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Articles from 1999 In February

Be Still My Beating Heart? A Shorter Detour Around Coronary Obstructions

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

An MD&DI February 1999 Column

Does a simplified procedure for coronary-bypass surgery signal a fork in the road for cardiac-care technology?

We tend to think of progress in medical technology as resembling the river that is the answer to an old riddle: something that follows the same course, never gets tired, and never reverses itself. Advances generally move in the direction of greater complexity: more-involved science, more-sophisticated instrumentation, increasingly difficult and intricate technique—what J. Robert Oppenheimer called the "vast, complex, ever growing, ever changing, ever more specialized and expert technological world."

Occasionally, however, progress arrives in the form of a radical simplification, as in the current revolution in coronary-bypass surgery. Although the heart-lung machine is among the marvels of medical engineering, it's long been acknowledged that the device is responsible for troublesome side effects in patients. The machine damages cellular blood components, increasing the potential for both infection and bleeding; risks inducing strokes by generating minute clots and air bubbles during oxygenation; and often imparts a profound systemic shock referred to by doctors as "pump head," with manifestations ranging from cognitive deficits to clinical depression. These are serious but heretofore unavoidable complications: after all, it is the machine that keeps the patient alive while the heart is stilled and the diseased arteries bypassed.

Now there is another option, one that takes the patient off the pump altogether: the beating-heart bypass. Steadily gaining momentum over the past two or three years, this procedure, long considered impossible, has arisen thanks to the development of a specially designed set of instruments. Replacing the heart-lung machine—with its draining and infusion lines, cardiotomy reservoirs, arterial filters, membrane oxygenators, precision pressure-control mechanisms, and fail-safe power supplies—are forks and spoons!

Individual surgeons, some of them tinkering at garage or basement workbenches, devised their own versions of a simple tool used to press down on the still-beating heart and stabilize the operative site so that bypass grafts can be sewn into place. One model looked like a two-tined dinner fork; another, a soup spoon with a small window cut in the bowl. Even though some of these devices have since been commercialized and refined (a recent variant uses suction cups to grip and hold the heart surface), the level of the "technology" can be compared to what emerges from an average high-school metal shop.

Follow-up studies of patients who underwent beating-heart bypass have shown the off-pump procedure to be as effective as traditional heart-lung surgery, with significantly fewer complications. It is also less expensive: the operation itself is some 40% cheaper, with a 60% overall reduction in hospital stays, fewer tests, and less time spent in intensive care. Apart from perfusionists and the manufacturers of heart-lung machines, everyone—doctors, patients, insurers—appears to have benefited from making things simple.

Will the next breakthrough feature a similar forks-and-spoons retreat from the ramparts of technological complexity? Should those searching for a small-diameter vascular prosthesis take a look at, say, coffee stirrers? The answer, of course, is that getting things to seem easy is hard, and simplification subtle. In this story, the real technological advance is the conceptual audacity of leading-edge scientific practitioners, whose hard-won skill and experience enabled them to rethink some of the bedrock principles of their discipline.

To appreciate what's really involved, invite a cardiac surgeon for dinner. Just be sure to count the silverware.

Jon Katz

Copyright ©1999 Medical Device & Diagnostic Industry

FDA Finalizes Off-Label Dissemination Rule

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

An MD&DI February 1999 Column


The agency's codification of requirements for companies communicating unapproved-use information reflects stringent interpretation of FDAMA.

James G. Dickinson

When device manufacturers want to disseminate independent reviews of their technology or product performance to anyone—including practitioners, procurement agencies, or even end-users—they must operate according to a new FDA rule. Enforceable as of November 20, 1998, the final rule, titled Dissemination of Information on Unapproved/New Uses for Marketed Drugs, Biologics, and Devices, provides scant comfort to those drug and device marketers who had been hoping that today's kinder, gentler FDA might adopt lenient interpretations to ameliorate less-than-friendly provisions of the FDA Modernization Act (FDAMA).

The 34-page, 36,000-word opus declines all such industry requests presented in the proposal stage, opting almost uniformly for stringent interpretations of the act. In the final rule, marketers lost out in the following ways:

  • Only those publications listed in the Index Medicus will be allowed to be used in disseminating new-use information.
  • Verbal communication of unapproved uses is outlawed.
  • Final manuscripts that have been accepted for publication in qualifying journals must not be disseminated until actual publication has occurred.
  • Admitting that peer-reviewed reference books will be disseminated less often now than before as a direct result of its final rule, FDA stipulated that only whole books—not just selected chapters—containing new-use information may be disseminated. Pending a final court decision in the Washington Legal Foundation case, however, FDA said such books may be disseminated without meeting all of the final rule's other requirements if the company does not focus on or point to a specific unapproved use and it includes a disclaimer that the publication includes information about unapproved uses.
  • The Internet was rejected as a source of balancing information (warnings, contraindications, etc.) for new uses described in disseminated articles.
  • The phrase "to the best of my knowledge" was rejected as a qualifier for corporate executives who might otherwise use it to certify the completeness of their documentation regarding existing negative information about a new use.

In all, FDA estimates that the annual industrywide cost for companies seeking permission to disseminate unapproved-use information will be approximately $1.8 million.

Against these restrictive losses, there were some modest gains for device manufacturers reflected in the final rule. For instance, FDA yielded to objections to its proposal to include comparative claims involving approved products among "new uses" that must be the subject of clinical study. The agency also toned down a related definition that would have put all subgroup analyses (e.g., the product's use in children, the elderly, different genders, etc.) into the new-use category.


In addition, FDA actually turned down an opportunity to interpret FDAMA as requiring additional paperwork from industry. Section 533(b) gave FDA free rein to require companies to keep records of the names of all persons receiving unapproved-use information, but the agency opted to do so only when public health was at risk.

FDA also heeded industry comments in abandoning complex criteria it had proposed for requests for exemption from FDAMA's requirement that clinical studies be conducted under an FDA-issued supplement for any new uses being disseminated. Those exemption requests, citing "economically prohibitive" grounds, will now be available to more companies and be a lot simpler than FDA had initially proposed.

However, the agency rejected a commenter's suggestion that it exempt a manufacturer from the new rule if the unapproved use of its product has been accepted as standard medical practice in such authoritative compendia as USP-DI or the American Hospital Formulary Service. FDA held that such citations may be used to apply for an exemption in specific cases.


Regarding Internet dissemination of unapproved-use information, FDA said in the preamble to the final rule that the practice could be permissible if manufacturers met all of the rule's requirements. For example, the manufacturer "would have to ensure that the recipients of the information are appropriately limited and that all of the required information and disclosures can be attached. . . . FDA may, in the future, issue guidance on this subject."

Responding to objections about FDAMA's quixotic provision that manufacturers should not use each other's published studies without prior permission when disseminating new-use information, FDA clung tight to the letter of the act. Even though a publication may have entered the public domain, said FDA, "the fact that an article has been published does not eliminate the need to get permission from the researching company. If it did, this requirement in the statute would be meaningless, because all information disseminated under this part must be published."

In a major concession, FDA abandoned its proposed eight-element definition of what constitutes "scientifically sound" clinical information that may be disseminated. The agency's new approach considers all qualifying journal articles and reference publications to be scientifically sound except "letters to the editor; abstracts of a publication; those regarding Phase 1 trials in healthy people; flagged reference publications that contain little or no substantive discussion of the relevant clinical investigation; and those regarding observations in four or fewer people that do not reflect any systematic attempt to collect data, unless the manufacturer demonstrates to FDA that such reports could help guide a physician in his/her medical practice."


One comment on the proposed rule asked what FDA would do if an article discussed multiple unapproved uses but the manufacturer wanted to focus on just one unapproved use. In its preamble, FDA said it expected requirements to be met for all such uses, but that it may consider exceptions—on a case-by-case basis—when the use of interest is the predominant one discussed in the article.

To a comment asking about separation of unapproved from approved uses during detail visits to a Web site, FDA said it did not intend to prohibit mixing the two kinds of visits, but that "any unapproved-use information . . . must be kept physically distinct from the promotional materials, and the sponsor may not verbally promote the unapproved use or include materials about the unapproved use, beyond those permitted or required. . . ."

As mentioned previously, not all of FDA's interpretations of FDAMA followed a stringent line. One comment urged the agency to require that disseminators of new uses list by name all the drugs approved for that use, rather than just say that other therapies have been approved. FDA responded, in the preamble to the final rule, that the statute doesn't require this, and that although such a stipulation would be useful, "it would be difficult to develop a complete and accurate list. Moreover, the information could be misleading if the manufacturer merely provided a list of names."


As authorized by FDAMA, FDA also volunteered to meet with any manufacturer that it decides must include additional material with its disseminated information. And FDA agreed to tighten wording that critics feared would allow it to extend the 60-day deadline FDAMA gives the agency to review materials before they can be disseminated. The concern, FDA acknowledged, was that it would, for example, advise a manufacturer on day 59 that the company's submission was not complete and that therefore the 60-day time period had not yet begun. "FDA is committing to give manufacturers a final decision within 60 days," the agency said in revising the appropriate section. The final rule also abandons the proposal's attempt to require disseminated new-use information to bear the phrase "and is being disseminated under section 551 of the Federal Food, Drug, and Cosmetic Act."

How much of the information that companies submit in seeking FDA permission to disseminate unapproved-use information should be open to the public? In its final-rule preamble, FDA said it received comments ranging from support for full release of all information to total confidentiality. Some even urged FDA to publish, in the Federal Register, the fact that a submission seeking dissemination had been received; to include the citation for the article and the bibliography; and to solicit additional published information that might be appropriate for dissemination.

FDA has decided not to require a notice-and-comment process before permitting dissemination to proceed or before granting an exemption. However, the agency said that "the Freedom of Information Act and FDA's regulations will dictate what information submitted under this provision can be disclosed." FDA will "continue to examine these issues separately."

What if the additional studies needed to justify dissemination of information about a new use would be unethical to conduct in human subjects? Both the proposal and the final rule include provisions for exemptions to be sought on this particular ground.


Extensions of the 36-month deadline set by FDAMA for conducting the studies required for new uses under the dissemination rule will be granted in two situations. For studies already under way at the time permission to disseminate is sought, the deadline may be extended one time, by 24 months. For studies not yet begun, FDA can grant unlimited extensions of the 36-month deadline.

If, after the dissemination begins, data come into FDA showing that the new use is either not effective or poses a public health risk, or if a company fails to comply with the rule's requirements, FDA may order corrective action. This generally will take the form of required "Dear Doctor" letters or corrective advertisements, although the rule gives FDA considerable flexibility to fashion the corrective action so as to remedy the underlying problem or deficiency. The agency may mandate that warning labels be placed on the affected products or require revised labeling that includes warnings. However, although commenters asked FDA to explicitly spell out its options with respect to possible corrective actions, this is not done in the final rule.

Further information about the new rule can be obtained from Byron L. Tart, FDA, Center for Devices and Radiological Health (HFZ-302), 2098 Gaither Rd., Rockville, MD 20850; 301/594-4639.

FDA's final regulation on the dissemination of unapproved-use information requires the following disclosures:
    (1) A prominently displayed statement disclosing:
  • For a drug, the fact that "this information concerns a use that has not been approved by the Food and Drug Administration." For devices, the fact that "this information concerns a use that has not been approved or cleared by the Food and Drug Administration." If the information to be disseminated includes both an approved and unapproved use or uses or a cleared and uncleared use or uses, the manufacturer shall modify the statement to identify the unapproved or uncleared new use or uses. The manufacturer shall permanently affix the statement to the front of each reprint or copy of an article from a scientific or medical journal and to the front of each reference publication disseminated under this part.
  • If applicable, the fact that the information is being disseminated at the expense of the manufacturer.
  • If applicable, the names of any authors of the information who were employees of, or consultants to, or received compensation from the manufacturer, or who had a significant financial interest in the manufacturer at any period ranging from the time that the study being disseminated was conducted until one year after the article/reference publication was written or published.
  • If applicable, the fact that there are products or treatments that have been approved or cleared for the use that is the subject of the information being disseminated.
  • The identification of any person that has provided funding for the conduct of a study relating to the new use of a drug or device for which such information is being disseminated.

