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Articles from 1996 In July


An Introduction to Rapid Prototyping

Medical Plastics and Biomaterials Magazine | MPB Article Index

Originally published July 1996

PROTOTYPING

TOM MUELLER

In January 1988, the first rapid prototyping system was installed at Baxter Healthcare for use in the development of medical devices. Now, eight years later, approximately 1500 systems have been installed worldwide, and an entire new industry has arisen to provide rapid prototyping services to industrial customers. Virtually every engineer involved in the development of mechanical components has a working knowledge of several systems, and many actively use rapid prototyping in the development of their products. This article, the first of two, will discuss the reasons for prototyping, present a brief overview of the available systems, and offer some considerations regarding the decision of whether to purchase a system or buy services from a service bureau. A subsequent article will cover the prototyping of injection-molded parts, the process of urethane casting, and the creation of prototype tooling.

THE COST OF DESIGN ERRORS

There are two primary reasons for prototyping a new product design. The first is to verify design adequacy—to ensure that the design will meet the requirements of the product. The second reason, less well recognized, is to identify design errors and problems as early as possible in the design process. The later in the development process design errors are discovered, the greater the cost to correct them. The price tag associated with correcting design errors after work on the tool has begun can be staggering. Elements of that cost can include tool rework, shorter tool life, late delivery of product, reduced design flexibility, and loss of goodwill within the production team.

Tool Rework. The most obvious cost is rework of the tool in order to correct the design errors. Discussions with several tool builders indicate that the expense of rework averages 10% of the cost of the tool, although actual cost varies with the extent of the changes made. Furthermore, 75% of all tools built come back for rework. The implications of these numbers are significant: on average, for every single project, companies spend 7.5% of the cost of the tool on changes made after the tool is begun. Given the cost of tooling, this can amount to several thousand dollars per part.

Shorter Tool Life. Every time a tool is reworked, its life decreases. Welding, annealing, and repeat heat-treating all reduce the integrity of the tool and the number of shots available before it must be replaced. Considering that 75% of all tools must be reworked, an average tool-life reduction of only 3% adds 2.25% of the cost of the tool to every development project.

Late Delivery of Product. In most cases, the additional time required to redesign and rework a tool will result in a late product introduction. At a minimum, a three-month delay in introducing the product represents three months of lost sales. However, the true loss is usually higher: if a product is late to market, it will ultimately garner a lower market share than if it had been delivered on time. A leading management-consulting firm concluded in a study that if a medical product is six months late to market, the total profits generated by it will be reduced by one-third. Obviously, this can represent a potential loss of millions of dollars.

Reduced Design Flexibility. One consequence of late rework not often recognized is that if a company discovers a design error after work on a tool has begun, it typically will only consider design changes that allow it to salvage the tool; changes that would require scrapping it will not be considered. The result is that the final version is a compromise design, not the best design—a liability affecting the quality of the part that goes to market.

Lost Goodwill. When a product must be reworked, goodwill is lost, regardless of whether the fault lies with the manufacturer, the tool builder, the molder, or some other processor. As a result, the chances of the same team of players working again on future projects is significantly diminished. A cohesive group working together on successive projects can learn how to be more efficient, reducing costs and lead times; a new team starts over again.

How can the tremendous costs accompanying late design changes be avoided? Arguably, the best way is to prototype the design before the tool is ordered. Critics maintain that prototyping only delays getting a product to market. However, the time and cost of correcting a faulty design far outweighs the time and cost of the prototyping process. In this sense, prototyping can be viewed as product development insurance—a way to minimize the downside effects of design errors.

New rapid prototyping methods introduced in the last few years have provided a means of creating prototypes faster than was previously possible, to the point where prototyping can often proceed concurrently with tooling acquisition. The first few weeks of ordering a new tool typically involve specifying the steel and preliminary configuration before any machining of cavity or core surfaces takes place. Rapid prototyping methods can now be used to complete the prototyping process during this period, so that any design errors found can be corrected without rework costs and without delaying the development process.

RAPID PROTOTYPING METHODS

There are currently nine rapid prototyping methods commercially available in the United States. These technologies share several common characteristics:

  • All build parts directly from a computer model, with no machining or tooling required.
  • All use a file structure called an .STL file as a starting point. The .STL file is a faceted representation of the exterior surfaces of the part and can be created by most major CAD systems. It does require a complete three-dimensional representation of the design to start with; a two-dimensional CAD file is not adequate.
  • All work by building the part in a succession of thin layers, each usually a few thousandths of an inch thick. Calculating these successive layers or cross sections is an integral aspect of the specific process and is controlled by software supplied by the manufacturer of that process.

Each of the methods will create reasonably accurate representations of a design directly from a CAD model. The systems do vary widely, however, in a number of areas, including the material used; the manner in which the layers are created; the size and accuracy of the part that can be built; the strength, surface finish, and functionality of the resulting model; and the ability of the model to be used as a pattern for a subsequent process such as urethane casting or investment casting. Which of the processes is best for a particular application will depend on the requirements of the prototype. Table I provides a short summary of each system.

THE MAKE-OR-BUY DECISION

As it does with many components or services, a company that needs rapid prototyping initially faces a "make-or-buy" decision. There are a wide variety of systems available, ranging in price from about $40,000 to well over $500,000. Whether it makes sense to purchase a system will depend on a number of factors:

  • Obviously, the higher a company's volume of prototyping, the easier it is to justify the purchase of a system. The break-even point depends on the purchase price of the system. However, if requirements are for 10 or fewer parts a month, it will be difficult to justify the purchase even of a low-end system.
  • Because each of the rapid prototyping systems works from a complete three-dimensional CAD model, a certain operator proficiency level is assumed. If a company does not routinely use solid modeling, it probably should not consider a system purchase.
  • If the rationale behind the prototyping is to create simple model parts to be used to illustrate new designs and convey ideas, any of the systems can be used. Creating functional prototypes, however, requires one of the more expensive, higher-end systems as well as shop support for operations such as mold making and part finishing.

The alternative to purchasing a system is to contract out with a service bureau—a company in the business of providing rapid prototyping services to industrial customers. Working with service bureaus has several advantages. By using different bureaus for different applications, a client can take advantage of the various rapid prototyping processes, choosing the best method for a particular job. In addition, most service bureaus have developed extensive experience in certain applications, and can greatly increase the chances of success in those types of projects. On the other hand, a manufacturer working with a service bureau cannot prioritize projects to the same extent as it can with its own equipment.

CHOOSING A SERVICE BUREAU

There are now more than 125 rapid prototyping service bureaus in the United States, and more than 230 worldwide.1 However, not all service bureaus may be capable of meeting a company's prototyping needs. Following are some of the questions a manufacturer might want to ask prospective service bureaus to help narrow the field:

  • What type of rapid prototyping process do you use? Of the nine current technologies, some have significant size limitations, others may not be accurate enough to make models that can serve as patterns. The service bureau should be able to describe the type of equipment used and explain how applicable it will be for a particular project.
  • Do you have the equipment yourself or are you subcontracting the work to another firm? A number of companies selling rapid prototyping services do not own equipment, but rather subcontract the work to other firms. Although they may be able to provide excellent parts, questions can arise about who is responsible should problems occur. In addition, it is generally more expensive to deal with a bureau that subcontracts compared with one that makes the prototypes itself.
  • How long have you been providing services? Operating virtually any rapid prototyping system requires substantial experience before quality parts can be reliably and consistently produced. If a service bureau received its equipment two weeks ago, the chances are minimal that it can make parts of the same quality as can a company that has been using the equipment for several years.
  • Can you handle our CAD data? Most service bureaus can handle a variety of CAD formats, but any incompatibility can add considerable time and expense to a project. If a customer can supply data in .STL format, there should be no problem; if it can't, the customer must make sure the service bureau can handle the data without having to remodel the geometry in its system.
  • Can you provide customer references? When asked by a new client, any reputable service bureau will gladly provide the names of customers for whom it has completed similar projects. If it declines to provide the information, it is likely that the bureau has little experience with the type of job requested.

CONCLUSION

Few markets can match the pace of technological innovation now occurring in the medical device industry. The benefits offered by rapid prototyping respond directly to the importance the industry places on research and development and to its critical need to bring products to market quickly. The second article in this series will describe some of the specific ways in which prototyping is currently being used to improve the development of medical products.

REFERENCE

1. Published sources for locating rapid prototyping service bureaus include the Rapid Prototyping Directory (CAD/CAM Publishing, Inc., San Diego); the Thomas Register (Thomas Publishing Co., New York City); and the MPMN Buyers Guide: The Medical Product Designer's Sourcebook (Canon Communications, Inc., Santa Monica, CA).

Tom Mueller is a founder and vice president of Prototype Express (Schaumburg, IL)—a rapid prototyping service bureau—where he is responsible primarily for sales and marketing. Prior to joining the company, he was manager of computer-aided engineering at Baxter Healthcare, and presided over the installation and operation of Baxter's stereolithography department.

