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Articles from 1996 In March


Shelf-Life Prediction Methods and Applications

Medical Plastics and Biomaterials Magazine | MPB Article Index

Originally published March 1996

 

LECON WOO, JOSEPH PALOMO, MICHAEL T. K. LING, EDDIE K. CHAN, AND CRAIG SANDFORD

One of the most important tasks for anyone involved in product design and manufacturing is to ensure that a product will function as intended when used by the customer. For the medical device industry, in particular, concerns over both patient safety and potential liability demand that manufacturers offer the absolute maximum in assurances that failures will not occur during use. At the same time, cost-containment policies and competitive pressures often dictate that the least-expensive material and manufacturing process be chosen. These two opposing forces--reliability and cost-effectiveness--together place heavy demands on the designer to satisfy both criteria simultaneously.

INTRODUCTION

No matter how much care is taken in areas such as material selection, tool design, and fabrication, the fact that a product meets all functional requirements upon initial testing does not guarantee its ultimate success. Before arriving in the hands of the end-user, a product must often be sterilized (frequently with ionizing radiation), shipped through various distribution channels, and subjected to shelf storage under varying environmental conditions-- all factors that can induce changes in a product and thus affect its performance. In the case of the alteration of a plastic material over time, real-time aging is undoubtedly the best way of accurately determining long-term performance. But real-time testing is impractical and arduous to perform. Given these difficulties, the use of accelerated-aging techniques based on a fundamental understanding of polymer behavior offers the possibility of obtaining the most reliable predictions of performance short of a total reliance on real-time observations and continual evaluation.

This article examines several commonly used acceleration techniques for shelf-life prediction, explores the basis for their validity, and cites several of the authors' own cases in which successful predictions were achieved. The fact that each case involved a different accelerating method serves to highlight the importance of understanding the basic science when designing the accelerating experiments and of maintaining concurrent real-time product-sample archives to substantiate and validate the method selected.

ACCELERATION METHODS AND MATERIAL-PERFORMANCE FACTORS

One of the most widely used test methods is that of thermal acceleration. This technique is based on the application of the Arrhenius kinetics rate equation--the so-called photographers' rule, which states that the rate of chemical reactions roughly doubles for every 10°C rise in temperature. Figure 1 depicts the ratio of reaction rate constants based on the Arrhenius relationship. However, before passing judgment on the validity or accuracy of the approximation as a predictive tool for a particular application, one needs to examine a number of general product-performance factors. These include (1) structural/mechanical values such as modulus, impact toughness, yield and ultimate strengths, and ultimate elongation; (2) optical properties such as haze, yellowness index, and gloss; (3) surface characteristics, including critical surface tension, wetting properties, and adhesion; (4) biocompatibility factors, among them hard- and soft-tissue compatibility, hemocompatibility, thrombogenicity, and complement activation; and (5) toxicity, both acute and chronic.

Molecular-Weight Alterations. Among the principal effects of ionizing radiation are polymer chain scission and cross-linking, which significantly reduce or increase molecular weight, respectively. Either of these processes can result in profound effects on polymer mechanical properties.

Low-Molecular-Weight Species Diffusion. Low-molecular-weight species--either inherent in the polymer or created from ionizing radiation during sterilization as a result of miscibility phenomena--tend to migrate with the passage of time toward the air/polymer interface. At the same time, oxygen diffusion toward the interior of the polymer has the effect of depleting antioxidants or combining with long-lived free radicals from radiation to form peroxy radicals, which has the effect of propagating the degradation chain of reactions and thus weakening the polymer over time.

Physical Aging. The process of physical aging, or free-volume relaxation, is a slow but perceptible densification of amorphous polymers toward the thermodynamic equilibrium state. The rate of aging is greatly accelerated at temperatures close to the glass-transition temperature, Tg. For example, significant aging can take place for PETG (Tg * 80°C) at preconditioning or drying temperatures of 50°­60°C. This physical aging process is frequently accompanied by dramatic changes in the polymer's physical properties.

SHELF-LIFE PREDICTION CASE STUDIES

Physical Aging of PETG. Numerous studies have established that amorphous materials age with time--a process that appears to be universal and irreversible.1 The authors have carried out extensive studies on PETG,2 for which the kinetics of the aging process (as indicated by the recoverable enthalphy determined by differential scanning calorimetry) were found to obey the following relationship:

H = Ha [K­exp (­t/*)]

where Ha is the apparent limiting value of the recoverable enthalpy at temperature Ta, and * is the time constant. The half-life time constant--the time required to attain 50% of the apparent recoverable enthalpy--is plotted in Figure 2 against the departure from the glass-transition temperature (Tg-Ta). The plot suggests that the half-life time increases exponentially with Tg-Ta.

Having determined the extent of aging and the kinetics involved, one merely needs to perform physical testing on samples with a known aging history in order to predict shelf life. In Figure 3, the interdependence of ultimate strength and elongation before and after physical aging is presented. Immediately, one notices the total divergence in the predicted properties before and after aging: elongation decreases drastically while strength actually increases. This seemingly contradictory result serves to emphasize the importance of selecting the most relevant material property for simulation. In most instances (such as the example just cited), the effect of elongation and the associated toughness (a measure of the fracture energy) is most important for product performance. Therefore, elongation should be chosen as the material parameter for prediction.

Cellulose Esters. For a class of cellulose esters suitable for extrusion, it was discovered that shelf-life aging under ambient conditions for very long times (up to 5 years) and high doses of radiation both produced very similar reductions in molecular weight.3 (A separate study analyzing the effect of molecular weight on performance has established minimum molecular-weight standards.) For these materials, a high dose of radiation, or any other suitable method of molecular-weight reduction, can be used to simulate the effect of real-time aging and give a reliable prediction of shelf life.

Irradiated Polypropylene. The authors have previously disclosed significant success in predicting shelf life of irradiated polypropylene.3 Extensive real-time studies and the findings of many other investigators4 led to the conclusion that the mechanical properties of polypropylene degrade with time after radiation sterilization. Evidently, oxygen migration and diffusion into the sample, combined with long-lived free radicals from the radiation, serve to propagate a series of chain reactions resulting in material degradation, even though molecular weight per se is not drastically affected. In addition, the postirradiated sample degradation is extremely heterogeneous in its reaction locus: that is, substantially degraded and embrittled samples will regain most of their ductility and toughness upon remolding. These results led the authors to conclude that the degradation reaction most probably was attacking the tie molecules in the amorphous domains surrounding the polypropylene crystals.

To simulate the postirradiation shelf life, very high surface area per unit mass must be created to facilitate the introduction and diffusion of oxygen. To this end, extruded solid filaments about 1.2 mm in diameter were first drawn and oriented to approximately 80% of the ultimate elongation. In nearly all cases, this resulted in a very porous, ultraoriented state. After irradiation with about 4 Mrd in a cobalt 60 source, testing was carried out immediately at ambient temperature. A specially constructed, multistation creep tester reported previously was used in this study; it is capable of running a maximum of six samples at different stresses simultaneously.5 A microcomputer logs any significant strain variations according to preset criteria. Upon completion of the experiment, creep rupture time tf is plotted against imposed stress on a semilog basis. A typical set of data is presented in Figure 4.

A brief summary of the factors contributing to tf would include: (1) stress imposed on the sample, (2) nominal radiation dose, (3) type of polymer (homo- or copolymer), (4) effectiveness of the stabilizer, and (5) type of radiation (dose rate). Clearly, the objective of using stress as the accelerating parameter instead of temperature has the merit of preserving and more accurately duplicating ambient aging reactions. By using a highly oriented sample, oxygen is freely available for degradation. At the molecular level, the following model can be proposed. The drawing process aligns most of the tie molecules along the stress direction. Some reorganization undoubtedly takes place, in the form of stress-induced recrystallizations and unraveling of the original crystal domains. The end result is a network of microcrystals connected together by fibrils aligned in the stress direction.6 Because the stress applied during the creep experiment is lower than that applied during sample preparation, additional crystalline-domain reorganization is not likely. Instead, the stress is borne at any cross section along the fiber by a large number of polymer chains mostly originated from the amorphous domain. A schematic model of the micromolecular stress distribution is shown in Figure 5.

Given the model just described, the creep-rupture process can be envisioned as follows. Free radicals created during the irradiation process combine with oxygen abundantly available in the matrix to form peroxides that cleave the tie molecules in the fibril under stress. Since all fibrils are mechanically connected in parallel, cleavage of any individual fibril would unload the stress on the remaining fibrils. The resulting higher state of average stress would lead to a greater probability of failure, and the process would accelerate until ultimate failure. Changing the chemical composition (through copolymerization with ethylene) would lead to a greater resistance to cleavage on individual tie molecules, and to readily measured improvements in rupture time. The use of stabilizer molecules would have a similar effect.

The data in Figure 4 can be extrapolated toward lower stresses to indicate failure times at these stresses, providing a quantitative accelerating prediction based solely on molecular behaviors. The validity of extrapolation and possibility of gross nonlinearities at low stress regimes can be verified only experimentally. Toward this end, we used existing real-time data to "calibrate" the approximate stress levels that are likely to exist in stored ambient-aged samples.