    (2) The official labeling for the drug or device.

    (3) A bibliography of other published articles (reports of clinical investigations both supporting and not supporting the new use) from scientific reference publications or scientific or medical journals concerning the new use of the drug or device covered by the information that is being disseminated. (This is required unless the disseminated information already includes such a bibliography.)

    (4) Any additional information required by FDA under Sec. 99.301(a)(2). Such information shall be attached to the front of the disseminated information or, if attached to the back of the disseminated information, its presence shall be made known to the reader by a sticker or notation on the front of the disseminated information, and may consist of:

  • Objective and scientifically sound information pertaining to the safety or effectiveness of the new use of the drug or device and which FDA determines is necessary to provide objectivity and balance. This may include information that the manufacturer has submitted to FDA or, where appropriate, a summary of such information and any other information that can be made publicly available.
  • An objective statement prepared by FDA—based on data or other scientifically sound information—bearing on the safety or effectiveness of the new use of the drug or device.

Copyright ©1999 Medical Device & Diagnostic Industry

The Narrowing Distribution Funnel: How to Get Your Medical Device to Market

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

An MD&DI February 1999 Column


Especially for smaller companies, creating a compelling product line and getting it to the buyers requires resourcefulness and considerable strategic planning.

Virtually every day there is news that the distribution network from medical device manufacturer to healthcare provider is becoming more and more concentrated. Hospitals and alternate-site care centers continue to consolidate, and physician practices are becoming more interconnected as publicly owned physician providers organize to confront the health maintenance organization phenomenon.

Cost containment and the need to be more competitive have spawned larger and more-sophisticated buying entities seeking lower procurement costs and value-added inventory management services. Prominent examples are group purchasing organizations (GPOs)—independent entities that represent groups of hospitals and other healthcare providers in obtaining volume-based pricing and other benefits. In reaction to the GPOs, and to gain more control over product purchasing, healthcare providers are themselves forming centralized purchasing groups, further reducing the population of medical device buyers. These groups are called integrated delivery networks (IDNs).

To make matters worse for many device manufacturers, buying groups and large distributors are joining forces with one another. Although the McKesson– Amerisource and Cardinal–Bergen Brunswig mergers failed in 1998 to pass antitrust muster, McKesson's acquisition of Red Line and Cardinal's pending combination with Allegiance signal that the "urge to merge" is far from satisfied.

Not only are distribution channels narrowing, but the choice of products offered by many participants in the chain is shrinking. We are in the age of "sole-source" and "preferred-provider" contracts, accompanied by measures to encourage compliance. The distribution funnel can be compared to the cable TV industry: device manufacturers are like television program producers, and distributors and buying groups are akin to monopolistic cable systems. Producers may have terrific television programs, but if they can't get a cable system to carry them, no one will see them.

With all this concentration in the distribution network, the spotlight is on those medical device manufacturers whose products are already included in the system. Yet, behind the scenes, hundreds of smaller manufacturers struggle to get their products to market through conventional and alternative means. Larger companies too face similar issues with lower-volume product lines that are unrelated to their core businesses.

It used to be that having an effective product itself provided enough impetus for a company to reach its ultimate customer. Now, expensive marketing campaigns and extensive distribution channels are vital. And after getting through the supply chain, continued product improvement, R&D, and marketing are required to remain competitive.

The implications of this change in distribution affect not only the companies involved but also society at large, as the public is denied exposure to a vast array of products. Perhaps survival of the fittest dictates that scaling-up leads to efficiency and lower costs throughout healthcare markets, and that smaller firms cannot provide products cheaply enough. However, opportunity is the engine that breeds innovation and entrepreneurship. Smaller device firms have often been the source of critical new technologies or otherwise valuable products. In today's market, how does a small company deal with the narrowing distribution funnel? This article proposes a few strategies.


First and foremost, device manufacturers need to review their product lines and marketing efforts to determine how they can be improved. To gain recognition, smaller manufacturers need to create a specialized product line that can be promoted to elicit strong trade name identification from the marketplace—an awareness that "the specialist in this area is company X."

Not only must the product line be specialized, it must also include a critical mass of related products so that a product grouping can be marketed and distributed as a complete line. Too often, small companies create a singular product or group of products that fails to cover the targeted niche in its entirety, making the limited line difficult and expensive to market. Other times, small companies expand beyond their area of specialization, becoming miniconglomerates and spreading themselves too thin.

If a manufacturer lacks the resources to produce a certain item that would complete its line, it should consider commissioning a subcontractor to make it. If the outsourced product sells well, the device manufacturer may be able to internalize production later on.


Once a specialized product line is created (or redefined), small manufacturers need to follow a two-pronged approach. The objective is to "sow the seeds" within different parts of the supply chain, so that a groundswell of support for the product builds up. Certainly, manufacturers must appeal to networks of independent dealers to distribute their products. But demand must also be created at the grassroots level—with the medical providers or, depending upon the product, even with the end-users or patients.

Because dealers have their own competitive issues, they often cannot be relied on to promote a manufacturer's products, particularly those of a small company. It is worthwhile for the manufacturer to identify key physicians in the relevant field and concentrate efforts on converting them to its product line. Influential physicians can often serve as "champions" or informal endorsers of a product line, leveraging the marketing effort.

Of course, an effective marketing program should include targeted advertising, publicity, and exhibitions at professional association meetings. But efforts should be focused on developing demand in defined segments of the market, such as in selected geographical areas or with certain hospitals or physicians groups. In developing this demand, the device manufacturer may gain important insight into marketing to broader segments. Once demand is established in the defined areas, it is easier to expand by citing the earlier customer relationships as success stories.


Device manufacturers—whatever their size—should stay in contact with group purchasing organizations and apply periodically for inclusion within their networks. Manufacturers should track competitive products that are included and respectfully convey the advantages of their product line to the key decision makers of the organizations. Often, a buying group considering a contract with one medical device manufacturer will entertain competitive products that are presented in a timely manner. With persistence, a device manufacturer may, over time, gain access to these large-scale networks.

If a manufacturer is losing out on buying-group relationships because its product line is not diverse enough, it should consider teaming up with other manufacturers selling complementary (noncompetitive) products that fill out the line. Together, manufacturers with this kind of relationship can often present a compelling package to organized buying groups.


Private-label programs can also provide a channel to market for medical devices. Provided the device company has the necessary manufacturing capacity to produce sufficient quantities, private labeling—especially for a large customer—can dramatically increase sales by taking advantage of the customer's marketing, advertising, and distribution resources. Obviously, private-label marketing carries risks. For example, a small company may be able to ramp-up production to meet the requirements of its larger customers, but a loss of such customers could be devastating to the manufacturer. However, once a broader market has been created for the product, the device manufacturer may be in a position to market the product under its own name.


A critical distribution strategy lies in finding supply niches—either domestically or abroad. Many foreign markets are less mature and concentrated than the domestic market, and their still-developing status creates distribution opportunities. Often, ambitious foreign distributors can build a strong, regular following for a small company's products, serving as another base to support subsequent increases in domestic distribution. Foreign markets can also serve as incubators and testing grounds for new devices before such products are exposed to the harsher scrutiny of the domestic markets.


It is not only the smaller, internally funded device manufacturers that face distribution roadblocks; well-financed companies can also encounter problems. Frequently, companies funded from venture capital firms, initial public offerings, or other financial sources have been set up with the expectation that if their products are compelling enough, distribution will naturally follow. Although this formula sometimes succeeds, it often fails. There are innumerable competitive and unpredictable forces that make establishing proper distribution difficult.

To provide a measure of security, manufacturers regularly enter into distribution and marketing arrangements with large, well-established companies. These manufacturers have decided to concentrate on their strengths—product conception, research and development, and production. They leave it to proven professionals, with appropriate distribution networks in place, to sell their products.

Although device manufacturers theoretically may earn less by entering into these arrangements compared with distributing their products themselves, it is often better to guarantee distribution with the "big guys" than to risk failure on one's own. In a global economy, such marketing and distribution agreements are becoming more commonplace, especially to address territories that are underserviced. These agreements can be structured to cover some regional markets or customer categories and not others.

Another form of partnering with larger companies involves technology transfers. These transactions often include a conveyance of technology in return for a royalty keyed to the sales volume of the product incorporating the transferred technology.


In light of the narrowing distribution opportunities, the corporate sale or divestiture of a business or product line may be the appropriate answer. In fact, both large and small companies are generally in the market as sellers and buyers of businesses. (Increasingly, large companies actively consider divesting discrete parts of their overall business that no longer fit their core competencies or offer compelling synergies with other parts of their operations.) Obviously, the decision of whether to sell can involve a variety of complex factors and should not be taken lightly. If a company's growth prospects are reasonably predictable given internal resources, then it may be worthwhile to continue operating the business independently. There are many benefits—both tangible and intangible—to retaining ownership of a business.

However, an honest assessment should be made as to the value of the business under the existing ownership and resources over time. A device manufacturer may have its greatest value when it is expanding but may lose value when larger competitors—with better distribution and deeper pockets—enter the fray. Sometimes, the anticipation of positive developments may be worth more than the reality.

In assessing a business or product line, it is worthwhile to prepare a 3–5-year projection, carefully analyze the steps required to realize its objectives, and then frankly assess the likelihood of meeting those goals.

Transactions can be structured as an outright sale or, in many cases, the original owners can retain a meaningful equity stake and management role and participate in the future growth of the company.


Consolidation of distribution sources has severely limited the channels by which medical device manufacturers—particularly smaller firms—get their products to market. To optimize distribution opportunities, device manufacturers first need to create a specialized and compelling product line. They should continue trying to break into organized buying groups and conventional distributor networks. At the same time, they should create demand at the provider level and pursue alternative outlets, including international markets. Consideration should also be given to forming a commercial relationship with a larger, well-established company to market or distribute the products in question. Under certain circumstances, a properly structured sale-type transaction may be the prudent course to follow.

Richard S. Cohen is president of The Walden Group Inc. (Franklin Lakes, NJ), a merger and acquisitions and corporate finance firm specializing in the healthcare industry.

Illustration by Ken Corral

Copyright ©1999 Medical Device & Diagnostic Industry

Susceptibility Testing Requirements for Medical Systems

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

An MD&DI February 1999 Column


Tests required in several basic and collateral standards are important to achieving marketability in Europe. Tougher standards are coming soon.

To be marketable in Europe, medical electronic equipment or systems must comply with the Medical Devices Directive (MDD) regarding electromagnetic compatibility (EMC) requirements. The product standard for medical devices, EN 60601-1-2, has been harmonized with the MDD. EN 60601-1-2 is identical to IEC 60601-1-2 and is the collateral standard to IEC 60601-1, which is the general safety standard for medical electrical equipment. IEC 60601-1-2, "Medical Electrical Equipment; Part 1: General Requirements for Safety; 2: Collateral Standard; Electromagnetic Compatibility—Requirements and Tests," was published in April 1993. EN 60601-1-2 was published in November 1993, and it was harmonized with the EMC Directive in August 1995 and with the MDD in September 1995. This article discusses the susceptibility tests required to comply with these standards. It also discusses modifications expected for the upcoming revision of IEC 60601-1-2.