Polycarbonate Stabilization during High-Energy Irradiation

Medical Plastics and Biomaterials Magazine | MPB Article Index

Originally published July 1996

CHARLES LUNDY

The growing popularity of high-energy sterilization of medical devices has necessitated the development of a radiation-stable polycarbonate (PC). Since 1986, several PC producers have added radiation-stable formulations to their medical product lines. The current practice in the stabilization of gamma- or electron beam­sterilized PC uses a polypropylene-glycol (PPG) derivative added to the PC in concentrations of less than 1%. It is generally believed that PPG derivatives act as radical scavengers, reducing the number of radical reactions that occur along the backbone of irradiated PC. Recent evidence shows that the addition of compounds thought to act as electron scavengers dramatically enhances PC radiation resistance. Of particular interest is that the combination of this second group of additives with PPG derivatives synergistically reduces the yellowness index (YI) of PC after radiation exposure. The goals of this article are to more fully explicate the nature of radiation stabilization in PC and to develop a model that explains the differences in stabilization efficiency between compounds considered radical scavengers and those thought to be electron scavengers.

BACKGROUND

Before discussing the effects of different additives on the radiation stability of polycarbonate, it is first necessary to describe what happens to a PC component during radiation exposure. Current consensus holds that an electron emitted from a gamma source or electron generator interacts with a host molecule such as PC, causing ejection of a lower-energy electron from an impacted chemical substituent into the polycarbonate matrix. (The mechanism is very complex, and depends greatly on which chemical substituents are impacted.) As the electron passes through the PC substrate, it impacts other PC molecules, forming local ionization clusters that relax into radicals. These radicals recombine, chain transfer, or are quenched into a stable product by oxygen or by other radical scavengers present in the matrix.

The end result of these various termination reactions is to produce a large variety of color bodies in the PC, inducing a characteristic discoloration in the part (see Figure 1). After irradiation, PC rapidly photobleaches from a dark yellow-brown material (indicative of charged or radical species), reverting to its original color in a process lasting 3 to 4 weeks. Ultraviolet light and heat help speed this reversion effect. (Figures not yet available on-line.)

Entrapped within the PC matrix, radicals formed during irradiation can survive for several weeks before being terminated. Unlike polytetrafluoroethylene, polypropyl-ene, or polymethylmethacrylates, the physical properties of PC remain virtually unchanged after low doses (<10 Mrd) of radiation.1 This occurs despite the relatively large chemical transformations and extremely long lifetimes of reactive species in PC.

Although we have learned a considerable amount about the effects of high-energy radiation on polymer degradation, much less is known about stabilization techniques, in particular PC stabilization.2 The best known and most effective method of stabilizing polymers is through the incorporation of radical scavengers such as aromatic hindered amines, phenols, and thiols.3,4 These compounds are normally capable of generating a large number of hydrogen radicals, which terminate radicals produced in the polymer and thus prevent further oxidation. PPG is another example of a radical scavenger, producing hydrogen radicals that terminate radical sites along the PC backbone.5,6 Figure 2 shows the mechanism by which hydrogen radicals are formed in PPG. The effect on YI of adding a PPG derivative to PC after gamma radiation is shown in Figure 3.

Whereas PPG is a radical scavenger, some compounds act as electron scavengers. Upon colliding with a high- energy electron, these substances typically degenerate into radical/ion pairs.

Such compounds are, by their nature, capable of dissociative electron attachment (DEA).7 This mechanism reduces the energy of the primary and secondary electrons, and can thereby reduce the damage caused by radiation in polymers like PC. Research showing that brominated aromatic compounds possess electron-scavenging properties was done as early as the 1950s.

The combination of both electron and radical scavengers in PC produces a synergistic protective effect. Although electron scavengers help stabilize a host polymer through DEA, they nevertheless cannot prevent the formation of radicals within the polymer matrix. These radicals must still be terminated with the help of radical scavengers. The electron scavengers can be thought of as accelerators of radiation decomposition, acting in unison with free- radical stabilizers.

EXPERIMENTAL

All compositions were extruded and molded under standard PC-processing conditions. The molecular weight of the PC used was nominally 28,000 g/mole. Injection-molded chips measuring 3 x 2 x 1/8 in. were irradiated to 3.5 Mrd by a cobalt 60 source. The YI was determined before radiation, 3 hours after radiation, and 10 days after radiation, as directed by ASTM D 1925. All YI values were determined for color chips that had been stored in the dark.

RESULTS AND DISCUSSION

Brominated Compounds. The study investigated the effect of brominated aromatic compounds as stabilizers in PC. We particularly wanted to discover whether a higher degree of substitution of bromine would improve the stability of the subsequent PC formulation. The additives looked at were tetra-bromo-bisphenol A-oligocarbonate (TOBC) and tetra-bromo-phthalic anhydride (TBPA), added in concentrations of 1% to unstabilized PC. As shown in Figure 4, both the TBOC/PPG system and compositions containing TBPA yielded excellent benefits in terms of the total shift in color (delta YI), defined as the difference between YI before and 10 days after radiation (the standard induction time). The TBPA gave significantly better results than TBOC, which can be attributed to its more highly brominated nature.

An examination of the rate at which color reversal occurs (photobleaching effect) in the different compositions studied reveals a stark difference between the additives (see Figure 5). Table I lists the additives and their relative photobleaching constant delta YI/delta T, defined as the change in yellowness index over time. TBPA derivatives have a much lower initial color after radiation--that is, a lower rate constant for color return after radiation. In comparison, TBOC has a higher initial color and higher color- return rate constant. The data for the brominated compounds suggest that a higher degree of substitution yields a better stabilization effect, following the order 4°>3°>2°>1°.

Radical concentration was monitored by electron spin resonance to determine the effect of bromine concentration on radical reduction. Because bromine is an electron scavenger, it should reduce the amount of radicals formed in subsequent reactions. Table II shows the results after 3.5-Mrd irradiation.

Tables I and II illustrate the significant stabilizing effect of the bromine compounds, with the more highly brominated formulations exhibiting the strongest effect. With both TBOC and TPBA, one can easily see the synergism between the brominated species material and PPG. Highly brominated aromatic compounds clearly act as efficient radiation stabilizers, particularly when used in combination with PPG.

Nonhalogenated Stabilizers. Although brominated aromatic compounds are effective as gamma-radiation stabilizers, questions about their safety have been raised: these compounds have the potential to form carcinogenic aromatic dioxins, both thermally and photochemically. For this reason, we directed our research toward the development of halogen-free radiation stabilizers.

We investigated a number of halogen-free aromatic compounds, based on their ability to form a stable radical/anion pair in the manner of aromatic bromine compounds. As mentioned, brominated compounds are thought to be effective as stabilizers because of their ability to undergo DEA or, more simply, their ability to form radical/anion pairs. This behavior normally can occur only with compounds capable of absorbing an electron--compounds with low-lying orbitals that exhibit thermodynamically favorable anion formation.8

In the course of our investigations, we have found a new class of materials that are nonhalogenated compounds capable of DEA, and therefore able to act as electron scavengers. Figure 6 shows the stabilizing effect of an aromatic disulfide (ADS) compared with that of the brominated electron scavengers TBOC and TBPA. ADS compounds equal the efficiency of tetra-substituted brominated aromatic compounds such as TBPA derivatives, and exceed the performance of di-substituted aromatics such as TBOC.

As do brominated compounds, this new class of materials seems to work most effectively in the presence of a radical scavenger such as PPG. The YI results given in Figure 7 illustrate the stabilization effects in gamma-irradiated (3 Mrd) PC of ADS compared with TBOC, both with and without PPG. The graph indicates that the synergistic effects of the different electron scavengers with PPG are very similar.

CONCLUSION

Radiation stabilizers for polycarbonate appear to be either free-radical scavengers or electron scavengers. Results of this study point to a synergistic effect when the two types of stabilizers are combined in PC. Electron scavengers are molecules with thermodynamically favorable anion/radical pairs that react with primary or secondary electrons during irradiation. Radical scavengers react with radicals produced along the polymer chain after irradiation. Combining the two can yield polycarbonate formulations that undergo virtually no yellowing after gamma or electron-beam radiation. Although brominated aromatic compounds are effective stabilizers, a new class of nonbrominated materials has proven equally effective in scavenging radiation in PC.

ACKNOWLEDGMENTS

The author wishes to express his sincere appreciation to Sivaram Krishnan, PhD; Rick Archey; and Douglas Powell, PhD, who made significant scientific contributions to this work.

REFERENCES

1. Encyclopedia of Polymer Science & Engineering, vol 13, New York, Wiley, p 686, 1988.

2. Encyclopedia of Polymer Science & Engineering, vol 13, New York, Wiley, p 667, 1988.

3. Encyclopedia of Polymer Science & Engineering, vol 13, New York, Wiley, p 695, 1988.

4. Dole M, The Radiation Chemistry of Macromolecules, vol 1, New York, Academic Press, 1973.

5. Archie et al., U.S. Pat. 5,187,211.

6. Jorissen et al., U.S. Pat. 5,006,572.

7. Dole M, The Radiation Chemistry of Macromolecules, vol 1, New York, Academic Press, 1973.

8. Trans Faraday Soc, 61:1960, 1965.

Charles Lundy, PhD, is currently vice president and general manager at Floralife, Inc. (Walterboro, SC). From 1986 to 1994 he worked in various research and marketing positions at Mobay/Miles, Inc. (Pittsburgh) and Bayer AG (Leverkusen, Germany).

