome for refractive ophthalmological procedures. The new device, which provides ease of use, accuracy, and safety while allowing for significant parts consolidation and cost containment, is made almost entirely of a polycarbonate resin.Developed by Alex Dybbs of Refractive Technologies, the FLAPmaker is an innovative, single-use, disposable microkeratome device designed to make a flaplike cut (about 0.16 mm) with a metal blade into the top layer of the cornea for refractive eye surgeries that involve the use of a laser. In these procedures, which are commonly performed to correct nearsightedness, the surgeon folds the flap back, applies laser sculpting techniques to reshape the cornea, and then puts the flap back in place. Dybbs himself was the first patient to receive this surgery using the FLAPmaker.

A Need for Improvement

As the popularity of refractive procedures has grown, there has been a need to improve existing metal microkeratomes, which require resterilization, extensive assembly, and precise blade positioning before every procedure. "The metal instrument dictates a high level of maintenance and knowledgeable technical support to ensure proper use," explains Dybbs. "There is also a learning curve involved with understanding how to correctly assemble the device and the safety risks involved with not assembling it correctly. The FLAPmaker was designed to eliminate these problems."

The FLAPmaker is the first predominantly plastic microkeratome for refractive ophthalmological procedures. Its manufacturer, Refractive Technologies, found that using plastic has helped make the device safer and easier to use than metal microkeratomes.

The FLAPmaker is molded out of a clear polycarbonate to allow the surgeons to easily see the cornea during the procedure. The device is gearless for smoother operation and features a fixed depth plate to reduce the risk of unwanted cuts to the cornea. It also saves time since it is preassembled, unlike metal microkeratomes, which contain many tiny parts that must be assembled before each procedure.

"The FLAPmaker device is identical in principle to other microkeratomes, but through the use of plastic, it's safer, more ergonomic, easier to take care of, and easier to use," explains Jeffrey B. Robin, a refractive surgeon and medical director of the NuVista Refractive Surgery and Laser Center in Cleveland. Robin is also president of the International Society of Refractive Surgery and has served as an adviser to Refractive Technologies throughout the development of the FLAPmaker.

According to Dybbs, surgeons performing these types of procedures are most concerned with the consistency of the instrument. For example, with existing microkeratomes, care must be taken to set the depth plate precisely to avoid making a larger cut in the cornea than is necessary. This complication is not possible with the FLAPmaker, as it features a verification of the depth plate "gap" and a microscopic photograph of the blade. "Each unit is inspected through quality control procedures to assure surgeons of the device's accuracy. The claim specification included with each unit lists the margin of error with regard to the thickness of the cut and the quality of the blade," explains Dybbs.

Surgeons also want to ensure that the flap cut does not go completely across the cornea, creating a free cap, and requiring additional recovery time. "Metal designs have a stop screw to prevent the blade from completely disconnecting the flap from the eye, but again, if the instrument is not set up correctly, this is a useless function," notes Robin. "The FLAPmaker is preset to go only a certain distance, thus eliminating these situations."

Choosing a Plastic

"Without a doubt, plastic was the material of choice for this application, due to its strength, its design flexibility, and its ability to allow the device to be delivered to the surgeon preassembled and to be disposed of after use," says Dybbs.

Refractive Technologies contacted Dow Plastics (Midland, MI) and requested a plastic with excellent optical properties and resistance to gamma sterilization. The material also had to be able to run in existing mold designs. Dow worked with Refractive Technologies to provide the selection, technical support, and material training assistance required to meet these needs. After conducting several tests, Refractive Technologies selected Calibre MegaRad polycarbonate resins.

"Calibre resins meet the processing requirements of the device while allowing the molder to maintain consistent dimensions in the finished part to within ±0.01% of the specified tolerances," says Karen Winkler, a senior applications development engineer at Dow Plastics.

The Benefits

According to Winkler, Calibre MegaRad resins were developed in direct response to the need for improved clarity in medical devices that undergo high-energy radiation (gamma or electron beam). Calibre MegaRad resins offer clarity, dimensional stability, high impact strength, and heat resistance. Available in a range of melt-flow rates, these resins enable the molder to design specific properties into the finished parts.

According to Dybbs, while the properties and processing characteristics of the polycarbonate resins used in the FLAPmaker were primary concerns, minimizing the cost and complexity of the device was also important. "The finished FLAPmaker microkeratome consists of only five plastic parts compared to the approximately 25 in existing metal microkeratomes," says Dybbs. "The use of plastic has made the FLAPmaker an economical alternative to existing metal microkeratomes, which can cost up to six times more."

Additionally, the flaps made with the FLAPmaker are thicker, more consistent, and of a better quality. "The flaps are smoother and fit back over the eye much easier than a thinner, uneven flap. This also helps speed up recovery time," says Robin.

To date, the FLAPmaker has been used successfully by more than 28 surgeons around the world. The device, which went from concept to prototype in four months and was developed in just under a year, is expected to receive FDA approval this year.

MPMN is actively seeking success stories like this. If your company has one to tell, please contact associate editor Karim Marouf at 3340 Ocean Park Blvd., Ste. 1000, Santa Monica, CA 90405; 310/392-5509 or E-mail

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Electronic Connectors

Electronic Connectors

Cylindrical push/pull connectors

Precision-engineered cylindrical push/pull connectors feature matte-chromated metal shells in different sizes. Inserts are made of various materials, including PEEK, LCP, PBT, and Teflon. Steam autoclaving is possible with connectors having PEEK or LCP inserts. A broad range of contact arrangements and contact styles offers the flexibility to address all design challenges. Contacts include signal, power, coaxial, fiber-optic, and air and fluid couplings. ODU-USA, 451 Constitution Ave., Unit A, Camarillo, CA 93012.

Microminiature connectors

A threaded metal housing is now available to fit all three shell sizes of a series of electronic connectors. The lightweight housings offer a high degree of durability and mechanical integrity. An O-ring is available to ensure a water-tight seal. Both the plastic-and metal-shell versions are polarized to prevent mismating. The units provide high reliability on a 0.050-in. centerline. They are suitable for medical applications requiring rugged durability and reliable performance. Omnetics Connector Corp., 7260 Commerce Circle E., Minneapolis, MN 55432.

