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Articles from 2001 In August

New Coatings and Processes Add Value to Medical Devices

Aug 01, 2001

Originally Published MDDI August 2001

Medical Plastics and Biomaterials

New Coatings and Processes Add Value to Medical Devices

Increased functionality, versatility, and ease of use are among the characteristics that the latest coatings can add to a medical product.

William Leventon

The latest generation of device coatings can strengthen the capabilities of many of today's medical products. Some coatings add such properties as lubricity, biocompatibility, and antimicrobial action to device surfaces. Other coatings can be used to release drugs or make implanted devices more visible to imaging systems. Still others offer combinations of these features.

Some medical devices would never reach their potential without the properties offered by new coating technologies, according to Lise Duran, vice president of product development for SurModics Inc. (Eden Prairie, MN). "You may have a very innovative device, but because of its surface you won't be able to get the full benefit from it," says Duran, whose company offers PhotoLink coating formulations for medical devices. "The device might even fail because of the surface. But add a coating to the surface, and the device will function the way it should."

Rendering of PhotoLink polymer molecule showing spacer arms with photogroups at their ends.

Many device coatings are polymer-based formulations. Hydrogel coatings manufactured by MCTec BV (Venlo, The Netherlands) are based on a single specially developed polymer rather than blends of different polymers, explains Hans Hanssen, technical director of MCTec, which was recently acquired by STS Biopolymers Inc. (Henrietta, NY). This approach can add stability to the coating formulation, Hanssen explains.

COATED COMPONENTS

Besides making coatings, MCTec has developed a process for adding lubricity to device component surfaces. The company coats cores that are made into balloon catheter hypotubes and various types of guidewires. Manufacturers who make devices out of coated components will find it simpler and less expensive than coating a finished device, says Hanssen. He emphasizes, as well, that coated components can improve the quality of the finished coated device.

Today, finished catheters and guidewires are usually spray coated with a thin layer of polytetrafluoroethylene (PTFE), which reduces their friction coefficient by as much as 50%. But spraying does not produce coatings that are smooth and uniform enough for many manufacturers. Consistency is prized by designers whose task can be complicated by core material with a varying diameter.

To address such issues, MCTec has developed a proprietary process in which spooled wire or tubing is pulled through a PTFE coating bath. "Think of it as a controlled dip and curing," says Michael Casalino, vice president of operations for Wytech Industries Inc. (Rahway, NJ), which works with MCTec to produce the coated components. When the coating process is complete, the wire or tubing is respooled. The process yields a spool of wire or tubing with a lubricious coating of very consistent thickness.

"Typically, in a spray coat, you would have certain imperfections along the length of the component," Casalino explains. "You might have a little bubble or coagulated area somewhere. But our coating is so smooth, its size is extremely consistent along the length. It doesn't vary at all."

This spool-to-spool process can coat tens of thousands of feet of wire or tubing at a time. "Rather than coating a piece of wire that's two feet long, we run very long lengths of wire continuously through the process," Casalino explains, adding that the process is about 20% less expensive than spray coating.

MCTec's process can also be used to coat components made of a variety of metals, including stainless steel, platinum, and even nitinol. Normally, nitinol can't be spray coated because heat from the process changes its properties. "But we can coat nitinol without affecting the properties, which is a significant advantage," Casalino says.

The coating is about 0.0002 in. thick—much thinner than a conventional spray coating, which measures about 0.001 in. This superthin coating lets designers increase the diameter of the core material. For example, device specifications normally limit guidewire cores used in percutaneous transluminal coronary angioplasty (PTCA) to a diameter of 0.014 in. To allow for the coating thickness, the specifications usually call for an uncoated wire diameter of 0.013 in. When the spool-to-spool process is used, however, the uncoated diameter can be increased to 0.0134 or 0.0135 in. "Our coating is so thin, [designers] can increase the size of the material to add stiffness to the component, which is a key part of a PTCA guidewire core," Casalino says.

For doctors who use the components, Casalino explains, the coating's stiffness provides 1:1 "torquability." "We grind the wire so that it has a 0.014-in. diameter at one end and a 0.002-in. diameter at the tip," he explains. "With 1:1 torquability, when the doctor makes one rotation at the 0.014-in. end, he gets one rotation at the 0.002-in. end."

Use of conventional spray coatings (below) usually result in more imperfections compared with spool-to-spool processes (above).

The new process can also be used to apply a number of very thin polymer layers on wires or catheters. This opens up a number of possibilities. For instance, a coating could be created that exhibits more-hydrophobic behavior on the inside, yet more-hydrophilic behavior on the outside.

On the other hand, MCTec's DuraSkin and LubriSkin PTFE coatings can break down under high temperatures, which makes them unsuitable for devices such as welding mandrels. For high-temperature applications, the company is working on a new coating variation called WeldSkin.

COATING ADHESION-RESISTANT DEVICES

Some difficulty is encountered when lubricious coatings such as PTFE must adhere to catheters and other devices made of silicone. To treat such adhesion-resistant surfaces, STS Biopolymers has developed Graft-Coat, a patent-pending formulation that creates a polymer coating right on the surface of a device.

To begin the Graft-Coat process, a device is placed in a water bath that contains a monomer. This monomer forms polymer chains by reacting with the surface of the device. Chemical bonds hook the chains to the surface.

The process creates a hydrophilic coating that gives silicone devices "both a dry and a wet lubricity," according to Richard Whitbourne, chief technology officer at STS. A soft polymer with a high coefficient of friction, silicone doesn't slide easily along surfaces. "If you try to pull [silicone] through your fingers while putting a moderate amount of pressure on it, it can feel like you're putting the brakes on," he explains. "But if you put the Graft-Coat treatment on it, you'll be able to pull it through your fingers easily even if you're applying pressure."

This kind of lubricity could smooth out the rough spots in many procedures. Syringe needles, for example, will have a much easier time penetrating Graft-Coat-treated rubber or silicone septa on pharmaceutical bottles. Treated catheters will slide more easily than uncoated catheters into a patient's urinary tract. "Imagine how painful that would be if the surface of the catheter had a high coefficient of friction—like a soft rubber stopper," says Whitbourne.

Inside the body, the coating's activation mechanism can provide other benefits. Although some coatings are activated by ultraviolet light, Graft-Coat is thermally activated in most cases. This lets doctors put treated devices in places UV light can't reach.

The company expects to begin marketing Graft-Coat in the 20022004 time frame. Variations of the coating will be specially designed for a number of applications.

CONDUCTIVE COATINGS

To protect medical devices from electromagnetic interference, manufacturers use paint, plating, or vacuum metallization processes to apply conductive coatings. In the past, conductive paint coatings had to be as much as 75 mm thick to provide adequate protection. Paint coatings also tended to flake or lose particles, causing worries that sensitive devices could be contaminated. As a result, many manufacturers stopped using the paint alternative.

Now, Spraylat Corp. (Mount Vernon, NY) is trying to renew interest in the process with a new line of conductive paint coatings. Series 599 SOS (safe on substrate) coatings are designed to provide better performance than their predecessors by requiring thicknesses of only 5 to 20 mm to protect devices, according to Gary Shawhan, Spraylat's corporate marketing manager. Shawhan adds that the integrity of the coating is better than that of earlier paint coatings. "There's no particle pickoff or flaking," he says. "It's a major advancement that's important to the medical industry."

Series 599 coatings come in three different types: pure silver, silver-coated copper, and a midrange hybrid that contains both copper and silver pigment. Shawhan claims that the coatings offer three to four times better performance than their predecessors while requiring as little as a third of the material. As a result, he says, the coating process is usually less expensive than plating or vacuum metallization.

Compared with previous paint coatings, the products are also more compliant to the substrate, Shawhan says. "So the stresses in our coatings are much lower, and they're much less likely to flake off the substrate over time."

IMPLANT COATINGS

Already on the market is a new STS Biopolymers coating designed to make medical devices used within the body more visible to ultrasound. Called Echo-Coat, this thin polymer coating "causes devices to light up very nicely under ultrasound," Whitbourne says. Applied to products such as biopsy needles, the coating incorporates micropores that trap air at the surface of the device. Rather than simply sending ultrasound signals back to the transducer, the bubbles reflect the signals in all directions. This enables ultrasound imaging systems to show a device's position in the body even when it is at an angle to the transducer. As a result, Whitbourne says, ultrasound can be used in place of MRI and fluoroscopy in many device-placement procedures.

In addition to the coating technology itself, STS now markets Echo-Coat-treated products. This year, the company is offering a variety of coated needles. Next year, it will add catheters and other devices to the coated-product line. The firm hopes to show device makers how the process can open up new possibilities for their products.

"We're marrying commodity items to this coating technology to make products that can be used in ways that uncoated products can't be," Whitbourne says. "We think the coating will greatly expand the use of a number of products."

Comparison of staphylococcus epidermis on coated and uncoated material.

Another group of application-expanding coatings are hemocompatibles. These coatings can be applied to reduce platelet adhesion and thrombus formation on devices, thereby extending their effective lifetime in the body. SurModics is working on a variety of blood-compatible coatings, including a photo-heparin formulation. Duran notes, however, that regulators in Europe are concerned about possible heparin side effects, which could make it difficult to bring heparin-coated products to market there. In response, SurModics is developing nonbiologic alternatives to heparin. Most of these are polyvinylpyrrolidone-and polyacrylamide-based polymers that are part of the company's PhotoLink line. "These are alternatives that could provide a faster pathway [to the market] in Europe," Duran says, adding that the coatings will be available to U.S. device manufacturers as well.

DRUG-DELIVERY COATINGS

At the moment, few device coatings are getting as much attention as those that deliver drugs. Drug-delivery coatings "are a very hot topic nowadays," says Hanssen of MCTec, which produces hydrogels that can be used as carriers for a number of drugs. When they come in contact with a liquid, the coatings swell, allowing drug molecules to flow out and react with body fluids. The drugs can help prevent infection, inflammation, thrombus formation, or other undesirable reactions to devices used within the body.

Drug-delivery coatings could also play a key role in processes that open blocked arteries. At present, many companies are working on stent coatings that slow or prevent restenosis—the reclosing of an artery opened by a medical procedure such as balloon angioplasty. An example of this type of coating is STS's Medi-Coat product. Medi-Coat is a patented hybrid polymer system that controls the flow of liquid into and out of the coating, ensuring that the restenosis-fighting drug is released at the proper rate. The coating's special polymer mixture also stabilizes the drug so it can endure the sterilization process. The coating also provides the flexibility and adhesion required by stent-related applications. A number of major stent companies have expressed interest in Medi-Coat, says Whitbourne.

Meanwhile, scientists at AST Products Inc. (Billerica, MA) have been working on an antimicrobial version of the company's water-based LubriLAST coating technology. Developed primarily for urinary devices, the new coating includes an active ingredient that is held in the polymer matrix by an ionic charge. This ingredient, a silver ion, is released via ion exchange. Unlike mechanisms that simply let the active ingredient seep out, ion-exchange technology provides controlled release that extends the period of antimicrobial activity, according to Maura Lane, business development manager for AST Products.

Introduction of products that incorporate antimicrobial coatings, however, could be hindered by regulatory issues. "Virtually every medical device presents the danger of infection," Duran notes. "So to prove efficacy, a company would have to put its device through a large-scale clinical trial. But many device manufacturers don't have the financial resources for a major clinical trial."

FDA and other interested regulatory parties are therefore trying to determine whether preclinical studies could take the place of large, costly clinical trials. At the same time, they are trying to decide which antimicrobial agents will be allowable on medical devices.

The difficulty of the latter task is illustrated by the case of chlorhexadine, an antiseptic that has been placed on the surfaces of some medical devices cleared or approved by FDA for marketing. A few years ago, however, a small segment of the Japanese population developed a hypersensitivity reaction to chlorhexadine. As a result, Duran reports, some regulators and device manufacturers have lost confidence in the substance. So now SurModics and other coating manufacturers are searching for alternatives to chlorhexadine.

"It's like looking for a needle in a haystack," Duran says. "Everybody agrees that there's a huge need for an anti-infective surface," she adds, "but people are really spinning their wheels right now trying to determine what preclinical testing is necessary and what's going to be an acceptable antimicrobial. We're working with the FDA and everyone else in trying to sort this out. But it makes the development environment very complicated right now."

In addition to the current crop of drug-delivery products, Duran sees other possibilities for such coatings. In time, she says, drug-delivery coatings may be capable of releasing antipain or even anticancer agents into the body.