Helpful Design Guidance, or Stealth Regulation?

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published July 1996

Last March, FDA released two important draft guidances on design, entitled "Design Control Guidance for Medical Device Manufacturers" and "Do It by Design." These are both important documents that everyone involved in device design should read, in part because they clarify FDA's expectations, but more significantly because they both offer useful guidance.

With things as they are, FDA would be challenged to release instructions on tying your shoes without becoming enmeshed in controversy. Unfortunately, the release of the design guidances has generated a lot of negative publicity without much attention to the truly helpful aspects of these documents.

In part, this is FDA's fault. In the Federal Register notice announcing the release of the drafts, the agency stressed that they do not "bind FDA or device manufacturers in any way." But this one statement is not enough. Fear that guidances are really stealth regulations is perennial in the industry. It's no surprise that the Health Industry Manufacturers Association should find the design control guidance "extremely prescriptive." No doubt a majority of industry shares HIMA's suspicion that FDA hopes to "use the guidance document as a means to include details that it was unable to write into the regulation."

Given this climate, FDA would do well to take HIMA's suggestion that it include a disclaimer in the design control guidance itself, stating that the recommendations are nonbinding and are not adjunct regulations. But beyond this, the agency would be well advised to recast the somewhat intimidating regulatory style of the design control guidance into the less intimidating, more readable approach of "Do It by Design." Not only would this change help dispel fear of closet regulations, but it would also make the valuable information in the guidance more widely accessible.

For the fact is, both of these guidances are extremely helpful. In producing them, FDA deserves great credit along with the inevitable criticism.

Anyone mystified by the handful of paragraphs on design control in the forthcoming revised GMP regulation will find the design control guidance a good starting point for enlightenment. The 35-page document comprises 11 explanatory sections keyed both to paragraphs of the new GMP and to subclauses of ISO 9001. The draft has its share of mistakes (such as calling the design history file a device history file), but these will doubtless be corrected in the final version.

To my mind, "Do It by Design" is an even more impressive document. Unlike the huge majority of government documents, this primer on human factors engineering is well written and easy to read. In its 53 pages, it offers an introduction to usability engineering, a comprehensive overview of issues involving the user interface of devices, and a helpful discussion of ways to conduct usability engineering in your company.

The final versions of these guidance documents are due to be released late this summer. If you have anything to do with device design, I urge you to get copies. They will be available from FDA as well as from Canon Communications, publisher of MD&DI magazine. For more information, feel free to call me at 310/392-5509 or E-mail me at john.bethune@cancom.com.

John Bethune

Low-Protein-Adsorption Biomaterials from Polymer Blends

Medical Plastics and Biomaterials Magazine | MPB Article Index

Originally published July 1996

Y. SAMUEL DING, CHUAN QIN, AND BARRETT E. RABINOW

Over the past few decades, the study of protein-resistant materials has been a very active field of research.1­18 Investigators have expended a great deal of energy in the attempt to minimize protein adsorption on biomaterial surfaces. The intensity of this effort reflects the importance of a wide range of blood-contacting devices for uses that include antithrombus applications, coatings to reduce biofouling, separation membranes, protein-drug-contacting materials, and immunoassays. Among the effective protein-resistant materials that have been studied are water-soluble polymers such as poly(ethylene oxide) (PEO), polyvinyl alcohol (PVA), and poly(vinyl pyrrolidone) (PVP). The mechanism by which these types of materials prevent protein adsorption has been explained as a combination of the steric stabilization effect, unique solution properties, and the particular molecular conformation in the aqueous solution. The steric repulsion resulting from osmotic pressure and elastic restoring forces competing with the van der Waal's attraction between water-soluble polymers and proteins determines the protein-adsorption process.

Because of their intrinsic nature, these water-soluble polymers cannot be used for direct water-contact applications by themselves. Most researchers involved in immobilizing water-soluble polymers--especially PEO--have resorted to chemical or chemical-physical modifications. Such measures have included covalent grafting, coating of PEO-containing block copolymeric surfactants, block copolymerization, inducing physical interpenetrating surface networks by solution swelling, and synthesizing PEO-containing interpenetrating networks.

In theory, the best way to immobilize water-soluble polymers permanently onto a surface is by covalent bonding processes, but such methods are generally difficult and too costly for commercialization. One alternative involves melt blending of the water-soluble polymer into the base polymer, accompanied by shear processing to drive the water-soluble polymer towards the surface. This technique will be much easier and more economical than covalent bonding, provided that the resulting surface modification can be made sufficiently permanent. In the present article, we provide examples of melt-blended materials that have achieved permanent hydrophilic surfaces, and discuss the factors that control the performance of melt-blended formulations.

EXPERIMENTAL

Materials. Several water-soluble polymers were used as surface modifiers in this study, including PEO (Aldrich Chemicals, five different grades with Mw of about 3400, 10,000, 100,000, 900,000, and 5,000,000); poly(ethyl oxazaline) (PEOX; Dow Chemical, Mw of about 500,000); PVA (Aldrich, 89% hydrolyzed, Mw from 13,000 to 23,000); and PNVP (Aldrich, Mw of about 40,000). The base polymers included ethylene-vinyl acetate copolymer (EVA; EU648, Quantum Chemicals); polypropylene (23M2C, Rexene Corp.); poly(methyl methacrylate) (CP-82, ICI Acrylic); styrene-butadiene copolymer (DR-03, Phillips); polyamide (Nylon-12 and L-20, EMS America Grilon); and polycarbonate (Makrolon, Bayer).

Testing. Procedures employed to evaluate the effectiveness of surface modification included contact-angle measurement, surface-protein-adsorption measurement, and long-term-leaching testing.

Contact-angle measurement--which assesses wettability--was used as the primary screening method to determine the effectiveness of surface modification. Contact angle was measured after the samples had been soaked in water from time zero up to one month, in order to monitor any changes in the specimens' surface hydrophilicity. A Wilhemy-Plate Tensiometric method with a Cahn Electrobalance and an LVDT was used to measure the receding contact angle between the sample films and an HPLC-grade water column.

We performed direct analysis of surface-protein adsorption according to a modified Micro-BCA method.18 After equilibrating the polymer films with different concentrations (for example, 2.5 ppm) of IgG solution for at least 18 hours, we rinsed the film with distilled water to remove loose protein and measured the level of surface-bound protein.

Film samples were stored in 40°C water for up to 48 days and monitored for organic leachables in the solution. This was done in order to prove that the achieved hydrophilic surface was permanent, and not simply due to continuous migration of water-soluble polymers towards the surface to replenish the lost, loosely bound polymers.

RESULTS AND DISCUSSION

Polymer blends based on different base polymers and water-soluble polymers at various blend ratios were tested for their contact angles in water. Figure 1 shows the contact angles of the EVA blends with water-soluble polymers such as PEO, PVA, PNVP, and PEOX. It is clear that the water-soluble, polymer-modified EVA surfaces are more hydrophilic than the base EVA. Among the four water-soluble polymers, we observed two types of performance. The use of PEO resulted in only a very small improvement in the EVA's surface hydrophilicity, and the change was almost independent of the level of PEO. This indicates that PEO is not an effective surface modifier for the EVA base polymer.

The other three water-soluble polymers--PVA, PEOX, and PNVP--formed a second group. At concentrations of merely 2 to 5 weight percent, their presence caused dramatic improvement in the hydrophilicity of EVA surfaces. It is also interesting to note that these three water-soluble polymers exhibited similar contact angles when added at similar levels in the blends.

Long-term leaching with water was used to assess whether the surface modification could be the result of the migration of water-soluble polymers towards the surface to replenish the lost modifier. Figure 2 shows the organic leachables detected in the aqueous solution, after the films were soaked for 48 days at 40°C. In comparison with the EVA control, we observed slight increases in the leachables level in the PVA, PNVP, and PEOX systems. In each case, the leached amount was insignificant compared with the total amount of water-soluble polymer in the formulation. However, in the PEO system, we saw a more dramatic increase in leachables, indicating that PEO was very mobile and loosely anchored on the EVA surface and could be easily leached out into the aqueous solution. This explained why PEO could not effectively modify the EVA surface, as shown in Figure 1. (Figures not yet available on-line.)

Once we had succeeded in improving hydrophilicity by adding some water-soluble polymers into the base polymers, we then needed to prove that the enhanced surface also brought about reduced protein adsorption. Results of surface-protein adsorption based on a modified Micro-BCA assay were plotted against the contact angle for the EVA/PVA system, as shown in Figure 3. For this blend, we observed good correlation between the contact angle and the level of protein adsorption. Since a reduction of contact angle indicates improved surface coverage by the water-soluble polymers, it is not surprising to see a correspondingly reduced protein adsorption, given that the water-soluble polymer adsorbs less protein than the base polymer. Similar correlations can be drawn for each water-soluble polymer/base polymer pair.