Insulation displacement connectors

Disconnectable, insulation displacement connectors feature a 2.5-mm pitch and a height and width of only 11.3 x 4.1 mm. Their small size and low cost make them especially suited for high-density electronic equipment. These insulation displacement connectors are offered with 2 to 13 circuits of AWG #28-26-24 wire. Current rating is 2.0 A ac/dc at 250 V ac/dc. Contacts are phosphor bronze, tin plated. A metallic strain relief secures the wire to protect the IDC connection from vibration, impact, or other external forces. J.S.T. Corp., 1957 S. Lakeside Dr., Waukegan, IL 60085.

Circular connectors

A company designs, manufactures, and distributes an extensive selection of electronic connectors for applications in medical electronics. More than 30 intermatable sealed and unsealed body types are available for cable and panel mounting. Contact configurations include coaxial, triaxial, multipole, mixed, high-voltage, and thermocouple. Standard and custom designs are available. The connectors feature precision-machined shells of brass, stainless steel, or aluminum, as well as high-performance plastic-shell versions. W. W. Fischer Inc., 115 Perimeter Center Pl., Ste. 1060, Atlanta, GA 30346.

Waterproof connectors

A series of high-performance waterproof circular connectors have been developed for interfaces used with a variety of electronic equipment. The JR-W connectors are also corrosion resistant in order to be used even in adverse environments. Plated with black chromium, the connectors offer smooth connections provided by five guide points. Various shell sizes and core numbers are available. Hirose Electric Inc., 2688 Westhills Ct., Simi Valley, CA 93065.

Binding posts

Binding posts are available with a selection of red, white, blue, yellow, black, or green rings embedded in the thumb nuts to ensure ready circuit and polarity identification. The Custom Color Ring 5-Way binding posts feature gold-plated brass current-carrying parts that provide maximum conductivity and corrosion resistance. Miniature fluted-nut types are rated for 15 A, 1000 V working. Standard hex-nut and fluted-nut types are rated for 30 A, 1000 V working. Hex- and fluted-nut types with larger studs are also available. Warner Electric, 383 Middle St., Bristol, CT 06010.

Waterproof locking ac power connectors

Locking ac power connectors are designed for test and measurement, computer, lighting, and industrial applications. The PowerCon system consists of the NAC 3 FPA A-type for power inlets and the NAC 3 FPB B-type for power outlets. Each offers a three-pole connection system with contacts for live, neutral, and protective ground handling power up to 20 A/240 V. Design specifications include meeting the safety requirements of prevailing international and European standards. Neutrik USA, 195 Lehigh Ave., Lakewood, NJ 08701.

Zero-insertion-force connectors

High-density zero-insertion-force connectors offer a pinless configuration. They are used primarily in high-resolution cable arrays for diagnostic ultrasound applications. Available in up to 648 positions, low-inductance Interposer contacts connect to the instrument through printed wiring board technology. AMP Inc., P.O. Box 3608, Harrisburg, PA 17105.

Micro PCB terminal block

According to its manufacturer, a micropitch PCB terminal block with 2.54-mm pin spacing and a 6-mm height is the smallest screw-clamp terminal block available. Rated at 6 A, 125 V, the Model MPT 0.5 has a generous cross section of 0.5 mm2 (#20 AWG) and is available in 2 to 12 positions. This terminal block can be used in any application where a wire needs to be brought to a PCB, and it will fit in applications where larger ones will not. Phoenix Contact Inc., P.O. Box 4100, Harrisburg, PA 17111.

Nine-position circular connector

A high-density cable-to-chassis and cable-to-cable nine-position connector is suitable for medical, process control, and test and measurement equipment. The compact plastic connector offers a 1.732-in. mating length and 0.512-in. OD with 1-A crimp or solder-cup contacts. The rugged Ultem housings and low-force contact system provide more than 10,000 mating cycles. Hypertronics Corp., 16 Brent Dr., Hudson, MA 01749.

Circular connectors

Circular connectors are available in single-, multi- or mixed-contact insert configurations including coaxial, triaxial, high-voltage, fiber-optic, fluidic/pneumatic, and thermocouple. They also feature a wide variety of shell styles including standard chrome-plated brass, environmentally sealed versions, and plastic or underwater threaded-type designs. Cable assemblies and custom designs are also available. LEMO USA Inc., P.O. Box 11488, Santa Rosa, CA 95401.

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Conducting Health-Based Risk Assessments of Medical Materials

Medical Plastics and Biomaterials Magazine
MPB Article Index

Originally published September 1998


Although every medical manufacturer desires to construct its devices from entirely safe materials, the reality is that not all materials are entirely safe. Generally, if one looks long enough at small enough quantities, some type of risk can be associated with every material.

A risk assessment of nitinol devices supported their use in vascular implants. Photo: David Fukumoto; Nitinol Devices & Components, Inc.

Risk can be defined as the possibility of harm or loss. Health risk, of course, is the possibility of an adverse effect on one's health. Risk is sometimes quantified by multiplying the severity of an event times the probability the event will occur, so that

While this equation appears useful in theory, in practice it is difficult to apply to the biological safety of medical devices. The process known as health-based risk assessment attempts to provide an alternative strategy for placing health risks in perspective.

Standards and Guidances

A paradigm for the risk assessment process has been detailed in a publication prepared by the U.S. National Academy of Sciences.1,2 Although devised primarily for cancer risk assessment, many of the provisions also apply to the assessment of other health effects. The major components of the paradigm are (1) hazard identification, (2) dosage-response assessment, (3) exposure assessment, and (4) risk characterization.3

This general approach to risk assessment was adapted to medical devices via the draft CEN standard Risk Analysis, published in 1993,4 and more recently via the ISO standard, ISO 14538—Method for the Establishment of Allowable Limits for Residues in Medical Devices Using Health-Based Risk Assessment, published in 1996.5 At the present time, FDA is also working to develop a health-based risk assessment protocol adapted to medical devices. Informally called the Medical Device Paradigm, the document is not yet generally available.6,7

Some manufacturers may object that regulators are once again attempting to impose a "drug model" on medical devices. However, we shall see in the following pages that judicious application of these risk assessment principles can provide a justification for using materials that carry with them some element of risk, and that may, under traditional biocompatibility testing regimes, be difficult to evaluate or be deemed unsuitable for medical device applications.