A significant difference between the European EMC standards and the medical device standards (such as EN 60601-1-2) is the performance criteria. For example, the immunity criteria for the collateral standard are based on safety. In contrast, all other EMC standards require evaluation of performance as defined by the manufacturer.

According to EN 60601-1-2:1993, the immunity criteria for medical products are defined as: "equipment and/or system continues to perform its intended function as specified by the manufacturer or fails without creating a safety hazard." Safety hazard is defined by IEC 60601-1 as a "potentially detrimental effect on the patient, other persons, animals, or the surroundings arising directly from equipment." This definition places a great deal of responsibility on the manufacturer and testing laboratory. For example, it is possible for a device to fail safely and still create a safety hazard by its unavailability, such as a diagnostic system that either fails to start or can be interrupted. The standard does not require manufacturers to inform users of such hazards. Although an accredited test laboratory is likely to identify such a malfunction in its test report, the manufacturer is not required to state it in the user manual. Other examples also illustrate a gap in EN 60601-1-2:1993 for defining pass/fail criteria (i.e., safety hazard). This problem has forced Working Group 13 of IEC Technical Committee 62 to define performance criteria more clearly.

EN 60601-1-2 is a generic standard designed to address many different devices. Some medical products, such as systems that measure human physiological signals, require specific immunity levels. Based on the low levels of these signals, it was necessary for the standard to allow for lower immunity levels, provided that the manufacturer instructed users about any necessary actions to be taken because of the lower test levels. This will be discussed in more detail later.


EN 60601-1-2 provides requirements for emissions and immunity. The required emission test is EN 55011 (CISPR 11) Group I or II, Class A or B. Immunity test requirements are provided in IEC 801 and EN 61000-4-3, which are the so-called basic standards. Specific tests are explained in the following standards:

  • IEC 801-2:1991, for electrostatic discharge (ESD).
  • EN 61000-4-3 and IEC 801-3:1984, for radiated immunity.
  • IEC 801-4:1984, for bursts and electrical fast transients (EFTs).
  • IEC 801-5:1984, for surges.

IEC 801-2:1991—ESD. This standard requires contact- and air-discharge testing. EN 60601-1-2 set up a requirement of ±3 kV for contact discharge and ±8 kV for air discharge since rise times and spectrums will differ as test levels change. The reliability of the air discharge presents another problem: temperature, humidity, and the approach speed of the loaded ESD tip can all influence the test. For this reason, contact discharge was included in IEC 801-2:1991, whereas only air discharge had been required in the 1984 version.

The test setup requires a horizontal coupling plane (HCP) of 1.6 x 0.8 m placed on a 0.8-m-high wooden table. The equipment under test (EUT) and cables must be isolated from the coupling plane by a 0.5-mm-thick insulation support. For indirect discharge, a vertical coupling plane (VCP) of 0.5 x 0.5 m must be used. The VCP must be parallel to the EUT at a distance of 0.1 m. Discharges must be applied to different positions of the coupling plane so that the four faces of the EUT can be completely illuminated. Where coupling planes are specified, they must be constructed from the same material (copper or aluminum) and same thickness (minimum 0.25 mm x 1 m2) as that of the ground reference plane (GRP). The HCP and VCP must be connected to the GRP via a cable with a 470-k resistor located at each end.

For both indirect and direct discharge tests, 10 discharges of each polarity must be applied. Discharges must be applied directly only to those points and surfaces of the EUT accessible to personnel during normal use. This includes areas accessible to maintenance personnel. For contact discharges, the discharge electrode tip must touch the EUT before the discharge switch is operated. For air discharges, the round tip of the electrode must approach the EUT as quickly as possible without causing mechanical damage. After each discharge, the ESD generator must be removed from the EUT so that it can be retriggered. This procedure must be repeated until all discharges are completed.

EN 61000-4-3—Radiated Immunity. This is the relevant basic standard for simulating the interference of transmitted electromagnetic waves to test for radiated immunity. The collateral standard requires 3 V/m from 26 to 1000 MHz, with an 80% amplitude-modulated signal. The modulation frequency must be within each functionally significant signal-processing passband. This often constitutes a severe test, because many devices—such as patient monitors with electrocardiocorder and electrocardiograph options—are more susceptible to amplitude modulation that falls within the range of frequencies used or sensed by the device for its normal function. For equipment that does not have a defined passband, the standard specifies 1-kHz modulation.

This test is usually done in an anechoic chamber. Special absorbant material (2 m in length) compensates for standing waves and reflections. The state-of-the-art standard for radiated immunity, IEC 61000-4-3, requires a uniform field of 1.5 x 1.5 m at a distance of 3 m, compared with 1 m required by EN 61000-4-3. The 3-m distance provides a more reliable test result.

IEC 801-4:1984—Burst/EFT. During testing, the bursts or EFTs should be coupled by using a coupling-decoupling network or by using a coupling clamp on the EUT cables. The coupling-decoupling network for an ac/dc main supply circuit allows the test voltage to be applied nonsymmetrically to the EUT's power-supply input terminals. The capacitive coupling clamp enables coupling of the fast transients to the circuit under test without any galvanic connection to the circuit terminals, cable shielding, or any part of the EUT. The clamp should be placed on a ground plane with a minimum area of 1 m2, and the ground reference plane should extend beyond the clamp by at least 0.1 m on all sides. The generator should be connected to the end of the clamp nearest to the EUT. EN 60601-1-2 requires test levels of 1 kV for plug-connected equipment, 2 kV for permanently installed equipment, and 0.5 kV for interconnecting lines longer than 3 m (i.e., lines using coupling clamps).

Manufacturers must determine whether a device creates a safety hazard as defined by IEC 60601-1 (Compliance Test Laboratories; Liberty, SC).

The test should last no less than 1 minute for each coupling point. Both polarities must be tested. For this test, high-voltage pulses are not the primary problem for the EUT. Problems can occur because of the very fast rise time of a single pulse, which can create a very high electromagnetic field.

IEC 801-5:1984—Surge. Although a surge is not a very fast pulse, it contains considerable energy. The surge test, according to IEC 801-5, is the most severe EMC test for medical device power supplies. The test simulates an overvoltage caused by switching and lightning transients, with a pulse coupled via a coupling-decoupling network on the power line of the EUT. The test voltage is 1 kV in differential mode with a 2- coupling resistor, and 2 kV in common mode with a 12- coupling resistor. At least five positive and five negative discharges must be tested at selected points of the power supply. The pulse must be repeated at a rate of at least one per minute, and it is recommended to increase the test levels from 0.5–1 kV to 2 kV. The selected points should be 0°, 90°, 180°, and 270° of the sine wave. Because of the high energy level of this pulse, great care must be taken when performing this test. It is important to ensure that the generator is in a safe mode, especially during counter measurement or modifications.


A revised version of IEC 60601-1-2 is currently being developed. This new edition is scheduled to be published this year but could be delayed depending on the comments received on the second draft and subsequent voting results. The changes from the first edition are expected to be extensive, with requirements updated to reflect the development of basic standards during the past 5 years. Performance criteria will change from being safety based to being based on continued utility of the device. Test levels will be increased for some tests, and additional tests will be required. Significant changes include a provision allowing emission tests to be based on CISPR/EN standards, such as EN 55013 for audio/video products, EN 55022 for information technology equipment, or EN 55014 for simple motor-driven devices (dentistry drills, for example). The requirements for harmonics distortion and voltage fluctuations according to EN 61000-3-2 and EN 61000-3-3 are also included in the draft version.

Major changes are also proposed regarding immunity testing. The failure criteria will be changed from its safety hazard focus to defined compliance criteria. The EUT must be fully functional, must be able to provide the intended clinical benefit, and must remain safe. The ESD contact-discharge level will be increased to 6 kV. Radiated immunity will require sweeps for all operating modes, and the frequency range will be 80–2500 MHz. Life-supporting equipment will require 10 V/m from 860 to 2500 MHz. To reduce test time, the modulation frequency will be either 1 kHz or 2 Hz, depending on the type of equipment. The differences between plug-connected and permanently connected equipment will be eliminated.

Test levels for the burst test will be 2 kV for main cables and 1 kV for input/output (I/O) cables, and patient cables will be excluded. If the EUT does not have a noise-protection component (a varistor, for example) to minimize surge, the test with the highest levels (1-kV differential mode or 2-kV common mode) will be sufficient. Conducted RF immunity testing according to EN 61000-4-6 will be added, with a level of 3 V from 150 kHz to 80 MHz. A magnetic immunity test with a level of 10 A/m will also be added, according to EN 61000-4-8. As required in EN 61000-4-11, voltage dips and interrupts with nominal line voltages of 0% Unominal for 0.5 periods, 40% Unominal for 5 periods, and 70% Unominal for 25 periods, and a separate test with restore-to-operation criteria at 0% Unominal for 5 seconds will be included. Additional disclosure requirements and warnings will be required for end-user documents. Information will be included in the "General Guidance and Rationale" annex of the revision to help manufacturers and test laboratories understand the requirements.


EN 60601-1-2:1993 can be difficult to use, and therefore has caused some confusion over how to conduct tests properly to meet the standard's requirements. A key example is correctly testing patient monitors, which often measure signals in the microvolt to millivolt range or the nanoampere to microampere range. Signals from the patient's body interact with radio frequencies, making it difficult for the monitor to discriminate signal interference. Another problem for performing the tests arises because of the response time for medical devices, which mandate a long dwell time for each frequency. The result is a long testing time.

Used to demonstrate compliance with the EMC Directive as well as with the MDD, EN 60601-1-2 has been in place for nearly 6 years. It is hoped that the current revisions will correct lingering problems like those described above. Innovative products and new technologies will certainly compel working groups and committees to continue to raise the bar for susceptibility test standards.

Harald Buchwald is EMC manager for MIKES Product Service GmbH (Strasskirchen, Germany).

Photo courtesy of CKC Laboratories (Mariposa, CA)

Copyright ©1999 Medical Device & Diagnostic Industry

Hyaluronan-Modified Surfaces for Medical Devices

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

An MD&DI February 1999 Column


A unique biopolymer with therapeutic applications is also gaining recognition as a versatile surface-treatment material for improving device biocompatibility.

Hyaluronan is a naturally occurring biopolymer used in medical applications ranging from cataract surgery and postsurgical adhesion prevention to hydrophilic coatings. The purpose of this review is to make readers aware of this increasingly important biomaterial and to survey the techniques for improving the biocompatibility of medical devices by modifying synthetic material surfaces with hyaluronan.


A unique biopolymer, hyaluronan is one of a number of polysaccharides that occur in the body's mucous membranes and are known as mucopolysaccharides. It was first isolated from the vitreous body of the eye in 1934 by Karl Meyer, who called it hyaluronic acid.1,2 The term hyaluronan is attributed to Endre Balazs, who coined it to encompass the different forms the molecule can take—for example, the acid form, hyaluronic acid, and the salts, such as sodium hyaluronate, which form at physiological pH.3

After 65 years, quite a lot is known about the appearance of the hyaluronan molecule; its behavior; its occurrence in different tissues and body fluids; the manner in which it is synthesized by the cells, metabolized, and cleared from the body; and the nature of some of the functions it performs.

Hyaluronan and related polysaccharides are called glycosaminoglycans. These substances are made up largely of repeating disaccharide units containing a derivative of an aminosugar. The most abundant glycosaminoglycans in the body are chondroitin sulfates; others are keratin sulfate, heparin and heparan sulfate, and dermatan sulfate.

Figure 1 shows the disaccharide unit of hyaluronan, consisting of alternating glucuronic acid and N-acetylglucosamine units, which are repeated over and over to form long chains. Each repeating disaccharide unit has one carboxylate group, four hydroxyl groups, and an acetamido group. Hyaluronan differs from the other major glycosaminoglycans in that it does not have sulfate groups.