As discussed, the PEO/EVA system did not successfully improve the surface hydrophilicity, and the subsequent leaching test also showed the inability of the material to hold the PEO additives on the surface. One might suppose that the molecular weight of the PEO could potentially affect the permanency of its surface anchoring. However, we did not find this to be the case, as illustrated in Figure 4, which shows the effect that increasing the molecular weight of PEO had on contact angle. As can be seen, there was practically no difference in contact angle through a wide molecular-weight range.

Figure 5 depicts a schematic of the melt-blending process for achieving surface modification. The water-soluble polymer, which is partially exposed and partially anchored in the matrix, will swell upon exposure to aqueous solutions. The swelling of the exposed chain will exert some pulling force on the anchored segment, which adds to the force generated by the tendency of the water-soluble polymer to migrate into the aqueous phase and dissolve into the solution. The permanency of the anchored water-soluble polymer on the surface of the base polymer depends on the ability of the embedded water-soluble polymer chains to resist the pull force from the exposed swollen segment. In the case of the PEO/EVA blend--where there was little anchoring force to prevent polymer-chain migration--the increase in molecular weight may have slowed down the migration process slightly, but apparently not enough to achieve sufficient permanency.

Reexamination of the data in Figure 1 led us to an interesting observation. The polymers that successfully modified the EVA surface have a glass-transition temperature (Tg) higher than room temperature, whereas the one that failed--that is, PEO--has a Tg far below room temperature. This suggests that reducing mobility or increasing chain friction through the selection of higher-Tg water- soluble polymers could provide the anchored chains with sufficient stability to stay on the polymer surface. Similarly, using a base polymer with a higher Tg could also be a promising method of anchoring the water-soluble polymers.

Figure 6 shows the contact-angle results of PEO blended with various base polymers. Among these base polymers, only the EVA could not hold the PEO onto the surface. The Tg of EVA is approximately room temperature, and the material apparently is too mobile to hold the already very mobile PEO chains. The other polymers, which all have higher Tgs, show strong indications of surface modification with the addition of PEO. These data clearly suggest that a high-Tg matrix will be able to hold the anchored water-soluble polymers in the aqueous environment.

In Figure 7, we compiled the protein-adsorption data of different combinations of water-soluble and base polymers. The results indicate that when either the water-soluble polymer or the base polymer has a Tg higher than room temperature, the surface properties show significant improvement. That is to say, we can modify a base-polymer surface through melt blending simply by ensuring that the Tg of either the base polymer or the modifier polymer is higher than the temperature of the intended application.

The approach described above can be used to reduce protein loss by adsorption that occurs in medical containers, as illustrated in Figure 8. When storing a 2.5-ppm concentration of human IgG protein solution, containers made of polypropylene, polyethylene, EVA, or plasticized PVC will lose 30% of the protein to the surface due to adsorption. Containers made of EVA modified with PVA, however, demonstrate a five- to tenfold reduction in protein loss. The difference can have a significant therapeutic impact on patients and represents substantial cost benefits for this type of expensive, genetically engineered drug.

CONCLUSION

This study demonstrates that a melt-blending method using water-soluble polymer additives can be employed to prepare hydrophilic surfaces. We further determined that increasing the molecular weight of the water-soluble polymer is not sufficient to ensure the durability of the surface modification. Rather, the glass-transition temperatures of both the base polymer and the water-soluble polymer were found to be most important, and should be higher than the end-use temperature.

REFERENCES

1. Brinkman E, Poot A, van der Dose L, et al., Biomaterials, 11:200, 1990.

2. Desai NP, and Hubbell JA, J Biomed Mater Res, 25:829, 1991.

3. Desai NP, and Hubbell JA, in Proceedings of the ACS Division of Polymer Materials: Science and Engineering, 62:731, 1990.

4. Mori Y, Nagaoka S, Kikuchi T, et al., Trans Am Soc Artif Intern Organs, 28:459, 1982.

5. Chisato N, Park KD, Okano T, et al., Trans Am Soc Artif Intern Organs, 35:357, 1989.

6. Nagaoka S, and Nakao A, Biomaterials, 11:119, 1990.

7. Gombotz WR, Guanghui W, and Hoffman AS, J Appl Polym Sci, 37:91, 1989.

8. Sefton MV, Llanos G, and Ip WP, in Proceedings of the ACS Division of Polymer Materials: Science and Engineering, 62:741, 1990.

9. Lee JH, Kopecek J, and Andrade JD, J Biomed Mater Res, 23:351, 1989.

10. Maechling-Strasser C, Dejardin P, Galin JC, et al., J Biomed Mater Res, 23:1385, 1989.

11. Merrill EW, Salzman EW, Wan S, et al., Trans Am Soc Artif Intern Organs, 28:482, 1982.

12. Hunter SK, Gregonis DE, Coleman DL, et al., Trans Am Soc Artif Intern Organs, 29:250, 1983.

13. Garinger DW, Nojiri C, Okano T, et al., J Biomat Mater Res, 23:979, 1989.

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15. Desai NP, and Hubbell JA, Macromolecules, 25:226, 1992.

16. Mukae K, Bae YH, Okano T, et al., Polym J, 22:250, 1990.

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18. Rabinow BE, Ding YS, Qin C, et al., J Biomater Sci Polymer Edn, 6:91, 1994.

Y. Samuel Ding, PhD, is a senior engineering specialist at the Medical Materials Technology Center of Baxter Healthcare Corp. (Round Lake, IL), where he specializes in developing biomedical polymers for disposable medical devices and drug-delivery systems. Chuan Qin, PhD, is an engineering specialist at the same facility, working on polymer structure and physical properties for biomedical material and product development. Barrett E. Rabinow, PhD, is the director of strategic development in Baxter Healthcare's IV Systems Division.

Manufacturers Turn to In-House Packaging

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published July, 1996

Packaging

Many medical device manufacturers are bringing their packaging processes in-house, according to a recent study by Frost & Sullivan (Mountain View, CA), a health-care market research firm. The report suggests that nationwide pressures to contain health-care costs in general are also having an impact on the shape of the market for medical device packaging and packaging equipment.

According to the report, U.S. Medical and Pharmaceutical Packaging Markets, an increasing number of device companies are purchasing rollstock and installing their own form, fill, and seal (FFS) machinery, instead of buying preformed bags or pouches. The report notes that rollstock is the fastest-growing segment in medical packaging.

The Frost & Sullivan study looks at key types of packaging used in the medical device and pharmaceutical industries. It predicts that use of rollstock, which totaled less than 10% of the market in 1991, will increase to more than 17% by the year 2001. Meanwhile, the sale of preformed pouches and bags, which respectively accounted for 4.6 and 4.0% of the market in 1991, will increase more slowly to 5.6 and 4.7%, respectively, by 2001.

Bringing packaging in-house enables manufacturers to eliminate the expense of using an outside contract packager (converter) or buying ready-made packages. Doing so, however, requires a significant capital investment, and companies must still maintain easy access to expertise in package design and machine operation.

According to one packaging consultant, "about 50% of all packaging processes involve FFS machinery. We expect that to increase to 65% of all device packaging over the next five years."

Because the cost of such equipment often ranges from $100,000 to $250,000 per machine, purchasing it is only economical for firms producing long runs of thousands of packages. "The purchase of FFS equipment depends on economics," says Jerry Bennish, business director at Rexam Medical Packaging (Vernon Hills, IL), a supplier of rollstock and preformed packages. "If the volume of packaging is significant enough to justify the equipment and conversion costs, FFS is a viable option."

To Ray Johnson, group president of Doyen Medipharm, Inc. (Morris Plains, NJ), a significant volume is 250,000 pouches a month. "Virtually all of our machines are being sold to medical manufacturers who are packaging their own devices," he says.

Employing FFS machines saves manufacturers the cost of paying someone else to do the work. "The real savings to manufacturers comes in doing the conversion of rollstock into pouches themselves, reducing labor and increasing productivity," says Donald Barcan, president of Donbar Industries, Inc. (Long Valley, NJ), a medical package engineering consulting firm. According to Johnson, manufacturers who buy rollstock can often avoid the markup on material they would usually pay when buying premade pouches or bags from converters or contract packagers.

Another way FFS machinery can save money is through the reduction of labor costs. For instance, some firms purchase premade pouches from converters and then set up an in-house assembly line in which employees place devices in the pouches and then seal them using tabletop or in-line machines. "FFS units eliminate the need to manually stuff devices into pouches--they form the pouches around the devices and seal them automatically in one process," Johnson says. "The switch from manual to automatic packaging can reduce labor costs up to 50­80%."

Manufacturers who purchase premade pouches can face the inventory nightmare of stocking too few or too many different packages. When the demand for particular products increases or decreases, these firms must either suffer the expense of unused packages or delay orders until the out-of-stock packages can be obtained from the supplier.

Although FFS machines are usually designed to produce only one type of package (e.g., a machine that produces blister packages cannot create pouches and bags), some permit a certain amount of flexibility in varying package shape and size. Maintaining in-house production of packages enables companies to produce packaging that is tailored to fit the dimensions of specific devices, as needed.