Hazard Identification. The first step in the risk assessment process is to identify the possible hazards that may be presented by a material. This is accomplished by determining whether a compound, an extract of the material, or the material itself produces adverse effects, and by identifying the nature of those effects. Adverse effects are identified either through a review of the literature or through actual biological safety testing.

Dose-Response Assessment. The second step is to determine the dose response of the material—that is, what is the highest weight or concentration of the material that will not cause an effect? This upper limit is called the allowable limit. There are numerous sources in the literature of data from which to determine allowable limits; some will be more applicable than others, and some may require correction factors.

Exposure Assessment. The third step is to determine the exposure assessment by quantifying the available dose of the chemical residues that will be received by the patient. This is readily done by estimating the number of devices to which a patient is likely to be exposed in a sequential period of use (for instance, during a hospital stay) or over a lifetime. For example, a patient might be exposed to 100 skin staples following a surgical procedure, or to two heart valves in a lifetime; thus, the amount of residue available on 100 skin staples or two heart valves would be determined.

Risk Characterization. Characterizing the risk constitutes the final step of the process. The allowable limit is compared with the estimated exposure: if the allowable limit is greater than the estimated exposure by a comfortable safety margin, the likelihood of an adverse event occurring in an exposed population is small, and the material may be used.

Case Studies

We can best get a sense of how these standards work by looking at some actual medical case studies that illustrate the risk assessment process.8

Nitinol Implant. Nitinol is an unusual alloy of nickel and titanium that features the useful property of "shape memory." A nitinol part can be given a particular shape at a high temperature, then cooled to a low temperature and compressed into some other shape; the compressed part will subsequently deploy to its original shape at a predetermined transition temperature. This feature is particularly beneficial for vascular implant applications in which the shape of the device in its compressed state eases the insertion process. The nitinol deploys as it is warmed by the surrounding tissue, expanding to take on the desired shape of a stent, filter, or other device. The transition temperature depends on the alloy's relative concentrations of nickel and titanium: a typical nickel concentration of 55–60% is used in medical devices, since this gives a transition temperature at approximately the temperature of the body (37°C).

Hazard Identification. One concern with using nitinol in implant applications is the potential release of nickel into the body. Although nickel is a dietary requirement, it is also highly toxic—known to cause dermatitis, cancer subsequent to inhalation, and acute pneumonitis from inhalation of nickel carbonyl, and to exert a toxic effect on cellular reproduction. It is a known sensitizer, with approximately 5% of the domestic population allergic to this common metal, probably through exposure from costume jewelry and clothing snaps. The biocompatibility question at hand is whether or not in vivo corrosion of nitinol releases unsafe levels of nickel.

Dose-Response Assessment. A search of the world medical literature revealed that the recommended safe level of exposure to nickel in intravenous fluids is a maximum of 35 µg/day.9 This value can be taken as an allowable limit of nickel exposure for a 70-kg (154-lb) adult.

The intravenous fluid data are based on subjects that are comparable to the patients who will be receiving nitinol implants. The data are for humans (not animals), for ill patients (not healthy workers or volunteers), and for similar routes of exposure (intravenous fluid and tissue contact). For these reasons, no safety correction factor need be applied to the allowable limit of exposure.

Exposure Assessment. The available dose of nickel from nitinol implants can be estimated from data found in the literature. In one study, dental arch wires of nitinol were extracted in artificial saliva, and the concentration of nickel measured in the supernatant. Corrosion reached a peak at day 7, then declined steadily thereafter. The average rate of corrosion under these conditions was 12.8 µg/day/cm2 over the first 28 days.

Risk Characterization. A comparison of the available dose with the allowable limit for intravenous fluid levels shows that there is approximately a threefold safety margin, assuming that the implanted device is a full 1 cm2 in surface area. (Devices with less surface area will contribute even less to the nickel concentration and have an even larger safety margin.) Considering the high quality of the data, a threefold safety margin is sufficient to justify using nitinol in vascular implants.

Wound-Dressing Formulation. Today's wound dressings are highly engineered products, designed to maintain the moisture content and osmotic balance of the wound bed so as to promote optimum conditions for wound healing. Complex constructions of hydrocolloids and superabsorbers, these dressings are sometimes used in direct tissue contact over full-thickness wounds that penetrate the skin layers.

Hazard Identification. There have been reports in the literature of patients succumbing to cardiac arrest from potassium overload, with the wound dressing as one of the important contributors of excess potassium in the bloodstream. The effects of potassium on cardiac function are well characterized. Normal serum levels for potassium are 3.8 to 4 milliequivalents per liter. As the potassium concentration rises to 5—7 mEq/L, a patient can undergo cardiac arrest and die. The biocompatibility issue to be explored is whether or not a wound-dressing formulation might release dangerous levels of potassium if used on full-thickness wounds.

Dose-Response Assessment. An increase of approximately 1 mEq/L of potassium is likely to provoke mild adverse events in most patients. Assuming that the average person's blood volume is 5 L, a one-time dose of 5 mEq of potassium may begin to cause adverse reactions. This value can be considered to be the allowable limit of potassium for most patients.

Exposure Assessment. Let us suppose that each dressing contains 2.5 g of potassium bicarbonate. Since the molecular weight of potassium bicarbonate is 100 g/mole, each dressing contains 0.025 mole of sodium bicarbonate, or 0.025 mEq of potassium ion. If a patient were to use four dressings in a day, the available dose of potassium would be 0.1 mEq/day.

Risk Characterization. Comparing the available dose of potassium (0.1 mEq) to the allowable limit (5 mEq) shows that there is a 50-fold safety margin. Considering that patients may be small in size, may have kidney impairment, or may receive potassium from additional sources such as intravenous fluids, this safety margin is too small, and so the dressing should be reformulated.