In the body, hyaluronan is synthesized by many types of cells and extruded into the extracellular space where it interacts with the other constituents of the extracellular matrix to create the supportive and protective structure around the cells. It is present as a constituent in all body fluids and tissues and is found in higher concentrations in the vitreous humor of the eye and the synovial fluid in the joints. In mammals, the highest reported concentration is found in the umbilical cord.

Figure 1. Hyaluronan molecule.


Hyaluronan possesses a unique set of characteristics: its solutions manifest very unusual rheological properties and are exceedingly lubricious, and it is very hydrophilic.

Rheological Properties. In solution, the hyaluronan polymer chain takes on the form of an expanded, random coil. These chains entangle with each other at very low concentrations, which may contribute to the unusual rheological properties. At higher concentrations, solutions have an extremely high but shear-dependent viscosity. A 1% solution is like jelly, but when it is put under pressure it moves easily and can be administered through a small-bore needle. It has therefore been called a "pseudo-plastic" material.

Lubricity. The extraordinary rheological properties of hyaluronan solutions make them ideal as lubricants. There is evidence that hyaluronan separates most tissue surfaces that slide along each other. Solutions of hyaluronan are extremely lubricious and have been shown to reduce postoperative adhesion formation following abdominal and orthopedic surgery.

Hydrophilicity. As mentioned, the polymer in solution assumes a stiffened helical configuration, which can be attributed to hydrogen bonding between the hydroxyl groups along the chain. As a result, a coil structure is formed that traps approximately 1000 times its weight in water.4,5


The classical sources for the isolation of hyaluronan have been either from mammalian tissues or from certain strains of cultured bacteria. At one time, the material was isolated from human umbilical cords collected in hospitals. One company, Pharmacia AB (Uppsala, Sweden), developed a special strain of roosters with very luxuriant combs, from which the compound was isolated. More recently, submerged cell-culture techniques using certain strains of streptococci have been developed to grow hyaluronan. The commercially available material comes in molecular weights ranging from less than 1 million to as high as 8 million.

Hyaluronan-based coatings are used on a variety of medical devices such as guidewires. (Photos courtesy of Lake Region Mfg. Inc.; Chaska, MN.)

There are a large number of hyaluronan producers around the world. Biomatrix Inc. (Ridgefield, NJ), a U.S. company, operates a plant that produces hyaluronan from mammalian sources in Canada. Anika (Woburn, MA), Genzyme Corp. (Framingham, MA), and Lifecore Biomedical (Chaska, MN) are other domestic suppliers. Pharmacia produces hyaluronan in Sweden, Fidia Advanced Biopolymers (Brindisi) in Italy, Bio-Technology General Corp. (Iselin, NJ) in Israel, and a number of companies, including Kibun Food Chemifa Co. and Seikagaku Corp. (both Tokyo), in Japan.


Balazs and his coworkers have written extensively on the medical applications of hyaluronan and its derivatives.6 The major application of the material in the United States has been as a viscoelastic in ophthalmic surgery, primarily during the implantation of intraocular lenses in patients with cataracts. Japan supports a large market for hyaluronan because it is used there as an injectable for arthritis. Recently, Biomatrix and Fidia have obtained FDA approval for that use in the United States.

Drug release represents another interesting application, and formulations of hyaluronan and its derivatives have been developed as topical, injectable, and implantable vehicles for the controlled and localized delivery of biologically active molecules.7

With the advent of cross-linked gels and films of hyaluronan, there are now a number of products on the market for the prevention of adhesions after abdominal surgery. Genzyme developed the Seprafilm and Sepracoat product lines, based on cross-linked hyaluronan to prevent adhesions after abdominal surgery. Lifecore has developed a gel form for similar indications.

Another prominent application of hyaluronan is its use in hydrophilic coatings for a variety of medical devices, including catheters, guidewires, and sensors. Use of such coatings can improve device biocompatibility and lubricity and reduce fouling and tissue abrasion.

An interesting application not yet commercialized—although some human clinical trials have been completed—is the injection of a hyaluronan gel, compounded with thrombin and other materials, for percutaneous embolization.8


The patent literature is extensive and offers evidence of a great deal of development work in this field in recent years. Of course, it is not always possible to know whether a particular patented invention has practical uses, and in some patents hyaluronan is mentioned as only one of a class of compounds (e.g., mucopolysaccharides or glycosaminoglycans) that can be used. The major inventors in this field and their corporate affiliations are summarized in Table I.

Many different processing techniques and uses for hyaluronan have been invented and patented by Balazs, Leshchiner, and their coworkers. There is the important Balazs patent, issued in 1979 and now expired, on hyaluronan isolated from animal tissue that does not cause an inflammatory response when tested in the eye of the owl monkey.9 The process involves extracting hyaluronan from the blood, deproteinizing the extract, and then treating it with chloroform. The result (marketed by Pharmacia as Healon) is described as a sterile, pyrogen-free, nonantigenic and noninflammatory, high-molecular-weight fraction of hyaluronan that is essentially free of proteins, peptides, and nucleic acid impurities. Various therapeutic uses are described for this material, including improvement of pathological joint function; prevention of postoperative adhesion of tissues, tendons, and their sheaths; and various uses in the eye.


There are many ways in which hyaluronan can be cross-linked to produce insoluble gels.6 The Balazs patent on chemically modified hyaluronan describes cross-linking with small amounts of an aldehyde (e.g., formaldehyde) to produce a unique soluble polymer fluid with very high viscoelastic properties.10 Also discussed is cross-linking of hyaluronan with divinyl sulfone to obtain a jellylike material.

In a 1990 U.S. patent assigned to Genzyme, Hamilton describes water-insoluble derivatives of polysaccharides that are activated with carbodiimides and reacted with an amino acid.11 Others have also reported on the cross-linking of hyaluronic acid with a water-soluble carbodiimide to produce water-insoluble films.12 Cross-linking can also be achieved with polyvalent cations (ferric, aluminum, etc.) and aziridines (e.g., cross-linker CX-100).


In addition to cross-linking, various chemical modifications of the hyaluronan polymer have been reported and patented over the years. According to Balazs, the earliest synthesized derivative of hyaluronan was its sulfate ester, which showed resistance to hyaluronidase and anticoagulant activity.6 More recently, a group of researchers at the University of Siena in Italy has published extensively on sulfated hyaluronic acid. They report that introducing sulfate groups in the hyaluronan molecule converts it to a heparin-like material with antithrombogenic properties and also makes it resistant to enzymatic digestion.13,14

There are several patents assigned to Fidia in which della Valle describes esters of hyaluronic acid, in which all or only a portion of the carboxylic groups of the acid are esterified by treatment of the free hyaluronic acid with alcohols in the presence of a catalyst.15–17 These patents disclose the many different types of alcohols that can be employed, the use of salts of the partial esters with metals and with pharmacologically active organic bases, and the differing degrees of esterification.

Applications of these compounds can include use in pharmaceutical preparations, cosmetics, and medical and surgical devices. It is claimed that the compounds qualitatively possess the same or similar physical-chemical, pharmacological, and therapeutic properties as hyaluronic acid, but that they are considerably more stable, especially with regard to enzymatic degradation by hyaluronidase. It is also claimed that most of the esters, unlike hyaluronic acid itself, have a certain degree of solubility in organic solvents, such as dimethylsulfoxide (DMSO), and poor solubility in water. These characteristics make it possible to form articles ranging from film and sheet to thread, sponges, and ophthalmic lenses.

Another example of a hyaluronan derivative—a conjugate with the naturally occurring, free-radical scavenger superoxide dismutase—was reported to have greater antiinflammatory activity in vivo than hyaluronan or superoxide dismutase.18 Amino groups of the superoxide dismutase were coupled with carboxyl groups in the hyaluronan molecule using carbodiimide.

Principal Inventors Assignee Subject Date Issued
Balazs Biomatrix Ultrapure HA 1979
Balazs Biomatrix Polymeric articles 1984–1985
Balazs Biomatrix PEO compositions 1986
Balazs Biomatrix Cross-linked gels 1986–1987
Leshchiner Biomatrix Embolization 1989
Balazs Biomatrix Drug delivery 1992
Beavers Biocoat Coated lens 1987
Halpern Biocoat Hydrophilic coating 1989–1991
Beavers Biocoat Free acid 1998
della Valle Fidia Esters 1989–1990
Hamilton Genzyme Insoluble derivatives 1990
Burns Genzyme Insoluble derivatives 1991–1996
Burns Genzyme Platelet function 1996
Giusti Italian gov't. IPNs 1997
Guire SurModics Photoimmobilization 1988–1993
Larm Carmeda Conjugates 1986–1989
Narayanan Cordis Stent coating 1994
Rowland Cordis Stent coating 1994
Yannas MIT Collagen composites 1981

Table I. U.S. patents related to hyaluronan (HA).


Hyaluronan lends itself to compounding or complexing with other materials to produce biomedically useful composites. Several Balazs patents on hyaluronan-modified polymeric articles describe how materials such as polyHEMA, polyurethanes, polyesters, or polyolefins can be rendered biocompatible by inclusion of or coating with hyaluronan.19,20 For example, the patent on cross-linked gels discloses mixtures of hyaluronan with substances that include other hydrophilic polymers, polysaccharides, proteins of various types, and synthetic water-soluble polymers.21

A recent patent, issued in 1997 to Giusti et al., describes a biomaterial comprising an interpenetrating polymer network in which one of the components is an acidic polysaccharide or a semisynthetic derivative thereof and the second component a synthetic polymer.22 The polysaccharide can be hyaluronic acid, a total or partial ester, or a salt of hyaluronic acid with an organic base.

One of the earlier patents, by Yannas at the Massachusetts Institute of Technology, was issued in 1981 and describes composites of collagen and mucopolysaccharides, including hyaluronic acid, that are cross-linked with aldehydes, carbodiimides, azides, and diisocyanates.23 Also discussed is dehydrothermal cross-linking, in which the material is first dehydrated and then heated. Many of the cross-linked composites were found to have mechanical and biocompatibility characteristics superior to those of collagen alone. The collagen and mucopolysaccharide can either be mixed together, or an article can first be coated with collagen and then have the mucopolysaccharide applied to it.


There are two basic methods for immobilizing hyaluronan to produce biomedically useful coatings. The material can either be reacted with or coupled to functional groups present or introduced on the surface, or a photoreactive group can be attached to the hyaluronan molecule, which then reacts with the surface upon being illuminated (i.e., photoimmobilization). There are many variations on these two schemes, depending on the nature of the substrate and the functional requirements of the coating.

Functional Groups. Halpern and Beavers describe a bilaminar graft configuration to immobilize hyaluronan (and other mucopolysaccharides) when suitable functional groups are not present on the substrate.24–26 An adhesive polymer coating is first applied. This first coat provides functional groups (for example, diisocyanates) on its surface, which can then be used to covalently bind the second coat of hyaluronan. In this process, the polysaccharide molecules, depending on their length and shape, may be tied down at multiple points along the chain and probably also through entanglement and interaction between polymer chains.

A recent patent by Beavers et al. discloses a process for producing the pure acid form of hyaluronan, which readily undergoes chemical reactions with substances such as epoxides, aziridines, and alcohols.27

Patents issued in 1986 and 1989 to Larm describe the "Carmeda process" (Carmeda AB, Stockholm) for the covalent coupling of conjugates of substances such as polysaccharides with specific reference to heparin (partially deacetylated), hyaluronic acid, dermatan sulfate, and chitosan.28,29 In this process, fragments of the substance are created that have reactive terminal aldehyde groups. These aldehyde groups are then reacted with amino groups on the substrate to form unstable Schiff's bases, which are converted to stable secondary amines with a suitable reducing agent, such as cyanoborohydride.