In addition to justifying the expense of purchasing FFS equipment, manufacturers must ensure that the right expertise is available to design the packages that the equipment will be used to produce. Consultants often assist companies with package design. Companies such as Rexam maintain a staff of field engineers to assist companies with in-house packaging issues.

"Manufacturers of FFS equipment usually design the packages to be produced on their machines," Barcan explains. "Consultants are called in after the machine is running to either redesign the packages or to suggest different types of materials as part of a cost-reduction program."

Despite the gradual shift toward performing more packaging processes in-house, Barcan says that manufacturers are still using contract packagers to package high-profile items, such as surgical procedure trays and urine-collection kits. "In-house packaging, however, is a viable solution for companies that produce both low- and high-profile devices and that are seeking to reduce their out-the-door packaging costs."

To obtain a copy of U.S. Medical and Pharmaceutical Packaging Markets, contact Frost & Sullivan at 415/961-9000; fax 415/961-5042.

--Daphne Allen

Roadblocks on the Medical Superhighway?

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published July, 1996

Thanks in large part to computer-aided medical devices and decision support software, it's only a matter of time before full-scale telemedicine is common practice. Many in the device industry agree that, in the near future, all patient files will be electronically stored, primary-care physicians will be able to easily connect with specialists for on-line consultations, and software programs will analyze increasing amounts of patient data to aid in diagnosis.

While such changes are already in progress, barriers appear to be blocking further expansion of this branch of the information superhighway. According to a March 1996 report issued by the Council on Competitiveness (Washington, DC), one such barrier is the lack of FDA regulations regarding the use of hardware and software in telemedicine systems.

The report, Highway to Health: Transforming U.S. Health Care in the Information Age, states that current policies, which are based on drafts issued in 1987 and 1989, are problematic in that they regulate software as a medical device, even though many of the corresponding requirements are inappropriate for software. For example, current medical device regulations require manufacturers to submit a new premarket notification (510(k)) or premarket approval (PMA) application each time a change is made to a controlled device. In the case of software, which often undergoes fine tuning, gaining continuous FDA approval could quickly prove unworkable for both software developers and the agency.

Recommendations and findings listed in the report stem from the council's one-year study of the health-care market. "We convened an advisory committee of many of today's health-care stakeholders--including physicians, health-care delivery organizations, medical device manufacturers, and insurers--to get their thoughts on how the national information infrastructure can be a significant tool for addressing various needs within the health-care market," explains council vice president Suzy Tichenor.

The report expresses concern that, as a result of the lack of a definitive regulation in this area, physicians and organizations that have developed decision support software tools are refraining from sharing them with others in the medical industry. To prevent this from continuing, the report recommends that FDA set clear limits on when software and other telecommunications infrastructures are subject to FDA regulations. The council also says FDA should work in partnership with medical specialty societies, manufacturers, and cognizant organizations as it develops these policies to ensure that they meet appropriate standards for patient care and are not so restrictive that they inhibit widespread use of these technologies.

Tom Shope, acting director of the division of electronics and computer sciences at FDA's Office of Science and Technology (OST), says the agency is doing just that. According to Shope, FDA recognizes that it needs to make a decision on how it will regulate computer-aided medical devices and stand-alone decision support software. "FDA is drafting a Federal Register notice--likely to be released this summer--that will announce a public meeting to address this issue," Shope says. "This meeting will assist the agency in determining the best approach to risk-based regulation of computer-aided medical devices and stand-alone software."

Harvey Rudolph, OST's acting deputy director, says the meeting--currently scheduled for this September--will attempt to answer the questions of which medical software devices FDA is going to regulate and how. "We may be able to come out with a policy fairly quickly after that," Rudolph says. "As I see it, the lack of a policy is doing more harm than good. People need to know what the requirements are. And even if there are FDA requirements for developers of these products, that doesn't mean those requirements will slow down their progress to market--so long as developers know up front what the requirements are and that the requirements are reasonable."

Still, FDA isn't the only agency that needs to answer questions and develop standards in this arena. According to Highway to Health, another barrier to the rapid advance of telemedicine appears to be a lack of common languages and standards that would facilitate communication and information integration. The report states: "The health-care industry faces a daunting task: to develop common standards that embrace communications protocols, data presentation formats, and data content definition. These must be widely accepted before health care can easily navigate the information superhighway."

So who will set these standards? "It's a decision that's going to be made through the consensus standards process," says Rudolph. He maintains that process should include input from regulatory agencies, manufacturers, and practitioners. "It's the only way that everybody who has a stake in the game can play."

Copies of Highway to Health are available for $25 each. To order, call 202/682-4292. --Romina Vitols

International Conference to Highlight European Union Markets

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published July, 1996

Packaging and Sterilization

Medical device packagers and manufacturers interested in the European market will soon have the chance to learn about that region's packaging and sterilization issues.

In September, industry representatives from around the world will gather in Vienna to present the first international conference and exhibition on medical packaging and sterilization. Organized by the European Sterilization Packaging Association (ESPA), a trade association representing medical packaging manufacturers and converters, "Packaging: Maintaining the Standard" will be held September 11­12, 1996.

Topics of the conference will include industry and hospital standards, barrier testing, packaging waste, and sterilization systems and practices. In conjunction with the conference, there will also be a small exhibition.

"The conference will provide U.S. medical device manufacturers with an eye opener to key packaging issues in Europe," explains Michael Baker, secretary-general of ESPA. "Manufacturers will also have an opportunity to learn about the packaging expertise that is available in Europe."

According to Baker, the conference will include a number of sessions of particular interest to U.S. companies involved in the packaging of medical devices. "Packaging Issues: Industry and Hospital Standards" will explain the approach of the European Committee for Standardization (CEN) to the harmonization of European standards, the development of CEN standard EN 868 for packaging materials, and the effects that the European Union's Medical Device Directive will have on packaging. Baker will describe ESPA's policy regarding packaging standards.

In "Barrier Testing: From Microbe to Customer Assurance," speakers will discuss the use of microbiological techniques to determine the barrier performance of porous materials. Michael Scholla, medical packaging segment leader for DuPont Nonwovens (Wilmington, DE), will emphasize the need for a single universally accepted barrier test procedure and describe approaches to developing such a standard through the International Organization for Standardization (ISO).

"The Environment Matters: Packaging Waste" is expected to cover current and proposed European legislation regarding such waste and practical methods of handling it in a health-care environment.

The final session will focus on sterilization systems and methods used for medical products. Speakers will cover ethylene oxide, gamma irradiation, and low-temperature sterilization procedures. Although their main purpose will be to discuss the procedures, they will also consider relevant issues related to packaging materials.

The conference will also offer three workshops that will give attendees the chance to network with industry representatives. Workshop themes include the fundamentals of medical packaging, the reuse of single- use products, and life cycle analysis. The last workshop introduces Eco-Audit, a move within Europe to ensure that firms are running environmentally friendly operations.

The major sponsor of the show is Canon Communications, Inc., publisher of European Medical Device Manufacturer and Medical Device & Diagnostic Industry; the show is also supported by the Austrian National Trade Association (AUSTROMED), the European Confederation of Medical Devices Associations (EUCOMED), and the European Surgical Dressings Manufacturers' Association (ESDREMA).

For information on attending, contact Louisa Rogers, IBC Ltd., London, +44 (0) 171 637 4383, fax +44 (0) 171 631 3214. --Daphne Allen *

FDA and the Cost of Health Care

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published July, 1996

Ronald C. Allen
President and CEO, Cohort Medical Products Group, Inc.,
Hayward, CA

As the Clinton administration and Congress grapple with finding ways to reduce the cost of health care, both have overlooked FDA, the one government agency that causes health-care costs to continually rise. Since the establishment of FDA in 1938, the cost of providing medical products to the U.S. health-care system has increased each year. Medical device manufacturers have continued to increase the number of staff assigned to managing FDA requirements and educating the agency about their products. In 1975, a medium-size medical product company might have had one person assigned to managing FDA requirements, whereas today a full department exists. For instance, the top 10 orthopedic companies in the United States have increased their regulatory affairs staffs by 39% over the past five years. In addition, a comparison of the advertisements for FDA consulting services in the June 1990 issue of MD&DI with those in the June 1995 issue shows an increase of over 20%.

In order to reduce the cost of health care, FDA should carry out a number of reforms. These include hiring reviewers knowledgeable about the particular products they review, communicating with industry about confusing or specialized application information rather than withholding approval, acknowledging its role in the practice of medicine, and creating and following straightforward policies. FDA may also benefit from modeling itself after a voluntary group such as the American Society for Testing and Materials (ASTM).

EMPHASIZING EDUCATION

After spending millions of dollars on the design, development, and testing of a product, manufacturers have to educate FDA staff, many of whom have no medical, design, business, or product experience. The reviewer is then responsible for reviewing the application and determining whether that product is approvable.