Perchloroethylene Solvent. A manufacturer of metal fabricated parts uses perchloroethylene to clean the finished pieces. Perchloroethylene has many advantages as a cleaner and degreaser: it is highly volatile, does not damage the ozone layer, and is very effective as a precision cleaning solvent (see Figure 1). The most common use of perchloroethylene is in the dry cleaning industry, but it is also commonly used in the electronics industry to clean circuit boards.

Figure 1. The chemical structure of perchloroethylene.

Hazard Identification. The downside of perchloroethylene is that it is highly toxic, with a material safety data sheet several pages in length listing adverse effects ranging from dizziness to death. Biocompatibility testing on solvent-cleaned parts would be meaningless; the solvent concentration on the part is so small that any effects of the solvent would be masked by the natural biological process of the test animals. The biocompatibility question that must be answered is whether or not sufficient residual perchloroethylene remains on the cleaned metal parts to pose a health hazard.

Dose-Response Assessment. Threshold limit values (TLVs) are values that indicate the maximum level of a chemical that a healthy worker could take in on a daily basis over the course of his or her work life without experiencing any adverse effects. The TLV for perchloroethylene is 50 ppm/day (50 ml of perchloroethylene per 103 liter of air) by inhalation. The average person inhales 12,960 L of air per day, making this equivalent to 650 ml of perchloroethylene per day. Since the vapor density of perchloroethylene is 5.76 g/L, the TLV is equal to 3.7 g of perchloroethylene per day by inhalation.

Because TLVs for inhalation—as opposed to direct tissue exposure—are determined based on healthy individuals (not ill patients), we will divide the TLV by an uncertainty factor of 100, i.e., 10 to account for a different route of exposure and 10 to account for healthy-to-ill persons. By this method, we obtain an allowable perchloroethylene limit of 37 mg/day.

Exposure Assessment. To calculate an available dose of perchloroethylene, we need some additional information. In this case, the manufacturer brought a number of cleaned metal pieces into equilibrium within a closed jar, then analyzed the headspace above the pieces by using high-pressure liquid chromatography to determine the concentration of perchloroethylene released. The concentration of perchloroethylene was undetectable by high-performance liquid chromatography. Since the limits of this analytical method are 2 ppb, this value was taken as the concentration of perchloroethylene in the headspace. Taking the weight of the metal pieces, the number of pieces tested, and the volume of the headspace, it was calculated that the amount of perchloroethylene per single piece was a maximum of 1.0 ng/piece. If we suppose that a patient might be exposed to a maximum of 50 pieces over a lifetime, then the maximum available dose of perchloroethylene from the pieces would be 50 ng.

Risk Characterization. A comparison of the available dose (50 ng) to the allowable limit (37 mg/day) indicates an ample safety margin.

Ligature Material. A manufacturer purchases commercial, black fishing line to use as a ligature in a circumcision kit. Because the ligature is not "medical grade," a cytotoxicity test is routinely conducted as an incoming inspection test. It was assumed that a negative cytotoxicity test would be associated with an acceptable incidence of skin irritation.

Hazard Identification. A newly received lot of the fishing line failed the cytotoxicity test. The extraction ratio of this material—of indeterminate surface area—was 0.2 g/ml, with a 0.1-ml aliquot of sample extract being applied to a culture dish. Thus, 0.2 g/ml x 0.1 ml = 0.02 g represents a toxic dose of fishing line.

Dose-Response Assessment. A titration curve was obtained on the sample extract. If the sample was diluted 1:2, the test was still positive; however, if the sample was diluted 1:4, the test was negative. Thus, 0.02 g/4 = 0.005 g of fishing line, the maximum dose that is not cytotoxic. This value was called the allowable limit of fishing line.

Exposure Assessment. Each circumcision kit contained about 12 in. of line, but only about 4 in. of the material was ever in contact with the patient. Since an 8-yd line was determined to weigh 5 g, the available dose of fishing line was calculated to be 5 g/288 in. x 4 in. = 0.07 g.

Risk Characterization. A comparison of the available dose (0.07 g) with the allowable limit (0.005 g) convinced the manufacturer to reject the lot of fishing line.

Sources of Data

Data for calculating the allowable limit of exposure to a material can come from many sources, most of them promulgated by industrial and environmental hygienists and related agencies.10

Threshold Limit Values (TLVs) are time-weighted average concentrations of airborne substances. They are designed as guides to protect the health and well-being of workers repeatedly exposed to a substance during their entire working lifetime (7–8 hr/day, 40 hr/wk). TLVs are published annually by the American Conference of Governmental Industrial Hygienists (ACGIH).11 Biological Exposure Indices (BEIs) are also published annually by ACGIH. These are the maximum acceptable concentrations of a substance at which a worker's health and well-being will not be compromised.

Other published guides include Workplace Environmental Exposure Levels (WEELs), from the American Industrial Hygiene Association; Recommended Exposure Limits (RELs), from the U.S. National Institute for Occupational Safety and Health; and Permissible Exposure Limits (PELs), from the U.S. Occupational Safety and Health Administration.12–14 In the United States, PELs have the force of law.

Another important limit measurement, Short-Term Exposure Limits (STELs), are defined as the maximum concentration of a substance to which workers can be exposed for a period of up to 15 minutes continuously, provided that no more than four excursions per day are permitted, and with at least 60 minutes between exposure periods. The STEL allows for short-term exposures during which workers will not suffer from irritation, chronic or irreversible tissue damage, or narcosis of sufficient degree to increase the likelihood of injury, impair self-rescue, or materially reduce work efficiency. Some substances are given a "ceiling"—an airborne concentration that should not be exceeded even momentarily. Examples of substances having ceilings are certain irritants whose short-term effects are so undesirable that they override consideration of long-term hazards.

Uncertainty Factors

An uncertainty factor is a correction that is made to the value used to calculate an allowable limit. It is based on the uncertainty that exists in the applicability of the data to actual exposure conditions. Typically, uncertainty factors range in value from 1 to 10. For example, a correction factor of 10 might be applied for data obtained in animals rather than humans, or to allow for a different route of exposure. In other words, for every property of available data that is different from the actual application, a correction factor of between 1 and 10 is applied. If our first example had been of a small amount of data obtained in animals by a different route of exposure, an uncertainty factor of 1000 might be applied.