INCREASING HEAT RESISTANCE

Parylenes are biocompatible polymer coatings that offer dry-film lubricity and electrical insulation. The coatings are also excellent moisture, gas, and chemical barriers, according to Lonny Wolgemuth, medical market manager for Specialty Coating Systems (SCS; Indianapolis).

Parylene coatings are formed molecule by molecule in a vapor deposition process. "Since the coating grows a molecule at a time, it can coat to very thin layers," Wolgemuth says. The process deposits coatings in thicknesses ranging from 500 Å to 75 mm with ±10% accuracy.

Although standard parylene coatings can handle temperatures up to about 150°C, the company's Nova HT coating can withstand temperatures as high as 450°C, Wolgemuth adds. To boost the coating's heat resistance, SCS added fluorine atoms to the standard carbon-hydrogen parylene molecules. Fortified with fluorine, Nova HT is suitable for electrosurgical devices and others that are subjected to high instantaneous temperatures.

SPECIAL CASES

To further enhance the benefits of their coatings, some manufacturers are incorporating two or more properties into one product. "Along with lubricity or biocompatibility, coatings are also giving you antimicrobial and antithrombogenic activity," AST Products' Lane explains. "So you get multiple benefits from a single coating."

According to Duran, SurModics' coatings are especially well suited to incorporate multiple properties. Unlike most traditional device coatings, those in the SurModics line are "combinable," she says.

To at least some degree, most coatings are customized for particular products. "Customers might want a thinner coating, a more durable coating, a more or less lubricious coating—any number of alterations of different parameters," Lane says. "From that standpoint, nothing is really just off-the-shelf."

Beyond this standard type of customization, AST will sometimes collaborate with a customer to develop a coating for which that customer will receive an exclusive license. Lane believes that reliance on exclusive licensing agreements is likely to become commonplace in the future.

CONCLUSION

Coatings give medical devices essential attributes that they lack by themselves. In that sense, they add value to products. But they can do more than that. In some cases, they actually make products possible. At least in part, devices with complex geometries are now being designed because new formulations and techniques have been developed to coat them. As an example, Duran offers the very fine mesh baskets used in distal protection. SurModics has come up with a special product and process for coating these baskets without clogging the pores.

"We definitely enable certain devices," Duran says. "They would never make it to market without a coating." By improving and enabling new technologies, coatings will continue to play a vital supporting role in medical device development.

Exploring Innovative Treatment Options for Degenerative Disk Disease

Aug 01, 2001

Originally Published MDDI August 2001

R&D Digest

A monthly review of new technologies and medical device innovations

THIS MONTH: Exploring Innovative Treatment Options for Degenerative Disk Disease | New Analytical Technique Could Provide Tools for Assessing Parkinson's Disease Patients

New Implants Offer Relief of Spinal Pain

A normal vertebral disk represents a complex structure between the bones of the spine. The nucleus, sandwiched in the center of the disk, contains fluid that serves as a cushion. Layered collagen fibers of the adjacent annulus provide strength. When the components of a healthy disk work together, they give the back both stability and flexibility. But when a disk deteriorates or gets damaged, the cushion can deflate, bulge, or leak, and the collagen loses its elasticity. Pain is often intense, especially when nerves get caught in the degenerative process.

To relieve the acute pain and strengthen the spine in such cases, fusion is a commonly used surgical treatment. Typical methods entail placing metal implants, such as plates, rods, or screws, into the vertebrae to immobilize that portion of the spine. The procedure can often involve the use of fusion cages to help new bone growth to complete the fusion process. Approximately 150,000 cervical fusion procedures are performed in the United States alone, with a growth rate of approximately 20% annually.

The BAK/C system can be implanted between any of the third through seventh vertabrae to create space.

In April, the BAK/C Cervical Interbody Fusion System from Sulzer Spine-Tech (Minneapolis) became the first cervical interbody fusion device to receive marketing approval from FDA. The company previously introduced the first lumbar interbody fusion device, according to Sulzer Spine-Tech.

The cylindrical titanium alloy implant is designed to be placed between any of the third to seventh cervical vertebrae to provide immediate stability and promote fusion between vertebral bodies. According to Rich Lunsford, Sulzer Spine-Tech president, "Most surgeons prefer to use bone harvested from the patient in cervical spinal fusion procedures. Due to its unique design, BAK/C collects local bone during implant insertion, resulting in autograft without the need for bone harvest from the patient's hip."

According to the company, results of multicenter clinical studies showed significantly higher fusion rates at every follow-up interval for BAK/C patients when compared with those for patients who had an anterior cervical diskectomy and fusion. There were also fewer complications reported by those receiving the BAK/C device—17% compared with 25% in the control group.

Another technology, developed as a nonfusion alternative for treating degenerative disk disease, is currently being studied at 10 centers in the United States. The investigational device from Link Spine Group Inc. (Branford, CT), the SB Charité Intervertebral Dynamic Disk Spacer, provides total disk replacement in the lumbar spine. Disk replacement is viewed as a desirable alternative for some patients—particularly those who are active adults.

The U.S. study recently received attention when 41-year-old triathlete Karl Nusch was treated at the Cedars-Sinai Medical Center Institute for Spinal Disorders (Los Angeles) using Link's SB Charité device. Nusch's treatment underscores one of the advantages believed to result from total disk replacement.

Patients who undergo fusion surgery must restrict their motion for up to a year. In contract, patients who receive artificial disks are encouraged to be mobile right away, according to Nusch's surgeons, John J. Regan, MD, director of research and education at the Cedars-Sinai Institute and Robert S. Bray Jr., MD, director of the institute.

Says Regan, "The main advantage of disk replacement is that joint motion is maintained. The alternative procedure for painful disk degeneration is spinal fusion. Spinal fusion stiffens the spine, decreasing motion, and, in some cases, leads to premature deterioration of the disk adjacent to the fusion." He adds that, with disk replacement, "in addition to relieving pain, the patient can begin moving the spine soon after the procedure. In the case of spine fusion, motion is restricted for 6 to 12 months."

The researcher explains that "one of the concerns we have with fusion is that long-term some people come back with problems at the next disk, either above or below. If something is going to move and one disk is not moving, it's going to increase the motion and stress on the disks next to it." He adds, "Part of the reason that this study is being done is to look at the impact of the adjacent disks, related to fusion versus artificial disk."

A spinal x-ray illustrates placement of the BAK/C device.

The SB Charité prosthesis consists of two cobalt chromium alloy end plates with an ultra-high-molecular-weight polyethylene sliding core between. Says Brian Cameron, president of Link Spine Group, "It is important to note that the SB Charité device is made of the same materials that have been implanted in millions of patients having had total hip or knee replacement surgery—cobalt-chromium alloy and polyethylene. We know that these materials are well tolerated by the human body."

The device is designed to closely mimic the normal function of a healthy disk using metal and plastic bearing surfaces to replicate normal movement—much like an artificial hip or knee. During implantation, the end plates are attached to the vertebral bodies by means of anchoring teeth along their edge, according to the company. The polyethylene sliding core is then placed between the articulating end plates. The resulting configuration is designed to allow near-normal physiological movement. The surgical procedure for the SB Charité requires placement of the implant using an anterior approach with a small incision just below the navel. The degenerative disk is removed at the affected level and the spacer is inserted.

Says Cameron, "The SB Charité disk prosthesis is designed to allow near-physiological segment movements with corresponding lateral mobility. While the results of the IDE currently under way here in the U.S. are not available, the device has been implanted, in its current design, in over 3000 patients worldwide since 1987. It has been reported in the literature based on the European experience that the device will mimic the function of a healthy disk. Obviously the same cannot be said for the fusion of a motion segment."

The cylindrical titanium-alloy implant is the first cervical cage available in the United States to treat pain caused by degenerative disk disease.

Commenting on the current U.S. studies, Cameron notes, "We will follow each patient for a minimum of two years before presenting the data to the FDA. We are looking for submission to the FDA sometime in early 2004."

Taking Aim on Neuromuscular Tremors

A novel method for analyzing the steadiness of a marksman's aim eventually may be useful in diagnosing and monitoring tremors in patients with certain neuromuscular disorders. Developed by researchers from Penn State and the University of Verona, Italy, the technique could provide the basis for a sort of steadiness profile or body tremor "fingerprint" for any individual.

Says Joseph P. Cusumano, MD, Penn State associate professor of engineering science and mechanics, "Such a 'fingerprint' can be useful in a clinical setting to diagnose and track the progression of a neuromuscular disorder or injury, or the recovery from such a disorder or injury."

Developed by Cusumano and coinvestigator Paola Cesari, MD, director of the University of Verona Movement Science Laboratory, the new analysis technique entails use of video cameras to collect movement data from a person shooting at a target. The subject's movements are then reduced to their basic elements, which enables the researchers to determine how and why tremor varies as the person adjusts his or her joint angles to try to maintain a steady aim. Cusumano and Cesari combined a method of statistical data analysis, called principal component analysis, with stability analysis that relates tremor in the body joint positions to tremor of the target point. Cusumano says, "This combination of analyses is familiar in robotics but is new in the area of movement science."

According to Cusumano, "The new procedure allows the researchers to evaluate individual athletes and understand the specific configurations in which they hold their limbs to maximize the way in which the natural tremor in their body is controlled when they aim at a target."

The researcher explains that from this perspective, the natural tremor functions as an input at the body's joints. The output is the tremor or vibration at the task level—the target of the pointing. "We can use our method to show how this input-output relationship is affected by different limb configurations, which one can think of as 'aiming strategies,'" Cusumano says. "Thus, instead of just saying 'person X has more tremor than person Y,' one can adjust the position of the body and see its connection to performance in a very detailed way that is unique to each person. In short, an effective strategy will diminish the effect of body tremor at the task, while an ineffective one will attenuate tremor less, or even amplify it."

Use of the technique in a clinical setting is easy to imagine, according to Cusumano. "The calculations could be automated, and an appropriate user interface can be designed to enable the clinician to use the results without needing to get into all of the mathematics. The equipment required is very modest and readily available—compared to an MRI machine, for example." Such equipment would probably consist of some data acquisition system, such as a force platform and a 3-D motion analysis system, and a PC with appropriate software. He adds, "The method is noninvasive and can be performed easily on clothed subjects in an open, general-purpose space."

In their study, the researchers asked 16 people with varying degrees of expertise to aim an air pistol and shoot at a target. All subjects had a reflective marker attached to the tip of their gun, and on their wrist, elbow, shoulder, neck, head, and hip. Two optoelectrical cameras equipped with infrared illuminators tracked the markers and collected movement data. Using a computer, the researchers analyzed each image from the cameras and extracted the position of each marker as a function of time to produce a data stream.

While the group has performed studies only on athletes so far, they are currently planning to look at Parkinson's disease patients next year. Cusumano notes that the researchers have "an affiliation with a hospital in Italy that will allow us to explore purely clinical issues related to eventual application."

Says Cusumano, "The main scientific problem that we need to address with the experiments on Parkinson's subjects is to examine the details of the coordination patterns adopted by individuals to manage tremor, and identify different categories of adaptations. Because our method does much more than just quantify tremor, it is a tool that should enable us to see the differences needed for such categorization, which is the first step in the direction of clinical application."

The researcher explains that current screening tests require individuals to accomplish some basic task, such as pointing or standing, possibly with impediments or under different perceptual conditions. The subject's performance is then evaluated according to different qualitative criteria. "Using our analysis method, we aim to make such screening tests both more comprehensive as well as more quantitatively precise," he says.

The researchers suggest that there are three stages at which the technique may eventually be applied—diagnosis, prognosis, and treatment. Cusumano comments, "In the short term we are looking primarily at just the identification of pathologies and the tracking of their course. Even for that, we need at least five years of hard work since the clinical testing has not even been begun. Further down the road, prognostic and therapeutic applications can be envisaged."

New Institute to Focus on Regenerative Medicine

The University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center Health System have formed a new institute to provide an operational base for the development of regenerative medicine technologies. Work at the facility, the McGowan Institute for Regenerative Medicine (MIRM), will encompass tissue engineering, cellular therapies, biosurgery techniques, and artificial and hybrid organ devices.

In addition to the development of clinical protocols, the institute is expected to "establish itself as a role model for technology transfer," according to the university. Plans for the McGowan Institute also include establishment of a location for a National Tissue Engineering Center.