The failure at zero stress is the induction period for the auto-oxidation with freely available oxygen. This is the condition that existed in the topmost surface layer of the molded sample. Of course, due to oxygen diffusion, the interior of the thick samples suffered far less degradation. Nevertheless, there are situations in which surface embrittlement could lead to bulk failures, such as upon impact. The slope of the failure time (tf) versus stress line represents the reduction in failure time due to incremental increases in stress. This can be viewed either as an activation process for chain rupture--in which the external stress simply reduces the activation energy of the reaction--or as the distribution of stress-bearing chains capable of withstanding the stress for a given period of time. Added stresses would simply shift the distribution toward a shorter time. From the above analysis, one can deduce that the slope should be dependent on the polymer type, morphology, and chemical effectiveness of the stabilizer system, while the zero-stress intercept would be primarily dependent on the total number of tie molecules and the molar concentration of stabilizer molecules.

An examination of the data proves to be very helpful. In Figure 6, data from the same resin source, sample lot, and processing history were used. Following the orientation process, samples were subjected to (1) no radiation (control), (2) 4 Mrd of gamma at a dose rate of about 0.3 Mrd/hr, or (3) 4 Mrd of a 1-MeV electron beam at a dose rate of about 30 Mrd/min. The nearly identical slopes observed for all three samples indicated that the reaction chemistries are very similar. The gamma-irradiated sample had the lowest intercept at zero stress, indicating substantial degradation during and immediately after the irradiation. The electron beam­irradiated sample behaved significantly better than the gamma-processed sample. This is one of the first reported instances of clear-cut evidence that at higher dose rates, with limited oxygen availability, electron-beam irradiation can result in much longer shelf lives compared with gamma. Undoubtedly, free-radical recombination at higher temperatures as well as limited oxygen availability during the high-dose-rate event all played major roles in protecting the material.

CONCLUSION

Based on actual simulation experiments, it was concluded that relying on temperature alone to accelerate shelf-life aging conditions is unrealistic. Consideration must be given to critical material-performance parameters and, further, to the molecular basis for the origin of these factors. Properly designed experiments, especially with supporting data from parallel real-time monitoring, will lead to the most realistic predictions.

REFERENCES

1. Struik LCE, Physical Aging in Amorphous Polymers and Other Materials, New York, Elsevier, 1978.

2. Woo L, and Cheung YW, "Physical Aging Studies in Amorphous Poly(ethylene terephthalate)(PET) Blends,"Thermochimica Acta, 166:77­92, 1990.

3. Sandford C, and Woo L, "Shelf-Life Prediction of Radiation-Sterilized Medical Devices," in Proceedings of the 45th Annual Technical Conference & Exhibition (ANTEC), Brookfield, CT, Society of Plastics Engineers, p 1201, 1987.

4. Williams JL, "Stability of Polypropylene to Gamma Radiation," Polymer Preprints, 31(2): 318, 1990.

5. Woo L, Sandford C, and Walters R, "Recent Advances in Medical Plastics Analysis," in Advances in Biomaterials, Lee SM (ed), Lancaster, PA, Technomic Publishing, p 52, 1987.

6. Samuels RJ, Structured Polymer Properties, New York, Wiley, 1974.

Lecon Woo, PhD, is the Baxter distinguished scientist in the Medical Materials Technical Center at Baxter Healthcare (Round Lake, IL), where he specializes in biomedical polymer development and polymer rheology and processing. Before joining Baxter in 1982, he worked at Du Pont and Arco Chemical on polymer characterization and product development. A fellow member of the Society of Plastics Engineers, Woo holds more than 14 U.S. and international patents and has coauthored more than 70 technical papers and book chapters. Joseph Palomo is the senior principal engineer in the custom sterile division of Baxter's surgical group, specializing in surgical disposables product development. Michael T. K. Ling is senior technical specialist in the Medical Materials Technical Center. His research field includes medical product development, mechanical and physical analysis, and process development. The late Eddie K. Chan was formerly the senior principal engineer in Baxter's corporate Material and Membrane Technical Center. Craig Sandford, now at Viskase Corp., was formerly associated with the Medical Materials Technical Center, where he conducted extensive research on the effect of ionizing radiation on medical materials.

FACTORS IN SELECTING MEDICAL SILICONES

Medical Plastics and Biomaterials Magazine | MPB Article Index

Originally published March 1996

Because of their inherently low toxicity, pure silicones present a low risk of unfavorable biological reactions and have thus gained widespread industrial and medical recognition and acceptance. The current health-care market supports a small group of manufacturers of silicone raw materials, companies such as General Electric, Wacker, Bayer, Dow Corning, Rhone Poulenc, Shin Etsu, NuSil Technology, and Applied Silicone. The primary differences among these suppliers involve their level of testing and commitment to serving particular applications. Historically, concerns over potential liability have driven most large silicone manufacturers to aggressively exclude themselves from providing silicone intended to be used in the human body for more than 29 days. The author knows of only two suppliers willing to continue serving the long-term implantable silicone market: NuSil Technology and Applied Silicone.

Material Grades and Test Protocols

When referring to silicones, the device industry often uses designations such as "industrial grade," "health-care grade," "medical grade," and even "implant grade"--terms that are not universally accepted and that typically depend on a particular supplier's definition. When using these terms, one must make certain that the context matches the intent of the supplier. At present, there are four levels of testing that are generally recognized in the medical products business.

Food Grade. As defined in the U.S. Code of Federal Regulations 21 CFR 177.2600, "food-grade" requirements for silicones comprise a list of approved generic ingredients and additives along with prescribed test methods to evaluate candidate materials. Although it has in the past afforded a certain level of security, the food-grade status is currently not widely used or accepted for assessing silicones for medical applications.

USP Class VI. Designed primarily as a means of evaluating plastics used in drug packaging, "USP Class VI" refers to a battery of biological tests defined in USP XXIII, part 88. Any food-grade material--which means most silicones--that has passed this test series can be designated USP Class VI. The series is a four-part evaluation involving animal (mouse and rabbit) testing of extracts of saline, vegetable oil, alcohol, and polyethylene glycol along with a 5-day rabbit intramuscular implantation test. While this level of testing is widely used and accepted in the medical products business, the significance of the results and their level of safety assurance for medical devices are limited. For example, it would be possible for a material to pass USP Class VI while still showing up as cytotoxic, mutagenic, hemolytic, or sensitizing in other biological testing.

Medical Grade. The next level of testing is sometimes called "medical grade"--as defined by Dow Corning-- and is based on widely accepted industry practice. In addition to performing USP Class VI biological testing, tissue cell-culture testing and a 90-day rabbit intramuscular implantation test with histopathology are performed. Additional tests sometimes include skin sensitization, pyrogenicity, and hemolysis. What is not obvious, though clearly true, is that Dow Corning performed a host of other mechanical, chemical, animal, biochemical, cell-culture, and clinical evaluations to create the database for determining that its silicone formulations were safe for human implantation. As a result, the tests listed in Dow's medical-grade protocol were meant to be simply confirmatory, not to represent a universally accepted criterion to be used by any other vendor of silicones or other biomaterials.

Dow Corning Medical-Grade Equivalent. The fourth level of accepted testing, often referred to as "Dow Corning medical-grade equivalent," was created by the Silicone Task Force, set up in 1992 by the Health Industry Manufacturers Association (HIMA) with the cooperation and participation of FDA, which wanted to make sure that a continuing supply of implantable silicones would be available after Dow Corning announced it was withdrawing these materials from general distribution effective March 1993. The objective of the Silicone Task Force was to develop a testing scheme--including chemical, mechanical, and biological analyses--that could be used to identify silicones that were "not substantially different" from Dow Corning medical silicones--the predominant implantable silicones, widely recognized as biocompatible.

The task force's guidelines, completed in May 1993, were published by FDA in July 1993 as a supplement to the Federal Register, volume 58, N. 127. The required testing is very extensive and calls for special equipment and training; a copy of the results of a typical test summary comparing a Dow Corning medical-grade 50-durometer silicone to an alternative 50-durometer material is shown in Table I. The test methods, test results, and other information have been assembled into master files by the raw material manufacturers and filed with FDA. When given authorization by the raw material supplier, device manufacturers can reference these data to support claims that their products are safe and effective.

Master Files and Testing

FDA material master files have been around for a long time, and many suppliers of health-care silicones have provided such files to FDA. The difference between most material master files and those that comply with the May 1993 guidelines is that the latter are in a format that is almost universally acceptable for all silicone devices submitted to FDA. In addition to satisfying the agency's preference for only having to look at the data once, a device manufacturer referencing May 1993­compliant files can avoid having to repeat expensive and time-consuming preclinical physical, chemical, and biocompatibility testing and instead concentrate on device design and performance. Because preclinical testing of the chemical and toxicological properties will only address the biocompatibil-ity of a silicone material, however, manufacturers must always carefully evaluate the required clinical performance of the completed device when selecting or changing vendors of an implant-quality silicone.

The most recent FDA-endorsed level of testing was published in May 1995 and is becoming known as the "Blue Book memorandum." Based on ISO 10993, part 1 ("Biological Evaluation of Medical Devices"), the memorandum covers a variety of biomaterials from IV tubing sets to dental cements to long-term implantable devices made of metals, ceramics, plastics, and elastomers. This testing protocol replaces the Tripartite Guidance, a sometimes-confusing and often-misinterpreted document. ISO 10993 allows for a multidisciplined approach to material qualification. In cases where extensive, valid scientific data and clinical experience have clearly established the suitability of a material--such as pure silicone compounds for use in medical devices--some tests can be avoided. This is important, since a typical cancer/long-term toxicity testing program should not be entered into lightly because it generally requires approximately four years and a minimum of $250,000 to complete. Manufacturers should always consult a reputable toxicologist, who can often demonstrate safety for a given application using an existing database. Frequently, the required testing can be accessed through the raw material supplier's material master file.

