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Articles from 1998 In December


Toy Story: Media Relations Are Anything But Child's Play

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

An MD&DI December 1998 Column

The increasing influence of the media as a source of medical information places a premium on effective public relations.

The first speaker at the "Town Hall Meeting on Media, Medicine, and Regulatory Affairs" opened the session with a startling statistic: more adult Americans (40%) name television as their primary source of medical and healthcare information than name doctors (36%). (Magazines, you'll be pleased to know, rate a close third.) Eighty-two percent believe that medical news reported by the media helps them lead a healthy life. And yet despite the proliferation of reportage, analysis, public-service announcements, infomercials, and every other sort of exhortation and cajolery, fully one-third of respondents claim they do not get enough medical and health news to keep them well-informed.

These and other results of a survey conducted by the National Health Council were presented at the annual conference of the Regulatory Affairs Professionals Society in Washington, DC, by Dee Ellison, the Council's director of communications. Ellison called on the media—clearly now "an integral part of the nation's healthcare team"—to provide "accurate, timely, complete, and balanced information." Other panelists were less sanguine. Mary K. Pendergast, executive vice president for government affairs at Elan Corp. and former deputy commissioner of FDA, termed the influence of the media in general (and TV's primacy in particular) "scary," given the "systematic biases in healthcare reporting" that include superficiality and an inclination either to overaccentuate the positive—whether a scientific test result or the com- mercial potential of a product—or to escalate any problem into a full-scale disaster.

When the discussion turned to media relations and industry crisis management, Pendergast stressed the importance of early, frequent communication, and underscored the critical role of regulatory personnel in notifying government agencies. A company must learn the particularities of using the media to its advantage: for example, how to get a story out quickly on the AP wire, or how to guard against television's tendency to obscure a message by reporting the news-gathering process rather than the news itself. Bruce Downey, president and CEO of Barr Laboratories, counseled companies to prepare a crisis management plan that can be printed on a single sheet of paper, and urged early notification and media involvement of the chief executive. The overriding rule for crisis management, said Barr, is "the golden rule": protect the public, and you'll protect the company and its shareholders.

Many of these same themes—media power, objectivity, and balance; media manipulation by advocacy groups; crisis management and how to define the public interest—are currently being played out in a "story" with important ramifications for the device industry. The setting is your neighborhood toy store. On November 13, the worldwide chain Toys 'R' Us announced that it was pulling from its shelves all direct-to-mouth toys (teething rings, etc.) containing phthalate-ester plasticizers. The action followed announcements from major toy manufacturers that they were discontinuing use of the plasticizers and—by extension—of flexible PVCs. The companies maintain that their products are safe, but say they are responding, in the words of one executive, "to the marketplace rather than to any scientific or regulatory imperative." In this case, the "marketplace" has been shaped by the highly effective media strategies of various environmental groups.

The loss of flexible squeaking ducks is perhaps not a major blow to world civilization, but what about flexible endotracheal tubes? A member of a chemical industry board, who has carried out exhaustive reviews of the literature on the plasticizers and finds them "completely harmless," nevertheless predicts that "the industry will go the way toys go." In the high-stakes arena of public opinion, will a product be safe and effective only when an increasingly powerful media declares it to be so?

Jon Katz
jon.katz@cancom.com


Copyright ©1998 Medical Device & Diagnostic Industry

FDA Promotes Shorter PMA Summaries, Faster Inspections : Shorter Device Inspections Tested : Yet Another Inspection Technique : FDA Web Link to Companies? : Five Reforms Emerge from FDA Stakeholders Process : Communications Change Boosts Dialogue

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

An MD&DI December 1998 Column

WASHINGTON WRAP-UP

Simplifying requirements appears to be a current theme at the agency.

Also:

In an example of what seems to be a trend within FDA, the agency's Center for Devices and Radiological Health (CDRH) is reducing the length of the safety and effectiveness summaries that it issues with each new premarket approval (PMA). According to Susan Alpert, director of the Office of Device Evaluation (ODE), the goal is to make the summaries—which start out as proposed texts drafted by each PMA sponsor—more usable for the health professionals, procurement agencies, and others who read them.

In the case of some of the lengthier summaries customarily issued, Alpert anticipates more than a 50% cut in volume—dropping from approximately 50 pages for a recent excimer laser summary down to about 20 pages, for example. "I want them to be readable, pithy," she explains. "Rather than describe preclinical studies in narrative, do it in tabular form."

Alpert pointed out that a template for her approach already exists in the Division of Ophthalmic Devices, and although there's too much variation across device categories for a cookie-cutter approach to work, the concept is transferable to all ODE divisions.

Ophthalmic division director Ralph Rosenthal says that the shorter summaries being produced in his division could get even shorter; however, the three examples he selected emphasize elements that have been retained rather than those that have been abolished:

  • A summary for two excimer laser systems (VISX, Inc., Santa Clara, CA) that were approved on April 24, 1997. The summary ran to 28 pages and comprised the following sections: General Information, Indications for Use, Contraindications, Warnings and Precautions, Device Description, Alternative Practices or Procedures, Marketing History, Adverse Effects of the Device on Health, Summary of Preclinical Studies (a one-sentence reference to an earlier approval for a related indication), Summary of Clinical Studies (a two-page narrative plus 26 tables and captions and a description of adverse reactions), Panel Recommendations, FDA Decision, and Approval Specifications.
  • A summary for a posterior-chamber intraocular lens (Pharmacia, Inc., now Pharmacia & Upjohn, London), approved on July 20, 1995. This document was four pages long and contained sections titled General Information, Indications, Summary, Safety and Effectiveness Data (with three tables), and Conclusion.
  • A summary for a multipurpose solution for contact lenses (Eurexpan Labo, Washington, DC), approved on June 20, 1996. This consisted of four pages, with sections for General Information, Indications, Summary, and Safety and Effectiveness Data (with one table of clinical data).

Clearly, the length of a summary varies according to the sophistication of the device and the degree of risk inherent in its use. Alpert cites another factor: the tendency of sponsors to write the first version in an overly optimistic or promotional tone. CDRH then has to cut through the fluff and produce an objective document, a process that only adds to any delay.

In conjunction with the simplification process for PMA summaries, CDRH is also reducing the deficit of summaries (going back to 1994) that are supposed to be accessible on its Internet home page. On October 1, the day after the close of the 1998 fiscal year, three summaries of FY '97 approvals and six summaries of FY '98 approvals were still unavailable.

FDA field investigators are currently trying out a new and purportedly shorter inspection technique in three of the agency's field districts. Until December 31, the investigators will be pilot testing CDRH's new Quality Systems Inspections Technique (QSIT) in Minneapolis, Denver, and Los Angeles.

The new technique is intended to result in faster and more-targeted inspections and to help FDA live up to its mandate to inspect device manufacturers once every two years.

QSIT inspections will be comprehensive evaluations of manufacturers' quality systems and will not terminate early—as had been proposed by FDA to save resources—if investigators find "fatal flaws" at a company.

Under QSIT, investigators will evaluate four subsystems of the quality system regulation: management controls, design controls, corrective and preventive actions, and production and process controls.