Often, in an effort to avoid making an error, reviewers find that rejection is the safest way to deal with applications that are beyond their understanding or that appear different from those recently reviewed. Under the guise of protecting the public health, applications for products have been and continue to be rejected because FDA reviewers fail to understand or even read them.

An example of an uninformed decision is the rejection of a recent 510(k) notification for a screw that is used to hold two bones together. According to FDA, it was rejected because the bone screw had not been approved to hold those particular two bones together prior to May 28, 1976. The fact that the worldwide orthopedic community has been implanting screws to hold two bones together every day since 1829 made no difference to FDA.

A manufacturer in this situation has but a few alternatives. The first is to drop the project and recapture its cost by increasing the prices of other products sold in the market. Another is to take FDA's recommendation and conduct a three-year multimillion-dollar clinical study to prove that the bone screw will hold the selected bones, just as screws have done for more than 100 years. A third alternative is to attempt to educate FDA on the clinical history of bone screw use. Unfortunately, no vehicle is in place that requires FDA to accept, read, or respond to such information.

A fourth alternative, as some manufacturers have found, is litigation to force FDA to prove that the product fails to meet the regulatory requirements. An increasing number of manufacturers are finding that the cost of litigation, when compared to the cost of an unnecessary clinical study, is the most efficient alternative for gaining approval for their products.

The fact that many current FDA reviewers have not had any practical experience in the areas they are responsible for reviewing is a threat to the public and a cause of the delay in new product approvals. If the agency is responsible for regulating medicine, food, drugs, and devices, it should employ individuals with experience in these areas and assign them to projects within their area of expertise.

COSTS OF INEFFECTIVE COMMUNICATION

FDA's treatment of pedicle screw applications demonstrates that the agency cannot communicate effectively with industry. FDA has received a number of 510(k), investigational device exemption, premarket approval, and down-classification applications from manufacturers seeking to market pedicle screws, which are used to hold a plate or rod to the spine during the fusion process. Such variation in applications is a result of manufacturers' receiving different instructions from FDA. Although early applications had demonstrated that there was preamendment use of pedicle screws, FDA either did not understand the information provided or failed to accept it. FDA's failure to accept data provided in the late 1980s has resulted in hundreds of patient lawsuits against manufacturers, surgeons, and hospitals in the 1990s. The basis of these suits is that the pedicle screw did not have marketing approval and that therefore all parties involved in its manufacture and use were endangering patients.

Manufacturers, surgeons, and medical societies supplied FDA with evidence to dem-onstrate the clinical safety and efficacy of these devices. In an effort to control a situation that threatened the care of patients with disabling spine conditions, FDA required manufacturers to change the labels on all orthopedic screws over a particular size and sent them warning letters stating that training surgeons on the use of pedicle screws was illegal. Changing the labeling requirements subsequently increased the cost of bone screws.

In April 1995 FDA accepted the information that was submitted in the 1980s as proof of the preamendment status of pedicle screws. However, the manufacturers had already spent millions of dollars on unnecessary clinical trials. Surgeons, hospitals, and manufacturers are still defending themselves against lawsuits, recently reported to number in the thousands. Many patients, caught in the middle of a regulatory fiasco, have lost trust in physicians and have become a target for attorneys seeking to litigate. The final cost of this regulatory mismanagement will be hundreds of millions of dollars. FDA will not pay the cost. Neither will the manufacturers, who have already paid for clinical study costs; consultant, lawyer, and legal fees; and those costs directly related to FDA policy changes. The only payers left are the patients and their insurance companies.

FDA inefficiencies and mismanagement, therefore, have a direct impact on the cost of U.S. health care. If the Clinton administration and Congress genuinely want to reduce and control the cost of health care, they should begin by reforming FDA.

FDA: DEFINING ITS ROLE

FDA must also realistically describe its role in medicine. When manufacturers were notified of the new regulatory requirements regarding pedicle screws, FDA announced to the surgical community that it does not control the practice of medicine. According to the agency, surgeons could use whatever procedures they felt were in the best interest of the patient. This announcement complicated the situation.

In order for FDA to become an agency upon which the public can rely, it must be truthful. For the agency to profess that it does not regulate the practice of medicine is just not true. The fact is that it regulates every product now used to treat patients in every hospital in the United States. Everything from the outside label to the function of the product is regulated by FDA. Physicians would not be successful in their specialty without the use of FDA-controlled products. Once FDA informs the medical community of its role, physicians can inform patients that various treatments are not available to them because the agency has not approved the necessary products.

FDA must also follow its policy of reviewing applications in the order it receives them. Since the first numbers were assigned to applications, the agency has failed to follow this procedure. Manufacturers, believing that FDA had established a method to organize and track the progress of applications, were disappointed that they were not being handled in such a manner. Such a failure directly affects the cost of products.

A MODEL SOLUTION

One way to control the cost of health care may be to dissolve FDA in its current form. Such calls for action have been heard over the past few years inside and outside Congress. If this were to occur, what would fill the void? We suggest a voluntary group com-posed of members of the public, medical doctors, manufacturers, and hospital administrators. One long-standing model, ASTM, comes to mind.

ASTM is a voluntary group that develops standards manufacturers follow voluntarily. The acceptance of such voluntary standards created by members of the public, industry, and government is so widespread that FDA routinely refers to them. What is ideal about this group is that there is no cost to the public, the group has the knowledge to review new technologies, and it reaches effective decisions. Members are experts in their fields and represent some of the best medical minds. This group has established itself as an effective nongovernment organization, through which testing, materials, and performance standards are established for all products. Perhaps FDA should be assigned to assist such an organization on compliance issues and to leave the establishment of standards alone.

The Future of Medical Device Regulation: A Global Perspective

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published July, 1996

An Interview with Gordon Higson

Consulting Director of MTC-BRI International, Staines, Middlesex, UK,
and Chairman of ISO TC 210

In the decade ahead, Gordon Higson envisions a globally harmonized system for regulating medical devices, one based on a comprehensive, coherent set of standards. Standing in the way of such global harmony are the existing regulatory systems throughout the world. But increasingly there are signs that these systems are showing flexibility--even in the United States, which constitutes the largest medical device market in the world and whose regulatory system might be expected to have the greatest inertia. There is serious talk of reform on Capitol Hill and in the trenches at FDA, and proponents of the European model--which emphasizes safety while leaving clinical practitioners to decide on efficacy--are being heard.

For years, Higson has supported the development of global standards. As chairman of the International Organization for Standardization's (ISO) technical committee that is working to apply quality systems standards to the design and manufacture of medical devices--ISO TC 210--he is involved in decision making that will affect the development of worldwide standards pertaining to the medical device industry. In this interview with MD&DI, Higson discusses the differences between the European and U.S. regulatory systems, the potential for harmonization between the two, and the challenges that lie ahead for efforts such as those of ISO TC 210.


How does the European regulatory system differ from the one used by FDA?

When the Europeans were developing their regulatory system in the 1980s, they learned a great deal from the U.S. system and tried to overcome some of the difficulties they found. In particular, the European system is based on a very clear definition of the approval requirements for devices. Known as essential requirements, these 40-odd items are written in general terms, and they cover all the known sources of danger to patients. The European regulation (directive) then goes on to use the principle of reference to standards. It specifically states that technical elaboration of the essential requirements for individual types of devices is to be contained in voluntary standards.

Those standards are written by the voluntary standards organizations: the European Committee for Standardization (CEN) and the European Committee for Electrotechnical Standardization (CENELEC). They are empowered to write standards on behalf of the member states of the European Union (EU), but mostly draw on standards produced by the international standards bodies. A manufacturer who complies with standards that have been recognized by these organizations is deemed to have satisfied its legal requirements. I think this is quite an advanced approach to lawmaking, and by defining the requirements in general terms the law itself is likely to remain stable for many years. And that's a good point, because it's very difficult to change laws. If we were to put technical detail into laws, we would soon find ourselves stuck with obsolete requirements. But by allowing technical elaboration to take place in the standards field, this system frees the requirements from the bureaucratic burdens of the legal system and enables them to draw on expertise that's available anywhere in the world rather than just in an individual European state.

How do these documents work from the manufacturer's point of view?

The essential requirements are written into the medical device directives. Technical details are written into standards. And all
of these documents are available to everybody--manufacturer and regulator alike. So the manufacturer has every opportunity to determine that its device is safe and satisfactory before submitting it to the regulatory process for approval. This helps things enormously. As far as I'm aware, it's actually quite difficult for a manufacturer in the United States to know that its device is approvable before it's submitted to FDA. The manufacturer submits the application and responds to questions from FDA. And that seems to me to be an inherently slow process, because the manufacturer can't quite know what the questions are beforehand. In the European system, the requirements are clearly defined in advance, so manufacturers can do the work necessary to gather supporting evidence. Indeed, manufacturers are expected to get supporting evidence of the safety of their devices before moving them into the regulatory process.

In recent years, FDA has become increasingly interested in having device companies develop clinical data about the safety and effectiveness of their products. Is there such an emphasis in Europe?

No. The European approach requires clinical evidence only when the safety of a device cannot be established in the laboratory. But for many devices it is possible to do so, and therefore no clinical data are required.