Choosing a Supplier

When evaluating what level of materials testing is needed, a manufacturer of a device incorporating silicone should consider a number of factors: (1) Will the device reside in the human body for more than 29 days? (2) What FDA regulations apply? (3) What qualifications testing and lot-to-lot testing must be submitted to FDA? (4) What testing is available from the raw material supplier and what testing must the device manufacturer perform itself? (5) What will the qualification cost, and how long will such testing take?

A second list of questions must then be posed by the manufacturer when choosing a silicone supplier for its application: (1) Is the vendor willing to serve the market application? (2) Does the vendor have the required staff and facilities? (3) Does the vendor understand and follow good manufacturing practices (GMPs) as defined by 21 CFR 820? (4) Does the vendor have in place an adequate quality system, such as ISO 9000? (5) Is the vendor willing to formulate a product to meet the manufacturer's physical and processing requirements? (6) Is the vendor willing and able to provide the information required to perform the qualification testing and evaluation?

If the answers to any of the above questions are not clear, companies should find a consultant with direct experience in qualifying materials for medical devices. Poorly qualified consultants can cause unnecessary delays and expenses, so the individual's references should be checked and performance monitored carefully. When in doubt, the manufacturer should ask for a second opinion. Often, competent advice can be obtained at minimal cost from the raw material supplier or a biological test laboratory. A new resource is also available: at the HIMA Device Workshop in July 1995, Bruce Burlington, director of the Center for Devices and Radiological Health, and his reorganized FDA staff demonstrated both the commitment and the ability to support medical device manufacturers by making advisory staff available to answer questions and provide manufacturers with guidance in preparing device approval submissions. However, manufacturers should whenever possible avoid burdening either themselves or FDA with unnecessary or redundant testing.

Conclusion

Finally, a word must be said about the ongoing controversy regarding supposedly unsafe medical silicones. The implantable silicone business, and particularly Dow Corning, has been subjected to severe and unfounded criticism by the legal community. It is highly unlikely that hundreds of scientists working over a period of nearly a half century could have overlooked obvious serious problems with silicones. As additional valid science has become available, the alleged silicone­autoimmune disease connection has been found to be as real as cold fusion.1 Recent reports from the New England Journal of Medicine,2 the American College of Rheumatology,3 and the British Institute of Health4 confirm that properly formulated silicones are among the most biocompatible materials available.

References

1. Taubes G, "Silicone in the System," Discover, December, pp 65­75, 1995.

2. Gabriel SE, O'Fallon M, Kurland LT, et al., "Risk of Connective-Tissue Diseases and Other Disorders after Breast Implantation," New England J Med, 330 (24):1697­1702, 1994.

3. American College of Rheumatology, "Statement on Silicone Breast Implants," October 22, 1995.

4. Tinkler JJB, Campbell HJ, Senior HJ, et al., "Evidence for an Association between the Implantation of Silicones and Connective Tissue Disease," Medical Devices Directorate Report no. MDD/ 92/42, February 1993.

Alastair Winn has been in the business of manufacturing silicone for medical device manufacturers since 1974. He is president of Applied Silicone Corp. (Ventura, CA) and has served as an active member of the HIMA Silicone Task Force and ASTM F04.

Achieving Precision Tube Extrusion for Medical Applications

Medical Plastics and Biomaterials Magazine | MPB Article Index

Originally published March 1996

EXTRUSION

JOHN COLBERT

Plastics have been used in medical devices for more than 40 years, from the time that plasticized PVC first replaced natural rubber and glass. Since then, rapid developments in technology have stimulated the increased use of plastics in a variety of medical applications. The global market for medical devices currently exceeds $100 billion, with average annual growth rates of 8%. In Western Europe and the United States, the advent of better health care has resulted in a higher proportion of both very young and aging populations--groups that form the majority of those receiving treatment by invasive surgical and after-care techniques. Along with the recent rise in infectious diseases, this trend has led to a substantial increase in the use of presterilized, disposable medical products.

Many medical procedures involve the transfer of fluids to or from the patient, and employ a wide range of flexible tubing products. Examples include taking/giving sets (for transfusion, infusion, dialysis); catheters (intravenous, cardiovascular); endotracheal tubes (for intubation or anesthesia); tracheostomy tubes; and cystoscopy instruments.

Although the use of plastics in medical applications represents less than 2% of total consumption, the high "added value" of the final products is of considerable commercial interest to material suppliers and end processors. In achieving this value, the medical market makes stringent quality demands on manufacturers that require a commitment to continuous material and process development. This is particularly true for current extrusion technology used to produce a wide range of disposable medical devices.

Today's extruded medical products require the careful application of precision processing concepts, especially for multilumen, microbore, coextruded, or cross-head- extruded tubes, for which the diameter tolerances can be as small as ±5 µm. Such products are part of the increasing trend toward minimally invasive surgery, examination by miniaturized optics, or microsurgery using laser techniques. Catheter tubes are also receiving attention, with tighter tolerances being set on tube dimensions. With medical plastic compounds costing as much as $10,000/tn, large cost savings can be an added incentive to attaining higher levels of accuracy in tube extrusion.

MATERIALS

A considerable variety of materials are available for medical tube extrusion, with properties to satisfy most end-user requirements while meeting strict regulations relating to biocompatibility and nontoxicity. PVC remains the leading polymer for medical tubing, with polyurethane, polyolefins, and blends or alloys such as thermoplastic elastomers also commonly used. For more demanding applications, engineering plastics such as polyamide/imide, polyester, polycarbonate, or various fluoropolymers can be selected. Many resins can be compounded with optical or x-ray opacifiers such as titanium dioxide, barium sulfate, or bismuth subcarbonate, further increasing the number of potential materials and grades. The challenge for manufacturers is to find the optimum processing conditions enabling each grade to produce high-quality, close-tolerance tubing capable of being run in a single operation at acceptable outputs.

Predrying of hygroscopic or moisture-sensitive materials--for example, polyurethanes, polyamides, and polyesters--is essential, particularly if high levels of inorganic filler are present.

When various types of wire are fed via a cross-head die, certain wire-conditioning stages are required to ensure that an accurate and consistent payout rate and tension are maintained on the wire. These may include a tension-controlling dancer, wire cleaner, wire preheater, or wire straightener.

EXTRUDER DESIGN

In order for a manufacturer to offer precision medical tube products, the various parts of the extrusion process need to be operated under optimized and integrated conditions. The layout of a typical medical tube extrusion line is shown in Figure 1.

The matching of extruder screw design to the melting and rheological characteristics of the plastic to be processed is fundamental to extruder performance. Screw design is a complex subject, but most screw elements fall within the ranges presented in the box shown below. The key extrusion criteria of output, plasticization, solids conveying, and power consumption are influenced by screw design variables such as channel depth, number of flights, helix angle, compression ratio, flight clearance, and flight geometry.

There is no such thing as a "general-purpose" screw. For medical tube production lines--which demand high levels of quality and performance--it is often sensible to carry a library of screws that suit all of the materials or grades used and to introduce screw changes as a standard procedure at each material change. Since it is rare to find more than four different polymer types used on the same production process, screws designed specifically for the polymer type are normally supplied.

Because medical-grade PVC contains low levels of plasticizer and stabilizer, a different approach is required than that used for cable-grade PVC. The mixing performance of the screw is very important in ensuring sufficient gel reduction to promote high clarity. An amorphous polymer, PVC has a very wide melting range, from 100° to 210°C. As a result, when processed at temperatures below 210°C, gels in the form of unmelts will always be present and must be removed by shear breakdown, higher temperatures, or screen filtration. Conversely, PVC begins to give off HCl gas when the degradation point is reached, which can occur above temperatures as low as 120°C. Unless "mopped up" by heat stabilizers, these "chain-scission" reactions result in discoloration and rapid thermal degradation at around 230°C.

For these reasons, several proprietary multiflighted barrier screws have been developed for PVC. All operate by confining the solid bed to the active side of the barrier flight, while the polymer melt is allowed to flow over the barrier flight into the passive side of the screw channel. This type of screw, if well-designed, ensures complete melting, often over a reduced length of screw, and offers enhanced mixing due to the high levels of shear developed through the barrier clearance. Various designs based on this theme are used, for example, in the Maillefer, Barr, Dray and Lawrence, Kim, and Inger Housz screws.

Fluoropolymers such as FEP need special materials for screw and barrel elements in order to overcome extremely corrosive hydrofluoric acid degradation products. Special corrosion-resistant alloys are often used--for example, Hastelloy for screws, and iron-free nickel/brass/chrome alloy bimetallic lining for barrels. It is important that the iron content be kept to less than 1% so as to eliminate melt contamination caused by iron-based specks that can form in corrosive environments.