The MIRM replaces the McGowan Center for Artificial Organ Development and will incorporate that entity's faculty and programs into its own program. Existing staff and faculty include scientists involved in adult-derived stem cell research, wound healing, and tissue engineering.

Projects under way at the former center will also continue at the MIRM. Among these are an axial-flow left-ventricular assist system for patients with end-stage heart disease, and a biohybrid artificial lung for long-term use.

The MIRM will be directed by Alan J. Russell, PhD, who is currently the associate director of the university's Center for Biotechnology and Bioengineering. The medical director of the new facility will be Bartley P. Griffith, MD, who has directed the McGowan Center since its founding in 1982.

FDA Performance Review Reveals Problems

Aug 01, 2001

Originally Published MDDI August 2001

Washington Wrap-Up

FDA Performance Review Reveals Problems

The CDRH director's year-end report admits to a marked slowdown in device review time.

James G. Dickinson

TMJ Patient Group Protests | Third-Party GMP Inspections | Unapproved IDE Changes Are OK | More on Reprocessed Devices

[Editor's Note: An article originally published in the print version of this column, "Lighter Bard Sentences," contained significant inaccuracies regarding the pleas, admissions, and sentences of the defendants in the case discussed. A complete response and clarification will be printed in the September 2001 issue of MD&DI.]

Although he expressed himself nonjudgmentally—at times even optimistically—CDRH director David W. Feigal's fiscal year 2000 review of center performance, CDRH: Looking Ahead, could not mask significant management problems with device reviews.

Not only did Feigal's report acknowledge that 510(k) product reviews got slower despite a diminishing CDRH workload, but it also revealed that in 83% of cases, industry complaints about center practices were decided in the complaining company's favor by CDRH ombudsman Les Weinstein. FY 2000 was Weinstein's first year on the job.

As one informed observer commented: "While it appears to be good news that 83% were resolved in industry's favor, the bigger picture is that ODE reviewers seem to be asking for too much or are off-base, because center superiors are clearly overruling their decisions."

Stepping past the confines of FY 2000, Feigal—a former ombudsman in FDA's biologics center—acknowledged that device PMA review time has slowed by 28% this year, and it is taking CDRH an additional 100 days, on average, to issue an approval.

Eighty percent of the slowdown is on the manufacturers' side, the report says, accounting for 80 days of the additional approval time. Last year, CDRH was reviewing PMAs within 363 days, on average; the average approval time this year has jumped to 463 days. PMA supplement approval time has remained relatively flat, taking 122 days this year compared to 118 last year.

Feigal says 510(k) clearance is taking 102 days this year, the same amount of time it took in 2000. Device sponsors are also using more nontraditional review clearances, such as third-party reviews and special or abbreviated 510(k) processes. For example, in 2000, 62% more special 510(k)s were submitted than were submitted in 1999 (583 vs. 361).

The fact that the majority of CDRH dispute resolutions are being resolved in industry's favor raised more than a few eyebrows at an AdvaMed submission workshop in June. The trend prompted center regulations and policy deputy director Linda Kahan to suggest that device reviewers might need more training on the center's "least-burdensome" principles.

As if to confirm an internal deficiency, Weinstein shared with the AdvaMed attendees recent survey data on what he referred to as "early collaboration meetings" between industry and CDRH. Industry respondents to the survey said CDRH reviewers were not applying least-burdensome principles during agreement and determination meetings. For example, the majority of industry respondents said preclinical testing was not considered in lieu of clinical data, and reviewers did not consider previously collected non–U.S. data, literature, or registry data.

CDRH science and regulatory policy deputy director Phil Phillips told the workshop that one of the obstacles in integrating least-burdensome concepts into CDRH practices is that bureaucracies like FDA don't change easily. "Those responsible for overly burdensome regulation do not recognize the unnecessary burden that they impose," he said. Phillips added that change will require a commitment and will need to be managed from the top.

Preliminary training for CDRH staff and advisory panel members has been completed, according to Phillips. The least-burdensome draft guidance was open for public comment until August 1, 2001. Phillips encouraged the audience to submit feedback, especially if the document seemed unclear or was missing critical elements. Once the draft is finalized, FDA will conduct additional training of its personnel, he added.

TMJ Patient Group Protests

Ideological arguments (i.e., those stating that FDA should approve only inherently safe products) surfaced again in a May petition to FDA from the TMJ Association, the largest U.S. patient advocacy group for people with temporomandibular joint (TMJ) conditions. The association sought a public hearing on the agency's February 27 approval of the TMJ Fossa-Eminence, a partial prosthesis from Golden, CO–based TMJ Implants Inc.

The device was approved after ODE director Bernard Statland intervened in a review-staff dispute with the sponsor. He ordered full labeling disclosure of device and procedure risks, thereby sharing FDA's risk-benefit assessment role with practitioners and patients.

In a press release, the association called the approval—which capped 20 months of acrimonious review—"unconscionable and cowardly," because it "doesn't just put patients painfully suffering from TMJ at risk, it asks the patients to share the risk." The association added that the approval "contradicted the scientific and medical conclusions of two dental products panels" and FDA's "own internal scientific staff."

In response, TMJ Implants CEO Robert Christensen said the association's petition ignored 40 years of successful surgeries that placed his device in over 10,000 patients. "Over 90%, perhaps even 95%, don't progress to total-joint replacement after receiving the Fossa-Eminence," Christensen said.

Third-Party GMP Inspections

Speaking during a break at a June 14 AdvaMed device submissions workshop in Washington, DC, center regulations and policy deputy director Linda Kahan said that device manufacturer inspections had dropped to an alarming level over the past five years. As a result, she said, CDRH is considering a third-party inspection program to help FDA inspect device companies every two years. Third-party inspections would allow outside certified auditors to perform quality system/GMP inspections in lieu of FDA investigators.

Budget cuts by the Clinton administration led to a 50% decline in inspections— falling from 3602 in 1996 to 1841 in FY 2000. Of these, 710 were classified as quality system/ GMP audits, 247 were for bioresearch monitoring, 156 were preapproval inspections, and 609 were related to mammography quality standards.

Kahan told the AdvaMed audience that FDA's device program performance plan targeted 28% of high-risk domestic manufacturing facilities for inspection last year. Only 13% were inspected, however, due to resource constraints. Optimistic that relief is on the way in President Bush's FY 2002 budget proposal (which calls for a $2.8 million increase for device- related inspections), Kahan said CDRH is projecting a rise in inspections to 22% of high-risk firms.

Kahan also said that FDA district offices are asking for alternative inspection programs to allow for faster inspections. She emphasized that CDRH discussions on new inspection techniques are in the early stages and could require regulation amendments or new legislation.

Unapproved IDE Changes Are OK

FDA says IDE changes are permitted to a device, its protocol, monitoring procedures, and labeling without prior FDA approval if the changes do not affect either patient safety or the "scientific soundness" of the study.

According to a new final guidance, Changes or Modifications during the Conduct of a Clinical Investigation, it is the sponsor's responsibility to consider the effect that any change made to the investigational plan may have on a clinical investigation and its data. The guidance is intended to implement a FDAMA provision that establishes criteria permitting sponsors to make certain modifications to investigational devices, including manufacturing changes and clinical protocols.

"Any change to the basic principles of operation of a device is considered to be a significant change and, thus, requires prior FDA approval," the guidance says. "In assessing the effect of a device design or manufacturing change, a risk analysis and supporting credible information should help to identify those changes that represent a significant change."

To assist sponsors in determining if a change represents a significant change, the document provides a decision-tree flowchart. To follow the flowchart, FDA recommends that sponsors use data generated by design control procedures or other credible information to determine whether the change has a significant effect on the device design. The guidance states that "credible information may include data generated under the design control procedures of [CFR sec.] 820.30, preclinical or animal testing, peer- reviewed published literature, or other reliable information gathered during a trial or marketing."

The new guidance may be accessed at http://www.fda.gov/cdrh/ode/guidance/1337.pdf.

More on Reprocessed Devices

FDA says it has identified several "technical concerns" as it formulates a policy on reviewing device premarket submissions for reprocessed single-use devices.

Speaking at a device reuse workshop in Phoenix on May 30, CDRH Office of Surveillance and Biometrics consumer safety officer Lily Ng said these concerns include controlling raw materials; defining specifications; identifying changes to OEM devices; cleaning, disinfecting, and sterilizing procedures; the functionality of reprocessed devices; and the labeling of reprocessed devices. Ng also outlined FDA's enforcement strategy for reprocessors, adding that the agency is implementing an inspection program for hospital reprocessors as it continues to inspect all commercial reprocessors.

Software Regulation for Patient Safety: Easing the Burdens of FDA and Industry

Aug 01, 2001

Originally Published MDDI August 2001

Editor's Page

Software regulation for patient safety: Easing the Burdens of FDA and Industry

The challenge facing the agency and industry alike is to develop a standard that allows for timely premarket review while still adhering to risk-based review criteria.

The integration of medical devices and information technology is reshaping healthcare delivery by dramatically increasing device functionality. Yet as new generations of software are developed to control an increasing number of vital functions in medical devices, they can also pose severe hazards should a software-related failure occur.

The need for effective regulation of medical software is clear. But devising a strategy for protecting consumers from software-related device failures without impeding the process of innovation poses significant challenges.

Today's software often becomes obsolete in six months or less. This can be a critical issue for the medical device industry, where lengthy review times by CDRH can delay the release of new products. The difficulty is to design a system that would provide timely premarket reviews of medical device software, use risk-based review criteria, and keep pace with the evolution of the software used in medical devices.

Sherman Eagles, technical fellow at Medtronic Inc., and John Murray, software expert with CDRH, have proposed one solution. If a manufacturer can demonstrate that device software has been "developed using good software engineering practices," questions concerning the development process can be eliminated, speeding up the review process. They argue that the role of software standards is "to precisely document and define what constitutes good software engineering practices."

Efforts to develop appropriate standards for medical device software have now spanned more than six years. Two important milestones, however, were passed this year: in March, the AAMI board approved a standard developed specifically for medical devices, and the document was approved by ANSI on June 5.

The next step will be to gain FDA recognition of the ANSI/AAMI SW 68—Medical Device Software—Software Lifecycle. At a meeting of the AAMI Medical Device Software Committee on June 28, it was noted that a letter from AAMI has been drafted requesting FDA recognition of the standard. An FDA recognition document could be published as early as November 2001.

During the recent AAMI/FDA International Conference on Medical Device Standards and Regulation, there appeared to be clear indications that FDA will recognize SW 68. It was also apparent that such action would do much to ease the agency's current premarket burdens. A fundamental problem for FDA has been the sheer volume of software to be reviewed. "We need a better way to do business," Murray says. "The FDA strongly believes that through the use of standards we can reach consensus and find a better way."

What remains to be done? SW 68 applies to low- and moderate-risk stand-alone and embedded medical software systems. The next challenge will be to identify or create standards that will apply to all remaining medical software, including high-risk systems. In addition, initial steps have already been taken to develop a new international standard—a process that could be completed by 2004.

Development of medical software standards represents an effort to gain control of a technology that is growing and changing with alarming speed. The standard will likely prove a valuable tool for easing the burdens of industry and FDA alike. Our hope is that recognition by the agency will occur quickly and that efforts to develop an international standard will be successful.

The Editors

Achieving Efficacy and Sterility in Flexible Packaging

Aug 01, 2001

Originally Published MDDI August 2001

Whether the priority lies in the sterilization method or the barrier level, packaging requirements can be easily met with a wide variety of material options.

Karen Berger and Dhuanne Dodrill

Packaging plays an important role in many industries, but few applications are as demanding as those found in the medical device and diagnostic industry. Packaging for medical devices may lack the glamour and glitz of that for consumer goods; however, nowhere else is package integrity as important. The job of the package is to maintain the sterility of the product through its intended shelf life, as well as ensure its efficacy at the time of use. The impressive range of flexible packaging materials available today helps to achieve these goals. This article will discuss tried-and-true methods of packaging, as well as introduce several new technologies for meeting packaging requirements.

FACTORS AFFECTING PACKAGE CHOICE

There are many important factors to be considered when a packaging system is required. All of these factors will, to a varying extent, influence the choice of materials. Ideally, they should be communicated to the packaging supplier as early as possible in the project.