The inspections will begin and end with an evaluation of management controls, according to CDRH reengineering inspection team leader Tim Wells. Conclusive decisions on management controls can't be performed, says Wells, until investigators have walked through each of the subsystems and determined that a firm's management has devoted sufficient resources to these controls.

Inspections will be preannounced, at which time the investigators will ask for voluntary production of the company's quality policy and top-level quality system procedures (including management review procedures, quality manual, quality plan, or equivalent documents). QSIT is designed so that only one investigator will inspect a device facility, rather than a team, Wells says.

It's still too early to tell if the new procedures will actually save any time. Since investigators began adding the new quality system and design control regulatory requirements to their inspections, FDA time in the plant has been extended to an average of 70 hours, almost double the 40-hour target maximum set out in agency policy for routine comprehensive device inspections.

While performing faster inspections is certainly a goal, says Wells, QSIT is also designed to produce more-focused inspections and to harmonize the process more closely with European inspections.

While the QSIT pilot program was getting under way, a second technique—based on principles of hazard analysis and critical control points (HACCP) that have been used in other industries for more than 30 years—was being developed at CDRH. HACCP will allow for inspections of participating firms based on the critical control points that can affect product safety.

The center expects industry and independent third-party organizations to play the major role in this effort, with CDRH providing direction and helping to kick off the program.

CDRH maintains that the technique will result in more efficient, streamlined inspections for participating companies and is considering allowing firms that voluntarily develop HACCP programs to use a symbol on their product labels indicating that they follow HACCP principles.

The seven HACCP requirements that form the basis of the protocol stipulate that companies:

CDRH has developed a chart showing how the seven principles tie in to elements in the quality system regulation and says the fact that they coincide means that new regulations are not necessary.

After the protocol is developed, a team at the agency will monitor the program to determine if it identifies critical problems with devices more efficiently than traditional inspections, according to a CDRH document giving current thinking on HACCP inspections.

CDRH is following the HACCP model developed by the National Seafood HACCP Alliance, which became a requirement for seafood processors in December 1997.

The center urges medical device manufacturers to receive necessary HACCP training so that they will be able to develop a plan. At present, no training course is designed specifically for medical devices, but industry representatives can attend seafood alliance courses. At two of these sessions, a member of the CDRH HACCP team has presented additional information pertaining to medical devices. (Editor's note: for more information, see our related story, Developing an HACCP Plan.)

One thing CDRH could do to maximize the dissemination of new product information would be to devote a special section of its Internet home page to hyperlinks to the Web sites of device manufacturers, suggested the Medical Device Manufacturers Association in September 10 comments to the agency.

It was the second time in a week that the agency had been asked to consider linking its page to company pages. At a previous internal agency meeting on Internet issues, the same suggestion was offered as a way of providing access to company responses to warning letters and untitled letters. However, that idea was soon rejected as too costly.

FDA has distilled to five main themes the hundreds of requests and suggestions it received during its recent "stakeholder" meetings, deputy commissioner for strategic management Linda A. Suydam says. These five principles are:

It's the biggest change I've seen in my five years here," says ODE director Susan Alpert, referring to a new series of intermanagement meetings the center is having with device sponsors to optimize its industry-agency communications. She declined to identify the companies, but says that five such meetings have been held, involving multiple levels of management on both sides. The goal of the process is to enable FDA and industry to work together more effectively and to better understand each other's philosophical outlook.


Copyright ©1998 Medical Device & Diagnostic Industry

Maximize Return on Investment by Patenting What Counts

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

An MD&DI December 1998 Column

BOTTOM LINE

Strategies for patent filing help companies get the most for their money and prevent competitor access.

Many companies struggle with how much they should spend on patents and what return they should expect on their investment. Somehow, patents always take too long to obtain and seem too expensive, and companies often are not quite sure what they have received for their money.

Unless the patent application had the proper focus, they may not have gotten very much. Too often, patents are filed based on which employee bothers to fill out an invention disclosure form, which inventor or company department has the most political pull, or what aspect of the company's product line constitutes a technological improvement.

Unfortunately, these approaches are not likely to maximize the return per dollar invested. To do so, a company must focus its patent investment on its competitors and base its strategy on how it wishes to influence their behavior, not its own. A patent is the right to exclude others from making, using, or selling the claimed invention. Since a patent is the right to exclude, a company's tactics should focus on precisely what to exclude its competitors from doing.

To be most effective, a patent program should:

  • Be implemented by a team of individuals within the company who have the necessary expertise, access to information, and political clout.
  • Identify and focus on the profit component.
  • Begin prior to development of the product.
  • Target resources at the patent office.
  • Leverage products through sales and marketing.
  • Incorporate technological developments and market feedback through periodic review.

THE PATENT TEAM

A successful patent team should include members from marketing, research and development, patent counsel, and management.

Marketing personnel must define and provide the team with detailed information on what products the market wants and what it will accept as substitutes, while the representatives from R&D develop options for satisfying the identified market opportunities.

The patent attorney should evaluate the various marketing and development options, advising the team about how its decisions affect the company's right to exclude competitors from manufacturing competing products. This coordinated effort allows the team to focus on its most promising opportunities.

Management participation emphasizes the importance of the process to the corporation's future and ensures that decisions are consistent with the company's strategic goals.

THE PROFIT COMPONENT

Once the market opportunity is defined, the next step is to determine the profit component, which is the aspect of the product or service that will generate most of the company's profits.

The majority of a company's patent resources should focus on protecting the market for the profit component. For example, a company may sell expensive lasers at a nominal profit margin for use with a disposable laser catheter, which brings in most of the profits. In this situation, the low-cost catheter, not the high-cost laser, is the profit component.

Accordingly, the majority of the company's patent resources should focus on preventing competitors from selling products that are identical to, or acceptable substitutes for, the catheter. Unless the patent strategy prevents competitors from selling acceptable substitutes for the company's product, return on patent investment will be nominal.

EARLY IMPLEMENTATION

An invention is patentable if it is nonobvious in view of prior art. The component need not work better, be cheaper to manufacture, or have a more pleasing appearance to be patentable. If patentability is identified as a goal early in the design process, it is almost always possible to design a product to meet the standards for patentability. When more than one technical direction is viable, development decisions should consider the impact on patentability.

If the profit component is to be sold in conjunction with another device, the other device should be designed so that it will only function with the company's profit component. For example, the high-cost laser could be designed with a safety shutoff switch that can only be actuated by a patented mating connector forming part of the company's disposable catheter. It would also be important to design the laser's connector so it cannot be economically modified to avoid using the company's separately patented catheter connector.

FOCUS EFFORTS AT THE PATENT OFFICE

Securing patent protection can require substantial resources. The key to maximizing investment return is to concentrate on securing meaningful protection for the profit component. Again, the focus should be on what a company wishes to exclude its competition from making, using, or selling.

A company should secure patents on profit-component variations that it never intends to sell, but which, if not excluded, competitors could use for their own products. Because each patent is entitled to its own presumption of validity, a company should secure families of patents covering different aspects of the profit component.

The patent portfolio should thus include broad claims, providing maximum deterrence and potential licensing revenue, as well as narrower claims, which will be easier to secure and harder to invalidate. The claims should cover the profit component alone, as well as in conjunction with the overall system, along with the method of making or using it. The company selling the laser and catheter, for example, should have patent claims covering its catheter, the combination of the laser and catheter, and the method of using the catheter. Each category should have both broad and narrow claims.