Safety Margins

A safety margin is the difference or ratio between the allowable limit (after correction by the uncertainty factor) and the available dose. How large does a safety margin need to be? Generally, a safety margin of 100x or more is desirable, but this can depend on the severity of the risk under consideration, the type of product, the business risk to the company, and the potential benefits of product use.


Medical device manufacturers have two predominant questions when it comes to material biocompatibility. The first is: "We have a material that we absolutely must use in our device, but it fails a biocompatibility test. Can we justify using the material anyway?" The second is: "We have a material that we absolutely must use in our device, but carcinogenicity and/or chronic toxicity testing are required. Can we justify omitting these tests?" Judicious application of health-based risk assessments can help with both of these issues, often providing a fast, cost-effective answer to both questions.


1. Risk Assessment in the Federal Government: Managing the Process, Washington, DC, National Research Council, 1983.

2. Hays AW, Principles and Methods of Toxicology (3rd ed), New York, Raven Press, pp 26–58, 1994.

3. Ecobichon DJ, The Basis of Toxicology Testing, Boca Raton, FL, CRC Press, 1992.

4. CEN BTS 3/WG 1Risk Analysis is available through the British Standards Institute.

5. Available from the Association for the Advancement of Medical Instrumentation, 3330 Washington Blvd., Ste. 400, Arlington, VA 22201.

6. Draft copies of the Medical Device Paradigm may be obtained by contacting Dr. Melvin Stratmeyer, FDA Center for Devices and Radiological Health, HFZ-112, Division of Life Sciences, Office of Science and Technology, FDA, Rockville, MD 20857.

7. Brown RP, and Stratmeyer M, "Proposed Approach for the Biological Evaluation of Medical Device Materials," in Proceedings of the Medical Design and Manufacturing East 97 Conference and Exposition, Santa Monica, CA, Canon Communications, pp 205-9–205-18, 1997.

8. Stark NJ, "Case Studies: Using the World Literature to Reduce Biocompatibility Testing," in Proceedings of the Medical Design and Manufacturing East 97 Conference and Exposition, Santa Monica, CA, Canon Communications, pp 205-1–205-7, 1997.

9. Stark NJ, "Literature Review: Biological Safety of Parylene C," Med Plas Biomat, 3(2): 30–35, 1996.

10. Hayes AW, Principles and Methods of Toxicology (3rd ed), New York, Raven Press, pp 366–367, 1994.

11. American Conference of Governmental Industrial Hygienists, 1331 Kemper Meadow Dr., Cincinnati, OH 45240.

12. American Industrial Hygiene Association, 2700 Prosperity Ave., Ste. 250, Fairfax, VA 22031.

13. National Institute for Occupational Safety and Health, Hubert H. Humphrey Bldg., 200 Independence Ave. SW, Rm. 715H, Washington, DC 20201.

14. Occupational Safety and Health Administration, U.S. Department of Labor, Washington, DC 20210.

Nancy Stark, PhD, is president of Clinical Design Group, Inc. (Chicago), a consulting and contracting firm for medical device safety, efficacy, and performance. The company frequently performs health-based risk assessments for device manufacturers.

Copyright ©1998 Medical Plastics and Biomaterials

Recent Developments in Sterilization Technology

Medical Plastics and Biomaterials Magazine
MPB Article Index

Originally published September 1998


Sterilization, as a specific discipline, has been with us for approximately 120 years, since the invention of the steam autoclave by Charles Chamberland in 1879.1 Since that time, we have seen progressive refinement in steam sterilizers: from the early, manually operated equipment to modern microprocessor-controlled, automatic machines. Although the efficiency, reliability, and performance monitoring of modern equipment is continually improving, the fundamental process remains essentially the same.

Sterilization processes cannot be considered in isolation; rather, they are inextricably related to the product to be sterilized. They are also related to the packaging of the sterilized product. Except for the rare instances when the sterilizer can be located where the sterile goods are to be used, there is a need for the sterilized products to be packaged in a manner that will preserve their sterility during storage, handling, and transport. The majority of sterile goods produced in the medical device industry and in healthcare facilities are terminally sterilized—that is, they are sterilized already packaged. They may be packaged only in their primary packaging or in multiple layers of packaging such as a unit pack, shelf pack, and shipping carton.

The PureBright system (PurePulse Technologies, Inc.) uses intense pulses of light to kill a variety microorganisms, viruses, and spores. Photo: Purepulse Technologies, Inc.

For a product sterilized in its packaging, the packaging material must be compatible with the sterilization process. This requires both that the packaging tolerates the process without adverse effects on its performance characteristics, and that it permits the attainment of the specified sterilization conditions in the product to be sterilized.

There is no single sterilization process that is suitable for all medical products. The diversity in sterilization processes—and of operating systems within each process—has arisen as a consequence of the efforts made to optimize medical sterilization and to meet the differing needs imposed by the vast range of products to be sterilized.

Traditional Processes

The sterilization processes that have traditionally been used for medical products include steam, ethylene oxide (EtO), ionizing radiation (gamma or E-beam), low-temperature steam and formaldehyde, and dry heat (hot air). These methods can be divided into three categories, based on the nature of the sterilant and its reaction with microorganisms: physical processes (ionizing radiation, dry heat); physicochemical processes (steam, steam/formaldehyde); and chemical processes (EtO, glutaraldehyde).

Chemical and physicochemical processes depend on direct physical contact between molecules of the sterilant and the microorganism to be killed. In consequence, access must be available to the surfaces of the product to be sterilized and the packaging material (for terminally sterilized products) must be porous or permeable to these molecules. For example, in the case of steam sterilization of dry products, the air must be removed from the package and replaced with steam in direct contact with the product. This is necessary both to provide the required thermal energy by condensation of the steam and the required water for the protein hydrolysis reaction to occur. At the same temperature in the absence of water, the degradation of proteins would occur at the much slower rate characteristic of dry-heat processes.

Purely physical processes such as ionizing radiation may be used for product designs and packaging materials that are impermeable to gases as long as they are "transparent" to energy of the wavelengths employed in the sterilization process.