Sterilization Methods. The first factor to be considered with medical packaging materials is the sterilization method. Many times the packager is committed to a certain method because of product restrictions, process economics, or equipment availability. If end-users are locked into autoclave sterilization, then heat-resistant materials must be used. Some medical products are incompatible with specific sterilization methods. For example, one would not sterilize liquids (such as filled IV bags) with ethylene oxide (EtO), as this process requires permeable packaging materials. For products that are terminally sterilized, the packager's choices are often significantly narrowed based on the sterilization method that will be used.

Barrier Level. Another key consideration is the level of barrier required. A product often needs to be protected from oxygen, moisture vapor, or light. In addition to keeping undesirable elements from entering a package, it is often equally important to keep critical product components from migrating out of the package. Aluminum foil is an excellent barrier material and, as a rule of thumb, a foil thickness of 1 mil or greater will be essentially pinhole free. Foil composites are available for both formed and nonformed applications. Aluminum metallized films, with a very thin aluminum layer on the order of 100–200 Å, are nonformable and are used to provide a lesser barrier at a lower cost than foil.

Package Clarity. Where package clarity is required, there are many options for both formable and nonformable packages. Formable barrier materials include ethylene-vinyl alcohol (EVOH) coextrusions, Barex polyacrylonitrile, and Aclar chlorotrifluoroethylene (CTFE) composites. Nonforming clear barrier webs often incorporate various barrier coatings onto 48-gauge biaxially oriented polyester (OPET), a substrate widely used for its strength, clarity, thermal stability, and chemical resistance. These coatings include silicon oxides (SiO_x) or aluminum oxide (Al₂O₃), also known as glass coatings; polyvinylidene chloride (PVDC); and polyvinyl alcohol (PVOH). Table I gives an overview of the most common barrier materials used in flexible medical packaging.

Package Size. Also important is the package size and geometry. Packages can generally be classified into two main categories: flat pouches (2-D) or formed (3-D) pouches. The formed portion of a 3-D package requires the use of an extensible material—one that will retain its critical properties after the forming process. Its shape is achieved via thermoforming or pressure (cold) forming.

Chemical Resistance. Chemical resistance is important for packages that contain alcohol, iodine, aromatic, fragrances, or other active substances. Since the sealant layer is the first line of defense against aggressive chemicals, special care should go into its selection. Polyester materials form the backbone of many chemical-resistant sealants, and chemical-resistant laminating adhesives and primers may be used for these types of applications.

The five factors discussed above are among the most important when specifying packaging materials, but other considerations should include:

Package unit cost and volume.
Opening features—peelable seals versus weld seals.
Type of packaging machinery—optimization of materials for certain machine types.
Printing.
Environmental and disposal advantages or disadvantages.
Shelf life requirements.

FLEXIBLE PACKAGING CONSTRUCTION

With the tremendous variety of packaging materials available today, there are many possible combinations. The simplest structures may consist of just one or two layers—for example, a monolayer forming web or the OPET/polyethylene web commonly found in a basic pouch. The more complicated structures can easily exceed eight layers, including all of the components such as primers, inks, and tie layers. Flexible packaging materials for medical packaging applications incorporate one or several elements.

Heat-Stable Material. This material serves as the outer layer of a flexible packaging composite. This side of the web is typically exposed to a heat-sealing die, so good thermal stability is important. OPET is most commonly used. A suitable print surface may be needed for in-line printing applications. Oriented polypropylene (OPP) film can be used where less thermal stability can be tolerated, although not all OPP films can be used for radiation sterilization. Biaxially oriented nylon (BON) is more expensive than OPET but has greater flexibility for better stress-crack and pinhole resistance. Cast nylon film is used as the heat-stable layer in many forming applications. Paper can be used for its excellent heat resistance and print surface, but it is prone to tearing and fiber generation.

Barrier Layer. The barrier layer provides the required barrier properties. The barrier layer can consist of aluminum foil, Aclar film, a barrier resin such as EVOH, or a barrier coating such as PVOH, PVDC, vacuum metallized aluminum, or one of the glass coatings. The barrier coatings are generally applied to a heat-stable material such as OPET; this type of coated film can serve as both the barrier layer and the heat-stable material. Barex, which is an excellent oxygen barrier, is used as a film lamination as well as a rigid tray material.

Figure 1. Common peelable sealant mechanisms.

Sealant Layer. The proper sealant helps ensure a hermetic package. It is the portion of the package that is in contact with the product. A sealant layer may be provided as a monolayer or coextruded film—either blown, cast, or extrusion coated. Both peelable and weld seals may be formulated from the entire range of extrudable resins: low-density polyethylene (LDPE), high-density polyethylene (HDPE), ethylene copolymers such as ethylene vinyl acetate (EVA) and ethylene methyl acrylate (EMA), other acrylate copolymers, Surlyn ionomer, polypropylene (PP), and extrudable amorphous polyesters. A weld seal is usually obtained by sealing like materials together, while the mechanisms for peelable seals involve "controlled incompatibilities" between polymer materials. Figure 1 shows some common peelable sealant mechanisms. The sealant layer can also be in the form of a solution-applied coating, typically a vinyl acetate or PP dispersion. Solution-applied coatings are losing ground in favor of film-based sealants. Because the film-based sealants provide the sealant function as well as sheer bulk, they are usually more economical.

Adhesives, Tie Layers, Primers. These are bonding agents that are literally the glue that holds everything together. A poor choice in this area means the package seal will delaminate either immediately or, worse, upon aging. Special challenges include retort and autoclave applications, bonding of greatly dissimilar materials, and difficult-to-bond materials such as Aclar film and some PP materials.

In addition to the major components, there are various ink, overlacquer, and epoxy systems and other functional coatings that can be applied. Given the huge variety of building blocks available, one can see why it is important to ensure that the appropriate materials are selected.

Material Type	Material	Trade Name	Thickness (mil)	MVTR	O₂TR	Formable	Autoclaveable/ Retortable**
Clear barrier materials	CTFE	Aclar 22C	1	0.035	N/A	Yes	Yes
	CTFE	Aclar UHRx 3000	1	0.015	N/A	Yes	Yes
	CTFE	Aclar SupRx 900	1	0.019	N/A	Yes	Yes
	COC	Topas 8007	1	0.071	N/A	Yes	No
	COC	Topas 6015	1	0.11	N/A	Yes	Yes
	Liquid crystal polymer	Vectran V200P	1	0.015	N/A	Yes	Yes
	OPET		1	1.5	4.5	No	Yes
	OPP		1	0.33	N/A	No	No
	PVC		1	1.8	9.1	Yes	No
	Oriented nylon		1	9	2	No	Yes
	Cast nylon		1	19	3	Yes	Yes
	Polyacrylonitrile	Barex	1	5	1	Yes	No
	PVDC-coated PET		*	0.5	0.5	No	No
	PVOH-coated PET		*	4	0.2	No	No
	Al₂O₃-coated PET	ClearFoil M	*	0.03	0.045	No	No
	Al₂O₃-coated PET	ClearFoil M2	*	0.3	0.04	No	Yes
	SiO_x-coated PET	ClearFoil F	*	0.02	<0.003	No	No
	SiO_x-coated PET	ClearFoil A	*	0.04	0.04	No	Yes
Opaque barrier materials	Metallized PET		*	0.05	0.1	No	No
	Aluminum foil (flat)		0.035	0.02	0.03	No	Yes
	Aluminum foil (flat)		0.5	0.01	0.02	No	Yes
	Aluminum foil (flat)		1	<0.00	<0.00	Yes	Yes
* The barrier for these materials is due to the coating and is not dependent on substrate thickness. ** Provided autoclaveable adhesives/sealants are used. Note: Thin-gauge aluminum foil may be formable but not functional due to pinholes. Generally, 1-mil or thicker foils are used for formable applications.
Table I. Common barrier materials used in flexible medical packaging.

PACKAGING MATERIAL SYSTEMS

As stated above, the sterilization method is a vital factor to consider in specifying packaging for medical devices, because once the sterilization method is known, the range of appropriate materials narrows. For each of the major sterilization processes, there are 2-D and 3-D packaging systems in place.

EtO Sterilization. For effective EtO sterilization the packaging material must be breathable to allow the high-humidity EtO gas mixture to infiltrate the package. A partial vacuum is drawn before and after the cycle to facilitate the movement (in and out) of the EtO and moisture vapor. If the package does not have sufficient permeability, the process will be ineffective. As stresses in the seal area are introduced due to the pressure difference between the inside and outside of the package, a seal failure phenomenon known as sterilizer creep may occur. The package must also withstand the moderately elevated process temperatures, although this is typically not a problem for most materials.

A typical 2-D breathable pouch consists of a PET/PE bottom web combined with a Tyvek or paper top web. The Tyvek or paper top web is the breathable portion, and it may be coated or uncoated. Uncoated Tyvek has a Gurley Hill porosity of about 20–25 sec/100 cm³ air per square inch; typical coated Tyvek has a porosity of 80–100 sec/100 cm³ air per square inch. A less-breathable coating can be applied as a patterned coating, such as a grid or dot pattern. Tyvek or paper also provides a suitable print surface and good aesthetics. Because one disadvantage to Tyvek is its expense, a great many 2-D pouch applications use a Tyvek header strip or vent, to save on material cost.

For 3-D packages used with EtO sterilization, the same breathability requirement exists as for 2-D pouches; therefore, the same breathable materials (paper or Tyvek) can be used. Instead of a flat, nonformable bottom web, some type of thermoformable web should be used. The traditional thermoforming webs of EVA/ionomer/EVA are being challenged by more cost-effective approaches, such as using linear low-density polyethylene (LLDPE) or Surlyn blends in the core, or even moving to a monolayer blend. The more costly coextruded-nylon forming webs provide outstanding toughness and impact resistance that is not easily matched by using strictly PE-based polymers and blends. To further improve pinhole and puncture resistance, multiple layers of nylon are often used. Given the wide cost range, it is important not to overdesign the package for the product.

Steam under Pressure (Breathable Autoclave). Packaging material requirements for steam sterilizing are similar to those for EtO in that the package must be breathable to allow for steam infiltration. An additional requirement is heat resistance. A typical steam autoclave cycle may be run at 121°C, but temperatures up to 140°C (284°F) may be used. For the breathable portion of the package, Tyvek—which is made of spun-bonded HDPE fibers—may be used, but only under very controlled conditions where temperatures do not exceed 127°C. Many papers will withstand the process without significant loss of physical properties. A suitable heat-seal coating could be based on PP or amorphous polyester.

In-hospital autoclave sterilizers have long used steam sterilization for 2-D packages. A typical structure is an OPET/PP bottom web and a paper top web. This type of package is very low cost and may not have all the desired properties for in-hospital use such as fiber-free opening and microbial barrier. Other, more-reliable 2-D pouches employ OPET with a peel-able sealant of sufficient heat resistance, based on PP or PET chemistry, and a high-strength, medical-grade paper.

A 3-D steam-sterilizable package must be breathable and heat resistant, as well as formable. This is a tall order for most packaging materials, particularly if one desires a peelable seal as well. Nylon-, PP-, or PET-based forming webs may be used with coated paper or Tyvek top webs. Alternatively, uncoated paper or Tyvek can be used if a peelable seal layer is provided as the inner layer on the bottom forming web (a more economical scenario).

If the peel layer is part of the forming web, one should be aware that the heat from the forming process can change the nature of this layer. In the case of a peelable polyester sealant, the heat from the forming station can crystallize the sealant, rendering it nonfunctional. There are also the aesthetic issues of shrinkage or snapback with some PP and nylon forming webs when subjected to autoclave temperatures. Developing a more cost-effective, peelable package for 3-D steam sterilization remains an active development area for several converters.

Radiation Sterilization. Flexible packaging for radiation sterilization has no requirement for heat resistance (other than for the heat needed to make the seals) or breathability. Although breathability is not required to achieve sterility, it is sometimes needed to allow outgassing of odors that can develop. In these cases, a Tyvek or paper top web can be used. The main limitation is that some polymers are not suited for exposure to radiation. Materials that may be adversely affected include PP and polyvinyl chloride (PVC). Adverse effects, which can occur to a modest extent in many materials, usually involve a loss of physical properties (such as embrittlement) or a color change.

Packaging for radiation sterilization can be supplied in high-barrier or nonbarrier versions. A high-barrier package would be used where the packaged product needs to be protected from oxygen, moisture vapor, and/or light. For a barrier package, both top and bottom webs will utilize a barrier material.