In order to derive the most benefit from its patent strategy, a company should identify and review the purpose of each patent. Properly conceived patents can be valuable tools for achieving a number of business objectives, such as:

  • Stopping competitors from selling a like product, thereby protecting the company's market share.
  • Securing royalties.
  • Gaining access to additional distribution channels.
  • Acquiring a license under a competitor's patent.
  • Deterring third-party infringement suits.
  • Providing a bargaining chip to settle potential controversies.
  • Securing financing.

Efforts at the patent office should be directed toward obtaining claims for a particular purpose. For example, if the desire is to secure a royalty from a competitor, the patent claims can be tailored to more clearly cover the competitor's product, rather than defining the broadest possible scope of protection.

LEVERAGING THE PRODUCT

Marketing personnel should always be kept informed of a product's patent-protection status. The company's advertising should stress the desirability of the patented or soon-to-be-patented features so as to leverage the impact of the patent protection. For example, if a catheter's safety connection is about to be patented, the specific aspects and advantages of the connector that will be protected should be emphasized in company advertising.

Patent protection can also be leveraged through a careful tailoring of sales contracts and use notices. For example, case law suggests that the effective scope of patent protection may be expanded by licensing rather than selling a device, selling the profit component separately, giving notice of restrictions at the time of sale to avoid an implied license, having the buyer affirmatively acknowledge restrictions, and limiting the buyer's right to repair through a single-use restriction.

PERIODIC REVIEW

As with anything based on assumptions about future events, patent strategies should be reviewed regularly in the event that they need to be modified to reflect changing conditions. The review process should ensure that the appropriate parties are still members of the patent committee, that the definition of the profit component and its substitutes is still accurate, that improvements to the profit component have been designed so they can be protected by new or existing patents, and that products are being marketed in a manner that maximizes the value of existing or anticipated patent protection.

CONCLUSION

The amount a company should spend for patents will vary depending on its individual circumstances. The goal, however, should be the same for every company--to derive the utmost benefit from the time and money expended in the patent process. Following the steps detailed in this article can help companies achieve this end. This approach demystifies patent investment and establishes clear goals for the patent program, a strategy for focused implementation, and a framework for evaluating results.

By continually applying this process to develop and refine a coherent patent strategy, a company can successfully maximize return on its patent investment.

Edward A. Schlatter is a registered patent lawyer and a partner of the firm Knobbe, Martens, Olson & Bear, LLP (Newport Beach, CA).

Illustration by Ken Corral


Copyright ©1998 Medical Device & Diagnostic Industry

Establishing a Supply Agreement That Benefits Both Parties

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

An MD&DI December 1998 Column

HELP DESK

Larry R. Pilot, an attorney with McKenna & Cuneo, LLP (Washington, DC), discusses how companies should establish supply agreements.

Could you give me any assistance regarding forms or precedents for medical device supply agreements?

The two companies should first establish their goals for the agreement. The contracting parties should determine whether they merely want one company to supply a specific quantity of finished, marketable medical devices for the other to distribute or whether they want to create a more involved agreement that establishes licensing rights to develop additional technology associated with the devices.

The terms of the agreement will vary depending upon the parties' needs. For example, company A may enter into a strategic marketing agreement with company B that requires company B to complete clinical trials and regulatory applications for marketing a product in a foreign country, and requires company A to provide all of the devices at an agreed-upon price in return for royalties (see, for example, Neoprobe Corp., Securities and Exchange Commission (SEC) 10-k filing, Commission File 0-26520, March 31, 1998). A manufacturing agreement, on the other hand, may only require company B to manufacture and supply one or more of its devices to company A.

The agreement should define all terms and clearly state the rights and duties of each party. Although some terms may be common in the industry, such as good manufacturing practices, they should be defined within the confines of the agreement. The agreement should also clarify which products are included within the terms of the agreement—even products not yet in existence. Companies entering into the agreement with existing technology should anticipate that the other party may develop complementary devices and should ensure that marketing and licensing rights for such new devices are stated within the agreement. For example, if company A develops a catheter and partners with company B to market it, their agreement should state who may market an updated catheter—for example, if company B developed a specialized coating for the product—and who would receive the profits or royalties from the sales. Also, the parties should determine who is required to seek regulatory approval and ensure regulatory compliance for the device or devices.

A company seeking to expand worldwide might consider entering into a marketing agreement with others who have experience selling and distributing medical devices internationally. Negotiations should specify which company would seek regulatory approval for the device (for example, securing the European CE mark). Obtaining regulatory approval means submitting applications, performing any required clinical trials, paying appropriate initial and maintenance fees, and ensuring continued regulatory compliance. Regulatory compliance may also require compiling and reporting information (e.g., adverse events) about the medical device or devices or handling a device recall.

All of these and other possible situations should be clearly addressed in the agreement to avoid disputes later. It can be costly for either party to assume that its partner has taken the steps necessary for regulatory compliance, and doing so risks punitive action against the companies by a government authority. Of course, there's always the threat of putting themselves at a competitive disadvantage by entering the market too late. It is particularly important, then, for companies to agree before any work begins as to who is responsible for ensuring full legal and regulatory compliance for clinical studies, manufacturing and facility regulations, and commercial distribution after the agreement goes into effect.

Other items to consider include the duties and benefits of any intellectual property rights associated with the device, whether the agreement is exclusive, and its financial terms. If one party wants intellectual property rights, such as patents or trademarks, then the parties should discuss who will apply for, pay for, and maintain those rights, including enforcement through litigation or arbitration. Parties should clearly state what information exchanged between them should remain confidential, which may mean that only specified employees may access confidential information after signing covenants not to compete. Covenants not to compete, however, may only limit information use for a specific time period (generally less than five years) and within a limited geographic area (i.e., not worldwide).

The degree of exclusivity in the agreement will affect some of its terms. For example, if company B receives exclusive worldwide rights to market a device, it might agree to pay company A higher royalties or invest more money in additional research and development. The financial terms also will be affected by obligations to pay for research or regulatory compliance and should address new devices that are developed after the agreement goes into affect.

Finally, conditions should be specified that provide liquidated damages in the event that a party breaches the agreement. The agreement also should state what would happen if a dispute arises between the contracting companies. It is particularly important in the global market that the parties make prior arrangement as to what laws will govern in the event of a dispute and whether arbitration can be pursued before litigation.

The parties should also stipulate when the agreement will end. An agreement may end on a particular date, but the parties should consider what to do when confronted with changing market conditions or product viability. For example, if two companies executed an agreement granting company B exclusive worldwide sales and marketing rights to one of company A's products, they could construct their agreement to enable them to terminate the partnership if changing market conditions significantly alter the basis for their agreement. The termination clause in most agreements allows one party to terminate the agreement upon written notice to the other, either within a specified time period or on the occurrence of a material breach of contract. For example, if company B fails to provide an agreed number of medical devices within 45 days after company A notifies company B, then company A could write to company B and terminate the agreement (see, for example, Faulding, Inc., SEC 10-k filing, Commission File 0-13588, exhibit 10, June 30, 1996). When the parties decide what law governs, however, they should determine whether the termination clause they have constructed is legal within that jurisdiction.