New Processes

What do we mean by a new sterilization process? New is often a marketing description for the latest outcome in a gradual development and refinement of an existing process. Continued development or refinement in one area allows, and sometimes requires, development in another. This advance may be driven by the product, the sterilization process, the packaging, economics, or other external forces.

Over the past two or three years, the development of the art of sterilization seems to have accelerated, with the introduction of several new processes. At least one reason for this is the potential decline in the use of EtO in hospitals. This is a result both of increased concern over the toxicity of residuals and of the need to eliminate the use of chlorofluorocarbons (CFCs), which had previously been employed to minimize the flammability and explosion risks of the EtO. Another prominent trend is the proliferation of various minimally invasive therapies, and the need for appropriate sterilization protocols for the equipment used in these procedures.

Medical instrumentation can be sterilized through a hydrogen peroxide gas plasma process with the Sterrad 100 system (Advanced Sterilization Products). Photo: Advanced Steilization Products

It is important to note that one must consider two very different fields of application for sterilization processes—industrial and hospital. Although the same level of sterility assurance should be provided in each case, the operational circumstances are sufficiently different that the two fields need to be considered separately. In industry, a sterilizer will typically be used to process virgin product with a known bioburden. The range of products will be limited and may be a single product type or single product family of closely related types. There will normally be good engineering and analytical laboratory support, and the process will be subjected to in-depth validation and routine monitoring. All of the personnel involved will be specifically trained in the process.

Contrast this with the situation found, all too often, in hospitals. A diverse range of reusable products will be processed after being subjected to a largely unvalidated cleaning process. The extent and nature of residual soiling and bioburden will be unknown. The process will be subject to minimal validation—certainly not covering the diversity of products processed—and only rarely will there be adequate support from an analytical laboratory. The expectation will be that the process should be simple to operate and safe for use by personnel with minimal training.

Chemical Processes (Gas/Liquid)

Whereas the most widely used traditional chemical processes were based on alkylating agents such as EtO and the various aldehydes, most of the new methods are oxidative processes based on "peroxy" compounds. These include sterilants based on compounds such as hydrogen peroxide, peracetic acid, peroxysulphates, chlorine dioxide, and ozone. For the most part, the microbicidal action of these chemicals has been recognized for many years.

Peracetic Acid. Peracetic acid is currently used in a number of sterilization processes. Examples include liquid systems such as the Steris machine (Steris Corp., Mentor, OH) for endoscopes, or use as a liquid sterilant in suitable disinfectors (e.g., Nu-Cidex from Johnson & Johnson Medical Ltd., Skipton, UK) for sterilization of thermolabile endoscopes. Vapor-phase generators employing peracetic acid are being sold for the decontamination, disinfection, or sterilization of products such as isolators.

The process itself is not new, as the bactericidal activity of peracetic acid was noted by Greenspan and MacKellar in 1951.2 It was used in solution as a sterilization process as early as 1955, and, in the vapor phase, by Portner and Hoffman in 1968.3 Aerosolized peracetic acid for the sterilization of surgical instruments was considered by Werner and others in the early 1970s.

Peracetic acid is a colorless liquid with a pungent odor, miscible with water. Commercially available as a 35% or 40% solution, it is generally unstable, decomposing to give oxygen, acetic acid, and other degradation products, which include hydrogen peroxide and water.

Acetic acid and hydrogen peroxide are invariably present in low concentration. Peracetic acid is corrosive to certain materials and it is lachrymatory, an irritant, and a vesicant (causing blistering) on prolonged contact. Its use as a sterilant therefore relies on obtaining formulations that inhibit corrosion of sensitive materials and stabilize the solution to give it a usable shelf life.

The Steris system currently available for the sterilization of endoscopes is—like the glutaraldehyde system it is intended to replace—a wet system. This limits its applicability, since it becomes difficult to provide a system for packaging and storage of the sterile product. In common with any other liquid chemical system, water is used to flush out any residual chemical at the end of the process. Ensuring that this water is of suitable chemical purity and microbial quality to prevent recontamination of the processed goods requires thorough control. The vapor-phase process has found applications within industry for decontamination of environmental spaces, but there has been no move toward the development of a general-purpose peraceptic-acid sterilization process, and none seems likely.

Hydrogen Peroxide. Hydrogen peroxide as a 3% aqueous solution has long been used as an antiseptic. For example, hydrogen peroxide potentiated by ultraviolet light has been used in the production-line sterilization of commodity items such as cartons for food products. The use of hydrogen peroxide as a vapor-phase sterilant was developed by Amsco in the United States as the VHP system. This process was originally developed in several formats, including a cassette system for endoscopes, a freestanding system for environmental decontamination, a system for use in sterilizing lyophilizers and isolators, and a general-purpose unit for the sterilization of medical devices. (Following the recent acquisition of Amsco by Steris, it appears that the company will emphasize the development of peracetic acid for endoscope sterilization and hydrogen peroxide for environmental and general-purpose applications.)

The deep-vacuum hydrogen peroxide process operates in a manner analogous to gas sterilization processes.4–6 Initial air removal allows for rapid diffusion, and humidity is controlled to optimize the microbicidal effect. The process is compatible with a wide range of materials, but traditional packaging is likely to interfere with the process because of its reaction with, or high absorption of, the hydrogen peroxide. Although the process is finding extensive use in the sterilization of lyophilizers, a general-purpose unit is not yet available.

Ozone. The bactericidal and sporicidal effect of ozone has long been recognized. Its use as a sterilant, however, has been limited because of its instability, which precludes storing it ready for use, and because of the difficulty of generating pure ozone. Ozone is produced naturally by the effect of sunlight or ultraviolet light on oxygen, and also by electrical discharge. Recent technological advances have made the generation of ozone a more practicable proposition, and commercially available sterilizers have been developed.7 The Cyclops Co. has introduced a machine for sterilizing endoscopes that pumps humidified ozone through the unit. Advantages of the system are said to include freedom from long-term toxic residuals and ease of use, with only medical-grade oxygen and electrical connections required. Potential disadvantages include the reactivity of ozone with certain materials.