In connection with hyaluronic acid, Larm states: "By covalent coupling of hyaluronic acid to plastic implants for, for example, eye surgery, the implants can acquire better tissue affinity. In this manner, one avoids complementary activation and activation of the mononuclear cell system. . . ."28,29

Larsson reported on the biocompatibility of surfaces prepared by immobilized heparin and hyaluronate.30 In creating the immobilized hyaluronate surfaces, carbodiimide chemistry was used to react carboxyl groups on the hyaluronate molecule to primary amine groups.

Two recently issued patents, assigned to Cordis (Miami), describe immobilization of polysaccharides to metallic surfaces, such as those used for stents. In the first of these patents, an organic polysilane coating with amine functionality is first applied, followed by the application of the polysaccharide, using carbodiimide as the coupling agent.31 In the second patent, a coat of hexafluorobutylmethacrylate is applied by RF plasma deposition, followed by RF plasma treatment with water vapor to create functional groups on the surface; carbodiimide chemistry can then be used to tie down the polysaccharide.32 Although heparin is the material used as an example in the patent, these processes may also be applicable to hyaluronan.

Photoimmobilization. A number of patents assigned to SurModics (Eden Prairie, MN) disclose methods for attaching all kinds of molecules—including heparin and hyaluronic acid—to substrates using spacer molecules with photochemically and thermochemically reactive groups.33–35 One of the patents, issued in 1990, describes biocompatible coatings for solid surfaces, in which the biocompatible agents, including hydrophilic polymers such as hyaluronic acid, are covalently bonded to the solid surface.35

Chen et al. have employed a photoimmobilization method for sulfated hyaluronic acid, using a water-soluble carbodiimide to attach photoreactive groups to carboxyl groups of the hyaluronic acid. The photoreactive groups then bond directly to a polymeric surface via UV activation.36

Benefits of hyaluronan-based coatings include reduced device fouling and tissue abrasion.


As one might expect for a material that is ubiquitous in the body, the biocompatibility of hyaluronan-modified surfaces has been well established. Various in vitro and in vivo tests have been conducted over the years by Biocoat Inc. (Fort Washington, PA) and its licensees that have demonstrated the biocompatibility of hyaluronan coatings. It has been shown that coated surfaces exhibit a marked reduction or absence of cellular attachment and fouling and of bacterial growth, compared with uncoated surfaces.

Larsson used various cellular systems and in vitro blood analyses to compare immobilized heparin surfaces with immobilized hyaluronate. He concluded that the two surfaces were indistinguishable when evaluated for short-term cellular compatibility—that is, for platelet activation and cell adhesion in contact with blood. However, the heparin surface could be clearly distinguished from the hyaluronate surface on the basis of its capacity to adsorb and inactivate thrombin.30

It is interesting to compare this finding with that of Burns, who postulated that hyaluronan is capable of interfering with the interaction of von Willebrand factor with platelets and components of the subendothelial matrix to inhibit platelet aggregation and adhesion.37 Burns also mentions that the coating of devices with hyaluronan to inhibit the interaction of platelets with the surface carries a substantially reduced risk of affecting overall hemostasis compared with heparin and warfarin.

Additional research has examined the resistance of hyaluronate coatings to hyaluronidase.38 Results indicate that coatings prepared by covalent binding with diisocyanates are not degraded by the enzyme hyaluronidase, in contrast with hyaluronan in solution, which is rapidly degraded by hyaluronidase.

A recently published study of various photochemically immobilized polymeric coatings on silicone rubber compared hyaluronic acid with synthetic materials such as polyacrylamide, polyethylene glycol, and polyvinyl pyrrolidone.39 The study included protein adsorption assays, fibroblast growth assays, leukocyte adhesion assays, and subcutaneous implantation in rats to study inflammation and fibrous-capsule formation.


Hyaluronan is a unique biomaterial that lends itself to cross-linking and immobilization in various ways to produce hydrophilic, lubricious, and biocompatible surfaces. The ability to derivatize and complex hyaluronan with other substances makes it possible to create a range of bioactive surfaces. Promising device applications might include using such surfaces, for example, to impart antithrombogenic and antibacterial properties or to interact preferentially with certain proteins and cells.

PC Interfacing for the Medical Market: Is a New Standard Emerging?

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

An MD&DI February 1999 Column


The development of high-speed serial buses has prompted the need for a specification to facilitate system expansion for the custom peripherals that are critical to fast-evolving medical device technology.

It is an unmistakable trend that personal computers (PCs) have become the brains behind many medical equipment systems, just as they are dominating a range of other embedded applications. Over the past decade, PCs have replaced proprietary designs in virtually every area of medical equipment, including CT-scan machines, ultrasound equipment, ECG and x-ray units, and numerous others. PCs have found their way into the medical market for several reasons. As the current standard for business applications, PCs offer the best price and performance value and a wider variety of development tools, operating systems, and peripherals than any other platform.


One constant in the evolution of the computer industry has been the call for increasingly higher bandwidths in bus interface technology. In the early days, when the XT was the PC standard, the 8-bit ISA bus was the standard for peripheral interface. With the advent of the AT, the 8-bit ISA bus was found to be short on resources and not fast enough, so the 16-bit ISA bus was born. This bus ran at the same clock frequency, but its data path was twice as wide. As the 16-bit ISA bus in turn became too slow for the processing power in the computer, other standards began to appear that had varying degrees of success.

The EISA and VESA buses were the first to be popular in the commodity computer market for expansion. Although both of these buses were enhancements of the existing 16-bit ISA bus and took bus interfacing to a higher level, they were short-lived and never truly gained popularity in embedded applications. Shortly after the introduction of EISA and VESA, PCI came along, offering more bandwidth and features. The currently used PCI bus has a 32-bit data bus and a clock frequency more than four times faster than that of the ISA bus. However, because many medical I/O applications don't require the performance of PCI, manufacturers of medical equipment continued to produce ISA-designed cards, which are relatively easy to customize and cost less than PCI components.

For several years, computers have been shipping with both PCI and ISA bus slots. These slots have given developers of industrial and medical applications the opportunity to leverage the high-volume, commodity PC platform as the basis of their control system. By using an off-the-shelf, standard PC, medical-control-system designers are dramatically reducing overall design time and costs. Buying most of the hardware and the operating system off the shelf can help the system designer achieve a shorter design cycle, which aids in getting the product to market quickly.

Using a commodity computer platform is not without problems, however. As the commodity market tries to make the computer experience easier for the user, some of the legacy bus interfaces fail to fit the envisioned model. The ISA bus is not particularly user-friendly, and raises a number of support issues. Because ISA peripherals are not fully plug-and-play compatible, the user must assign the resources of the card at the time of installation. During the configuration process, the installer must know which resources the peripheral uses as well as the resources used by all other components in the system.

It would thus seem logical that PCI would become the standard for PC expansion for the near future. Given the high bandwidth and plug-and-play nature of PCI, many of the problems characteristic of ISA do not exist in the PCI standards. As PC peripherals continue to require more and more bandwidth, PCI has kept up by beginning to migrate from the current 32-bit, 33-MHz version to a higher-performance, 64-bit, 66-MHz version.


There are significant disadvantages associated with designing to the PCI bus, however. First, PCI is much more complex and less forgiving than ISA. This makes new peripherals more complex and expensive to design as well as to manufacture. In addition, the 33-MHz version of PCI typically limits the available expansion in a system to four slots or less, with the 66-MHz version offering only two slots. As a result of these inherent problems with the PCI bus, a new generation of high-speed serial buses—USB and IEEE 1394—has been created. These new serial buses are intended to make new peripheral designs easy to develop, inexpensive to manufacture, and simple to install and service. The peripherals can also be deterministic, unlike what is possible with other serial communication standards such as Ethernet. As such, they promise to eliminate a number of potential problems in both medical and business applications.

Figure 1. The percentages of ISA- and USB-enabled PCs sold in the past two years show a trend in favor of the newer bus. Data retrieved from USB Technology and Market Report (San Diego: Annabooks, October 1998).

USB (Universal Serial Bus) is an interface that has been widely available on the PC platform since 1996. The USB Specification V1.1 defines the physical layer and protocol for a medium-bandwidth serial bus operating at 1.5 or 12 Mb/sec. This hot-swappable, plug-and-play, half-duplex serial bus began to achieve widespread acceptance at the end of 1998 (as was apparent at the fall 1998 Comdex show in Las Vegas)(Figure 1). USB permits nearly unlimited expansion by allowing a single externally accessible port to support up to 127 peripherals.

With USB, expanding the PC became as straightforward as plugging a cable into a running computer. Following insertion of a four-wire cable into the USB port on the computer, the operating system enables the device and loads the drivers, so that the peripheral becomes available for use almost instantly. Commonly available commodity USB devices are mice, floppy drives, speakers, and keyboards, to name a few. In the industrial and medical markets, common uses of USB include instrumentation applications such as digital and analog I/O systems.

Complementary to USB is a higher-speed serial bus, IEEE 1394, commonly referred to as 1394. IEEE 1394 is a hot-swappable, plug-and-play, full-duplex serial bus. The current version of 1394—known as 1394-1995—was ratified by IEEE in December 1995 and allows for transfer speeds up to 400 Mb/sec (Figure 2). Version 1394b is currently in draft form and will provide for speeds up to 3.2 Gb/sec. Although 1394b devices are not yet available, vendors are already shipping devices capable of using the full 400-Mb/sec bandwidth. With these faster speeds permitting throughput higher than that of standard PCI buses, 1394 has found a place in applications starved for bandwidth. A new approach to device interfacing, 1394 can feature up to 63 devices with a peer-to-peer relationship on a single bus. Like SCSI, 1394 devices can communicate directly with one another, eliminating the need for the computer to arbitrate communication; in fact, even with the computer off, most 1394 implementations allow the peripherals to continue to operate. Among the current uses benefiting from 1394 are video and imaging applications.

Figure 2. Comparative maximum data-transfer rates of ISA, PCI, and IEEE 1394 buses.

Although USB and 1394 are rich with technological advances, a few implementation issues present difficulties for certain industrial and medical applications. One is the issue of surprise removal of devices. Because USB and 1394 are hot-swappable and plug-and-play by nature, a user may decide at any time to remove the cable that connects the device to the computer. This could happen at an inopportune moment—for example, during a motion operation or during data acquisition. Such surprise removal could cause a catastrophic failure in a control or instrumentation system, rendering the machine useless.

Another implementation problem with USB and 1394 in industrial and medical applications concerns the power required for the device. Though both the USB and the 1394 cable can provide power to devices, the use of this power is limited to low-current devices using a single voltage rail. Most industrial and medical applications require a relatively large amount of current at several voltage levels, and often this power must be clean. Most developers would therefore choose to design in power supplies or to provide power from an external power supply, increasing system cost and complexity.

A final implementation difficulty has to do with mechanical issues. Neither USB nor 1394 has an associated specified mechanical enclosure for devices. The problem this creates is that every device in the control system could conceivably be a different size and have a separate set of requirements for mounting to the machine. This can render service difficult, because the machine may need significant disassembly to remove damaged components from the chassis. Upgrading also becomes more complicated, since changes in mechanical dimensions may necessitate housing and panel redesign.