Although on-line information about supply agreements appears scarce, companies may be able to obtain samples from industry groups. They can also obtain information from the Securities and Exchange Commission under the Freedom of Information Act. The SEC retains copies of company filings, including some 10-k and 8-k filings that disclose agreement terms.


"Help Desk" solicits questions about the design, manufacture, regulation, and sale of medical products and refers them to appropriate experts in the field. A list of topics previously covered can be found in our Help Desk Archives. Send questions to Help Desk, MD&DI, 11444 W. Olympic Blvd., Ste. 900, Los Angeles, CA 90064, fax 310/445-4299, e-mail helpdesk@devicelink.com. You can also use our on-line query form.

Although every effort is made to ensure the accuracy of this column, neither the experts nor the editors can guarantee the accuracy of the solutions offered. They also cannot ensure that the proposed answers will work in every situation.

Readers are also encouraged to send comments on the published questions and answers.


Copyright ©1998 Medical Device & Diagnostic Industry

Shielding against Electrostatic Discharge

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

An MD&DI December 1998 Column

EMI FIELD NOTES

When electrostatic discharge cannot be prevented, effective shielding is key to protecting devices.

Electrostatic discharge (ESD), although troublesome for portable electronic medical devices, is controllable with effective shielding. Lack of complete shielding leads to compromises that leave devices open to several paths for ESD to follow. A recent article discussed avoiding ESD problems by implementing preventive measures.1 Preventing discharge to the enclosure eliminates the major ESD problem of direct discharge, leaving only indirect discharge, a much less severe problem.

It is not always possible, however, to prevent discharge. Metallic members may need to be exposed, or a metallic shield may be needed to control other electromagnetic interference. For cases in which discharge cannot readily be prevented, a means must be found to protect the circuits within the enclosure. It is important to keep in mind that if ESD cannot be prevented, then shielding problems multiply.

UNDERSTANDING DISCHARGE

ESD has a rise time of less than 1 nanosecond. In that brief period, the voltage and associated electric field fall from the initial voltage (8–15 kV) to near zero, and the current and attendant magnetic field rise to 10 A or more. Both electric and magnetic field effects can be troublesome, as shown in Figure 1. In Figure 1a, the discharge is to a plane, with the charge capacitively coupled to internal circuits. In Figure 1b, the discharge is to a wire or trace, which may cause a voltage drop along the wire itself, and the current may couple magnetically to adjacent wires. Electric field coupling is dominant in larger devices, but in smaller devices, the current is the problem. This article concentrates on current.



Figure 1. Effects from discharge. I represents current; H is the magnetic field, which arises from current.

The current can follow several paths. The first, and simplest, path is when discharge occurs to a grounded metal member. The current density at the point of contact is very high, and hence the magnetic field immediately surrounding the actual arc is also high. Once the charge reaches the metal member, it spreads out to the farthest extent possible, depending on the amount of metal available. Discharge directly to a plane spreads out very quickly, confining the intense magnetic field to the immediate vicinity of the discharge point and to the current's constrictions downstream.

Discharge to a wire can't spread out very much because it must follow the wire. This is bad news for two reasons. First, the inductance of the wire causes a substantial back voltage along the wire path. Second, the magnetic field remains intense along the entire run of the wire.

The second possible current path involves a floating piece of metal. Metal that is completely isolated and fairly small presents little concern: such metal accepts a modest charge, but the problem ends there. Unfortunately, metal is not usually very well isolated, and there is always the other end to worry about. For example, the end of a screw securing plastic pieces may be near an internal circuit (Figure 2). In this case, the discharge actually produces two arcs, with the floating member connecting the two. The problem in this scenario is that the metal member can carry the arc to places it would otherwise never be able to reach. Accordingly, it is imperative to ground all metal members.

Figure 2. Discharge via screw to metallic member.

An ungrounded enclosure, such as a portable device, provides a third current path. In this case, the device accepts as much charge as allowed by the capacitance between it and the ground. If the device is small, little charge transfer occurs. However, if the device is large or in close proximity to a ground plane, then most of the charge transfers to the device. Thus, a device can accept ESD even if it is not grounded.

The fourth type of current path can occur when an enclosure is grounded solely via a power-line ground wire. Following discharge, the current eventually finds its way out of the ground wire, but the leading edge of the current is through capacitive or planar paths. Depending on the wire length, stray capacitance, and resistive losses, poorly dampened oscillations will follow. This is a key point when addressing ESD: an earth ground via a green wire ground is not particularly desirable.

KEY PARAMETER

The key concern in coping with ESD is to keep the current density as low as possible. Because the current density reaches its maximum at the discharge point, an engineer can take several preventive actions. The first is to arrange the conductors so that the current densities fall off as quickly as possible. When this is not possible—as with a wire entry point—one should keep some distance from internal circuits and wires. It is also important to avoid subsequent current constrictions.

SHIELDING

Shielding is the next step in protecting unavoidable exposed metal surfaces. A well-shielded enclosure embodies the following features:

  • A metal or metallized enclosure providing essentially 100% coverage.
  • Mating seams that make frequent conductive contact (at least every 2 in. or 5 cm). Conductive gasketing is preferred.
  • Cable shields terminated directly at the metal enclosure; no pigtails allowed.
  • Nonshielded cables (including power lines) with filter capacitors grounded directly to the case. (Recognizing the leakage current limitations doesn't change the laws of ESD.)
  • All conductors (such as switches) bonded to the enclosure.
  • No internal cables and wires routed close to enclosure seams.

Often, compromises need to be made, but it is crucial to be aware that any deviation from the above recommendations involves a significant risk. It will take considerable time and money to make a poor shield adequate, if it can be done at all. Nevertheless, many designers insist on trying. The following guidelines are useful when good shielding practices cannot be implemented.

First, if full shielding is not possible, then providing a ground plane to which cable shields and filters can be referenced is mandatory. The ground plane should have a footprint at least as large as the internal electronics and wiring. It is not necessary to connect the ground plane to the earth ground and, in fact, the ground can be completely contained within the enclosure as an internal ground reference or as an additional layer of the printed circuit board (PCB) itself.

Second, if the cable or power-line filter capacitor cannot be connected to an enclosure ground, then it should be tied to a circuit ground and supplemented with a series ferrite between the capacitor and the connector pin. Multilayer circuit boards are required if filter capacitors are connected to the circuit ground; two-sided boards are not sufficient.

CONCLUSION

The first line of defense in fighting ESD problems is to prevent discharge from occurring directly to the equipment. When discharge cannot be prevented, a significant burden is placed on the shielding. Although ESD is controllable when recognized shielding practices are employed, deviation requires much trial and error to effect an acceptable solution. Lack of complete shielding inevitably involves a major trade-off, leaving no room for other compromises. Most notably, multilayer boards become mandatory.

The bottom line is that a ground plane must be present for ESD control. That ground plane may be the conductive enclosure, a plane under the PCB, or a plane in the PCB.

REFERENCE

1. Kimmel WD, and Gerke DD, "Blocking ESD at the Enclosure," Med Dev Diag Indust, 20(5):102–106, 1998.

William D. Kimmel, PE, and Daryl D. Gerke, PE, are principals in Kimmel Gerke Associates, Ltd., an electrical engineering consulting firm specializing in EMI/EMC issues, with offices in Phoenix, AZ, and St. Paul, MN.