For 2-D nonbarrier radiation pouches, the packaging materials can be very cost-effective. A simple PET/PE laminate can be used for both sides of the web. The PE side can be supplied to give either a peelable seal or weld seal. Prefabricated linear-tear or snap-tear bags, made from a single coextruded film, can be used. For barrier applications, one would need to incorporate aluminum foil or one of the other materials mentioned above in the discussion on barrier materials.

For 3-D radiation, a formable bottom web is used. For nonbarrier applications, the same webs used as bottom forming webs for 3-D EtO packages are employed. For barrier applications, one of the formable barrier webs, such as a coextruded film containing EVOH, an Aclar lamination, or a formable foil, can be used.

Retort Sterilization (Nonbreathable Autoclave). In some nonbreathable autoclave applications, a liquid-containing package is sterilized in a retort process. Seal integrity is extremely important in these applications because, unless the engineer has precise overpressure control, the pressure difference between the inside and outside of the package may easily result in seal failures. This is an area where very strong peelable seals are often specified. The same high heat resistance needed for breathable steam applications is also required. In general, a barrier package for this type of sterilization can use either clear barrier or foil barrier composites. Not all of the barrier materials are autoclaveable, and not all of the autoclaveable materials are thermoformable. Table I indicates which barrier materials apply for retort and autoclave sterilization.

A 2-D barrier pouch for retort or autoclave sterilization can be made from aluminum foil or from one of the nonfoil autoclaveable barrier materials. Autoclaveable clear barrier materials are often more expensive than foil; therefore, a pouch can be made of foil on one side and the clear barrier material on the other. This will suffice provided the end-user does not need clarity on both sides of the package and the packaging equipment can accommodate two different webs.

For this sterilization method, 3-D packaging usually consists of a rigid thermoformed tray and a flexible film lidstock. The lidstock can be foil based or use a nonfoil barrier material.

Other Sterilization Methods. Although the previously mentioned sterilization methods represent the major applications, other methods are well worth mentioning. Dry-heat sterilization is used for products that do not lend themselves well to other sterilization techniques, do not contain moisture, may be damaged by contact with moisture, and are stable at elevated temperatures. This technique requires a long exposure time (as long as several hours) at elevated temperatures (275°F and above). Heat resistance is the main packaging requirement. Some examples of dry-heat-sterilized products include orthopedic implants, collagen products, and surgical instruments.

Hydrogen peroxide (H₂O₂) gas plasma sterilization is drawing interest as a substitute for EtO sterilization. Developed by Advanced Sterilization Products (Irvine, CA), the Sterrad system is gaining acceptance in both institutional and industrial use. A breathable package is required for the gas to permeate the package. Although this is done in a drier and slightly cooler environment than EtO sterilization, the same types of package materials are appropriate. The only known exception is paper, which cannot be used; the cellulose fiber in paper can absorb enough H₂O₂ to make the process ineffective. Since this method is relatively new, not all materials have been thoroughly tested. One of the main benefits of this process is greatly improved cycle time; since the primary by-products are water and oxygen, there is no aeration required. This is very important to help achieve quick turnaround in clinical settings. Compared to EtO, the environmental and regulatory concerns are minimal.

PurePulse Technologies (San Diego) has developed PureBright broad-spectrum pulsed light (BSPL) technology, a sterilization process used primarily in applications involving blood components, vaccines, and other biopharmaceuticals, as well as dry surfaces. Highly intense, short flashes of broad-spectrum light (ultraviolet, visible, and infrared) are used to rapidly deactivate organisms without the use of intense heat, hazardous chemicals, or by-product generation. Packaging materials compatible with this process will transmit light over the broad spectrum employed. LLDPE, LDPE, nylon, Aclar, HDPE, and PP have all been used. Polystyrene, PET, and glass are all very clear to the eye, and one might expect these materials to work well. In reality, these materials do not transmit light in the ultraviolet region of the spectrum and, therefore, are not suitable for use with this method. Package geometry should not allow any shadowing on the product or the light exposure may not be sufficient.

Film Sample
(4-mil except where
noted)

Ultimate Tensile Strength
(psi)

MD**

TD**

Elongation
(%)

Elmendorf Tear
(g)

Cost Rank*

EVA/ionomer/EVA

3300

3200

530

580

100

130

FlexForm B

4000

3400

800

850

500

1200

PE/nylon/PE***

5800

5900

460

420

110

160

Nylon/PE***

6200

460

470

420

LLDPE

3400

2600

550

830

500

810

* 1=least expensive.
** MD=machine direction; TD=transverse direction.
*** 3-mil sample. Note: Differences in the amount and type of nylon used can significantly change the properties. These values represent only one version of this structure.

Table II. Flexible bottom-web comparison.

NEW MATERIALS

Polymer Blends for Thermoforming Webs. For years, the standard thermoformable bottom web used in the United States has been an EVA/ionomer/EVA coextrusion. More recently, PE/nylon/PE and nylon/PE structures—always popular in Europe—have made the transition from the food industry to the medical industry. With the drive to reduce costs, film manufacturers have been challenged to find more competitive alternatives to the old standards.

The availability of new high-performance packaging resins such as metallocenes, ultra-low-density polyethylene (ULDPE), and very-low-density polyethylene (VLDPE) has made the use of polymer blends in thermoforming applications a viable alternative. Costs are reduced as more-expensive materials, such as ionomers, are replaced with less-expensive resins. As many of these blends can be produced on monofilm lines, which are often fully depreciated and underutilized, manufacturing costs are further reduced.

Lower cost need not be equated with reduced performance. Table II provides a comparison of performance and cost for several blends and the traditional thermoformable bottom webs. For less-demanding applications, lower-performance blends of LDPE and PE copolymers can result in significant cost savings, and may be perfectly suitable for soft goods packages with shallow draws. Special care should be taken when evaluating these packages over the life cycle of the product.

Sealants for Uncoated Paper and Tyvek. In the drive to reduce costs, there has been a significant focus on developing high-performance sealants for use with uncoated paper and uncoated Tyvek. A successful sealant needs to provide the look and feel of a seal made to coated paper or Tyvek, prevent fiber tear from occurring when the seal is opened, and provide an impressive total-package cost savings.

Figure 2. Peelable pouch for EtO and gamma sterilization using tamper-evident seal technology.

The sealant technology that has been most successful is based on a cohesive peel mechanism. Rather than adhesively peeling from the paper or Tyvek and risking fiber tear, the sealant is designed to fail internally, leaving a small amount of sealant on the paper or Tyvek (see Figure 2). Core-Peel, from Rexam Medical Packaging (Mundelein, IL), and Allegro T from Rollprint Packaging Products (Addison, IL) use this approach. By marrying this sealant technology with bottom forming webs, the transition from a 2-D pouch to a 3-D package can be accomplished.

The choice of paper is extremely critical and will determine the success of the program. The use of uncoated paper provides some unique challenges. Because coated paper has a better microbial barrier than the same paper without coating, many papers used for coated applications are not appropriate for uncoated use from a microbial-barrier standpoint. In addition to a microbial barrier, the paper should provide durability, be sufficiently porous, and have high internal bond to prevent fiber tear. Kimberly-Clark (Dallas) recently introduced Impervon paper, which has been designed specifically to be used as an uncoated paper for medical applications.

Chemical Resistance. One of the most exciting developments in chemical resistance has been the introduction of extrusion-coated amorphous polyester sealants. The sealant technology has long been available in film form; however, its relatively high price and various performance issues have limited the film's market to specialty applications.

Polyester sealants are extremely clean. They are very unlikely to leach from the packaging into the product or to scalp from the product. As a result, they are excellent for holding products where there may be a very small amount of an active ingredient present.

Polyester sealants are superior when it comes to containing hard-to-hold chemicals. They can also protect other, more-vulnerable materials. For example, aluminum foil will discolor and pinhole when exposed to oxidizing agents such as iodine. A polyester sealant will serve the dual purpose of protecting the aluminum foil while also providing the desired seal properties.

Extrusion-coated polyester sealants are available to provide both peelable and weld seals to a variety of materials, as illustrated in Table III. In many applications, a polyester barrier is needed to protect a substrate—such as aluminum foil—from the product, but a polyolefin sealant is desired. Advances in extrusion coating technology now allow polyester and polyolefin to be coextrusion coated onto the foil (or other substrate), economically reaping the benefits of both polymer systems.

High-Heat Resistance. Extrusion-coated amorphous polyesters have also widened the material choices available for applications requiring high-heat resistance. Historically, polypropylene sealants, either as films or coatings, have been used for autoclave applications. The sealants are designed to seal to themselves or other polypropylenes (e.g., rigid polypropylene trays).

Extrusion-coated polyester sealants maintain stability at higher temperatures than either PP or HDPE. This makes them ideal for autoclave applications and makes dry-heat sterilization a realistic option. Melt temperatures are 266°F for HDPE, 329°F for cast PP, and 469°F for APET sealant. (Temperatures for dry-heat sterilization can range from 275° to 350°F.) They can be sealed to themselves or to other polyesters. For lidding applications, the use of CPET, APET, or polycarbonate trays becomes an option.

Figure 3. Schematic of a typical O₂ scavenger material.

Oxygen Scavengers. Oxygen scavengers are ideal for applications requiring extremely low-oxygen environments. The scavenger absorbs oxygen remaining in the package headspace, as well as oxygen ingress through the packaging material. Oxygen absorption occurs through an oxidation reaction. Because the amount of oxygen that can be absorbed in the reaction is finite, a passive oxygen barrier (e.g., foil) must be used. In addition, gas flushing or vacuum packaging is recommended. The oxygen scavenger is part of a multilayer structure and is generally buried between the passive barrier layer and the sealant layer (see Figure 3).

Ferric (iron-based) compositions have been the traditional oxygen scavenger. These systems are moisture activated; the oxygen-absorbing capacity is highly dependent on the relative humidity (RH) level. At an RH of 40% or less, these systems are not activated. This precludes their use with moisture-sensitive or dry product applications. To preserve the oxygen-absorbing capacity, resins and films must be stored at low RH prior to use.

Recognizing that many polymers oxidize and therefore could be used as scavengers, researchers have been concentrating on identifying polymers that do not degrade during the oxidation process. Degradation is undesirable as the degradation products could potentially migrate into the product. Chevron Phillips (San Francisco) has developed an oxygen-scavenging polymer (OSP) system that is stable and has controlled activation. The system consists of an oxidizable polymer, a transition metal catalyst, and a photoinitiator. Films made with the OSP system remain in a nonscavenging state until triggered by exposure to UV light—typically during the filling process.

With the use of appropriate barrier materials and filling techniques, oxygen-scavenging polymers can provide a virtually oxygen-free environment for products.

Moisture Barriers. CTFE films have long set the standard for clear, high-moisture-barrier films. The fact that they can be thermoformed makes them a distinctive packaging product. This impressive performance comes at a significant economic price, however.

The introduction of cyclic olefin copolymers (COCs) provides a thermoformable alternative to CTFE. Although their moisture barrier capability is not quite as good as that of CTFE, they cost much less. COCs thermoform at relatively low temperatures and have rapid cycle times, making them very attractive for clear forming applications requiring a moderate moisture barrier.

In nonthermoforming applications, such as pouches and bags, COC/polyethylene blends can dramatically increase film stiffness and improve the moisture barrier without affecting clarity and oxygen permeation.

Liquid crystal polymers (LCPs) offer another new moisture barrier option for multilayer packaging. They can be designed to be coextruded with polyolefins. LCPs are highly inert, offer excellent thermal stability and chemical resistance, and also provide good moisture, oxygen, CO₂, and aroma barriers.

The excellent performance and relatively low cost of aluminum oxide (Al₂O₃)–coated polyesters make them a very popular barrier choice. Because of the cost considerations, they are often considered as a replacement for silicon oxide (SiO_x) coated polyester. Al₂O₃-coated polyesters offer a range of barrier and price options. They are thermally stable, offer excellent clarity, and can be combined with virtually any sealant option. In addition, some grades are autoclaveable.

Sealant	APET	CPET	PETG	Polycarbonate	PVC	Barex	Itself
Allegro P	P	P	P	P	P	P	—
Allegro O	P	P	P	P	P	P	—
Forté	W	W	W	W	—	—	W
Forté PI	W	—	W	—	—	—	W

P = Peelable
W = Weld

Table III. Types of seals achieved when extrusion-coated polyester sealants are used with various materials.