Chlorine Dioxide. Chlorine dioxide (ClO2), which is a gas at temperatures above 11°C, was discovered by Sir Humphry Davey in 1811 and is another chemical that has long been known to have microbicidal properties and that has, like ozone, been used in water purification systems. The germicidal and sporicidal properties of chlorine dioxide have been recognized since 1936 (Leseurre) and 1949 (Ridenour et al.), respectively.8,9

Many disinfection technologies employ chlorine dioxide in aqueous solution and, when necessary, use nitrogen or air purging to remove the traces of residual gas. The major problems with this technology have always been that chlorine dioxide gas cannot be safely liquefied or stored under pressure for transport and subsequent use (since under these conditions it is explosive), and that as an aqueous solution it is unstable and corrosive. Recent developments have seen the use of both gaseous and liquid chlorine dioxide systems.

Gaseous Systems. In the system developed by Johnson & Johnson, the chlorine dioxide is generated in situ by the action of chlorine on sodium chlorite. The chlorine is presented as 2% Cl2 in N2, in a cylinder filled initially to 2700 psig and then emptied to 300 psig; the chlorine accounts for a pressure of 60 psig. The generator employs a two-column system, with discharge of the chlorine into the first column pressure controlled and monitored, and output from the generator monitored by a fiber-optic UV absorption system. The working life of the column is limited to 70% of its theoretical capacity, as established by validation studies, in order to ensure that the conversion process will always take place effectively. The second column is used as a backup.

The sterilizer is operated at slightly above room temperature (32°C), which allows for good control over the process. The process uses a cycle analogous to that of EtO sterilizers, with a vacuum air-removal stage followed by a dynamic conditioning stage to humidify the chamber and load to an RH of about 70%. At the end of the conditioning phase, ClO2 gas is admitted to give a concentration of 30 mg/L. This is then topped off by the addition of N2 at pressures of 80 kPa. A total gas exposure time of about 60 minutes is standard. At the end of the cycle, the ClO2 is removed using a four-pulse dynamic air exchange.

Advantages of this process compared with EtO are that—because ClO2 does not have the chemical solubility of ethylene dioxide—there are no significant levels of residual sterilant within the product material, and that ClO2 is not flammable in air at the concentrations employed.

Gaseous ClO2 may be removed from the effluent airstream by scrubbing with Na2S2O3. Residual levels for discharge to the atmosphere can be well below 1 ppm and are usually undetectable.

The gaseous chlorine dioxide system is currently being used in several medical applications, including the sterilization of contact lenses and the secondary sterilization of overwrapped foil suture packages.

Liquid Systems. Solutions of chlorine dioxide are also commercially available as liquid sterilants—under trade names such as Tristel and Medicide—and as such compete with glutaraldehyde and peracetic acid solutions. While the microbicidal efficacy of chlorine dioxide has long been recognized, there have been two problems associated with the use of liquid systems. First, the solutions are unstable, with the concentration of ClO2 rapidly diminishing; second, because chlorine dioxide is highly oxidative, it is potentially corrosive to many materials. The development of usable solutions has therefore required formulations that incorporate stabilizing agents, usually based on boron components and anticorrosion compounds. These comprise a base solution and an activator which, when mixed, yield a solution of approximately 0.1% chlorine dioxide, with a 14-day shelf life. Solutions of this type are increasingly being used for the sterilization of fiber-optic endoscopes.

Physicochemical Processes

Plasmas. Plasma is the fourth state of matter, and as such is distinguished from solids, liquids, and gases. Plasmas are produced at very high temperatures, or at low temperatures in strong electromagnetic fields (the so-called "glow-discharge" plasmas). The plasma usually consists of a reactive cloud of ions, electrons, free radicals, and other neutral species.

The plasma process seeks to produce a sterilizing effect using lower concentrations of sterilant—with a higher reactivity—than would be possible in a normal gas process.10–12 Because the active species are only present when power is applied to the system and disappear quickly when the power is turned off, the very active species that act as the sterilant will not be present as a source of toxicity at the end of the process.

The precursor gas selected for plasma generation will determine which active species are present, and these may be expected to influence the comparative microbicidal activity of the system.

When a plasma contacts the surface of an item to be sterilized, the collisions between the active species and other molecules cause a significant proportion of the active species to return to the ground state. Packaging material can thus cause a serious depletion in the concentration of active species reaching the item to be sterilized, soiling on the surface may have a significant inhibitory effect, and the extent of diffusion into narrow lumens may be limited.

The Sterrad Process. The Sterrad process (Advanced Sterilization Products, Johnson & Johnson Medical Inc., Arlington, TX) is a plasma system that uses hydrogen peroxide as the source of the active species. The process seeks to overcome the inhibitory effect of packaging materials by using a gas-diffusion phase to allow gas to penetrate to all parts of the load before the plasma is created. The adequacy of this approach depends on the certainty with which one can ensure that the hydrogen peroxide gas diffuses to all parts of the load and that the nature and construction of load items will not inhibit subsequent plasma formation. Although this system is becoming widely adopted, there are still reservations about its use in hospitals—where product cleaning prior to sterilization may not have been well controlled, where inappropriate products may be processed, and where parametric release may be used without supporting evidence comparable to that required for other processes.

Steam. The inclusion of steam sterilization in the context of recent developments in sterilization technology may at first seem strange. However, there is a continuing evolution of the equipment, packaging, and monitoring systems used for the process. The publication of EN 554 has stimulated renewed interest in ensuring appropriate steam purity for product contact. One continues to see progressive refinement of the microprocessor-based control systems and, in particular, of secondary or supporting functions, such as providing users with a prompt when maintenance is required. Control systems are becoming much more user-friendly, with touch screen systems becoming commonplace. Improvements continue to be made in related steam sterilization supplies such as packaging materials and biological and chemical indicators.

Synergetic Processes

Psoralens and UVA (PUVA). An interesting example of the development of sterilization techniques for specific applications is the recently reported use of ultraviolet light in combination with psoralens to purge blood plasma and platelets of pathogenic organisms. Psoralens are naturally occurring substances found in a wide range of plants, in which their role is to fight infection from pathogenic fungi.