Copyright ©1998 Medical Device & Diagnostic Industry

EtO Sterilization: Principles of Process Design

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

An MD&DI December 1998 Column

ETO STERILIZATION

By following a structured method, process engineers can design and validate safe and efficacious EtO steilization cycles.

Among the sterilization technologies currently available to the medical device industry, 100% ethylene oxide (EtO) gas remains one of the most popular. Validated EtO processes can be run in sterilizers ranging from BIER vessels of a few cubic feet to industrial-sized vessels exceeding 4500 cu ft. Typically, the EtO process can be broken down into four basic phases, each of which needs careful planning to ensure a safe and efficacious process. The four phases are: (1) air removal, (2) steam injection and conditioning dwell, (3) EtO injection and gas dwell, and (4) gas purge and air inbleed.

Mid-infrared gas spectrometer measures EtO and water vapor during sterilization. Photo courtesy Spectros Instruments, Inc. (Whitinsville, MA).

This article is intended to guide the reader through the components of each phase of two hypothetical 100% EtO with nitrogen processes. The following assumptions were made for the purpose of explaining the rationale behind the design of the cycles and the options available:

  • Water vapor and process nitrogen are the only inert gases considered in the flammability calculations performed during the air-elimination and gas-purge phases.
  • There is no stratification of process gases.
  • All process gases are presumed to behave as ideal gases.
  • Preconditioning and aeration are performed externally to the sterilizer.
  • Atmospheric and barometric pressure are constant, with atmospheric pressure at 14.7 psia.

An effective EtO process can be properly designed for almost every type of medical device and permeable packaging configuration, provided that all variables are assessed through thorough process design and development. It is here, in fact, that one notices how EtO processes possess a greater number of variables in comparison with other sterilization technologies. However, by following a structured method that systematically examines and considers each of these variables, the process engineer can design, validate, and routinely sterilize with a safe and efficacious process.

The critical parameters of an EtO sterilization cycle are typically given as temperature, pressure, humidity, EtO concentration, and gas dwell time. However, the process engineer must also identify and evaluate relationships that may exist between any given process parameter(s), the product being sterilized, and the equipment used.

The sterilization process must consistently deliver all critical process parameters to each and every component contained within the load, to a degree that will ensure a 10-6 sterility assurance level (SAL) without causing any deleterious effect to the product or its sterile barrier packaging. In addition, this process must occur under controlled conditions that will protect the sterilization personnel monitoring the operation, the equipment employed, and ultimately the end-user.

Each product component contained in the load must be examined for the following characteristics: natural bioburden, physical configuration, raw-material composition, sensitivity to both negative and positive pressure changes, maximum heat tolerance, and chemical reaction to water vapor and ethylene oxide. For example, surgical sutures may present an extreme sensitivity to what are often considered even moderate temperature levels. Other materials, especially those containing salts, may react strongly with EtO to form ethylene chlorohydrin (ECH), a residual chemical produced during the EtO process. Some materials may bind, through a positive reaction, large quantities of EtO molecules, presenting the problem of excessively high postprocess levels of EtO and ethylene glycol (EG), another process residual.1 Those components presenting the greatest challenge to the process—due either to physical configuration (obstruction of gas permeation) or high bioburden (natural fibers, for example)—should be selected for the microbiological challenge. Other product sensitivities should also be noted, as they will determine maximum ramp rates and set points employed in the cycle. For the validation of the process, a reference load must be selected that will represent the most difficult combination to heat, humidify, sterilize, and aerate.

Each level of packaging, from master cartons to the unit package (the primary sterile barrier), must be examined and evaluated for its ability to allow heat, moisture, and sterilant to permeate. Gas delivery to and permeation within the product, in addition to aeration of the gas from the product, are all important considerations. Data obtained from fractional studies can provide the basis for the calculation of the dwell times for the conditioning and gas exposure. The process engineer must be cautious of excessively long gas-exposure dwells or high gas concentrations, as they can result in the need for long multiple evacuations and/or aeration times that will delay product release. The objective is to decide whether to adopt a cycle using a long gas-exposure time with low EtO concentration or one with brief gas exposure and a high EtO concentration. Naturally, if gas is easily aerated from the product, production times are improved by a short exposure to a high concentration of sterilant.

Before a preliminary cycle plan can be drafted, the process engineer must have a thorough knowledge of the process equipment, including the minimum and maximum operating ranges of the preconditioning facility, the sterilizer and ancillary equipment, and the aeration facility. The sterilizer control system must be able to perform all evacuations and gas injections (nitrogen, steam, EtO, and air) at steady, preprogrammed rates. Accurately calibrated proportional valves facilitate the delivery of these rates. The objective is to perform each process ramp at gradual (linear) rates.

Both in the first part of the sterilization cycle (air removal) and in the final stage (sterilant removal), the safety of the facility and personnel are paramount issues. During the air-removal phase, the sterilizer is evacuated and then backfilled with nitrogen. After each vacuum/nitrogen sequence, a calculated amount of air is displaced. Depending on the depth of each vacuum and the final pressure achieved by the nitrogen addition, the process engineer must determine the minimum number of sequences necessary to bring the air content of the sterilizer atmosphere to a composition at which there is insufficient oxygen left to pilot a combustible reaction. EtO is flammable and can ignite in the presence of static electricity.2 It is, therefore, essential to know, prior to EtO injection, the volume percentage of air (%volair) left in the chamber before deciding upon the maximum amount of sterilant to be used. Later, when the volume percentages of air, of the inert gases (%volsteam and %volnitrogen), and of EtO (%volEtO) are known, they can be plotted on a flammability chart to confirm the nonflammability of the cycle.3

Following gas contact, the EtO must be displaced from the load and removed from the chamber. In planning this segment of the cycle, the same routine—postvacuums followed by nitrogen flushes—is followed. A volumetric calculation of the percentage of EtO left in the sterilizer after each vacuum/nitrogen sequence will determine when the level of EtO has been brought down to an acceptable level. Usually, after the final evacuation is performed, the sterilizer is backfilled with ambient air instead of nitrogen. In the final stage of the cycle, the sterilizer rear exhaust is activated while fresh air is allowed into the sterilizer either through a dedicated vent or by partially opening the door. Sufficient time must be allotted to flushing the sterilizer headspace so that the EtO concentration is brought to a safe level before the sterilizer is unloaded. Some workers wear industrial respirators with catalytic filter canisters rated for atmospheres containing not more than 50 ppm of EtO.

Flammability is not the only factor that determines the number of evacuations. In most cases, increasing the number of evacuations will also lower the EtO residuals left on the product, thus decreasing the amount of time the load must be quarantined for aeration. Although in this case "more is better," limitations are imposed by product and packaging tolerances as well as by equipment demands. A greater number of evacuations will subject the load to increased physical stress, which, when combined with EtO, heat, and humidity, could have a negative effect on product and packaging constructions such as, for example, glues or seals. Time spent for additional postvacuums also reduces the overall productivity of the sterilizer, which can affect facility profitability.