CONCLUSION

With myriad options available today in the field of flexible packaging, the device producer has several alternatives for meeting product packaging requirements. Traditional packaging materials are being replaced by more cost-effective structures, and many new materials are just entering the arena. These expanded choices will help to optimize package performance, resulting in cost savings for the packager. In today's competitive climate, few can afford to overengineer (or underengineer) their packaging systems.

Optimizing EtO Sterilization

Aug 01, 2001

Originally Published MDDI August 2001

EtO Sterilization

Optimizing EtO Sterilization

The use of advanced monitoring technologies in four key aspects of EtO sterilization can yield substantial business and regulatory benefits.

Paul J. Sordellini, Frank R. Bonanni, and Gregory A. Fontana

The use of ethylene oxide (EtO) gas has long been a dominant mode of terminal sterilization. Today, close to half of all medical devices produced in the United States are processed with EtO. But while it remains a popular method of sterilization, the pressures of global competition demand greater cost-effectiveness and flexibility of the process. At the same time, compliance with regulatory requirements must be maintained.

Fortunately, the application of spectroscopic and electronic analytical equipment during process development, validation, and operation is allowing EtO users to increase the efficiency and efficacy of the process while reducing turnaround times, labor requirements, and raw material use. To gain these improvements, EtO users are focusing on four key areas:

The DataTrace system from Mesa Labs measures process temperature, pressure, and humidity.

Releasing product parametrically.
Managing product load configuration within validated parameters.
Adopting new products into already-validated product families.
Determining process equivalency across multiple sterilizers.

Correctly implemented, programs addressing these areas will increase productivity, reduce costs, and yield a more controlled process. At the same time, manufacturers will have increased flexibility to adjust their sterilization practices quickly in response to changing market conditions.

PROCESS MONITORING TECHNOLOGY

When a chemical process is developed and validated, the resulting data are used to establish and verify the acceptable range for each of the critical process parameters. Process repeatability is therefore predicated on the routine control of each parameter within the validated ranges. The simplest and most accurate way of verifying process conformance is to directly monitor each critical parameter and then compare the data collected during and after processing to the validated specifications.

Direct analytical technology using nondispersive mid-infrared (NDIR) spectroscopy allows the real-time simultaneous monitoring of headspace water vapor and EtO concentrations during an EtO sterilization process. An analyzer with the ability to measure 0300 mg/L of water vapor and 01200 mg/L of EtO, and to operate at 070°C whether above or below atmospheric pressure, can be mounted on an EtO sterilizer to confirm process conformance with minimum validated parameters.

Proper design and installation of a direct EtO sterilizer gas analyzer requires selection of an appropriate sample point from which analyte gases are drawn.¹ Provided that a sterilizer has ample internal recirculation to minimize stratification, a single sample point is sufficient to obtain a gas stream representative of the process conditions. The current standard makes no mention of a minimum number of either sample points or a sampling frequency. As a result, the user can be asked to justify the selected locations and sampling plan.

The EOS-200 from Spectros Instruments Inc. (Whitins-ville, MA) uses a nondispersive infrared analyzer.

The optimum position from which to sample is toward the top of the sterilizer. Stratification, if it occurred, would result in the heavier gas settling toward the bottom of the sterilizer. Therefore the first signs of stratification caused by recirculation obstruction or failure would appear as lower-than-expected EtO gas concentrations beginning in the top of the headspace. By attaching a length of flexible tubing to the sample port, the port can effectively be moved around the sterilizer during a series of identical cycles. In this way different areas of the sterilizer may be analyzed for comparison and the most challenging location identified and documented for regulatory review. A report can then be generated showing details of gas distribution throughout the chamber.

External sample lines are sealed and heated to prevent leakage and condensation. In proximity to the sample point, the analyzer may have independent pressure and temperature sensors. Besides providing data for the gas analysis, these extra sensors can be used as a redundant process monitoring system. The results can be compared with the pressure and temperature data recorded by the sterilizer's main control system.

The user who reduces the definition of parametric release to simply replacement of biological indicators (BIs) with a gas analyzer is throwing away the opportunity to achieve an unprecedented level of process control, process optimization, and final assurance of sterility. With appropriate modifications to the sterilizer hardware and control software, the scope of process-gas analysis can be expanded from simply monitoring headspace gases to actually controlling the addition and maintenance of process-gas concentrations.

A data feedback loop, where concentration data from the analyzer are ported directly to the command logic of the sterilizer controller, allows the user to deliver accurate levels of water vapor and EtO to the process. Using this approach, processes can be developed and maintained to within ±4 mg/L. Direct gas analysis eliminates the concern of EtO depletion during sterilant dwell. EtO gas makeup is automated and controlled to add compensatory sterilant whenever the concentration drops due to load absorption. It must be noted that while this approach works with pure EtO systems, EtO-diluent systems (EtO/CO₂, for example) safety features to avoid overpressurization during makeup.

All measurement and test equipment that may directly or indirectly affect the quality of process output must be routinely calibrated.^2,3 Analytical hardware for water vapor and EtO measurement must be calibrated to bracket the full gas concentration range specified in the sterilizer operational qualification manual. Calibration efforts can be aided by infrared (IR) detectors that automatically (e.g., at the start of each cycle) switch to a stable and constant blank reference gas in situ for background correction. Based on the user's selection, the analyzer automatically isolates itself from the sterilizer by closing the sample intake valve and then proceeds to flush the gas cell with nitrogen. Nitrogen, like all other diatomic molecules, has no IR absorption, making it the most secure method of rezeroing a gas analyzer. The nitrogen, making up 100% of the volume of the gas cell, is optically scanned and provides the instrument with a true zero reference for both water vapor and EtO detectors to read.

This type of self-referencing analyzer uses the spectrum from the blank signal as a zero in calculating the absorbency units, thus allowing for the automatic correction of drift in the system. Any technology that is unable to self-reference a blank reference gas will require a more-stringent calibration schedule and procedures to constantly correct drift. Drift is inherent to all IR, chromatographic, and electronic sensors.

During validation of all minimum and maximum parameters, the headspace EtO level is measured at intervals (e.g., every 1 to 5 minutes) throughout the entire phase of gas contact. This generates an EtO concentration profile. What is characterized, especially in those processes that use a single-charge method, is the EtO affinity of that particular challenge load. Typically, sterilant dwell will begin with EtO at its highest concentration. As the gas permeates all levels of packaging in the load, the concentration profile decays, reaching its minimum at the end of sterilant dwell. The EtO concentration decay is related to the process set-point program and the totality of the physical attributes of the load. Therefore, gas profiling during validation will yield an acceptable minimum-maximum range for EtO concentration.

If an EtO profile exhibits excessive decay during routine processing, postprocessing data review will detect the condition, quantify it, and possibly reject the cycle for falling outside validated parameters. A direct headspace-gas analyzer, when properly designed, can consistently measure both process gases with an accuracy of ±2% full scale or better. Even small variations in load absorbency can be detected in real time, allowing the user to quantify the impact that variations in load configuration of any magnitude have on the process. Sample charts and graphs showing the anatomy of a pure EtO process are presented in Figures 14.

For processes that add makeup EtO during sterilant dwell in an attempt to compensate for EtO that migrates into the load, direct gas analysis improves process control, safety, and product quality. Typically, in this approach, any decrease in headspace pressure triggers the addition of EtO. With continuous direct analysis, the user can distinguish between pressure loss due to temperature fluctuations, water-vapor loss through condensation on the load and sterilizer surfaces, and pressure loss due to true migration of EtO into the load. Interfacing the gas analyzer with the sterilizer control system allows the addition of EtO to take place only when the headspace EtO concentration truly decreases. Adding EtO to compensate for a drop in temperature or condensation of water vapor can increase EtO chemical residues on the product, which will require longer aeration times.

Figure 1. Example of an EtO set-point graph.

PACKAGE MONITORING TECHNOLOGY

The object of an EtO sterilizer is to heat, humidify, and expose all product surfaces to EtO gas for a specified time. This is achieved primarily by effecting pressure and temperature changes in the sterilizer headspace. Process elements introduced into the headspace act physically on the load to bring forth the conditions inside each primary package necessary to achieve a targeted sterility assurance level (SAL). In essence, the microenvironment inside every single primary package included in a load becomes an individual sterilization chamber. Direct characterization and documentation of the minimum required levels of heat, water vapor, and EtO concentration that must integrate inside the primary packaging in order to sterilize a device to a specific SAL are the keys to achieving advanced process control. Again, the interests of science, regulatory compliance, and business can all be well served through the implementation of technology, this time on a primary-packaging level.

Figure 2. Example of a graph showing percentage volume of air.

Early attempts at process monitoring practices were incomplete. Technology offered BIs that could be sealed inside the primary package to confirm lethality, and thermocouples that could be attached to the packaging to monitor the product temperature. Water vapor and EtO concentrations inside the packaging could be inferred to be sufficient only by negative BI growth, but were rarely measured in situ during the entire process.

In 1994 the United States adopted ANSI/AAMI/ISO 11135 as the new sterilization standard.⁴ For the first time, verification of product level humidity became a requirement during all validations.⁵ Because most users sterilized with pure EtO, temperature/humidity sensors were eventually developed to comply with the new practice. Because EtO inside the package was still practically impossible to measure, however, BIs continued to serve as the final process indicator.

The implementation of an additional package-level sensor, together with the previously mentioned water vapor sensor and BIs, now makes it possible to individually monitor each of the critical process parameters from within the load and create simultaneous profiles of headspace and load conditions. At the end of in-chamber conditioning dwell, the pressure inside the product packaging is at equilibrium with that of the sterilizer headspace. The next phase consists of the vaporization of EtO into the sterilizer.

Figure 3. Example of a volumetric profile.

As EtO gas is added to the sterilizer headspace, the sterilizer control system will immediately detect and monitor the headspace pressure rise. As the gas penetrates the load, the pressure sensors inside product packaging will detect and record the pressure rise. The time lag between the pressure rise in the sterilizer head-space and the resulting pressure rise inside the product packaging will depend on and characterize the physical load attributes.

By simultaneously monitoring the headspace pressure rise during the addition of EtO and the pressure rise inside select pallet locations, the user can determine the rate of penetration into specific products. The matrix of EtO pressure data will reveal the relationship between the headspace pressure rise and the rise occurring inside the selected combinations of products and packaging studied. During process development this information helps estimate the exposure time needed to inactivate qualified BIs placed in the most difficult product/packaging type. In addition, differences in delivered parameters due to pallet location within the sterilizer are also identified.

Figure 4. Example of a partial pressure profile.

PARAMETRIC RELEASE

Parametric release of EtO-sterilized product is defined as "declaring product as sterile, based on physical or chemical process data rather than on the basis of sample testing or biological indicator testing."⁴ The alternative--conventional product release--requires the routine placement of BIs throughout the load. The BIs are retrieved following processing and tested for up to 7 days before the load is released to market. The main difference between parametric and conventional release is the number of process parameters directly measured.

In conventional release, the user directly measures the time of each phase, the pressure throughout the process, and the headspace temperature. The remaining two critical parameters, headspace water vapor and EtO concentrations, can be quantified indirectly by thermodynamic calculation based on pressure rise and temperature.⁶ Acceptance of the two indirectly measured gas concentrations is supported by the negative growth of the exposed BIs. Thus the BI data serve as a process parameter integrator that confirms delivery of appropriate levels of heat, water vapor, and EtO concentrations.

Parametric release, in compliance with the current international sterilization standards, yields an immediate return on the investment by increasing the productivity of the manufacturer and the sterilization operation. Given a choice, good science would choose direct real-time monitoring of all critical process parameters. Business logic would agree: releasing product parametrically the moment it completes aeration saves both the time and the materials needed to routinely place, retrieve, and test BIs. In some cases this represents a reduction in turnaround time of as much as a week, bringing a significant decrease in inventory requirements for the manufacturer.

It is important to realize that from a scientific and regulatory point of view, the technology needed for parametric release also increases the quality of sterilization process monitoring and the degree of process control. The BI data, as used in conventional release methods, will detect only gross process failures. They will not reveal small drifts in the performance of the processing system or reductions of delivered lethality due to interfering factors, such as variations in load configuration. The achievement of an SAL cannot be empirically supported with BI test results. The way to scientifically confirm that each and every process delivers the required SAL is to directly measure all parameters that influence the SAL and then compare the data with those collected during validation. Routine processes, proven empirically to meet or exceed every minimum requirement set forth by the validation, will deliver the required SAL for release to market. The jump in the quality of EtO sterilization process control is what sets direct process analysis apart from biological process compliance monitors.