DIE DESIGN

A crucial component of the overall extrusion process for medical tube production is the die. Different sets of tooling are often used, with varying pin and bush dimensions, to match the rheological characteristics of the chosen polymer at the defined output rate and line speed. Also, streamlined flow paths are used to prevent holdup within the die, and to minimize degradation and dwell time. Thus, approach angles in the die adapter should be as low as possible, and all changes in section geometry should be radiused.

Dies should be designed for uniform flow of material, producing uniform product with minimal internal stresses. Many postextrusion properties of tubing are related to the viscoelastic nature of the polymer and the level of shear deformation that occurs during die shaping. Elastic recovery causes die swell, and tube reversion or poststerilization shrinkage can result from poorly designed dies.

Given the small dimensions of many intricate multilumen tubes (see Figure 2), high drawdown ratios are often employed to allow die dimensions to be large enough to be practical. With PVC and PUR, however, reversion specifications are critical, and reversion reduces with lower drawdown ratios. Thus, the design and manufacture of small-diameter PVC or PUR tubing becomes more difficult. By contrast, high drawdown ratios can be used with PA and many fluoropolymers, which are therefore more commonly specified for precision microbore or multilumen tubes.

Many tubes incorporate a colored and/or x-ray-opaque stripe down their length to aid in identification or for precision insertion and inspection. The stripes are produced by coextruding another material into the tube die from a second extruder. It is possible to create external or internal surface stripes or to fully encapsulate the stripes in the tube wall to prevent leaking of additives.

The production of precision multilumen tubes or the insertion of forming wires or guidewires requires cross-head die extrusion. In this process, the polymer melt enters the die at right angles to the outlet, which allows lumen characteristics to be controlled by individual, pressurized air supplies fed from the back of a cross-head die and into the tube via precision-bore injector needles. Forming wires are inserted through a cross-head die in a similar way. Because of the very fine gauge of wire used, wire payout systems may include units to control and monitor wire diameter and tension.

Dies are normally stainless steel, which must be hardenable and capable of achieving a good polish. In the case of fluoropolymers, Hastelloy C should be used for all components likely to come into contact with the molten material.

TUBE SIZING

To ensure that a manufacturer's multilumen tubing will sustain precise flow levels, the extrusion process must include some means of maintaining the consistency of all tube dimensions. A typical tolerance range is ±1%, which for a tube with an internal diameter of 1.6 mm translates to accuracies of ±10 µm (the diameter of an average human hair is only 75 µm).

Increasing product accuracy will lead to significant reductions in material usage and resultant cost savings. For example, reducing the tolerance from ±0.08 mm down to ±0.01 mm on a 1.00-mm-ID tube with a 0.225-mm wall thickness yields material savings of 12.5%. Assuming material costs of approximately $10,000/tn, this would represent cost savings of $12.50/hr at a 10 kg/hr production rate.

Outside diameter is controlled by vacuum calibration. Most extruders feature accurate low-level vacuum control, which keeps the outside diameter of the tube stable.

Internal lumens must also be accurately controlled. In a multilumen tube (see, e.g., Figure 3), each lumen has a defined end use, with the cross-sectional area controlling the flow rate, a minimum internal diameter for guidewire insertion, and shape-related draw characteristics for postforming operations. There are two principal methods used for controlling the shape of each lumen. In the first, bore-forming mandrel wires can be inserted temporarily into the tube: as the polymer overlays the mandrels, accurate lumens can be formed by removing the precision-gauge wires after cooling. Alternatively, separate air-pressure control for each lumen can be achieved by using air injection needles. Recent developments in low-pressure regulators along with an increased understanding of such instruments make it possible to accurately adjust and maintain pressure differentials at low pressures. For example, a pressure of 0.017 bar can be maintained to within ±0.002 bar. The relative flow rate required to maintain lumen size at a given die speed can be computed, but care must be taken to ensure that the air supply used for pressure regulation is subject to the same influences as the ambient air surrounding the extrusion line.

POLYMER MASS FLOW

To accurately maintain diameter and wall thickness of intricate polymer tubes, a uniform flow rate of melt from the extruder must be guaranteed. All extruders producing extremely tight tolerances will exhibit some surging as a result of electrical drive control fluctuations, screw design, and the normal rheological variation in the polymer. Clearly, high reject rates and waste levels will result if the process relies solely on the extruder stability. To overcome this, a precision rotary gear pump is used to provide steady pressure and accurate metering of the polymer to the die head in a controlled, surge-free manner.

The melt gear pump consists of a pair of precision-ground, closely intermeshing gears and acts as a positive-displacement pump to supply melt at a set volumetric rate. The pump is driven by a dc motor with tachogenerator feedback and voltage-regulator control, providing speed holding to ±0.01%. A rapid-response, closed-loop microprocessor controller senses the melt pump inlet pressure--or pressure differential across the pump--and automatically adjusts the extruder speed to maintain a constant value.

Placed between the extruder and the die, this pump becomes the main extruder control device, minimizing the inefficiencies inherent in conventional extrusion operations. Discharge pressure, and hence mass-flow variations, can be held to less than 1%, yielding greater dimensional accuracy.

PRODUCT HAUL-OFF

Each extruded tube is pulled through a cooling bath by a precision haul-off unit. For tubes less than 2 mm in diameter, a capstan haul-off gives the best tension control, whereas caterpillar haul-offs are used for larger tubes. Good motor speed control is required, as drawdown ratio and haul-off speed are fundamental for forming accurate small-diameter tubes. Dc motors with tachogenerator feedback and digital speed-loop control can offer speed holding to better than 0.01%. The tube product is then cut to length in-line, or coiled into reels. To retain precision profile and uniform properties, care must be taken to ensure that product collection imparts only low longitudinal tension to the product.

LINE CONTROL

When a manufacturer is working to the accuracies outlined above, all process parameters must be under close control, and constant monitoring is required to ensure compliance with such demanding specifications. Historically, this has involved process data logging and off-line product measurement. However, current trends are toward on-line, real-time monitoring of key parameters so as to achieve "processed-in quality." Automatic control of processing parameters is therefore used to keep the product within specified quality limits.

Precision tube products must be made correctly the first time, every time. This means that the manufacturing process must be stable, and that all personnel involved with the process must seek to improve process performance and reduce variability in the key parameters. However, no process can be controlled until one knows what to measure and how to measure it. Therefore, the first step is to determine how to measure quality, and then identify which process variables can be manipulated to influence that quality. The key quality parameters in medical tube production are dimensional stability and tolerances on all dimensions. The relationships presented in Figure 4 offer the potential for closed-loop control mechanisms, with feedback loops being controlled by high-precision equipment for gauging tube dimensions.

Laser gages offer accurate and rapid measurement of outside diameter by measuring a shadow created when the tube obscures a fine beam of rapidly scanning light. Dual-plane laser gages measure OD in two planes, providing both average OD and ovality with a resolution of 1 µm.

Gamma backscatter probes use gamma-radiation backscatter to determine wall thickness down to 0.05 mm (with a resolution of 1 µm) for tubes with diameters as small as 1 mm. Probes measure wall thickness at a single point around the tube; a number of probes can be used if measurements of multiple points around the diameter are required.

Ultrasonic reflection involves aligning the product in an ultrasonic gage placed in a water bath and arranging transducers (typically four) around the product. Each transducer sends out a transmission pulse that is partially reflected off the outer wall of the tube. While the partial reflection returns to the transducer, the remainder of the initial transmission pulse continues through the product wall. The difference in density between the air and the product creates a second reflection, and the time differential between the two pulses allows wall thickness to be calculated. Enhancing the signal with digital processing can allow measurement to an accuracy of ±5 µm of tubes as small as 1.0 mm OD, with wall thicknesses of 0.13 mm or less.

Statistical process control (SPC) can be achieved by using measuring instruments such as those discussed previously. Data can be gathered (typically at 100 scans/sec) and rapidly converted by a process controller to provide waveform readings or live trend charts. When the data are viewed statistically, deviation trends can be seen, allowing process adjustments to be made by a control feedback loop. The most advanced current technology allows two independent loops to be used (see Figure 5). Typically, one loop controls haul-off or screw speed and the other controls air pressure or vacuum. Any two of the product dimensions may thus be controlled at any one time. SPC control-group data and functions can be used to improve the process capability indices relating to a product's dimensional accuracy (see Figure 6).

FUTURE DEVELOPMENTS

Closed-loop control methods have led to major advances in the extrusion of precision tubes for medical and health-care applications. However, the extrusion process is complex and interactive, and attempts at using multiple control loops have invariably led to instability.

Given the power of modern microcomputer systems, it is now possible for extrusion specialists to work in real time with multiple-interaction algorithms. There are signs that, in the near future, this real-time control may allow for "intelligent processing" in the demanding field of precision small-diameter medical tube production.

John Colbert is technical director of Betol UK (Luton, Bedfordshire, UK), where he specializes in all types of extrusion as well as general polymer processing. Betol manufactures twin screws for compounding and complete extrusion lines for the production of fine-tolerance tubing and multilayer film and sheet.

The Device Industry Looks Up--and to the East

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published March 1996

Although grousing about FDA remains prevalent in the medical device industry--I still get the occasional wild-eyed letter flogging MD&DI for featuring interviews with the "enemy" FDA--it's been refreshing this year to see that the industry is equally quick to acknowledge and reinforce improvements in FDA performance.