AIR REMOVAL

Before 100% EtO can be introduced into the sterilizer, the original air content (%volair = 100% of the initial sterilizer atmosphere) must be displaced and substituted with an inert gas such as nitrogen (N2). The physical parameters for the air-removal phase are determined by the tolerances of the most sensitive products or packaging (e.g., nonpermeable foil pouches or sealed cavities). If data are not available from the respective component or product manufacturers, they can be generated by conducting preliminary studies during which samples are exposed to different ramp rates (i.e., change in pressure per unit time) and vacuum set points. Each set of samples is then tested (both product and packaging) for conformity to original manufacturing specifications until the fastest permissible ramp rate and deepest acceptable evacuation set point are determined and recorded in the sterilization process design history record.

The initial pressure inside the sterilizer at the moment the door is closed is equivalent to atmospheric pressure (14.7 psia at sea level). The first evacuation will remove a quantifiable amount of air. For example, an initial evacuation from Pinitial = 14.7 psia to a depth of Pfinal = 7.35 psia will eliminate 50% of the original air content in the sterilizer. While the volume percentage of air is still 100%, the partial pressure of air is reduced in direct proportion to the pressure change:

The sterilizer is programmed to backfill with nitrogen to a set point of 14.7 psia. The resulting sterilizer atmosphere is now 50% air and 50% nitrogen. After this first vacuum/nitrogen sequence, the volume percentages of air and nitrogen are represented as:

After the second vacuum/nitrogen sequence, the amount of air in the sterilizer reduces again by half (%volair = 25%), while the nitrogen increases by half (%volnitrogen = 75%). This sequence is repeated as many times as necessary, until the %volair is reduced to a safe level.

Ethylene oxide requires oxygen to ignite. The term safe level is intended to mean that the air originally contained in the sterilizer at the beginning of the process has been reduced to the point that there remains insufficient oxygen to allow a reaction to occur should a source of ignition be available.4 Here it should be easy for the reader to see the relationship between the final set point of each vacuum/nitrogen sequence and the total number of sequences that will be required to render the cycle safe.

In selecting the ramp rates and set points for the vacuum/nitrogen sequences of an EtO process, there are various options. In general, a deep vacuum set point is preferred because it allows the air-removal process to be completed more efficiently. As stated earlier, determination of a maximum vacuum set point is a function of product/packaging tolerance as well as equipment limitations. Once the maximum ramp rate tolerances are determined for the vacuum and nitrogen sequences, the process engineer must decide what rate is best for the given product configuration. While the air-removal phase ensures that the sterilizer atmosphere is almost void of air, a consequence of these purges is loss of product moisture. The goal of process design is to displace air as efficiently as possible while minimizing load desiccation.

Deeper vacuums can complete air removal with fewer sequences. When dealing with a vacuum-resistant product, one vacuum from atmospheric (14.7 psia) to 2.0 psia, followed by a nitrogen backfill to 14.7 psia, will quickly reduce the %volair to 13.6% (Table I). Products that can withstand this rate and depth of vacuum will usually tolerate an equally rapid nitrogen injection. Fast ramp rates for nitrogen backfilling also minimize product-level moisture loss.

Process
Phase
Cycle
Segment
Set Point
(in. HgA)
Set Point
(psia)
Ramp Rate
(psi/min)
Segment
Time
(min)
Cumulative Cycle
Time
(min)
Cycle start 29.914.7N/AN/A0.0
Air removalEvacuation 14.12.01.0012.712.7
 Nitrogen purge 1 29.914.71.0012.725.4
 Evacuation 24.12.01.0012.738.1
HumidificationSteam injection6.33.10.0255.093.1
EtO injectEtO injection 17.98.80.2028.5121.6
 Nitrogen overlay 29.514.50.2028.5150.1
 Gas contact 29.514.50.00480.0630.1
EtO removalPostevacuation #14.12.01.0012.5642.6
 Nitrogen flush #129.914.71.0012.7655.3
 Postevacuation #24.12.01.0012.7668.0
 Nitrogen flush #2 29.914.71.0012.7680.7
 Postevacuation #34.12.01.0012.7693.4
 Final air inbleed 29.914.71.0012.7706.1
 Total cycle time (min)   706.1706.1


Process
Phase
Cycle
Segment
Partial
Pressure
Air (psi)
Partial
Pressure
Inerts (psi)
(nitrogen
and steam)
Partial
Pressure
EtO (psi)
Total
Partial
Pressures
(psia)
Cycle start 14.700.000.0014.70
Air removalEvacuation 12.000.000.002.00
 Nitrogen purge 12.0012.700.0014.70
 Evacuation 20.271.730.002.00
HumidificationSteam injection0.272.830.003.10
EtO injectEtO injection0.272.835.708.80
 Nitrogen overlay0.278.535.7014.50
 Gas contact0.278.535.7014.50
EtO removalPostevacuation #10.041.180.792.00
 Nitrogen flush #10.0413.880.7914.70
 Postevacuation #20.011.890.112.00
 Nitrogen flush #20.0114.590.1114.70
 Postevacuation #30.001.980.012.00
 Final air inbleed12.701.980.0114.70
 Total cycle time (min)    


Process
Phase
Cycle
Segment
%Volume
Air
%Volume
Inerts
(nitrogen
and steam)
%Volume
EtO
%Volume
Total
Cycle start 100.000.000.00100.00
Air removalEvacuation 1100.000.000.00100.00
 Nitrogen purge 1 13.6186.390.00100.00
 Evacuation 2 13.6186.390.00100.00
HumidificationSteam injection8.7891.220.00100.00
EtO injectEtO injection3.0932.1464.77100.00
 Nitrogen overlay1.8858.8139.31100.00
 Gas contact1.8858.8139.31100.00
EtO removalPostevacuation #11.8858.8139.31100.00
 Nitrogen flush #10.2694.405.35100.00
 Postevacuation #20.2694.405.35100.00
 Nitrogen flush #20.0399.240.73100.00
 Postevacuation #30.0399.240.73100.00
 Final air inbleed86.4013.500.10100.00
 Total cycle time (min)    


Table I. Process calculations for cycle 1—deep-vacuum type.

In the case of a vacuum-sensitive product, such as a kit containing multiple devices, the air-removal phase could require multiple slow vacuums—down to 7.0 psia, for example. The first vacuum/nitrogen sequence will only bring the %volair from 100% down to 47.62% (Table II). In this case, the process engineer must consider that the desiccating effect inherent in this process is further amplified. Multiple vacuum/nitrogen injections coupled with slow ramp rates mean that there is more time for moisture to be driven out of the load by the induced pressure gradient. Water becomes more volatile as temperature is increased and pressure is decreased. In these circumstances, one must begin the steam-injection phase as soon as possible in order to replace some of the moisture lost during the multiple slow-vacuum phases.