LOAD CONFIGURATION CONTROL

For device manufacturers with an extensive product catalog or customized multicomponent products, the master product family may include any combination of thousands of different items. During routine production, an almost infinite number of different sterilizer load configurations are possible. That is, loads may differ from one another in density, product material characteristics, packaging material type, and quantity.

All potential side effects originating from the attributes of every different load configuration must be identified and evaluated during process development in order for a maximum challenge load to be assembled for validation purposes. The logic is that once a process is validated for the most challenging load configuration, every different load configuration generated during routine production will be equally or less challenging and therefore will respect the conditions established by the validation.

Variations in load configuration can occur daily and may influence the efficacy of the sterilization process or cause a particular product lot to absorb a level of heat, humidity, or EtO that falls outside the validated ranges. Certain packaging materials are more difficult to permeate than others. Certain product materials are more difficult to heat or humidify. Certain loads have a higher density and require a greater sterilizer heating capacity. A welcome by-product of parametric release is that the user has the tools to scientifically verify that every different load configuration placed inside the sterilizer does not exceed the physical demands of the challenge presented during validation.

Once a direct gas analyzer is installed and programmed to routinely profile sterilant dwell, routine data monitoring and review simply involves comparing the EtO concentration profile for each routine process with the validated profile to verify that the minimum and maximum validated concentrations were within tolerance. Each time a different load configuration is presented for processing, the material constitution is compared with that represented in the validation. In cases where a load configuration appears to differ significantly from the validation load, product temperature, humidity, and pressure sensors are placed inside primary packages and then distributed throughout the load, occupying positions that were monitored during the validation.

Following processing of this new load configuration, data detailing headspace temperature, water vapor, and EtO concentrations are compared with the resulting packaging levels of those concentrations. This data set, when compared with the headspace and product data obtained during validation, will allow the user to determine empirically whether the validated process continues to deliver the same minimum required process parameters to the product. If so, then the new load configuration is recorded in an amendment to the validation report and further monitoring is no longer necessary.

As more new load configurations are generated, monitored, and equated to the validated load configuration, significant historical data are created. Eventually, enough varying load configurations will have been tested and documented so that no further packaging-level monitoring of water vapor and EtO will be needed. Routine parametric release can then continue with the requirement of product temperature verification as prescribed in the requirement section of ANSI/AAMI/ISO 11135-1994.

With parametric release and the accompanying ability to monitor and evaluate load configuration influences, the sterilization operation upgrades the quality of process control. Manufacturing operations can vary load configuration according to market demands and regulatory bodies can be presented with a scientifically sound system for justifying the freedom exercised in building constantly changing product loads.

PRODUCT ADOPTION

Expansion of the medical device industry may bring frequent modifications to existing products and the development of new product lines. The most efficient way to deal with this growth is to allow new products (candidate products) to be quickly added to an existing sterilization product family (cycle group) already covered by a validated EtO process.

Following a program of product adoption, a candidate product is added to an existing cycle group after a thorough assessment of its physical and chemical characteristics and comparison with the other members of the cycle group. This is a documented study performed by a person with appropriate sterilization experience, and may include different degrees of physical, chemical, and microbiological testing to assess the product's suitability for the adoption. Provided that the candidate product is no more challenging to the penetration of heat, water vapor, and EtO than the original validation challenge, and that the product bioburden is no more difficult to sterilize than the indicator organism, product adoption into a cycle group is acceptable and becomes an important tool used to cope with business growth.

By distributing physical-microbiological test packs (PMTPs) throughout a validation load, a user can characterize the complete set of physical parameters delivered to the product site and correlate these conditions to the delivered lethality. A PMTP consists of a primary package containing a challenge product, a BI placed in the product location that is most difficult to sterilize, and a humidity/temperature and a pressure/temperature data logger both placed adjacent to the BI location. The PMTP is assembled and packaged under routine manufacturing conditions. Depending on the size of the load, a number of packs are seeded into the pallets so as to monitor an efficient selection of locations. The data loggers are programmed to monitor conditions at predetermined time intervals and store the data in nonvolatile memory.

Following completion of the process, the test packs are removed for analysis. The BI incubation results will map the delivered lethality throughout each pallet and the sterilizer. The humidity/temperature data will reveal the amount of water vapor and heat associated with the lethality achieved at each location. The user will see the amount of heat and humidity added as a result of preconditioning, the amount of heat and humidity lost during in-sterilizer air removal, the amount of heat and humidity added during the conditioning phase, and the heat added during sterilant dwell. The uniformity of the heat and water vapor distribution will also be charted. In this way, distribution variations can be attributed either to the product or packaging (in heterogeneous loads) or the physical pallet location within the sterilizer.

Monitoring pressure within the primary package to characterize gas penetration rates represents a novel and important aspect of this exercise. The user first identifies the start and stop times for EtO addition and sterilant dwell as recorded by the sterilizer. From this, a headspace EtO concentration profile can be derived, either by thermodynamic calculation using the EtO pressure rise and temperature, or through direct gas analysis in the case of parametric release.⁷ The pressure profile for the same two time periods is then extracted from each package-level pressure sensor. Package-level gas penetration can be revealed.

The headspace pressure and concentration profiles and the package pressure profiles can be overlapped, enabling the user to characterize the migration of gas from the moment it enters the headspace to the moment it penetrates across each pallet and enters the primary packaging. This type of headspace-and-product comparative study will reveal and quantify all the physical conditions inside the primary packaging that achieve the resulting level of sterility. For the first time, the user will be able to characterize with complete sets of data the degree of physical resistance that a particular product-package configuration and process-challenge device (or test pack) offers to the three physical elements of the sterilization process (heat, water vapor, and EtO).

Useful information derived from this study is headspace-product hysteresis, that is, the time lag exhibited by the load and process-challenge devices in reacting to physical changes made to the sterilizer atmosphere (addition and removal of heat and both process gases).

To aid in adopting a new product, package, or load configuration into a validated cycle group, the user needs to include the new candidate product in a routine process. An appropriate number of PMTPs, using the candidate product, are distributed throughout the load. Following processing, the PMTP data can be compared with the same data collected during the original validation of the cycle group.

If the validated process is shown to successfully deliver to the candidate product the same levels of heat and water vapor, and gas penetration rates are similar to those in the validation, this lends support to the adoption. If the candidate product turns out to pose more of a physical challenge than validated products, the user needs to construct a microbiological validation to complete the adoption. Finally, the candidate product is tested to confirm product functionality, package integrity, and chemical residuals. It is then added to the cycle group.

PROCESS EQUIVALENCY

Increases in production volumes can exceed the capacity of a validated preconditioning room, sterilizer, and aeration room. Manufacturers need to efficiently expand the sterilization of a cycle group to additional rooms and sterilizers that can be proven equivalent to the validated site in their ability to deliver minimum validated parameters to the primary package environment. This is achieved through a scientific program of process reproducibility that is more commonly referred to as process equivalency.

By implementing the sensor technology described in this article, EtO process development will yield a complete set of physical parameters that are confirmed to achieve a goal at the primary packaging level. Validation then confirms the acceptability of the results and the repeatability of the process. The actual parameters programmed into the sterilizer (heat, water vapor, and EtO additions) as well as the physical characteristics of the equipment (recirculation, heat medium, capacity) have no importance independent of what resulting conditions are delivered inside the primary packaging.

Once a cycle group is validated in a particular sterilizer (the predicate sterilizer) using the two-tier process and package-level monitoring described herein, additional sterilizers (candidate sterilizers) can be certified equivalent. They must be able to deliver to the primary packaging the same minimum process parameters as detailed in the validation of the predicate sterilizer. To verify this capability, the same load configuration as employed in the original cycle group validation is used in the candidate sterilizer. PMTP packs are assembled and distributed throughout the load according to the validation pattern. Following processing, the BIs will confirm delivered lethality and the physical sensors will characterize the heat, water vapor, and gas penetration to the primary packaging.

Any candidate preconditioning room proven to deliver the same levels of heat and water vapor to the product site can be considered for equivalency. Each candidate sterilizer proven to deliver the same minimum levels of heat, water vapor, and EtO to the product site can also be considered for equivalency. In addition, each aeration room proven to deliver the minimum level of heat to the product site can be considered for equivalency. Whether or not candidate equipment is physically comparable and programmed identically to the validated predicate equipment is not always important. The final SAL of a processed load is based solely on the successful delivery of a specific set of physical conditions to all product surfaces.

CONCLUSION

Ethylene oxide has been used as a medical device sterilant for the better part of a century. Although advances have been made in computer-controlled automation and worker safety, achieving the increased process flexibility and improved process economics necessary to meet changing business demands has often conflicted with the requirements of both scientific and regulatory authorities. New technology that details process parameters as they are delivered to the sterilizer headspace and the primary packaging can assure the industry that EtO will continue to be the sterilant of choice.

Once a cycle group is validated using direct analysis of headspace gas and ample distribution of PMTPs, the resulting data can be used to implement scientifically sound programs of parametric release, load configuration control, product adoption, and process equivalency. The completeness of the data collected in the validation and the scientific nature of each optimization program enable users to respond with confidence to all regulatory bodies, as every conclusion is supported by integral sets of empirical data. The result is a harmonious relationship between sterilization, manufacturing, and the regulatory authorities. Management of EtO sterilization services can now respond more quickly than before to changes in market demands.

REFERENCES

1. Paul J Sordellini, "Speeding EtO-Sterilized Products to Market with Parametric Release," Medical Device & Diagnostic Industry 19, no. 2 (1997): 6780.
2. Cheryl A Boyce, "Guidance on the New QS Regulation Calibration Requirements," The Validation Consultant 4, no. 7 (1997): 1214.
3. Code of Federal Regulations, 21 CFR Part 820, "Quality System Regulations."
4. Medical Devices—Validation and Routine Control of Ethylene Oxide Sterilization, AAMI/ANSI/ISO 11135 (Arlington, VA: AAMI, 1994).
5. AAMI/ANSI/ISO 11135, (Arlington, VA: AAMI, 1994), sects. 5.3.4, 5.5.2.1, and 5.5.2.2.
6. Ethylene Oxide Sterilization Equipment, Process Considerations, and Pertinent Calculations, AAMI TIR No. 15-1997 (Arlington, VA: AAMI, 1998).
7. AAMI TIR No. 15-1997(Arlington, VA: AAMI, 1998), sect. 6.0.

Photo courtesy of Mesa Laboratories

Preparing for Successful Design Transfer

Aug 01, 2001

Originally Published MDDI August 2001

Planning ahead for design transfer and using it as a management tool results in a smoother, less costly transition from development to production.

Terry Zenner

It has become popular to say that all medical products, from small point-of-care devices to large high-volume analyzers, go through a life cycle. The metaphor is apt. Not only are there distinct stages in each product's life, such as proof of principle, engineering prototype, and commercial product, there are also distinct and critical transitions between each stage that determine the ultimate success of the product.

Of these transitions, design transfer, the introduction of a design to production, may be the most important. Effective design transfer requires a thorough assessment of the product's design documentation, selection of components, and careful definition of production methods. Failure to transfer a design effectively can lead to situations in which specified parts are either unavailable or higher in cost than expected, production workflow is interrupted, and product quality suffers. Conversely, the rewards of effective design transfer are great: it can lower material and production costs, decrease product time to market, increase product quality, and generate customer enthusiasm.

Medical device developers often transfer their product designs to an in-house production facility. There is a growing trend, however, to transfer them to an outside contract manufacturer. Given the amount of design and process information that typically needs to be transferred, a sound design transfer process can make or break an outsourcing relationship. This article is written from the perspective of a medical product developer working with an outside contract manufacturer. The information presented will help both parties establish and manage an efficient design transfer process to transform engineering designs into manufactured products successfully and consistently.

THE DESIGN TRANSFER PROCESS

Design transfer is an integral process in the early life of a product. It must be well executed, especially for complex medical devices. FDA's quality system regulation requires the manufacturer to complete the following steps in order to satisfactorily complete the design transfer process:

Establish and maintain procedures to ensure that the device design—its components and configuration—is correctly translated into production specifications.
Transfer the product design into production methods and procedures.
Create a production environment that ensures the product complies with regulatory requirements and industry standards.