As indicated in this year's business climate survey, beginning on page 60, last year may well prove to have been an important turning point in the relationship of FDA and industry. Our evidence shows that the device industry is encountering fewer FDA delays in 510(k) reviews and that changes in FDA policies and procedures are improving prospects for many companies.

Discussing these results with medical device industry representatives last month at the MD&M West meeting in Anaheim, CA, I was interested to find that most shared the upbeat assessment of our survey respondents. Clearly the agency has some distance yet to go to meet the statutory benchmarks for product approvals, but the improvements to date have made an important difference.

To me, another striking finding of our survey is that industry is not only looking up, but looking to the East. As noted in this issue on page 65, the interest of device company executives in the markets of the Asian Pacific Rim has risen dramatically during the four years we've been conducting this survey.

In 1993, just 14% of the respondents cited Pacific Rim markets other than Japan as top growth markets for their companies. This percentage shot up to 24% last year, and 35% this year. Among executives at large medical device companies, the East Asian market outside Japan is cited as a top market more often than any other except the United States.

A representative view is expressed by Roger Stoll, president and CEO of Ohmeda, in MD&DI's Executive Roundtable, beginning on page 68. He notes that "there's tremendous growth taking place in those areas, and as economies grow there's a commensurate desire for expanded and more-sophisticated health-care capabilities." By comparison, he adds, the United States, Europe, and Japan are stable markets with only nominal growth. Accordingly, Ohmeda is putting an emphasis on expansion into Asia.

Now, if you're an executive at a small medical product company--the kind that dominates the U.S. device industry--you may be thinking, "Going to Asia is fine for the big boys, but how can I do it?" I had a chance to discuss this question with Ames Gross, a frequent contributor to MD&DI and the president of Pacific Bridge (Washington, DC), a firm that helps U.S. businesses break into Asian markets.

Ames recommends that small companies start by building up a distributor network in such East Asian markets as Hong Kong, Singapore, Malaysia, Thailand, and Indonesia. This process, he says, can be completed in about a year for a cost of $50,000 to $100,000. Because companies will need to see some return on their investment relatively soon, he suggests not going to Japan until business develops in smaller markets.

Building up business in Asia requires a lot of attention, he adds, but the payoff in the long run will be worth the effort. Indeed, according to Ames, the time to enter the Asian market is now, when the competition is still relatively sparse. Wait too long, he says, and your competition may end up using Asia as a base for beating you in the U.S. market.

John Bethune

Literature Review: Biological Safety of Parylene C

Medical Plastics and Biomaterials Magazine | MPB Article Index

Originally published March 1996

COATINGS

NANCY STARK

A typical acute biological-safety testing profile, as specified in FDA's General Program Memorandum G95-1, can cost in the neighborhood of $6000 and require 90 days to conduct. Subchronic, chronic, and carcinogenicity testing can add several thousand more to the price tag, and there is no guarantee that a material will pass the tests or that the test results won't raise further questions.

Some manufacturers are turning to biological-safety literature reviews as a way of predicting the outcome of safety tests, and of sparing themselves the effort of rediscovering already established information. The article that follows is an example of such a technical report on the surface coating parylene C.

Biological-safety literature reviews are not a new concept. Memorandum G95-1 states that "some devices are made of materials that have been well characterized chemically and physically in the published literature and have a long history of safe use. For the purposes of demonstrating the substantial equivalence of such devices to other marketed products, it may not be necessary to conduct all the tests suggested in the FDA matrix of this guidance." The implication is that a suitable literature survey may suffice to establish substantial equivalence. Investigational device exempion submissions may also require biological-safety reviews. The report of previous investigations must include all prior animal and laboratory testing, including summaries and bibliographies. A 510(k) summary should also include a review of the biological-safety literature when such a review helps support the argument of substantial equivalence. "The summary of adverse safety and effectiveness data . . . should be based upon a reasonable search of all information known or otherwise available. . . . "

FDA's Procedures for Obtaining FDA Approval to Export Unapproved Medical Devices requires a manufacturer applying for an export permit for an unapproved device to submit (1) a statement certifying that a search of Medlars and Dialog databases has been made to identify adverse safety data for similar devices; (2) a summary of adverse safety data; and (3) a summary of available animal safety data. These requirements are intended to enable FDA to determine that export of the device is not contrary to public health and safety.

The ISO/DIS 10993 Part 1--Guidance on Selection of Tests emphasizes that the decision as to whether or not a certain test is performed should be based on the individual characteristics of the material or device under consideration, and that not all tests are necessary or practical for a given material or device. On the other hand, the document also stresses that additional tests not listed in the guidance may be important.

Clinical investigations of medical devices in Europe, per EN 540, require preparation of an Investigator's Brochure that includes, among other things, "a description of the materials used in the device; a summary of the in vitro, ex vivo, and in vivo data relevant to the device; preclinical biological studies; nonclinical laboratory studies; and any animal studies." The Investigator's Brochure shouldn't simply contain a summary of work conducted by the manufacturer, but a literature survey of all known information. Clinical investigations of medical devices subject to ISO 14155 face a similar requirement, in that the Investigator's Brochure must include "a collection of all relevant information known prior to the commencement of the clinical investigation."

When a company applies to market medicinal products in Europe, the European Commission requires the submission of three Expert Reports in the areas of chemical, biological, and pharmaceutical evaluation; pharmacological and toxicological evaluation; and clinical evaluation. While these rules don't apply to medical devices, they bring to light the extent to which the European Union relies on technical reports.

How do you go about conducting a literature search on a material or a device, and what do you look for once you've got one? You'll need access to a computer and modem and an account with a host information provider such as Dialog (Knight-Ridder Information Services, 415/858-3810) or Medlars (National Library of Medicine, 800/638-8480).

As a first step in Dialog, do a quick search in a database called DialIndex. Enter the name of the material or device of interest in DialIndex and it will provide a summary of the number of "hits" in every other database in the Dialog system. The DialIndex search is fast and inexpensive (a couple of dollars) and will tell you quickly whether or not there is any information available about your material or device.

From the DialIndex summary you can tell which databases to search for further information. Those most likely to contain biological safety information are Medline, Toxline, Diogenes, F-D-C Reports, Health Devices Alerts (a very important database covering all medical device reports submitted to FDA), Biosis, Ei Compendex*Plus, and CA Search--all databases available through Dialog. Next, print out the abstracts for each of the "hits" located through the on-line search.

Now the work begins. Each abstract must be read and processed: did the author perform a biological-safety test, a subchronic-safety test, or a chronic-safety test, and report on the outcome? Every instance of biological safety or biological toxicity should be tabulated for the technical review. Many times, the abstract will indicate that safety work was conducted, but the data are in the body of the article. In these instances, the entire article must be obtained from a supplier, and reviewed. In addition, manufacturers and suppliers of the materials should be contacted for toxicity summaries and technical information. Sometimes, even basic textbooks can be consulted to ensure that chemical formulas or other fundamental items are correct.

Finally, the information is assembled into a biological- safety technical report that follows a logical, user-friendly format. The format of the parylene C report is modeled after the Toxicological Expert Reports required by the European Commission's Rules Governing Medicinal Products. The report consists of an introduction giving general technical, chemical, and processing information about the material; a section reviewing the findings on material degradation; a section summarizing the biological-safety data reported in the literature; a section summarizing the medical device reports sent to FDA; a recommended test profile based on General Program Memorandum G95-1; a conclusion; and, finally, the references and citations for each item of data mentioned.

Apart from its multiple uses, taking the time to generate a biological-safety technical report before actual animal testing is undertaken can give the manufacturer a solid sense of the material under investigation. The material's suitability for the current application or other uses, subtle performance problems, and biological-safety profile can all be evaluated in advance to ensure the responsible use of animals in testing.

The following document is the biological-safety literature review on parylene C.

INTRODUCTION

Parylene C is the polymeric form of the low-molecular-weight dimer of para-chloro-xylylene. Supplied by Specialty Coating Systems (Indianapolis), parylene C can be deposited as a continuous coating on a variety of medical device parts to provide an evenly distributed, transparent insulation. This deposition is accomplished by a process termed vapor deposition polymerization, in which dimeric parylene C is vaporized under vacuum at 150°C, pyrolized at 680°C to form a reactive monomer, then pumped into a chamber containing the component to be coated at 25°C. At the low chamber temperature, the monomeric xylylene is deposited on the part, where it immediately polymerizes via a free-radical process. The polymer coating reaches molecular weights of approximately 500,000.

Deposition of the xylylene monomer takes place in only a moderate vacuum (0.1 torr) and is not line-of-sight. That is, the monomer has the opportunity to surround all sides of the part to be coated, penetrating into crevices or tubes and coating sharp points and edges, creating what is called a "conformal" coating. With proper process control, it is possible to deposit a pinhole-free, insulating coating that will provide very low moisture permeability and high part protection to corrosive biological fluids.1

Primer--A-174. Parylene C adherence to substrate metals is not sufficient to achieve the necessary lifetimes required of many implants. Adherence is a function of the chemical nature of the surface to be coated. Yamagishi reported that tantalum and silicon surfaces could be overcoated with silicon dioxide, then with plasma-polymerized methane, and finally with parylene C to achieve satisfactory adherence.2

Pretreatment with a dilute methanol-water solution of the organic silane gamma-methacryloxypropyltrimethoxysilane (A-174) prior to parylene coating is the recommended surface preparation.3 Clean metal surfaces are inorganic. Parylene monomers are organic, and do not bind readily to the electron-rich metallic surface. The organic silane has both inorganic and organic molecular surfaces. During the priming operation, the inorganic surface of the A-174 binds permanently to the inorganic metal, presenting an organic face to the incoming para-chloro-xylylene monomers.