Feature ISA PCI USB IEEE 1394 Device Bay
Parallel interfaceUp to 16 bitsUp to 64 bits
Serial interfaceYesYesYes
PC99 compliantNoYesYes YesYes
Can be installed inside computerYesYesYesYesYes
Can be installed outside computerNoNoYesYesYes
Isochronous transfersNoNoYesYesYes
Fair-access policyNoNoYesYesYes
Plug-and-play compatibleNoYesYesYesYes
Power managementNoYesYesYesYes
CRC/Data checkingNoNoYesYesYes
Defined mechanical form factorYesYesNoNoYes
Surprise removal allowedNoNoYesYesNo
Voltages supported±5V, ±12V3.3V, 5V, ±12V5V8V to 40V3.3V, 5V, 12V
Expansion1 to 5 slots typical4 slots typical (33-MHz)
2 slots typical (66-MHz)
(without bridging)
Up to 127Up to 63Up to 127 USB devices
and 63 IEEE 1394
devices simultaneously

Table I. PC bus feature comparison.


In order to solve the aforementioned implementation problems and to open USB and 1394 to a wider gamut of devices, a new industry standard has recently emerged and is building some momentum in the embedded-computer market. Authored by Compaq, Intel, and Microsoft, the Device Bay specification enhances the USB and 1394 specifications (Table I). Device Bay is the electrical and mechanical form factor for the USB and 1394 high-speed serial buses, and is designed to allow hot-swappable, plug-and-play expansion for computer peripherals. The Device Bay standard allows for typical computer devices like hard drives, CD-ROMs, and DVDs to coexist on the same bus with custom-designed, embedded devices that perform, for example, patient monitoring or medical system control.

The Device Bay standard allows for three physical options. The largest of the three resembles a 5¼-in. hard drive in its dimensions. Referred to in the Device Bay specification as a DB-32, this form factor—the only one currently in production—measures 1.26 in. high X 5.75 in. wide X 7.01 in. deep. Device Bay incorporates a single connector that supports both USB and 1394 and provides additional power to accommodate more power-hungry devices.

Commodity PCs have become very attractive for many applications that require the latest computer technology. Previously, designing in the latest technology required a large amount of research to ensure that the proprietary portions of the system were compatible with the other resources of the computer. By its nature, Device Bay is inherently portable; any computer that has a USB port, a 1394 port, and a Device Bay–compatible operating system is capable of using Device Bay technology. If the devices work on one system with a particular configuration, they will work on all platforms.

Unlike ISA and PCI, USB and 1394 devices require no system resources: they do not rely on the PC's I/O or memory map, interrupts, or DMA channels. In the past, these legacy issues have prevented system designers from developing complex systems. Systems were limited in functionality because the designer often ran out of resources in the base platform before implementing all of the necessary features.

In many designs, the specifications change during the life of the product in order to keep it competitive in the market. Currently, designers do their best to guess the amount of expansion that will be necessary over the product's life, and try to design it in to prevent complete system redesigns. Providing such expandability in advance is not only costly, it often goes unused. If, on the other hand, the designer underestimates the need for expansion, expensive system redesign is the only option.

An ongoing concern for medical systems designers has been the problem of maintaining certifications when using commodity PC components. Many times manufacturers of computer components—such as hard drives or video cards—will discontinue components faster than the system designer can get certifications done. With the Device Bay technology, two separate subsystems that are independently certified make up the computer system.

The first is the computer itself. The computer will contain the processor, RAM, video, and possibly a hard drive. This type of stripped-down computer—commonly known as a Net PC or "legacy-free" PC—will typically carry certifications from the manufacturer such as CE, UL, and CSA designations. Because the computer carries its own set of certifications, it becomes a "component" that can be replaced by another computer marked with the same set of certifications.

The second subsystem would be Device Bay–based and contain all of the application's proprietary components and other interfaces, such as a floppy drive or CD-ROM. Since the medical system manufacturer controls the manufacturing of the proprietary components, this portion of the system will remain constant. Changes made to this second subsystem can be anticipated and planned in advance.


One vision of the future of medical devices entails eliminating the need for multiple pieces of equipment through "virtual instrumentation." Each hospital room could be equipped, for example, with a low-cost Net PC, a display (LCD touch panel or CRT monitor), and a Device Bay condo. Whenever a particular instrument is needed, a Device Bay module containing the specific instrumentation electronics would be installed into the condo. The PC would recognize that a device had been inserted, automatically load the appropriate drivers, and in essence transform the computer system into the instrument.

For instance, a patient in a hospital room might require blood-pressure monitoring, ECG monitoring, and blood-oxygen analysis. Normally this would require three separate pieces of equipment. With Device Bay, however, a medical technician could simply insert a separate module for each function into the condo. The application software would automatically load the required drivers and run and display the desired application. All patient testing and monitoring would be run from a single PC, with all patient data displayed on the same screen. Medical personnel could use a mouse, a touch screen, or a keyboard to set up the instruments to certain parameters such as alarm limits, data-logging information, etc. Because the PC would be networked to a central computer, all patient data could be saved and monitored at a main nursing station, including alarm information. The patient's medical data and medical history would also be available to medical personnel on-line in the patient's room. Although another patient in another room may require no tests or monitoring, the system could still be used for functions such as retrieving medical charts or x-rays.

The versatility of such an open, modular system is virtually unlimited. As more computer power is required, only the computer itself would need to be updated, not the complete system. As more devices become available or are improved, only the device modules would change. Because this is an open standard, modules from multiple vendors could coexist in the same system. This would allow the hospital to buy the best device for each type of instrument without having to be locked into one particular vendor.


What would a medical device, such as an ECG or an ultrasound machine, that incorporated Device Bay technology look like? The following example describes a stand-alone piece of medical diagnostic equipment. Inside the chassis would be a low-cost PC such as a Net PC. A Device Bay condo with four bays would be accessible from the front, connected to the embedded PC through the USB and IEEE 1394 connections. For the display, an LCD panel or standard VGA monitor can be used. Pointing-device options include a touch screen, mouse, keyboard, or a combination of these; if not installed initially, the mouse and keyboard can be added at any time through the USB walk-up port. This is the basic construction of the machine, which is generic in nature and can be tailored to meet a variety of needs.

With Device Bay technology, removing a device is as straightforward as removing a tape from a VCR. Security features operated through a combination of software and hardware prevent surprise removal of devices and potential data loss.

For an ECG machine, current ISA or PCI designs would be ported to Device Bay modules. The modules would have an on-board, low-cost microprocessor to communicate with the Device Bay controller and handle the communications for the USB or IEEE 1394 interface. This microprocessor would also be used to add local intelligence to the device: in this example, it could initialize the high-speed A/Ds, perform a power-up self-test, and handle background functions such as polling the A/D channels and signal conditioning the inputs. The microprocessor can also compress, time-stamp, and organize the data in a logical way—sparing the PC from having to perform these functions.

Because the computer platform was previously configured to use the ECG module, the module can be inserted into any available bay within the base instrument. Since Device Bay is plug-and-play, the unit can already be powered up when the module is inserted. The operating system and application will immediately recognize the device, load appropriate drivers, and run the ECG application. Recorded information can be logged through a network interface, a hard drive, or a read/writeable CD.

A USB or 1394 camera can be added to visually record the patient and synchronize these images with the ECG data. This would, for example, eliminate the need to have a medical technician mark the chart whenever a patient coughs or makes other movements. Installing this option would merely require plugging the camera into an available USB or IEEE 1394 walk-up port. Data from the camera could be incorporated with the ECG test record.

This roughly sketched example illustrates how a low-cost computer with Device Bay can very much simplify a piece of medical test equipment. The modularity of the architecture design offers flexibility and expandability while reducing the system design cycle and simplifying its manufacture.


Medical equipment continually requires more sophisticated computer performance. PCs can fulfill this thirst for performance and are the most cost-effective way to implement computer power. However, as this article illustrates, PCs have been something of a moving target for medical OEMs, who try to maintain consistency and longevity of components within their products. Older PC technology brings in a variety of legacy issues that make these older systems difficult to implement and expand in a dedicated environment. Device Bay represents one practical and long-awaited solution to these shortcomings.

USB and IEEE 1394 are already replacing ISA devices and soon could be replacing PCI in many applications, including medical devices. By providing the standard needed to integrate these relatively new technologies into practical medical applications, Device Bay offers system designers numerous new opportunities to make their products better by making them easier to manufacture, upgrade, and service.

Kent Tabor is president and Clint Hanson is director of hardware engineering at Granite Microsystems (Mequon, WI), an engineering and manufacturing company that specializes in medical and industrial embedded OEM computer solutions.

For More Information on PC Interface Standards

Device Bay Web site—

USB Web site—

1394TA Web site—

PCI SIG Web site—

PC 99 Specification—

USB Specification V1.1—

IEEE 1394-1995—

Photo by Roni Ramos

Copyright ©1999 Medical Device & Diagnostic Industry

Validating Radiation Sterilization in a Global Marketplace

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

An MD&DI February 1999 Column


A review of current standards and their implementation and validation and how they affect product release times to the marketplace.

When choosing irradiation to sterilize medical devices, U.S. manufacturers have historically relied on FDA guidance and generally followed validation methods prepared by AAMI. Although this is still true, manufacturers must now also consider the European Medical Devices Directive (MDD). AAMI members have been working with ISO and the American National Standards Institute (ANSI) to produce voluntary, harmonized guidance for validation and testing methods. The European Union (EU) has also enacted mandatory standards for its members. Although efforts toward harmonization are still ongoing, there have been sufficient changes in the regulatory guidance to generate questions as to how to achieve simultaneous compliance with these various standards.


Section 820.752 of FDA's quality system regulation (QSR) requires that "all processes used to produce medical devices be validated."1 Manufacturers may follow accepted sterilization validation guidelines or develop their own. For companies selling solely within the U.S. marketplace, compliance with ANSI/AAMI/ISO sterilization standards is sufficient.

Any medical devices sold into EU-member countries are required to meet relevant EN sterilization standards. Fortunately, there is a good deal of congruence between ANSI/AAMI/ISO and European standards for radiation sterilization (Table I).

Document Europe ISO United States
Estimation of population EN 1174 11737-1:
No. 8: 1991
Microbiological sterility * 11737-2:
No. 8: 1991
methods 1 and 2
EN 552:
ST 31: 1990
ST 32: 1991
Validation sterilization
small lots and
single batch
13409: 1996
15844: 1998

Table I. A comparison of the various guidance documents being used for radiation sterilization process validation. (* signifies that guidance is currently unavailable.)

The current primary ISO standard regarding irradiation of medical devices is ANSI/AAMI/ISO 11137, "Sterilization of Healthcare Products—Requirements for Validation and Routine Control—Radiation Sterilization."2 Some techniques developed in previous AAMI guidelines ST 31 and ST 32 were adopted into ANSI/AAMI/ISO 11137.3,4 The validation methods in ANSI/AAMI/ISO 11137 have been referenced in European Standard EN 552, "Sterilization of Medical Devices—Validation and Routine Control of Sterilization by Irradiation."5

Additional approved ISO and European standards focus on test methods to support validation programs. These documents address bioburden enumeration (ISO 11737-1; EN 1174-1) and sterility testing (ISO 11737-2).6–8 Three segments under development—EN 1174-2, EN 1174-3, and EN 1174-4—will provide specifics on sampling methods, validation of test methods, and test methodology.9 Technical comparison of these documents shows great uniformity in testing methods, including incubation times, media selection, and temperature conditions used during validation and routine-audit bioburden and sterility testing.

The procedure for establishing a 25-kGy minimum sterilization dose for small or infrequent production batches is not fully harmonized. Validation was previously addressed in AAMI ST 32 as method 3. In 1997, this document was superseded by an enhanced method in AAMI 13409, "AAMI/ISO Technical Information Report (TIR) 13409 Substantiation of 25 kGy."10 At present, AAMI 13409 has been approved in the United States, but it has not been adopted internationally.