Process
Phase
Cycle
Segment
Set Point
(in.HgA)
Set Point
(psia)
Ramp Rate
(psi/min)
Segment
Time
(min)
Cumulative Cycle
Time
(min)
Cycle start 29.914.7N/AN/A0.0
Air removalEvacuation 114.37.00.2530.830.8
 Nitrogen purge 129.914.70.2530.861.6
 Evacuation 214.37.00.2530.892.4
 Nitrogen purge 229.914.70.2530.8123.2
 Evacuation 314.37.00.2530.8154.0
 Nitrogen purge 329.914.70.2530.8184.8
 Evacuation 414.37.00.2530.8215.6
 Nitrogen purge 429.914.70.2530.8246.4
 Evacuation 514.37.00.2530.8277.2
HumidificationSteam injection16.58.10.0255.0332.2
EtO injectEtO injection28.113.80.2028.5360.7
 Nitrogen overlay29.514.50.203.5364.2
 Gas contact29.514.50.00480.0844.2
EtO removalPostevacuation #114.37.00.2530.0874.2
 Nitrogen flush #129.914.70.2530.8905.0
 Postevacuation #214.37.00.2530.8935.8
 Nitrogen flush #229.914.70.2530.8966.6
 Postevacuation #314.37.00.2530.8997.4
 Nitrogen flush #329.914.70.2530.81028.2
 Postevacuation #414.37.00.2530.81059.0
 Nitrogen flush #429.914.70.2530.81089.8
 Postevacuation #514.37.00.3030.81120.6
 Final air inbleed29.914.70.2530.81151.4
 Total cycle time (min)   1151.41151.4


Process
Phase
Cycle
Segment
Partial
Pressure
Air (psi)
Partial
Pressure
Inerts (psi)
(nitrogen
and steam)
Partial
Pressure
EtO (psi)
Total
Partial
Pressures
(psia)
Cycle start 14.700.000.0014.70
Air removalEvacuation 17.000.000.007.00
 Nitrogen purge 17.700.0014.7047.62
 Evacuation 23.333.670.007.00
 Nitrogen purge 23.3311.370.0014.70
 Evacuation 31.595.410.007.00
 Nitrogen purge 31.5913.110.0014.70
 Evacuation 40.766.240.007.00
 Nitrogen purge 40.7613.940.0014.70
 Evacuation 50.366.640.007.00
HumidificationSteam injection0.367.740.008.10
EtO injectEtO injection0.367.745.7013.80
 Nitrogen overlay0.368.445.7014.50
 Gas contact0.368.445.7014.50
EtO removalPostevacuation #10.174.072.757.00
 Nitrogen flush #10.1711.772.7514.70
 Postevacuation #20.085.611.317.00
 Nitrogen flush #20.0813.311.3114.70
 Postevacuation #30.046.340.627.00
 Nitrogen flush #30.0414.040.6214.70
 Postevacuation #40.026.680.307.00
 Nitrogen flush #40.0214.380.3014.70
 Postevacuation #50.016.850.147.00
 Final air inbleed7.716.850.1414.70
 Total cycle time (min)    


Process
Phase
Cycle
Segment
%Volume
Air
%Volume
Inerts
(nitrogen
and steam)
%Volume
EtO
%Volume
Total
Cycle start 100.000.000.00100.00
Air removalEvacuation 1100.000.000.00100.00
 Nitrogen purge 152.380.00100.007.00
 Evacuation 247.6252.380.00100.00
 Nitrogen purge 222.6877.320.00100.00
 Evacuation 322.6877.320.00100.00
 Nitrogen purge 310.8089.200.00100.00
 Evacuation 410.8089.200.00100.00
 Nitrogen purge 45.1494.860.00100.00
 Evacuation 55.1494.860.00100.00
HumidificationSteam injection4.4495.560.00100.00
EtO injectEtO injection2.6156.0941.30100.00
 Nitrogen overlay2.4858.2139.31100.00
 Gas contact2.4858.2139.31100.00
EtO removalPostevacuation #12.4858.2139.31100.00
 Nitrogen flush #11.1880.1018.72100.00
 Postevacuation #21.1880.1018.72100.00
 Nitrogen flush #20.5690.528.91100.00
 Postevacuation #30.5690.528.91100.00
 Nitrogen flush #30.2795.494.24100.00
 Postevacuation #40.2795.494.24100.00
 Nitrogen flush #40.1397.852.02100.00
 Postevacuation #50.1397.852.02100.00
 Final air inbleed52.4446.600.96100.00
 Total cycle time (min)    


Table II. Process calculations for cycle 2—shallow-vacuum type.

A Practical Guide to ISO 10993-12: Sample Preparation and Reference Materials


ISO 10993

Critical to all types of biocompatibility studies, the methods for preparing device materials for testing are covered in this standard. Note: this is the continuation of an ongoing series of articles on ISO 10993. Last month's installment covered hemocompatibility.

Developed by the International Organization for Standardization (ISO), the set of standards known as ISO 10993 address the important issue of proving the safety of medical devices by identifying various types of biocompatibility tests. Because the method used for preparing device materials for testing is critical to each study, sample preparation and reference materials are covered in ISO 10993-12. The standard describes the types of test samples, suitable extraction vehicles and conditions, and appropriate reference materials to be used as controls. This article reviews the standard's requirements and recommendations in each of these areas.

TEST MATERIAL SELECTION

To ensure patient safety, the biological evaluation of medical devices must go beyond the testing of constituent materials. The goal of such testing programs is not only to confirm the safety of individual device materials but also to confirm that manufacturing steps will not compromise the biocompatibility of the device. Processing aids, mold release agents, lubricants, and other additives, as well as cleaning agents and sterilants, can have adverse effects if they contact the body; therefore, the samples used for testing must be selected to take these factors into account.

The standard recommends testing medical devices in their final product form and condition whenever possible, except for selected tests (e.g., implantation) that may require that individual materials be evaluated separately. If finished devices will not be available for testing, the evaluation of representative subcomponents of the device is acceptable in some cases. As a last option, representative samples of the formulated materials that have been preconditioned by the same processing steps as the final product should be tested. If the device is too large or cannot be tested as a whole for some other reason, each individual material having the potential of coming in contact with body tissues should be represented in the same proportion in the test sample as it is in the final product. In all cases, the standard requires that the samples be handled in such a manner as to avoid contamination.

PREPARATION OF EXTRACTS OF TEST MATERIALS

Medical device materials present a unique challenge to toxicologists, whose experiments usually involve chemical substances that can be delivered to a biological test system such as a cell culture in a measurable dose. Because devices are made of plastics, metals, and other solid materials, defining specific doses of the substances of interest is generally not possible. For most tests, the preparation of fluid extracts of the device materials is the most appropriate technique to provide test samples for determining the biological reactivity of possible chemical leachables (Figure 1).

Figure 1. A 50-ml extraction vial containing 60 cm2 of test article covered with 20 ml of minimal essential media for cytotoxicity testing.

According to the standard, the fluid used for extraction and the extraction conditions should be appropriate to the final device and its end use. It is critical that the various extraction media selected for testing represent the environments in which the final product will be used. Physiological saline and vegetable oil are usually sufficient to provide polar and nonpolar environments. The saline extracts water-soluble chemicals, while vegetable oil extracts lipid-soluble chemicals; both types of chemicals can be extracted by various fluids in the body. Depending on the nature and use of the device or requirements of a specific test method, other fluids also may be used as extractants provided that the effects of the fluids are known.

Extraction should be carried out at temperatures that are high enough to maximize the amount of extractable substances as well as to simulate the highest temperatures the device may be exposed to before or during use. However, extraction conditions should not cause deformation or degradation of the test or control articles. A number of specific acceptable extraction conditions are outlined in the standard, including 37ºC for 24 hours, 37ºC for 72 hours, 50ºC for 72 hours, 70ºC for 24 hours, and 121ºC for 1 hour.