Even when such data are needed, in Europe the requirement is to show clinical evidence only for safety and performance--not for effectiveness. There is no efficacy requirement in the European law. Our approach is to determine whether the technology performs in accordance with its labeling; we leave it to the medical profession to decide whether one diagnostic or therapeutic methodology is preferable to another for an individual patient.

How does the European system of device classification relate to the requirements for clinical testing?

Most of what the Europeans learned from the United States was, of course, related to the classification system. The Europeans have followed many of the U.S. approaches to classification and the use of quality systems. In the European system, clinical evidence of safety is required for devices in Class III (the highest class), for implants in Class IIb, and, of course, for any device representing a new kind of technology. Such clinical evidence must examine all possible dangers, including the potential for side effects resulting from use of the device. The manufacturer must also carry out a risk-benefit analysis to make sure that any risks or side effects presented by the device are actually worth accepting because of its benefits. So an efficacy element can be introduced in cases such as this.

Are there Class IIa devices that don't present much danger and, therefore, would not necessarily have to go through much testing?

That's correct. They have to go through
an approval process, but it probably would not involve clinical studies.

Class I devices are the simplest?

They are very simple, and can be put onto the market with only the manufac-turer's declaration that they conform to the essential requirements of the directive and that there is some documentary proof of compliance, in case the authorities wish to examine it. But normally the manufacturer doesn't have to go to any approval authority to put a Class I device on the market.

So European regulatory agencies are mostly concerned with protecting the public health and prefer to let the market decide what devices should be used?

I think we would use the term professions instead of market. We think it's for the clinical professions to decide what devices are used, and when. Every patient is different, so generalizations about the effectiveness of a particular device or particular condition are quite hard to make.

You said earlier that European regulators looked at the U.S. system as a model upon which to base their own. What can FDA learn from the Europeans?

There are quite good relations between the authorities in Europe and at FDA. They meet quite regularly, and I'm sure that kind of learning process must go on all the time. For example, the United States has had its GMP regulation in place for a long time, and for many of those years the equivalent European programs operated on a much smaller scale. The wholesale use of quality systems standards as part of the regulatory process was adopted by the Europeans from the United States--but with a difference. In the United States, the GMP regulation has always been considered a follow-up to device approval, but the Europeans brought quality systems in as part of the premarket process. Now, we're beginning to see the United States leaning toward the European practice. I believe it's now the case that
premarket approvals won't be processed unless the manufacturer demonstrates it has an adequate quality system. I think this use of quality systems as a premarket requirement rather than as a postmarket check-up system is significant.

The quality systems now in place are built mostly around the ISO 9000 family of quality system standards. Can we expect any changes in these standards in the future?

The international standards community is already talking about a new version, which will come out perhaps around the year 2000 and will be considerably different from the current version of ISO 9001. The revision is expected to consider total quality management and the efficiency of the manufacturing company. Members of TC 210 have noted that such revisions might take the standard beyond its current use in medical device regulations. And our committee has sent a message to TC 176, the committee that is working on this revised standard, to request that it bear in mind that such changes could seriously compromise the usefulness of the standard as a regulatory tool, not only in the case of medical devices but also in many other product areas. We asked TC 176 to consider whether the present versions of the ISO 9000 standards could remain active in some way. To accomplish this, we may have to preserve the present texts of ISO 9001 and 9002 in some other form, perhaps as medical device­specific quality standards.

Many U.S. device companies have been certified to an ISO 9000 standard, with the idea that this would also bring them close to conformity with FDA's forthcoming revised GMP regulation.

Yes, of course. It's my understanding that the forthcoming GMP revision is modeled very closely on ISO 9001--as are the European, Japanese, Australian, and forthcoming Canadian systems. For those reasons, I think it will be essential for this standard to be preserved in one form or another. It will be interesting to see how TC 176 responds to our request, because we in TC 210 work very closely with them. But it may end up as a task for TC 210 to preserve the present requirements of ISO 9001 in some form or another.

What would happen if the emphasis of the ISO 9000 standards was changed dramatically?

I think what we would do then would be to provide a mechanism so that the regulatory systems that work by reference to standards would still have standards available to refer to. They have the 1994 version now, and TC 176 could agree to preserve that version in some way even after the revision of 2000 is completed. But if TC 176 decides to supersede it with a new version, I think the current version of ISO 9001 will still have
to be preserved in some way by TC 210--perhaps as a specific quality standard for medical devices.

WASHINGTON WRAP-UP

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published July, 1996

James G. Dickinson

Two opposing cultures collide whenever FDA and industry meet. Most of the time the impact is gentle, with each side respecting the other's difference. But occasionally the impact results in a real explosion.

And an explosion with aftershocks is what has come from what some see as an enviably close relationship forged by David Muller, CEO of Summit Technology, Inc. (Waltham, MA), between his ophthalmic laser manufacturing company and the Office of Device Evaluation (ODE) in FDA's Center for Devices and Radiological Health (CDRH).

At first, Muller may have seen little in the culture difference to lose sleep over. By now, however, he may have reflected on the downside of mixing too closely with FDA--nasty little consequences that, in an extreme case like the generic drug scandal, cost 6 FDA employees and nearly 20 industry executives jail time.

Summit's FDA aftershocks haven't risen to nearly that level, but they're pretty discomforting in terms of media headlines, drops in company stock prices, and in-depth investigations by both FDA's Office of Internal Affairs and the FBI.

While the situation falls short of the generic drug scandal, there is a common denominator: excellent FDA relations that some came to view as a little too excellent. According to some observers, Muller and his team learned to work the agency with a dexterity that baffled rivals and angered ophthalmologists who were subjected to FDA inspections that they attributed to Summit's influence at the agency (they were using reimported Summit lasers without paying royalties to Summit).

According to its trade and professional critics, including former Summit executives now employed by competitors, Summit and David Muller were able to use their FDA skills to build a dominant position in the fledgling U.S. excimer laser eye sur-gery market even before the company's devices were approved for that indication last year.

The company's winning streak only faltered at the end of last November, when the U.S. Postal Service brought to Muller's home an FDA envelope containing confidential agency documents about a still-pending excimer laser marketing application from rival Visx, Inc. (Santa Clara, CA). Included were a draft approval letter, engineering data, another competitor's data, and internal CDRH memoranda. The previous month, Summit's own corneal surgery laser had been approved for its second indication, so the package wasn't valuable for approval purposes. But some speculate that the data would have been very useful in Summit's ongoing patent litigation with Visx, as well as for a possible premarket approval (PMA) supplement to upgrade its approved product. While saying that he did not examine the materials closely (he returned them to FDA, says a company representative, within one business day of receiving them), Muller suggested to this writer that given Summit's technological lead over Visx, the materials could not have been helpful to his company.

Whatever its value to Summit, the packet's return launched both FDA and FBI investigations into all those effective connections Summit had evidently enjoyed at CDRH for at least two years. Close company and FDA observers of some of those connections say they seemed so friendly as to cross the conventional boundary separating official business from personal relations.

For example, Summit vice president for regulatory affairs Kim Doney is said to have regularly (some say even routinely) engaged in lengthy telephone conversations two or three times a day with the lead CDRH reviewer on Summit's pending PMA submission. Frequently, observers say, those conversations veered into nonbusiness subjects. Doney declined to comment to this writer about her FDA contacts, but, in an interview, Muller pulled no punches about the company's familiarity with CDRH people, stating that he has made himself well known to "everyone" in the ophthalmic devices and other divisions, both during numerous personal visits and over the telephone.

When does such rapport become too close and run the risk of unleashing a backlash against the company that cultivated it? That point may not yet have been reached in Summit's case. But some medical practitioners who have been using the company's earlier-model lasers claim that Summit had a way of getting FDA to do just what it wanted, even to the point of helping it build market domination. The ways Summit did this, they allege, include the following:

* Influencing FDA to issue an import alert last February on all previously exported Summit lasers so that ophthalmic surgeons couldn't buy them more cheaply overseas. Clinically, these surgeons say, most of the reimported devices are identical to the recently approved model, except that they lack a built-in procedure counter and a Summit-devised lockout device to block their use in a newer procedure known as photorefractive keratectomy (PRK). Both these add-ons are necessary to ensure that Summit collects $250 in royalties on each PRK procedure performed in the United States.

* Leading FDA to inspect practitioners who bought reimported lasers that don't carry royalty mechanisms and to cite them for investigational device exemption (IDE) violations or misbranding.

* Persuading FDA, in the terms of its approval of Summit's new laser, to limit PRK surgeries to devices approved for ablating corneal tissue in a 6-mm optical zone. All predecessor devices had approval only to 5 mm or less; until last April, when the Visx excimer laser was approved, only Summit's newest model had approval for 6 mm, effectively giving the company six months of competition-free marketing.

* Using its influence with FDA staffers to slow down the review of the Visx PRK laser.