The first step in ensuring medical device sterility is determining the appropriate sterility assurance level (SAL), a measure of the probability that one unit in a batch will remain nonsterile after being exposed to the sterilant. Product lot sterility can only be expressed in terms of probability. For example, an SAL of 10-3 means that one device in a thousand might be nonsterile. Selecting the SAL occurs during the dose-setting phase of radiation sterilization validation. In many cases, the intended use of the device will dictate the need for a particular SAL. The commonly accepted SAL for invasive medical devices is 10-6.

Some European countries, however, recognize only 10-6 SAL for a "sterile" label claim. The European Pharmacopoeia Commission concurs. Therefore, the minimum SAL may be based on the regulatory requirements of the country in which the device will be sold as much as on the device's intended use.


The desired goal for radiation sterilization validation is determining the minimum exposure dose that can routinely be used to meet the preselected SAL requirements and allow dosimetric release, which is the determination that a product is sterile based on physical irradiation process data rather than sterility testing. Dosimeters measure the absorbed radiation dose (physical data) delivered to the product at given locations. These data can verify that the dose absorbed by the product meets validated specifications.

Sterilization using 25 kGy did not require validation prior to implementation of the QSR. However, tests have evidenced microbiological issues that indicate that 25 kGy may not always yield the desired product SAL.

The model microorganism population used in ANSI/AAMI/ISO dose-setting validation procedures is designed so that a 25-kGy dose is expected to sterilize a device to an SAL of 10-6 when its bioburden—the sum population of viable microorganisms on the device—is less than 1000. Many devices, however, have a bioburden greater than 1000 microorganisms, and some microorganisms have sterilant-resistant characteristics that make them harder to kill than the model population. In such cases, 25 kGy may be insufficient to achieve an SAL of 10-6.


Methods 1 and 2 of the ANSI/AAMI/ISO 11137 guideline involve establishing a sterilizing dose using a bioburden resistance model. Method 1 is preferred because of its reasonable cost and study time. Because it employs model population data from Whitby and Gelda that is based on historical data received from manufacturers, it provides a greater challenge than the natural bioburden on a device.11 With method 2, the dose is determined experimentally based upon the resistance of the device under study.

The substantiation of 25 kGy as a sterilization dose (AAMI/ISO 13409) uses bioburden to establish a minimum acceptable product release dose of 25 kGy. Although the three methods require different numbers of samples to complete the validation, they all specify quarterly dose audits to confirm the continued validity of the sterilization dose (Table II).

Samples Required
Method 1136110
Method 2643110
25 kGy66–30620–100

Table II. A comparison of the various requirements that different sterilization modes have to verify the continued validity of their doses.

The applicability of methods 1, 2, or 25 kGy to a specific product is based on a combination of factors. Table III illustrates some of the issues to be considered when choosing which method is most appropriate for a given situation. Note that this table factors in both technical and financially based considerations.

Sterilization Methods  1    2  25 kGy
Bioburden <1000 CFU
>1000 CFU
Lot size500
X X 

Table III. Practical considerations when selecting which sterilization method to use for a particular application. CFUs are colony-forming units.

Method 1. This method is commonly called the bioburden method because the number of organisms on the product must be determined prior to sterilization. Ten samples from each of three lots are tested for a total of 30 samples. The bioburden results are used to calculate an experimental radiation dose called the verification dose, which is anticipated to yield an SAL of 10-2. An additional 100 samples from a single production lot are exposed to this dose and sterility tested. A bacteriostasis/fungistasis test also is conducted with selected microorganisms to examine whether the presence or absence of various other substances inhibits their growth. Additional samples are required for this test. If there are no more than two positive (nonsterile) cultures in the 100 sterility test samples, the validation is considered successful, and a routine SAL sterilization dose is calculated based upon the original bioburden data. Method 1 generally requires 136–146 samples and is usually considered the method of choice because method 2 requires a much larger number of test samples.

When using method 1 on a large or costly device, the manufacturer may not have to use the full number of samples noted above. For example, instead of using a full complement of complete finished devices, a large device might be divided into five portions equal in anticipated bioburden makeup, both in overall number of organisms and number of types. Twenty such devices would be cut into five pieces, yielding 100 portions with a sample item portion (SIP) equal to 0.2% of the original device.

If a large device consists of several dissimilar components, each with a different level or mix of bioburden organisms, this practice will not work. There are, however, often other ways to reduce the total number of devices needed to fulfill method 1 requirements. If an SIP of less than 1.0 is chosen, it must be validated to document the bioburden equivalency by performing a sterility adequacy test with 20 nonsterilized units that yield at least 80% positives.

Method 2. This bioburden resistance method requires the manufacturer to determine the radiation resistance of the organisms actually resident on a product. In method 2, device units from each of three production lots are exposed to incremental radiation doses (e.g., groups exposed to 2, 4, and 6 kGy, etc.) and then sterility tested. The results are used to determine a verification dose expected to yield an SAL of 10-2. A group of 100 devices is then exposed to this verification dose. If fewer than 2 of the 100 units are nonsterile, the data are used to calculate a routine SAL sterilization dose.

Method 2 is composed of two protocols. Both require a greater number of samples during validation than the other methods. For protocol 2A—validation for normal product bioburden distribution with an SIP of 1.0 or less—the minimum number of samples used is 640; 540 are used for the incremental dose series and 100 for the verification dose experiment. For protocol 2B—validation for product with consistent and low bioburden and an SIP of 1.0 (i.e., the entire device)—approximately 580 are generally tested. In each method—2A and 2B—an extra 200 samples (100 from each of the lots not used for the verification dose experiment) must be available. It they are not consumed in the study, they will be discarded if the SIP is <1.0, or they can be returned to the manufacturer for terminal sterilization if the SIP is 1.0.

A good reason to choose method 2 is its ability to validate a lower dose than method 1. Method 2 is based on a device microorganisms' average resistance to radiation, whereas method 1 is based on a theoretical model population that may or may not be similarly resistant to radiation as the organisms under study. Based on the ability of DNA ligase to repair radiation-caused DNA damage, it could conceivably take a smaller dose of radiation to destroy the less-sensitive organisms on the actual device than it would to inactivate the model population used to establish the method 1 doses. Thus, a method 2 study on such a device would allow a lower minimum routine sterilization dose.9 Conversely, if the ambient bioburden organisms would require more radiation than that indicated by the method 1 chart, method 2 can be an alternative method for validation. Another tactic involves identifying ways to lower bioburden levels and revalidating using method 1.


Methods 1 and 2 are not practical when there is limited test sample availability. The substantiation protocol for 25-kGy radiation sterilization was designed for use with small-volume production of fewer than 1000 units per lot, for single special-order lots and lots used in clinical trials and field studies, and for release of the first lot produced by a manufacturer. Given problems of failures associated with its use, the historical AAMI method 3 was not included in ANSI/AAMI/ISO 11137 and will not be discussed here except as a counterpoint to method 13409. The industry has had only limited experience in application of the latter method. Both methods use data developed from the inactivation of the microbial population in its natural state and are based on the probability model for inactivation of microbial populations provided in ANSI/AAMI/ISO 11137.

Method 13409 targets substantiation of 25 kGy for a single batch of products or for routine production of small batches of fewer than 1000 devices. Bioburden testing and dose-verification experiments are conducted on samples from each of three production lots.

Method 3 allowed test sample sizes to be selected based on production lot sizes from 7 to 1000 units. AAMI 13409 takes into account the pitfalls associated with taking samples from small batches and requires a minimum sample size of 10 devices for each of the bioburden and sterility experiments. The rationale for this change is that the distribution of the natural bioburden on products in batches of less than 20 may vary and not be sufficiently represented if fewer than 10 units are tested, potentially leading to validation failures.

Another significant difference between method 13409 and method 3 is the acceptance criteria when testing 30 or more samples in the verification experiment. Method 3 had allowed only one positive culture; method 13409 allows two. The acceptance limit in method 13409 is more in line with the acceptance criterion established in method 1.

Method 13409 requires only three successful verifications, as long as product batches are produced more frequently than one batch every 3 months. The verification dose is recalculated and tested for each subsequent dose audit after validation completion.

For method 13049, the average adjusted bioburden of each device may not exceed 1000 colony-forming units (CFU) per device. When working with a device with a high bioburden, it is important to consider that the 1000-CFU limit applies to average device bioburden, not to each individual sample result. Bioburden spikes—individual device unit values that are significantly higher than the average bioburden of the tested sample group—can potentially lead to a validation failure. If false spikes are used in calculating the verification and sterilizing doses, prohibitively high irradiation doses might be set. It is also possible that doses could be set too low if spikes exist but not in sufficient numbers to be factored into the dose-setting calculations. Spikes within the 100 sterility test sample lot can cause a verification dose failure.

Manufacturers should investigate bioburden spikes and determine their source. Spikes can result from the following causes: lack of environmental control in manufacturing, faulty handling during or after sampling, packaging problems, or lab contamination. For additional information regarding controlling manufacturing environments, see USP Supplement 8, 1998.12 The destruction of microorganisms can be characterized by their survival curves, and resistance data in the literature can guide a course of action during a failure investigation.13 A detailed review of source-specific factors known to be associated with the product—e.g., human handling or contact with air, equipment, or water—should occur. If the organisms associated with product bioburden can be identified or characterized, it is possible to determine their resistance to irradiation. High levels of resistant microorganisms may reduce the SAL to less than 10-6.

Manufacturers that have used method 3 should review their data in light of the AAMI 13409 substantiation method requirements. Rather than invalidating the previous results, it is possible to simply adopt the AAMI 13409 audit procedure based on the testing that has been performed, although manufacturers that use fewer than 10 samples should be aware of the increased probability of failure. For example, products composed of stainless steel/titanium are manufactured under harsh conditions that reduce the microbial populations to such low levels that the population may have a resistance probability greater than that assigned to the model population. The manufacturer should increase the test sample size whenever possible to avoid validation failures. If revalidation is required, it is acceptable to continue sterilization based on the method 3 data until the revalidation process is complete.


Although still used for some materials produced in sterile fill operations that are not subjected to terminal sterilization, or to determine sterility of products selected from field sampling, USP sterility testing is not acceptable as a lot-release criterion for irradiated devices.

Many factors support the release of devices, and there are five steps to achieving a successful validation. They are:

  • Product qualification.
  • Installation qualification.
  • Process qualification.
  • Certification.
  • Maintenance of validation.

The product qualification phase addresses product and packaging materials evaluation, as well as sterilization dose determination. The installation phase deals with equipment testing calibration, mapping, and documentation by the sterilization facility. The manufacturer and sterilization facility should then address process qualification, which includes establishing a product loading pattern, followed by dose mapping for the identification of minimum and maximum dose within the product load. Once the data have been collected for the first three phases of validation, the documentation is certified in accordance with ISO 9001 or ISO 9002. Routine validation maintenance ensures the validity of the sterilization dose, equipment, and dosimetry systems. (For more details, refer to ANSI/AAMI/ISO 11137.) After validation is successfully completed, each product lot is released by dosimetry.

The validation process covers the product sterility assurance requirement. USP testing cannot achieve this level of assurance because it is only conducted on a subset of the total sterilant-exposed samples. While the results are accurate for the samples tested, they cannot be extrapolated to determine the sterility assurance level of the remainder of that lot. Since the test results do not demonstrate the desired SAL characteristic, product sterility testing cannot be used in lieu of validation.