The transfer of a product design into a manufacturing environment requires a comprehensive set of processes to coordinate many tasks simultaneously. Experience, well-executed procedures, and careful review are the keys to a successful transition. This is especially true when a product design is transferred to an outsource manufacturer because of the greater potential for miscommunication. Differences in corporate cultures, business styles, quality systems, and perceptions of what constitutes design transfer can contribute to problems.

Consider the example of a product developer contracting the manufacture of a handheld point-of-care diagnostic device. From the developer's point of view, the scope of design transfer was to deliver a prototype and electrical schematics. To reduce costs, the developer insisted on using an off-the-shelf enclosure to package the electronics. Although the prototypes function in most respects, the enclosures did not consistently pass the fluids-resistance test required for use in a clinical environment. As a result, the design and procurement of a custom gasket and rework of the enclosure parts was required. It was then discovered that the required EMI coating applied to the inside of the case softened the parts, requiring additional drying time before final assembly. Thus, failure to fully consider regulatory requirements during design transfer resulted in increases in the total number of parts, the total cost of parts, and the cost and time for parts rework; workflow modifications; and, ultimately, a delay in the planned product introduction to the market.

POTENTIAL CHALLENGES AND CONSEQUENCES

The effectiveness of the best-conceived design transfer process will be diminished if it is not properly supported and carried out. Some of the more common problems that arise include the following:

Product developers do not have a finalized design.
Business managers and technical experts do not grasp the scope of the design transfer effort and underestimate the amount of time and effort required.
Manufacturing processes have not been developed, documented, or validated.
Developers have not created a vendor supply chain based on an approved-vendor list.
Developers bring unresolved cost, reliability, or safety issues to the manufacturer.
The design transfer process is well understood by both parties, but the inability to plan the transition of a product design into a controlled manufacturing environment results in slow starts and unacceptable delays.
The purchasing department does not have enough time to identify and approve new vendors, verify component specifications, and update the manufacturing planning system.
The workflow of the manufacturing organization is disrupted by having to wait for released materials, procedures, and test fixtures.
Delays occur even after all the documentation is approved, because manufacturing must receive, inspect, and finally release parts for production.

Failure to appreciate these challenges inevitably leads to unnecessary project delays, frustration, and misunderstandings between the developer and manufacturer. It is a reason some firms have not taken full advantage of the benefits that an outsourcing relationship can provide.

DESIGN TRANSFER QUESTIONNAIRE

A design transfer questionnaire (see sidebar) can help a developer and manufacturer ascertain the former's readiness to transfer a device design into manufacturing. The use of this document, or one similar to it, can result in a better understanding of the device from a technical, business, and regulatory perspective. The questions are useful in evaluating the status of the project, identifying shortcomings that could put the project at risk, estimating unit costs of the product, and determining what resources will be required to prepare the product for formal design transfer.

DESIGN TRANSFER QUESTIONNAIRE

The following are questions a designer should be able to answer prior to the start of a design transfer.

Are the test plan, procedures, and test fixture documentation complete and validated?
Is there evidence of design verification and validation?
Is the process validation report complete?
Is a completed hazard analysis available?
Has a product-failure mode and effects analysis been performed and documented?
Is a final acceptance test report available?
What regulatory approvals are required (FDA, UL, CE, etc.)?
How many off-the-shelf parts are in the device?
Are standard components specifications available for all off-the-shelf parts?
How many custom parts are used in the device?
Are specifications and drawings available for all custom parts?
Have all parts been assigned part numbers?
Does an approved-vendor list exist?
Is the device designated Class I, Class II, or Class III?
Does the product have FDA market approval?
If not, how does the product developer intend to submit?
- 510(k)
- PMA

Is the bill of materials complete and fully costed?
Are all part drawings and schematics complete and ready for production?
Are complete assembly procedures available?
Are assembly fixtures required?
What is the estimated time required to manufacture the device?
Are there vendor requirements that must be met, e.g., audits, first-article inspection, supplier survey?
Is the incoming materials inspection plan complete?
How may parts will require first-article inspection?
Are the in-process and final inspection plans complete and validated?
How much time will testing the device take?
How much time will testing the device take?
Have safety, compliance, and packaging tests been performed and passed?
How many devices will be produced and according to what schedule?

REGULATORY CONSIDERATIONS

It is important to determine whether a product will be submitted for 510(k) or premarket approval. Preparation for each of these reviews requires considerable time and effort; delays can be avoided through planning and allocating resources.

In some cases, a device that uses new technology or that is designed for a new intended use may not be immediately assigned a class designation by FDA, thus causing another possible delay in design transfer. Class III device manufacture requires significant documentation and administrative cost. To mitigate regulatory and scheduling risk, the product may need to be treated by the designer and manufacturer as a Class III device until FDA makes its final determination.

COMPLIANCE FACILITATES DESIGN TRANSFER SUCCESS

First and foremost, successful design transfer requires planning for and assessing compliance with regulatory requirements. Compliance is essential to meeting the developer's product, business, and financial objectives. It also leads to improved quality and savings in cost and time throughout the manufacture and support of the product. Regulatory compliance will help ensure that each device includes all the quality features established during the design phase. It will also assist the device developer and the contract manufacturer in coordinating their methods for managing the volumes of documentation associated with design control, design transfer, and the engineering change process.

Additionally, complying with regulations aids both the developer and manufacturer in verifying that each device is built to approved specifications using the same materials and components; assembly, inspection, and test methods; and quality procedures as the approved design. Concurrent planning for production, sustaining, and value engineering is facilitated by regulatory-compliance efforts, as is assuring that the final product design meets quality, reliability, budget, and schedule goals. Finally, maintaining regulatory compliance aids both parties in verifying component and subassembly lead times, identifying manufacturing process constraints and production bottlenecks, and determining spare parts and support requirements.

OTHER KEYS TO SUCCESS

To coordinate a comprehensive design transfer effort, the following guidelines are recommended.

Start Early. Device designers should begin thinking in terms of manufacturing the product early in the design stage.

Create a Cross-Functional Design Transfer Team. This team should include representatives from the engineering, manufacturing, materials management, quality, and business development departments.

Plan the Design Transfer. The developer should use a checklist (see sidebar for an example) to see that all requirements are being met on schedule.

Merge Process and Design Expertise. Manufacturing engineers should actively participate in the initial product design process.

Focus on Quality. The developer must create solid design documentation, including a quality plan, product-failure mode and effects analysis, and a product validation plan.

Time to market is critical to a developer's seeing a return on its investment. The following precautionary measures can help reduce delays in a product's transition to manufacturing.

Identify Obsolete or End-of-Life Parts. Take, for example, the case of a product developer who outsources the manufacture of a medical imaging device. The device includes commercial, off-the-shelf components such as a computer, display, printer, and other electronics with short life cycles of 12 to 18 months. If the developer is knowledgeable about the end-of-life issues, then both the designer and the manufacturer can help the engineering and business principals work with key supply-chain partners to resolve technical, documentation, and purchasing issues early on. This shared knowledge not only strengthens the relationship between the parties, it also creates a better working relationship among all the supply-chain partners. Identifying obsolete or end-of-life parts allows adequate time to consider any needs for revalidation, document the appropriate changes, and introduce them into the manufacturing system in a controlled manner, thereby avoiding production delays.

Secure Parts through Approved Vendors. A developer planning to manufacture an electronic monitoring device that attaches to a patient's belt, for example, requires several passive components and integrated circuits commonly used in cellular telephones, PDAs, and pagers. Because of their performance characteristics and small size, these components are popular with medical device designers. Obtaining these electrical components in the relatively low volumes needed for clinical units and early production is a challenge to even the most experienced and savvy buyers. A setback in locating these parts can extend the scheduled production start date for the device. Requesting quotes from a number of bidders to secure a supplier and a good price is a beneficial use of time and reduces the possibility of manufacturing delays.

Four additional guidelines for successful design transfer include:

Use off-the-shelf components whenever possible.
Identify manufacturing process constraints and potential bottlenecks.
Determine spare parts and product requirements.
Validate parts in advance of release to production.

RESPONSIBILITIES OF THE DESIGNER BEFORE DESIGN TRANSFER

Prior to production, a manufacturer must obtain a complete documentation package that accurately reflects the product design and the required manufacturing processes. This package should include all product and process documentation listed in the design transfer checklist.

DESIGN TRANSFER CHECKLIST

A product development quality plan has been established.
Design verification and validation results are up-to-date.
A detailed risk analysis is complete and available.
Documents outlining product requirements are created. These include:
- Software requirements documents.
- Custom parts specifications.
- A manufacturing quality plan, including:
  - Critical process control points.
  - Process flow.
  - Process validation.
  - Process control.
  - Environmental requirements of the production equipment.
  - Materials handling and control.
  - Materials receiving inspection.
- A device master record, including complete and accurate:
  - Bill of materials.
  - Component, subassembly, and finished product specifications.
  - Assembly drawings and schematics.
  - Manufacturing and assembly procedures.
  - Component incoming inspection procedures.
  - Manufacturing in-process inspection and test procedures.
  - Finished product test and inspection procedures.
  - Labeling and packaging specifications and procedures, and acceptance criteria.
  - Product servicing procedures.
- Device history record forms.
- Manufacturing final-acceptance test report.
- Copies of labeling including service and operation manuals.

In many cases, product developers are surprised to discover that their project is not ready to transfer to manufacturing. Lack of resources, limited experience, or the inability of the developer to freeze the product design may render a product unready for production. Regardless of a developer's enthusiasm or determination to bring the product to market, all design transfer activities must be complete and documented for regulatory and business requirements to be met. Using a design transfer checklist will help the developer in the preparation of complete and accurate documentation.

Transfer of an engineering design into production will typically require a formal review and approval of the product specifications and manufacturing procedures. Transfer may also require the product developer to provide evidence of the adequacy of specifications, methods, and procedures through documented process validation—including the testing of the finished product in actual or simulated conditions.

Important elements of the checklist that are often missing or incomplete, and can therefore cause delays, include:

The bill of materials. It may not reflect the current, complete configuration of the product.
The manufacturing in-process inspection and test procedures. In particular, the validation of the procedures and the inclusion of test-fixture calibration and preventive maintenance may be overlooked. These should all be addressed in the manufacturing quality plan.
The finished product test and inspection procedures. Like the bill of materials, these procedures may not reflect the final configuration of the product. These tests need to be validated, also.
Labeling and packaging specifications. Design changes may not be tracked or may not reflect the current configuration of the product.

DESIGN TRANSFER REVIEW

FDA generally requires developers to conduct a design review to confirm that all aspects of the design transfer have been executed. Results of clinical tests and design verification and validation are reviewed. This measure determines whether established processes yield finished devices that meet the project requirements. At the time of the design transfer review, the manufacturing quality plan must be made available for review. The manufacturing procedures and test methods are drafted and controlled through an engineering change order management process. When procedures and other documents reach their final form, the developer releases them to production.

The minutes of the design transfer review should include open issues, assigned responsibilities, necessary follow-up activities, and the scheduled date of design transfer completion. The sidebar on this page lists the documents that the developer should have available for release at the time of the review.

REFERENCE DOCUMENTS FOR DESIGN TRANSFER REVIEW

FDA market approval.
Any agency approvals other than FDA.
Employee training program.
Clinical field trial report, if available.
First-article inspection reports.
Device history records for:
Prototypes.
Clinical test units.
Product development audit report including action item resolution.
Process validation plan, if required.
Automated test equipment.
Equipment software validation.
Calibration documents.
Process and test equipment validation and qualification reports.
Index for transferred design history file.
Vendor master maintenance form (for new suppliers).
Manufacturing proposal, contract, and any amendments.

The design transfer checklist provides the agenda for the design transfer review. A copy of the completed and approved checklist is added to the design history file and attached to the design review minutes. The review minutes and checklist are published and distributed to the transition team members and the device developer. Any issues identified in the review minutes must be resolved prior to transfer to manufacturing.

CONCLUSION

The process of design transfer involves more than simply negotiating a maze of tasks as a product undergoes its metamorphosis from engineering prototype to commercial product. In addition to the help it provides in ensuring product requirements are met, the design transfer process serves as a valuable project management tool for meeting regulatory, technical, business, and financial goals. Regulatory requirements are clearly articulated at design transfer, and plans for achieving, monitoring, and validating them are established. Technical hurdles are identified early in the process, providing time for solutions to be implemented. The business issues of forming supplier relationships and freeing production bottlenecks are managed at their inception, and, finally, financial goals are met as time to market is minimized and quality, service, and customer enthusiasm are maximized.

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