Applications. Most applications of parylene C coating in the medical device industry are for protecting sensitive components from corrosive body fluids or for providing lubricity to surfaces. Typical anticorrosion applications include blood pressure sensors, cardiac-assist devices, prosthetic components, bone pins, electronic circuits, ultrasonic transducers, bone-growth stimulators, and brain probes. Applications to promote lubricity include mandrels, injection needles, cannulae, and catheters.

MATERIAL DEGRADATION

Parylene C is extremely stable chemically and biologically. It is also electrically stable; that is, it does not degrade in the presence of electrical current and is an effective electrical insulator.4 In addition, it is stable to organic-solvent attack, being insoluble in all organic solvents up to 150°C.5 Finally, it is thermally stable and can be expected to survive continuous exposure to air at 100°C for 10 years.6 No known biological degradation reactions or pathways have been reported.

There have been reports of parylene C undergoing stress cracking after repeated cyclic stressing. Parylene-coated wires were mechanically stressed in a flex stress machine and analyzed for current leakage, which was shown to increase as a result of repeated cyclic stressing.7

Schmidt reported stress cracking and pinholing of parylene C after a period of implantation. He implanted 11 parylene C­coated microelectrodes in the dural matter of 6 monkeys in order to monitor neural responses, and found that the impedance of 8 of the 11 electrodes fell drastically within a few months of implantation.8 Explantation and scanning electron microscopy revealed longitudinal stress cracking in the parylene C coating of some of the electrodes. Others exhibited surface craters (pinholing). The remaining 3 electrodes were still operational upon explantation after 3 years.

BIOLOGICAL SAFETY

Acute Tests. There are numerous references to parylene C as biocompatible, but very few actual data show up in the literature. Negative cytotoxicity results have been reported by Ibnabddjalil9 and Bondemark.10 Cell-growth studies using WI-38 cells have been reported by Burkel.11 In that study, either nylon, polyester, or polypropylene microfibers were coated with parylene C and seeded with WI-38 cells. The cells produced from 54 to 100% coverage of the scaffold, depending on the microfiber composition, indicating good compatibility of parylene C with human cell growth.

Blood-compatibility studies have also been reported. Baskin observed that a parylene C coating on polypropylene/polyurethane fabric rendered the fabric nonthrombogenic.12 Blood coagulation was investigated by Kanda, who found that the clotting time was longer for parylene C­coated substrates than for ceramics, aluminum, glass, or substrates coated with silicone or parylene N.13

Test reports on acute systemic toxicity, intracutaneous toxicity, and 5-day implantation have been disseminated.14 The acute systemic toxicity tests, the intracutaneous toxicity tests, and the macroscopic examination of the 5-day implant test were all negative. (No microscopic examination was conducted.)

Finally, there is one report of a severe inflammatory

reaction with a parylene C­coated substrate, although the authors of the study believe the reaction was probably due to an infection in the test rabbits.15

Subchronic and Chronic Tests. There are four reports of long-term cerebral implantation tests using various substrates coated with parylene C. Yuen reported that parylene C­coated materials exhibited little tissue reaction after 8 and 16 weeks of implantation in the cerebral cortex of the cat.16 Hahn reported moderate reactivity after 8 weeks of meningeal implantation in the rabbit.17 Loeb implanted parylene C­ coated microelectrodes into the cerebral cortex of monkeys for 4 months; the long-term presence of electrically active neurons within microns of the plastic surface provided evidence of parylene's biocompatibility.18 Schmidt reported no untoward reactions following implantation of parylene C­coated substrates after 3 years in the motor cortex of monkeys.8

MEDICAL DEVICE REPORTS

Although parylene C­coated devices have been used for more than a decade, only two reports of device malfunctions mention parylene C. The first dates from 1984 and describes a "void in the parylene coating" of an explanted pulse-generator electrode that had been causing pectoral-muscle stimulation in the recipient patient.19 The second dates from 1986 and describes "slight erosion of the parylene coating on the lower edge" of an explanted cardiac pacemaker lead.20 Neither report mentions any biological incompatibility.

BIOCOMPATIBILITY OF A-174

The manufacturer has provided a toxicology summary of A-174, hav- ing conducted eye-irritation, oral and dermal LD50, vapor-inhalation, Ames mutagenicity, Chinese-hamster ovary-mutation, sister-chromatid-exchange, blastogenicity, and aerosol-exposure studies.21 All test results were negative, except that repeated aerosol exposure resulted in granulomatous laryngitis.

RECOMMENDED TEST PROFILE

Test Article. The quantity of parylene C coated onto a device is often quite small. Rather than test actual--and expensive--final products, it may be more practical to fabricate simulated devices of larger dimensions for test purposes. For example, a substrate representative of the fabricated device could be primed with A-174 and coated with parylene C--a less-costly but satisfactory test article so long as the manufacturing process used in the final product is followed exactly. Both parylene C and A-174 can be evaluated in the same tests.

Microtests. Many biocompatibility tests can be run on a "micro" scale, reducing the weight and surface area of test articles needed to conduct the tests yet still maintaining the recommended ratios of test article to extractant. Microtest protocols are recommended wherever possible to further reduce the amount of test article required.

ISO 10993/Tripartite Biocompatibility Guidance. Parylene C­coated devices are frequently permanent, blood-contacting implants. It is worth noting that the quantity or "dose" of material that is likely to be implanted in any one patient is extremely small, possibly on the order of micrograms. However, because the implants are permanent, the device manufacturer is required to consider the profile of biocompatibility tests described in FDA's General Program Memorandum G95-1 (see Table I).

Additional Testing. There are a few other concerns with regard to the biological safety of A-174/parylene C­coated materials that are not adequately addressed through the ISO/Tripartite standards. These have to do primarily with process control. Final, manufactured product should be examined via appropriate analytical chemistry techniques for the presence of unreacted dimers of para-chloro-xylylene, and the manufacturing process adjusted and controlled so that the dimer is essentially absent. Fourier-transform infrared spectroscopy or gas chromatography/ mass spectroscopy can be useful detection techniques. A sampling of final product should also be examined under an SEM to ensure a lack of pinholes, stress cracks, or other breaks in coating integrity. For microelectrodes, it may be possible to use a bubble test, in which the electrodes are immersed in a saline solution and subjected to a current; any subsequent hydrogen evolution indicates a break in a coil insulation.8 In all such cases, the thickness of the coating must be established and controlled to ensure adequate electrical insulation.

CONCLUSION

There is a general belief, and it is probably true, that parylene C is biocompatible and nontoxic. The notable absence of untoward reactions associated with more than a decade of medical use supports this belief. On the down side, however, there is a substantive lack of published evidence available to support parylene C biocompatibility.

ISO/Tripartite Required Tests Recommendation

Cytotoxicity Conduct -- While there are several examples of cytotoxicity tests in the literature, this fast, inexpensive test provides good baseline information for future process checks.

Sensitization Conduct -- There are no cited examples of sensitization testing. The probability of passing the test is high, however, since there are no suspected incidences of sensitization associated with the material.

Irritation or intracutaneous Omit -- There is no need to repeat an intracutaneous test, since there is little opportunity for variability in the formulation of parylene C and the manufacturer has provided recent data for this test.

Acute systemic toxicity Omit -- There is no need to repeat an acute systemic toxicity test, since there is little opportunity for variability in the formulation of parylene C and the manufacturer has provided recent data for this test.

Subchronic toxicity Omit -- There are four examples of long-term (weeks to years) implantation studies in the literature and a notable lack of associated, untoward reactions.

Genotoxicity Omit -- Genotoxicity depends on a chemical reaction taking place between cellular DNA and leached or degraded components from the implanted material. Assuming there are no contaminating dimers, this test can be omitted, since A-174 is nonmutagenic and there is substantial chemical evidence for parylene C stability and lack of reactivity.

Implantation Conduct 7-day test with microscopic examination -- While there are several examples in the literature of cerebral implantation tests and cellular "health" at the site of implantation, there are no examples of muscle implantation. The manufacturer has supplied a 5-day muscle-implantation test with negative results, but it lacks a histological (microscopic) examination.

Hemocompatibility Omit -- Depending on device application and quantity of parylene C exposure. The literature indicates that the material is nonthrombogenic.

Chronic toxicity Possible -- However, the long-term effects of the device as a whole outweigh the toxicity effects of implanting microgram quantities of A-174 and parylene C. Consider a postmarket surveillance study.

Carcinogenicity Omit -- Carcinogenicity depends on a chemical reaction taking place between cellular DNA and leached or degraded components from the implanted material. Assuming there are no contaminating dimers, this test can be omitted, since A-174 is nonmutagenic and there is substantial chemical evidence for parylene C stability and lack of reactivity.

REFERENCES

1. Parylene Conformal Coatings Specifications and Properties, Indianapolis, Specialty Coating Systems, p 3, 1994.

2. Yamagishi FG, "Investigation of Plasma-Polymerized Films as Primers for Parylene-C Coatings on Neural Prosthesis Materials," Thin Solid Films, 202(1):39­50, 1991.