Once a validation is conducted, product lot-release sterility testing is not required as long as the manufacturer periodically conducts audits to verify continued validity of the minimum sterilization dose. Barring the need for other release tests, such as pyrogen testing, the product is ready for release if the dosimeters indicate that the required minimum sterilization dose has been achieved. Although there is no rule that says that validation can't be augmented with USP sterility testing, there are issues that render this impractical. Because a USP sterility test requires a 14-day test period, its use can create a 2-week delay for a product otherwise ready for release. Also, devices used in a USP sterility test cannot be sold, and are thus a sunk cost. If the product is expensive to manufacture, product sterility testing adds significant unnecessary expense to lot release.


The validation methods discussed in this article require methods developments testing to ensure the reliability of bioburden and sterility test results. These tests include bioburden recovery bacteriostasis/fungistasis and SIP adequacy (discussed previously).

Questions concerning bioburden recovery validation are becoming more frequent as manufacturers and contract sterilizers realize the importance of this test in establishing a routine sterilizing dose. Although bioburden recovery validation is not a new concept, it has become a specified part of ANSI/AAMI/ISO TIR 11737-1 and EU Standard EN 1174-1. Understanding the purpose of the recovery test is critical to understanding its use.

A bioburden recovery validation generally involves three to six samples and determines the efficiency of the bioburden testing method. Based upon the materials used for manufacturing the device and the complexity of its design, there is a possibility that a specific bioburden test can only remove a fraction of the existing microorganisms from the device for bioburden counting. The recovery test makes allowance for the residual organisms remaining on the device after the assessment, yielding either a percent recovery or a recovery factor used to adjust the bioburden counts. Because the results gained from both AAMI 11137 method 1 and AAMI 13409 rely on mathematical calculations based on the device bioburden, using the correct bioburden number is critical. An underestimated bioburden results in a lower verification dose, risking validation failure and product recall.

For example, if bioburden test results yield 750 CFU per device, knowledge of the method's efficiency may be critical to the selection of the validation test method. If the 750-CFU total is a nonadjusted figure, and a subsequent recovery study of the device indicates that the bioburden test method recovers only 40% of the organisms on the device, then the assayed bioburden must be divided by 0.4, resulting in an adjusted bioburden of 1875 CFU, well over the method 13409 maximum limit of 1000.

Quality Management for Cleanroom Operations

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

An MD&DI February 1999 Column


Efficient contamination control requires a system that applies total quality management principles.

Designing medical devices, building controlled environments, and submitting devices for FDA approval are time-consuming, costly activities for medical device manufacturers. Such activities generally have a defined time line with a set completion date and budget. However, the day-to-day operations of manufacturing in a controlled environment present continual challenges that vary as regulations change and the cost of manufacturing increases. This article presents a system designed to help ensure efficient contamination control operations.


The PACT—prevention, assessment, corrective action, and training—system (Figure 1) is designed to assist supervisors, managers, and engineers with contamination control management. It embraces the continuous improvement principles of total quality management.

Training and proper gowning are essential preventive activities. Photo courtesy of Burron OEM Division of B. Braun Medical Inc. (Bethlehem, PA).

Prevention. Personnel training, proper gowning, and housekeeping maintenance are essential preventive activities for controlled environments. Manufacturers have known for decades that people are a major source of contamination. Therefore, training employees and providing appropriate garments are critical tools for controlling contamination caused by humans. Workers' normal activities—for example, rapid arm motions or fast walking—can compound contamination because these actions are difficult to control and impossible to police. Such seemingly innocuous activities become a serious issue in the proximity of the process and product.

Human-generated contamination can be isolated by a body filter that creates a barrier. Cleanroom garments are designed to provide this barrier and reduce the inherent contamination from human debris such as hair, dandruff, clothing lint, coughing, skin flakes, dust particles, skin oils, and so on. Although the cleanroom's particulate and microbial control levels govern the minimum gowning requirements, the product and process may require additional personnel gowning protection. The Institute of Environmental Sciences and Technology provides guidance on garment selection, specifications, and testing.1

The cost of a garment system can be a significant portion of the total operational budget. Reducing the laundry cycle, rewearing hairnets and shoe covers, or eliminating gloves are not viable approaches to operational cost control. Such shortcuts will result in increased foreign matter, increased contamination from skin and oils, increased bioburden, and increased housekeeping maintenance. Ultimately, they can lead to product reworks or rejects. A risk assessment must be performed to address any cost-savings program that could affect product quality or reliability.

Prevention, assessment, corrective action, and training help ensure efficient cleanroom operations (Rexam; Matthews, NC).

Assessment. Routine monitoring, internal auditing, and third-party auditing are essential ingredients in any quality program, including cleanroom operations. Monitoring of air, surfaces, and personnel provides the data required to evaluate compliance and review environmental control. Routine particle counting should be performed at least weekly, with critical operations monitored daily. Although monitoring at 0.5 µm is the industry standard, additional monitoring at 5 µm and larger offers additional information about product quality and exposure in the controlled environment.

Surface monitoring should be performed weekly to determine whether housekeeping measures are adequate. Visual inspections can be used to assess the frequency of general housekeeping maintenance activities, including wiping, mopping, and sanitizing. This inspection can be limited to a wipe test but can also include ultraviolet or high-intensity, oblique white-light inspection techniques.2

Microbial monitoring of air and surfaces should also be performed routinely, with critical areas monitored daily. (Noncritical areas can be monitored weekly.) Contact plates or swabs provide an effective means of monitoring surfaces. Air sampling can be performed using a variety of methods, including impacters—slit, sieve, and centrifugal—impingers, and settling plates.

A multidisciplinary team should perform internal auditing. In general, the team should use checklists, specification requirements, and other methods to assess compliance and should note observations and discuss them with appropriate managers. Compliance issues must be identified so that managers can determine both corrective and preventive actions for each issue. The team should also ensure that the identified compliance issues are tracked to their final resolution. For example, internal audit findings could be assigned to a department or an individual for final resolution. The auditing team would subsequently review all responses, verify that the corrective actions are satisfactory, and confirm completion.

An external audit provides a different perspective and often takes a different approach than an internal audit. For example, because external auditors work with other device manufacturers, they have a basis of comparison that internal auditors cannot provide. External auditing and assessment should be performed annually. Benchmarking the results can provide not only the ranking of achievements, but can also identify areas in which further improvement is necessary.

Figure 1. The PACT system of quality management provides a method for tracking cleanroom operations.

Corrective Action. When an out-of-specification issue is identified, a corrective action program, resolution deadline, and preventive plan should be implemented. For every issue, the root cause should be identified and appropriate measures established to prevent recurrence. This ensures that the underlying problem is addressed. Implementing a quick fix usually addresses only the symptoms. Quantitative reports on the causes and corrective actions provide a tool to track the corrective action plan and evaluate the effectiveness of preventive measures.

Annual Training Session. A thorough training session is critical for establishing and maintaining efficient controlled-environment operations. An annual training program must include the quality system regulation, proper hygiene, basic microbiology, and contamination control. Employees cannot work effectively in controlled environments without a clear understanding of the science behind contamination control. Discussions of contamination control principles should address gowning, disciplines, restricted items, prohibited personnel actions, and other measures to minimize contamination. Classroom instruction followed by hands-on training in gowning and workstation procedures works best for training adults. Additional training or retraining needs may result from subsequent assessments or corrective action plans.


It is imperative that contamination control operations run efficiently to ensure product quality. Total quality management principles do apply to contamination control. Prevention, assessment, corrective action, and training are essential to a successful operation.

A certification program is in the future for all controlled-environment personnel. This type of program would include competency testing for all levels of worker performance. Testing would cover not only contamination control issues, but also product procedures, product specifications, equipment and manufacturing specifications, and regulatory requirements.


1. IES Recommended Practice 3.2: Garment System Considerations for Cleanrooms and Other Controlled Environments (Mt. Prospect, IL: Institute of Environmental Sciences and Technology, 1993).

2. IES Recommended Practice 18.2: Cleanroom Housekeeping—Operating and Monitoring Procedures (Mt. Prospect, IL: Institute of Environmental Sciences and Technology, 1992).

Anne Marie Dixon is managing partner of Cleanroom Management Associates (Carson City, NV).

Copyright ©1999 Medical Device & Diagnostic Industry

Not Settling for the Silver Lining:New technology adds silver's benefits to polymers

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

An MD&DI February 1999 Column


Many people seek solace in the silver lining of the proverbial dark cloud, but if Edward W. Kelly had his way, the silver wouldn't just line the cloud—it would be mixed throughout it. Kelly has a keen interest in silver's antimicrobial properties, and it was this fascination that lured him away from his consulting practice last year to his current position as president and CEO of Implemed (Watertown, MA).

"People have known about the antimicrobial benefits of silver for centuries," says Kelly. "Silver nitrate is put in babies' eyes immediately after birth, colloidal silver has been given orally, and silver sulfadiazine is used to treat burns. It's well tolerated by the body."

Implemed's proprietary technology incorporates silver and a dissimilar metal into medical-grade plastics. On contact with fluids such as saline, medications, or body fluids, an electrochemical reaction releases silver ions that depart on a search-and-destroy mission against "microbes that grow on implanted medical devices, such as catheters," Kelly explains.

Edward R. Kelly believes that products containing silver help ward off disease.

An attorney by trade, Kelly has been involved in the medical device industry for more than 20 years. His industry sojourn began in labor relations, where he developed a comprehensive understanding of manufacturing processes and day-to-day procedures before moving to an operations role. A temporary one-year assignment in Davol's (Cranston, RI) vascular-access business provided him with an opportunity to learn about sales, marketing, and R&D.

Kelly thoroughly enjoys general management. "I like the diversity of being involved in every aspect of a business. You have to learn something about everything. I enjoy the intellectual challenge, the exposure to new techniques, finding out where products are eventually going, and interacting with customers."

As a consultant, Kelly certainly used his wide range of knowledge to turn businesses around. However, "as much as I enjoy consulting, my first love is the medical device industry," he admits. "When Implemed came calling, I jumped. When you are in a start-up, it's not a part-time activity. That's what makes it fun. I like start-ups very much, I was captivated by the technology, and I saw the market need for it."

According to a 1992 CDC study, hospital-acquired infection is the nation's sixth leading cause of death. Antimicrobial properties are being added to medical devices in the hopes that they can drastically reduce the rate of infection and death. Whereas other companies have added silver to the coating of some of their products, Kelly believes that Implemed's Oligon technology is the first to add silver to the actual polymer of its catheters, which allows the antimicrobial reaction to be constant and on all surfaces of the catheter.

"I like Implemed's technology because of its long-lasting effects," says Kelly. "A coated product stops reacting after a day or two. With our technology, release of the silver ions is still strong for an extended period of time.

"The product is really why I came to Implemed," he explains. "It fits such an important clinical and market need. Catheters are used in such a wide range of applications, from parenteral nutrition to delivering chemotherapeutic agents. Many patients already have compromised immune systems, so the risk of this population contracting a hospital-acquired infection is great."

According to Kelly, another potential benefit of the Oligon technology is that there are no side effects from its use, something a regimen of strong antibiotics can't claim.

Kelly believes that the technology will have a tremendous impact both in decreasing hospital costs and in saving lives. "These are the kinds of motivators that initially attracted me to the industry," he says, "and a tremendous motivation for causing me to stay. I think you'll find most people in this industry feel the same way. Virtually everyone who is a success in this business has something else in common: a real desire to improve healthcare. We have to thoroughly understand the needs of buying groups, along with the requirement needs of the clinicians.

"The most important key to success is to be a student," advises Kelly. "I'd bet that the majority of successful people are working in the medical industry with undergraduate degrees that didn't directly prepare them for this field, yet they've flourished. Successful people have usually taken on large tasks and given total commitment in order to reach their goals."

Jennifer M. Sakurai is managing editor of MD&DI.

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