According to former Summit western sales manager James C. Fallon, who has sued Summit for wrongful dismissal, these alleged actions were all part of a broader plan to gain a lock on the U.S. eye surgery laser market before FDA approval. Summit's strategy, he claims, was developed in 1990 and included selling upgradable holmium lasers (which have limited glaucoma indications) in anticipation of eventual FDA approval of the Summit device for more advanced phototherapeutic keratectomy (PTK) and PRK. Covered by 510(k)s, these holmium lasers were sold as "workstations" at six times the price of competitive holmium lasers, Fallon claims, because they could be easily and quickly upgraded after FDA approval. Ophthalmologists who did not buy early would be faced with postapproval delays of 12 to 18 months.

Fallon says he was fired for not accepting oral orders to participate in this alleged preselling scheme while the company was issuing written directives (for FDA's benefit) warning its sales team not to presell the unapproved lasers.

"Summit management practiced a web of deceit by instructing the sales force in writing not to promote, market, or sell the excimer laser," Fallon says in a declaration dated March 3, 1996. "Factually, Summit management including but not limited to J. Frantzis, Peter Litman, and David Muller himself put tremendous pressure to secure sales of the Summit laser, prior to its FDA approval. The sales force were told that Summit needed the cash flow to stay alive as it was hemorrhaging red ink, because of the delay in securing FDA approval."

Another Summit employee who was fired, former vice president of sales and marketing William Kelley, told this writer he was miserable the whole 10 months he was at Summit, mainly because Muller "dominated everything" and used questionable tactics, including the preselling of the excimer laser through the holmium workstation. "He's a power guy. He . . . pushes things to the limit. During the time I was there, he used the expression 'pushing the envelope.' I remember one time, regarding the FDA, he said we were going to go until we were nose-to-nose with them, and they would have to say 'Stop doing this' before we would stop doing some of the things we were doing and saying in terms of getting sales."

Kelley said Summit sold 80 to 100 holmium systems using the excimer sales carrot. "There were lots of commitments by sales reps and even the sales manager that 'You'll have the excimer head within six months of approval,' or 'You'll be the first one in line,' that sort of thing."

Amid a barrage of ophthalmologist and trade complaints extending over three years, FDA finally received something it couldn't ignore: a four-page purported internal Summit memo to Muller dated July 11, 1990, describing the scheme. This moved CDRH compliance director Lillian J. Gill to send Summit a warning letter that was followed by an eight-day inspection in January 1995. The resulting FDA-483 notice made no mention of preselling, however, merely citing Summit for inadequate rework documentation, use of an obsolete test data sheet, and failure to calibrate a digital thermometer, observations to which Summit readily consented.

Not all the sales during this preapproval period were of the holmium workstation, according to Fallon. In a memo dated December 15, 1995, to pioneering laser surgery ophthalmologist William Ellis, MD, he named four such purchases, with the handwritten notation: "The physicians above bought [the] excimer laser before approval! I'm not talking about workstations but actual lasers."

Some ophthalmologists balked at paying up to $380,000 for a $60,000 holmium laser with upgrade commitments from Summit. An estimated 30 to 40 bought exported and foreign-built Summit lasers overseas and in Canada for a fraction of the U.S. price, and began using them immediately as "investigational" or "custom" devices exempt from FDA interference. Eventually, however, FDA began interfering, allegedly at Summit's behest, sending "adulteration/misbranding" warning letters to Ellis and several others, even though these devices were clinically identical to the lasers Summit used in its U.S. clinical trials to gain approval for the PTK and PRK indications. According to Ellis (also now in litigation with Summit) and others, the only difference between the various models is that Summit's postapproval models have counters and card-reading lockout attachments for assessing per-procedure royalties due. There is another difference, however--Summit is now refusing to service the reimported devices, or to provide operating manuals.

When I asked Summit's David Muller what made the reimported Summit devices clinically different, he seemed unsure. While acknowledging that "the counter has no clinical effect," he insisted that "there's a whole variety of things that could have a clin-ical effect." Asked to elaborate on the differences, he declined, other than to say that the imported devices can "treat patients over a much larger range of treatment parameters" than the FDA-approved models.

When I asked ODE director Susan Alpert about the clinical differences and the justification for the import alert, she said that the imported devices did not bear current approved labeling and that the PRK lockout feature could have some clinical significance, although she could not discuss that. Informed that Ellis and others claimed they could not obtain copies of the approved labeling in order to bring their machines into compliance, Alpert said: "The labeling is FOI-able." Ophthalmologist Ellis, however, told me later that he has been unable to get final labeling from the agency, despite filing a Freedom of Information Act request for it last December.

Ellis has also raised the issue of the Summit device's safety, claiming that its 6-mm beam width releases too much energy in the eye and can cause retinal detachments, as reported by overseas clinicians. Muller denied this, pointing to an absence of such reports in the company's data used to gain approval: Why would these be popping up overseas, and then only in isolated instances, while hundreds of U.S. case reports cleared by FDA are free of such implications?

Alpert said she believes the overseas reports result from improper patient selection; some people are by medical condition predisposed to retinal detachments and should be screened out before being subjected to 6-mm PRK surgery.

Ellis has a darker suggestion. Thirty of Summit's total of 89 U.S. case reports with the 6-mm beam involved young, mostly male naval recruits in San Diego who are not representative of the surgery's patient population overall, and who have a natural ability to "accommodate" the overcorrection of the Summit PRK device, he said. When they reach their 40s, these subjects will likely have weak vision attributable to the procedure, he claimed. As for all the other case studies submitted by Summit, Ellis claimed they were done in England using different software.

Summit, however, strongly denied that any of its studies were foreign. In a recent letter, Summit attorney William Lee declared that "all of the data submitted by Summit to obtain FDA approval was from standardized, multicenter clinical trials in the U.S."

On other aspects of the controversy, Alpert declined to comment, in view of the current Office of Internal Affairs investigation into the leak of confidential documents. She did say, however, that her office has increased document security since the leak, through intensified employee training and the addition of locks to offices and desks that contain sensitive documents. In a separate conversation, again constrained by the investigation, CDRH director Bruce Burlington admitted that the new security measures might result in slower reviews by impeding the previous "flexibility" that reviewers enjoyed.

Neither official would acknowledge that Summit may have had "too much" familiarity with their employees. That, after all, is what the investigation is all about.

James G. Dickinson is a veteran reporter on regulatory affairs in the medical device industry.

SUMMIT RESPONDS

In response to MD&DI's request for an interview with a company official, Summit Technology provided a written statement through a Washington, DC, public relations firm, Apco Associates. In a preface to the following questions and answers, the statement included a comment that two of the sources, William Ellis and James Fallon, quoted in the accompanying Washington Wrap-Up article, "have been involved in litigation against Summit." According to the statement, "both have a vested interest in the spread of misinformation about the company." The statement did not identify specific elements of such alleged misinformation.

What was Summit's role, if any, in FDA's February import alert on previously exported lasers, and what role did Summit play in FDA's decision to inspect practitioners who purchased these lasers?

Summit has no influence or role in FDA's decision-making processes. Importation of unapproved devices has been a concern for FDA throughout its review of this technology. As a result, per the approval letter Summit received from FDA with respect to PRK, Summit is required by the agency to report anyone using gray market equipment. The specific language in that letter is as follows:

In addition to the postapproval requirements . . . , the following information must also be submitted to the Agency:

4. reports to FDA CDRH's Office of Compliance at the address below of any instances of device tampering or usage outside of the approved indications, and any excimer systems that were exported under a 801(e) order and are now back in the U.S.

In compliance with that regulatory requirement, Summit reported information to FDA as requested in the above paragraph.

Did Summit sell upgradable holmium laser workstations that could be upgraded with excimer lasers?

Summit has always complied with FDA's commercialization rules and, as part of that compliance, the company never presold any excimer lasers. Our efforts to prevent commercialization of excimer lasers was extensive. All of Summit's quotations and invoices, which physicians were required to sign before purchasing the product, bore the following legend, or one similar to it:

This system contains only a holmium laser, not an excimer laser. Purchase of this system does not entitle the purchaser to purchase, use, license or otherwise benefit from any excimer laser, which currently is an investigational device under applicable FDA regulations.

While Summit never promised or presold excimer lasers as part of the holmium workstation package, it was clear that the holmium workstations were designed to accommodate excimer lasers in the event that (i) excimer lasers received FDA approval and (ii) physicians purchased such lasers in the future.

Did Summit ever sell any excimer lasers before they were approved?

Excimer lasers sold by the company prior to approval for use in the United States were only sold to legitimate IDE sites or animal research centers. As permitted by the U.S. export laws, Summit also sold excimer lasers to parties for use outside the United States.

Was there a 1994 warning letter from FDA in response to an internal memo about sales strategies? Was the memo real or fake?

No. The obviousness of the forgery was blatant, and the purported author provided an affidavit that he did not write it. Any assertion to the contrary is simply false.

FDA paid considerable attention to the erroneous allegations made that Summit was preselling excimer lasers in violation of the commercialization rules. In fact, FDA sent a warning letter to Summit on that topic, citing erroneous reports. Summit addressed each incident in great detail and to FDA's satisfaction. The company demonstrated that the only excimer lasers sold prior to U.S. approval were sold to legitimate IDE sites or animal research centers.