3. Parylene Conformal Coatings Specifications and Properties, Indianapolis, Specialty Coating Systems, p 10, 1994.

4. Ibid, pp 4­5.

5. Ibid, p 8.

6. Ibid, p 7.

7. Nichols MF, "Flexible and Insulative Plasmalene Wire Coatings for Biomedical Applications," Biomed Sci Instrum, 29:77­86, 1993.

8. Schmidt EM, McIntosh JS, and Bak MJ, "Long-Term Implants of Parylene-C Coated Microelectrodes," Med Biol Eng Comput, 26:96­101, 1988.

9. Ibnabddjalil M, Loh IH, Chu CC, et al., "Effect of Surface Plasma Treatment on Chemical, Physical, Morphological, and Mechanical Properties of Totally Absorbable Bone Internal Fixation Devices," J Biomed Mat Res, 283:289­301, 1994.

10. Bondemark L, Kurol J, and Wennberg A, "Orthodontic Rare Earth Magnets--In Vitro Assessment of Cytotoxicity," Br J Orthod, 21(4):335­341, 1994.

11. Burkel WE, and Kahn RH, "Cell-Lined, Nonwoven Microfiber Scaffolds as a Blood Interface," Annals--NY Acad Sci, 283:419­437, 1977.

12. Baskin SG, Navarro LT, Sybers HD, et al., "Tissue Cultured Cells: Potential Blood Compatible Linings for Cardiovascular Prostheses," Polym Sci Tech, 14:143­151, 1981.

13. Kanda Y, Aoshima R, and Takeda A, "Blood Compatibility of Components and Materials in Silicon Integrated Circuits," Electron Lett, 17(16):558­559, 1981.

14. Reports provided by Union Carbide, the parylene manufacturer at the time these tests were conducted in 1992.

15. Ansbacher L, Nichols MN, and Hahn AW, "The Influence of Encephalitozoon cuniculi on Neural Tissue Responses to Implanted Biomaterials in the Rabbit," Lab Anim Sci, 38(6):689­695, 1988.

16. Yuen TG, Agnew WF, and Bullara LA, "Tissue Response to Potential Neuroprosthetic Materials Implanted Subdurally," Biomat, 8(2):138­141, 1987.

17. Hahn AW, York DH, Nichols MF, et al., "Biocompatibility of Glow-Discharge-Polymerized Films and Vacuum-Deposited Parylene," J Appl Polym Sci, 38:55­64, 1984.

18. Loeb GE, Bak MJ, Salcman M, et al., "Evaluation of a New Biocompatible Dielectric Coating: Parylene Insulated Chronic Microelectrodes," Proc Annu Conf Eng Med Biol, 17:46, 1975.

19. PRP-90108, report date 4/24/84.

20. MDR-11993, report date 2/7/86.

21. Toxicology Summary: Organofunctional Silane A-174, Gamma-Methacryloxypropyltrimethoxysilane, Indianapolis, Specialty Coatings Systems, 1989.

Nancy Stark, PhD, is president of Clinical Design Group (Chicago), an independent firm specializing in safety, efficacy, and performance testing of medical devices. The firm provides consulting in biological safety and clinical research, preparing material safety reports and clinical profiles, conducting public and on-site training, and contracting clinical research investigations.

IPO Market Best in Years, Say Analysts

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published March 1996

Financing

Faster FDA review and the force of the managed-care marketplace are contributing to one of the best financing climates for young medical device companies in the last 18 years, according to industry experts. Analysts point to a variety of reasons for the improvement, but disagree slightly on where the newly available financing is being invested.

"The public market today is more open to early-development-stage medical device companies than I have ever seen in my 18-year career practicing law," says Casey McGlynn, chairman of the Life Sciences Group for the law firm Wilson Sonsini Goodrich & Rosati (Palo Alto, CA). "Investors are willing to take on young companies and to absorb the regulatory and other risks associated with taking them public."

McGlynn says an increased number of young companies have filed initial public offerings (IPOs) since June 1995. That trend has continued through the first quarter of 1996. A significant difference between these filings and those of 1992--another good year for the device industry--is that many companies may be just now applying for FDA premarket approval; previously companies would wait until they had FDA clearance before filing an IPO.

McGlynn sees the improved responsiveness of FDA, especially with regard to premarket notifications (510(k)s), as the major reason for today's good fund-raising environment. "The agency has improved its ability to turn documentation around, to respond with meaningful comments, to meet before filings are made, and so on. All of that creates a great deal of additional clarity with regard to the regulatory pathway for young companies. Also, the speed with which many 510(k) approvals have come has made investors more comfortable with investing in this arena."

Other analysts concur. "FDA lightened up a lot on their barriers to product approval in 1995," says Thomas Gunderson, senior analyst for Piper Jaffray, Inc. (Minneapolis). "In the past, a lot of funding was held up and could not be invested until after a long delay; faster product approval is now making it possible to get funds invested with less regulatory risk."

Gunderson agrees that 1995 was one of the best years in a while for accessing funding. Investors have always been interested in medical devices, he says, and in addition to an eased regulatory environment, there is also a lot of new technology in the marketplace. "Medical device companies have shown good stock market performance over the last year and a half, and, at the other end, companies have moved out of the system by merging with others. From Wall Street's perspective, this has made room for new companies."

The basic need for large companies to fill out their product lines in order to compete in the managed-care marketplace is the reason for the recent and relatively significant number of acquisitions by large medical device companies. This trend also helps small companies by encouraging entrepreneurs and "ensuring their path to liquidity," according to McGlynn.

In addition to the improved regulatory environment, McGlynn points to the fact that more-mature medical device companies are looking again at their product lines to determine what they need in order to capture the managed-care market. He says this brings them full circle, back to the smaller companies where innovative products are being developed.

As always, it is the unique and innovative companies that get funding, says Jack Cumming, senior partner and president of WDI Capital Markets (Hilton Head Island, SC), a health-care advisory and investment banking company. However, in the absence of cost benefits that address the needs of managed-care companies, being unique means nothing. "The easier regulatory environment is not really attracting any more investor interest than usual except for devices that fall into categories that meet specific health-care needs, such as cardiac devices, which have done tremendously well because of the aging population and high rate of heart disease," Cumming says. "Devices that attract financing must be less invasive and provide a cost-effective alternative in a managed-care environment. Groups such as American HealthCare Systems [San Diego], Premier Health Alliance [Westchester, IL], and Sun Health Alliance [Charlotte, NC] are buying bundled contracts and will save some $600 million in vendor costs. Ultimately, this money comes from the providers and the medical device companies."

Cumming says that although the current market is one of the better markets for funding, the number of medical device companies that have gone public in the last couple of years is significantly less than the number of provider-side companies that have done so. He agrees that the financial performance of device companies has been improving, but investment has been mostly in such provider companies as Sterling Health (Coral Gables, FL) and Met Partners (Birmingham, AL), which have both gone public.

"While I continue to be impressed with how well a number of them are doing, I'm sure they recognize that their stock prices won't continue to have this kind of growth. They may continue this way for another year, but then growth will probably be a little slower," McGlynn says.

The entrepreneur has a choice, according to McGlynn. For some companies the public market is pretty open today, and they can get a valuation that's similar to what they could get by selling out to a large medical device manufacturer. In such cases, the company has to make a choice about which of two paths to liquidity it finds most appealing: merger, which is a path traditionally available to medical device companies, or a public offering, which is a path increasingly available even to very young companies.

Innovation is going to continue to drive down health-care costs and improve medicine, McGlynn speculates. He believes that the industry will go through cycles, and that there will undoubtedly be public offerings for companies that are less attractive or higher risk than they should be. "The market may tire of those offerings, and that may cause the window to close for a while; I don't expect that a year and a half from now the market will be as receptive to public offerings as it is today." When that occurs, he says, there will still be room for real quality companies to make good public offerings, but it will be a little bit more difficult for younger companies to do so.--Sherrie Steward

Design and Fabrication of Polyester-Fiber and Matrix Composites for Totally Absorbable Biomaterials

Medical Plastics and Biomaterials Magazine | MPB Article Index

Originally published March 1996

ROBSON F. STOREY AND JEFFREY S. WIGGINS

Several semicrystalline polyesters exhibiting blood compatibility are widely used as resorbable material for implantable devices and surgical articles (see Figure 1).1­3 These polyesters biodegrade hydrolytically, and the resulting biologically active or nontoxic carboxylic acids are processed through normal metabolic pathways. Cross-linked analogs of semicrystalline polyesters can be used as matrix resins in bioabsorbable composites that possess physical properties uniquely suited to rigid fixation applications such as bone plates. (Figures not yet available on-line.)

For example, replacing high-modulus metal bone plates with a material whose modulus more closely resembles that of bone could promote healing of fractures.4 Current rigid fixation devices shield the fracture site and surrounding bone area; loads are transferred through the plate, often leading to stress-protection osteopenia. The shielded bone resorbs, becomes porous, and remains susceptible to refracture after surgical removal of the metal bone plate. Instead of acting as a shield, a plate made from absorbable polymers would gradually transfer loads into the fracture area as it degrades, enhancing bone regeneration. In addition, hydroxyapatite or other minerals and nutrients can be incorporated into the composite and, once released, can often stimulate bone growth. Of course, totally resorbable composites eliminate the need for surgical removal.