For most test materials, extractions are performed under static conditions. However, agitation may be deemed appropriate as an effort to more closely mimic an end use or to ensure that the extraction media come in contact with all relevant device components. In any case, when agitation is considered appropriate, the method used should be documented.

Thickness
(mm)
Extraction ratioa
±10%
Examples of Material
0.5 6 cm2/ml Metal, synthetic polymer, ceramic, composite film, sheet, and tubing walls
>0.5 3 cm2/ml Metal, synthetic polymer, ceramic, composite tubing walls, slab, molded items
1.0 3 cm2/ml Natural elastomer
>1.0 1.25 cm2/ml Natural elastomer
Irregular 0.1–0.2 g/ml,
6 cm2/ml
Pellets
a Expressed as the ratio of the surface area or mass of the test sample to the volume of extractant used.

 

Table I. Suitable extraction ratios for test materials of various thicknesses. (Adapted from ISO 10993-12.)

The amount of test material used in the extraction process is usually expressed as a ratio of sample surface area to extractant volume or sample mass to extractant volume. Generally speaking, the surface area ratio should be used whenever possible, with a mass-to-volume ratio used only for the testing of irregularly shaped devices or representative device components. The extraction ratios specified in the standard are outlined in Table I. However, in some rare cases it may be necessary to deviate from these ratios and doing so is considered acceptable as long as the ratio of test material to extractant simulates or exaggerates the conditions that will be encountered during clinical use and the ratios used are documented in the test results.

The standard also notes that there are no standardized methods available for testing absorbents and hydrocolloids and suggests the following protocol. Using 2 g of the material as a test sample, determine the absorption capacity of the sample—that is, the amount of extractant absorbed by the material. The extract volume should then be 20 ml more than the sample's absorption capacity.

REFERENCE MATERIALS

In nearly every biocompatibility test, reference materials are used to serve as experimental controls. Negative controls, in the form of blanks, are used in most biological evaluations where test article extracts are prepared. The use of these blanks provides the basis for a comparison of the effects of the test material extract with a validated negative test result.

A number of materials have been used extensively in biological testing as negative or positive controls. High-density polyethylene, obtained from the U.S. Pharmacopeia, is a standard negative control. The nonreactive plastic can be implanted into living tissue and the results compared with those for a test material that has been similarly implanted. Likewise, a polyvinyl chloride formulation containing organotin additives serves well as a positive control.

CONCLUSION

ISO 10993-12: "Sample Preparation and Reference Materials" clearly indicates that it is preferable to evaluate medical devices in their final product form. The reasoning is simple—the biological testing must incorporate everything involved in making the device. Obviously, the constituent materials must be safe for patient contact; equally important to device biocompatibility are the processes and materials used during manufacturing. For most devices, the use of fluid extracts of the test materials prepared in a fashion to mimic or exaggerate the expected clinical conditions is the most appropriate technique for determining the potential effects of chemical leachables. Extraction fluid selection, extraction conditions, and material-to-extractant ratios are all outlined in the standard. The selection and use of appropriate experimental controls also is important in evaluating device materials for safety and is also covered in ISO 10993-12.

Timothy Jansen is acting manager of toxicology, California division, and Richard F. Wallin, DVM, PhD, is president of NAMSA (Northwood, OH).


Copyright ©1998 Medical Device & Diagnostic Industry

A company's devices aim to change the nature of Healthcare Delivery

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

An MD&DI December 1998 Column

SNAPSHOT

A 1995 inductee to the Chicagoland Entrepreneur Hall of Fame, K. Shan Padda was nominated, among other reasons, for having successfully launched his third start-up company by the tender age of 27. Before cofounding Sabratek Corp. (Niles, IL), Padda had already sold his interests in his first two companies to his partners after two and three years, respectively, and spent a year in China and Southeast Asia. Was he full of confidence, dreaming of new frontiers to conquer once he got home? Not exactly. The plain and simple truth is that he was bored.

K. Shan Padda found an industry that keeps him from being bored at work.

So what made Padda think that the third time would be the charm—let alone give him the confidence to summon the commitment of energy and time it takes to start a business? As he put it, at 27 he felt "too old to run a software company and too young to run a medical device company." Feeling at odds with his future, Padda realized that he was able to listen to what others needed and that he was creative and flexible in looking for new solutions. And that he wanted to help people.

So when they decided to tackle the concept of the virtual hospital room and attempt to change the face of long-term care, Padda and Sabratek cofounder Doron Levitas listened carefully. They learned that one reason why healthcare is so expensive is that 70% of the cost is for labor. The two men wanted to find a way to reduce the amount of labor necessary while maintaining the quality of care.

"The first year, we did nothing but run around to CEOs, healthcare providers, nurses, and doctors, and asked them to put aside any perceived limitations and to simply tell us what they really need," says Padda. "We wanted to recreate all the functions of a hospital, where medical personnel interact with patients, oversee complex therapies, ensure patient compliance, make sure the therapies are not killing the patients, and monitor how the therapy is affecting the underlying disease state."

Sabratek's aim is to create devices that are "perceptive" and "intelligent" but also user-friendly. Examples of such devices include stationary and ambulatory infusion pumps with multiple-language capabilities and remote communications and preprogramming abilities. A Sabratek software system oversees the remote programming, monitoring, data capture, and reporting that the infusion pumps undertake, and a portable, automatic diagnostic tool performs on-site testing of the infusion devices.

These devices can be linked via intranet to monitoring stations where a patient's status can be closely monitored without someone having to physically spend time visiting them for routine checkups. This frees up medical personnel and also provides patients with some independence and ability to move away from a hospital setting into an alternative-care site or even back home.

"A technophobe can use these devices," insists Padda, "so there is a high patient-compliance rate. The stuff we're developing is pretty cool technically. I like to interface with R&D, and I like thinking that something I'm doing is improving the quality of life for people."

Padda says that the biggest obstacle he faced while getting Sabratek up and running was that the company was trying to "fundamentally change the way healthcare is delivered. It was a challenge to get the marketplace comfortable with using technology to make the process more cost-effective. Change is difficult, because we all want to keep doing what we're used to. You have to look at and challenge all assumptions."

The other major problem for the small, unknown company was competing against giants such as Baxter and Abbott. Sabratek struggled with its initial finances with only the aid of a few small venture funds and some high-worth individuals. The only big corporate sponsor it managed to woo was Blue Cross/Blue Shield. "We were too stubborn—or stupid—to give up," Padda says with a chuckle. "Basically, everybody had written us off. You know it's bad when your mother asks you why you're continuing to do something."

Those days are long gone. In 1996, Sabratek went public and has continued to grow. However, Padda has been around the block too many times to take his success for granted. He knows that the company must continually reinvent itself to meet the demands of the industry.

Sabratek is full of hard-working, committed people, Padda explains. One reason is that most of them have stock options: "Everyone is focused on providing value to the customer. If something isn't successful, I want 500 people in addition to me who aren't sleeping well at night.

"Life is meant to be a constant, interesting challenge," he says. "The only credit we deserve is that we went out and executed the customer's wish list. We gave the marketplace what it was asking for."

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


Copyright ©1998 Medical Device & Diagnostic Industry