Irradiation of blood with UV light has been recognized as a method of treating otherwise intractable infections ever since its development in the 1930s for use with polio patients. It is reported that the fundamental effect of exposure to UVA is to stimulate the body's biochemical and physiological defenses.13,14 Researchers have speculated that this is related to the low concentration of ozone produced from the oxygen circulating in the blood.

Ultraviolet blood-irradiation therapy is currently under investigation for the treatment of diseases such as HIV infection and hepatitis, and is the method of choice for the treatment of cutaneous T-cell lymphoma. The use of UV is also noted for its ability to inactivate viruses while preserving their antigenic properties for the preparation of vaccines.

The recent proliferation of novel blood-borne viruses has led to demands for better safety guarantees for blood products, and hence many methods of sterilization have been extensively examined.15,16 It has become clear that most viruses are quite sensitive to UVB or to UVA when used with psoralens as photosensitizing agents. The psoralens form a labile bond with DNA and RNA which, upon exposure to UV light, becomes a firm bond. Recent work by Cerus Corp. (Concord, CA) appears to show that synthetic psoralens and UV irradiation can be used to destroy infectious agents such as HIV, hepatitis viruses, and toxemia-inducing bacteria. However, it has been thought that producing viral inactivation of sufficient magnitude was not feasible without causing intolerable damage to vital blood components—especially erythrocytes, in which hemoglobin blocks the penetration of UV light.

The absence of genetic material in platelets, however, means that these would remain unaffected by the PUVA mechanism, and it should therefore be possible to use the technique to sterilize plasma and platelets. This possibility is currently under investigation in clinical trials. Although the psoralens and dead microorganisms would remain in the product, it is considered unlikely that they would pose a risk, given the extensive clinical history of psoralens.

Microwave and Bactericide. Sterilization methods are being marketed that propose the use of microwaves in conjunction with a bactericidal solution—a modern version of the century-old process of heating with a bactericide. The technique is being promoted for use with dental instruments and relies on heating a solution of a quaternary ammonium compound (benzylkonium chloride) to approximately 100°C. At present, these processes are applicable only to unpackaged instruments.

Low-Temperature Steam and Formaldehyde. Low-temperature steam in combination with formaldehyde is another traditional process that has continued to evolve. It is an example of synergism in that it brings together steam at subatmospheric pressure and formaldehyde gas—neither of which is markedly sporicidal—to produce a highly efficient sporicidal effect.

The process has been in and out of fashion several times over its 100-year history. Concerns over the toxicity and carcinogenicity of formaldehyde have limited its acceptance in the United States, despite potential advantages over ethylene oxide. More recently, improved process control has allowed the production of sterilizers with negligible environmental emissions and very low product residual levels. Other developments have included the use of operating cycles at temperatures comparable to those employed for ethylene oxide instead of in the 70°–80°C range that was traditionally employed.

Physical Processes

Microwaves. The inherent advantage of microwave heating compared with other forms of heating lies in its lower power requirements. The interaction between microwaves and biological materials does not of itself appear to be lethal: rather, the lethality obtained is directly derived from the heating effect, which in turn depends on the composition of the microorganism being targeted, including its water content. Limitations related to the specifics of microwave reflectance, transmittance, and absorbance may limit applicability for device sterilization.

Pulsed-Light Systems. A novel sterilization method introduced in the past several years uses high-power electrical energy to produce intense pulses of light that are claimed to provide unique bactericidal effects.17 Called the PureBright system (PurePulse Technologies, San Diego), the technology rectifies and converts normal building ac to high-voltage dc and uses it to charge a capacitor, which is then discharged through a specially designed xenon lamp unit. The high-voltage, high-current pulse applied to the lamp causes it to emit an intense pulse of light, which typically lasts for a few hundred microseconds. The light produced by the lamp includes a broad spectrum of wavelengths, from ultraviolet to infrared, with an intensity some 20,000 times greater than sunlight.

The process is reported to be highly successful in killing microorganisms, viruses, and spores, as well as in deactivating enzymes. Its effectiveness depends in part on the ease with which the organisms to be killed can be directly illuminated. For example, organisms on porous surfaces or those suspended in turbid solutions will require higher treatment levels compared with those on smooth, continuous surfaces or transparent materials. Parametric release should be practicable, since the factors controlling the microbicidal activity can be directly, and continuously, monitored. These include both the energy output in the UV range and the lamp current, on which the intensity and spectrum of each flash depend. In use, the normal operating ranges for the system are from 0.1 to 3.0 J/cm2 per flash, with total accumulated fluences of 0.1 to 12.0 J/cm2. The number of lamps, their configuration, and the flash rate depend on the particular application. The economics of the process are encouraging, with costs as low as one cent per square meter of surface sterilized.

Potential applications include the surface sterilization of packaging materials for aseptic packaging or for bioburden reduction, and the terminal sterilization of parenterals packed in transparent plastic bags or bottles (e.g., from a blow, fill, seal machine). The photoproducts from treated substrates are reported to be generally similar to those induced by exposure to sunlight and similar to, but fewer than, those produced by thermal sterilization processes. When the process is used to sterilize the surface of opaque materials, any degradative effects would, of course, be restricted to the surface.

Validation of Sterilizer Processes

In the development of new sterilization methods, a key consideration is the data that are needed to demonstrate the efficiency of a process. Although in the United States there is a well-defined process for review of new types of hospital sterilizers, this is not the case worldwide. Furthermore, the FDA approval system does not apply to sterilizers for use in industry.

The lack of any universally accepted approach to validation or process approval for new sterilizers has led to considerable difficulty for both manufacturers and users as new processes have been introduced. There is also a need for a suitable European standard providing a means for presumption of conformity to the Medical Devices Directive for sterilizers, since these have become devices within the scope of the directive. These factors have stimulated work on a standard for Validation and Routine Control of Sterilization Processes—General Requirements, which is being developed within ISO TC 198 as a common international and European standard under the Vienna agreement. A draft for public comment is expected to be published some time this year. It is to be hoped that the standard will provide a format establishing a common standard for the acceptance or rejection of new sterilizing processes.