The degradation behavior of cross-linked, amorphous, absorbable matrices is also advantageous for rigid fixation applications. Semicrystalline polymers display heterogeneous degradation due to distinct amorphous and crystalline regions.5 The differing rates of degradation yield a product that decreases in physical strength at a faster rate than it decreases in mass. Heterogeneous degradation produces a composite matrix that will prematurely lose its physical strength, whereas degradation of wholly amorphous, cross-linked polyesters should show a more linear decrease in physical strength with loss of mass, thus retaining properties over time.

Monomers that typically yield semicrystalline polymers can be used to produce cross-linkable, amorphous prepolymers through careful selection of comonomer composition and control over molecular weight. Totally absorbable composites may be fabricated by using biodegradable fibers for directional reinforcement in a degradable matrix. The matrix resin used in the present work, poly(D,L-lactide-co-glycolic acid) fumarate, was chosen for its design flexibility and the manner in which it facilitates composite fabrication via free-radical curing techniques. Polyglycolic acid surgical mesh, a knitted fabric with high tensile strength, provided the directional reinforcement for the composite. The physical properties exhibited by this combination of materials justify continued research into the development of totally absorbable composites for surgical applications.

EXPERIMENTAL

Matrix Resin Synthesis. Unsaturated poly(D,L-lactide-co-glycolic acid) fumarate oligomer was synthesized as reported previously.6 To a 500-ml, three-necked reaction flask equipped with a mechanical stirrer and West condenser were added 44.05 g (0.50 mole) 2-butene-1,4-diol as initiator; 144.02 g (1.0 mole) racemic D,L-lactide; 76.05 g (1.0 mole) glycolic acid; and 1.02 g stannous octoate. Under nitrogen purge, the reaction temperature was slowly raised to 120°C and held for 24 hours, at which time a 2-torr vacuum was applied, maintained for 8 hours, and slowly increased to 0.1 torr over an additional 8 hours. The hydroxy-terminated oligomer that resulted was reacted under nitrogen purge with 116.12 g (1.0 mole) fumaric acid at 160°C for 40 hours, and at 180°C for an additional 10 hours. At this time the reaction was continued for 48 hours at 165°C, as the vacuum was slowly increased from 10 to 4 torr. The resulting oligomer was dissolved in chloroform, vacuum filtered, precipitated into cold methanol, stored under methanol at -5°C for 16 hours, collected by filtration, and vacuum dried for 72 hours at 60°C.

Curing Techniques. Oligomer (175 g) was dissolved in 35 g tetrahydrofuran (THF) to make a stock resin that was prepromoted with 1.05 g cobalt naphthenate and stored under dry nitrogen until use. For the curing studies, 2- butanone peroxide was used in varying concentrations as a free-radical initiator. This curing system was chosen because of its known efficiency; its biological activity has not yet been addressed.

Samples were cured by adding approximately 2 g of prepromoted resin to an aluminum dish; 2-butanone peroxide was subsequently added in varying amounts from 1 to 10 wt% relative to polymer, and cured for 48 hours at 60°C. All cured samples were then stored in a desiccator until evaluation by differential scanning calorimetry (DSC).

Composite Fabrication. Polyglycolic acid surgical mesh was cut into 1.5 x 3-in. samples and saturated with initiated polyester prepolymer. In some cases, the mesh--prior to saturation with resin--was immersed for 2 hours in a mixture of 3 g of bis(dimethylamino)-methylvinylsilane diluted in 100 g of absolute ethanol, and then dried overnight at room temperature. Laminated plates consisting of four layers of mesh were fabricated using standard vacuum bagging techniques. These plates were cured for 5 hours at room temperature, removed from the vacuum bag, and cured for an additional 40 hours at 60°C. The reinforcement-to-matrix weight ratio for all composites was approximately 40:60, reflecting minimum air voids.

Characterization. Tensile strengths for the composite samples were measured on an Instron Model-1130 universal test machine using a 500-kg load cell at 40% range, with chart and crosshead speeds of 5 cm/min. Fourier transform infrared spectroscopy (FTIR) was performed on a Perkin Elmer Model 1600 spectrophotometer. The molecular weight of the matrix prepolymer was obtained using a Waters Associates gel permeation chromatograph (GPC) equipped with a Rheodyne injector, a Model 6000A solvent-delivery module, four Ultrastyragel columns with nominal pore sizes of 100, 500, 103, and 104 Å connected in series, and a 410 differential refractometer.

THF--freshly distilled from calcium hydride--served as the mobile phase and was delivered at a flow rate of 1.0 ml/min. Adalab Chromatochart software with GPC enhancement was employed to determine molecular weight as compared with polystyrene standards (Polysciences Corp.). Scanning electron microscopy (SEM) was performed with an Electro Scan Model E-20 and DSC was carried out using a Mettler Model 30 calorimeter with a heating rate of 10°C/min. The glass-transition temperature (Tg) was taken as the midpoint of a straight line drawn between the inflection points of the peak's onset and end point.

DISCUSSION

Chain extension reactions by esterification of the hydroxy-terminated oligomers with the Kreb's cycle intermediate fumaric acid (see Figure 2) have proven effective for incorporating unsaturated moieties into the backbone of a bioabsorbable polyester, and for providing control over the polymer's final molecular weight. The presence of hydroxyl end groups after the initial synthetic step has been confirmed by FTIR. Based on initial reaction conditions, the original hydroxy-terminated oligomer has a theoretical molecular weight of 546 g/mole--below the range of the polymer standards used in our GPC calibration yet within the range of molecular sizes separable by our particular combination of gel columns. In fact, based on the sharp individual peaks in Figure 3a, the product is most likely a series of dimers, trimers, tetramers, etc. Reaction of this hydroxy-terminated oligomer with excess fumaric acid gave an acid-terminated polymer with a final molecular weight of approximately 9200 g/mole (see Figure 3b).

Free-radical curing of unsaturated polymer with 2- butanone peroxide yielded matrices for which the glass-transition temperatures increased with increasing peroxide concentrations (see Table I). The breadth of the polymer's glass transition from onset to end point also increased with increasing peroxide concentration.

Curing was monitored using FTIR by observing a decrease in the absorbance due to the olefinic groups. Although the unsaturations in the resin are all 1,2-disubstituted, and thus low kinetic chain lengths are expected, sufficient network properties may still be obtained with high conversion. The nearly complete reaction of double bonds was confirmed by observing the essentially quantitative disappearance, after complete curing, of the C=C peak in the FTIR spectrum of the matrix polymer. Cross-linking was further confirmed by insolubility of the matrix in THF after curing.

Completely absorbable composites were fabricated by reinforcing the resin with polyglycolic acid surgical mesh. The authors have demonstrated that increasing interfacial adhesion between fiber and matrix is necessary for maximizing the properties of the bioabsorbable composite.

Bis-(dimethylamino)-methylvinylsilane was evaluated as a coupling agent for reducing the interfacial surface-energy difference between fiber and matrix. Dimethylamino groups of the coupling agent are expected to form a strong dipole-dipole interaction with carbonyl groups of the polyglycolic acid mesh in the initial pretreatment of the fiber. The vinyl group of the silane will then cross-link--via free radicals--into the matrix resin, forming a covalent bond within the network. Improved wetting of the fiber surface with the matrix resin should yield an increased physical strength for the composite. An approximately 10% overall increase in the tensile strength--from 84 to 92 MPa--was observed following pretreatment of the surgical mesh fibers with the selected coupling agent (see Figure 4). SEM revealed a visible gap between the fiber and matrix and clear regions of fiber pullout in untreated samples. In the composites formed with silane-treated mesh, SEM indicated improved fiber wetting through more complete encapsulation of the fiber with matrix resin and less occurrence of fiber pullout.

DSC thermograms for the composite show a glass transition for the amorphous, cross-linked matrix at 55°C and a crystalline melt transition for the fiber at 225°C (see Figure 5). Thus, the composite is pliable at temperatures above 55°C but maintains rigidity at biological temperature. This means that the composite can be custom formed for use in specific surgical devices through the application of heat--a feature that could prove quite useful.

Degradation of the composite was studied in vitro by immersion in a buffered saline at 37°C. Figure 6 shows a plot of mean mass change versus time: the composites were observed to degrade rapidly, displaying an approximately 26% loss in mass in 43 days, by which time fragmentation of the samples had begun. The initial weight gain during the first 7 days is attributed to uptake of immersion fluid.

CONCLUSION

Poly(D,L-lactide-co-glycolic acid) fumarate, when cured by free-radical initiation, demonstrates properties suitable for use as a matrix resin in totally absorbable composites. The incorporation of polyglycolic acid surgical mesh provides directional strength for the material. A critical design consideration for resorbable composites is the use of a silane coupling agent to reduce the interfacial energy between the fiber and matrix. Thermal evaluation shows that the composite can be easily contoured at a temperature slightly above biological temperature. Because of their unique properties, completely absorbable composites warrant further investigation as candidates for biomaterials.

ACKNOWLEDGMENTS

This paper is based on research supported in part by the National Science Foundation (grant #RII-8902064), the State of Mississippi, and the University of Southern Mississippi. The authors gratefully acknowledge Robert Pope of the University of Southern Mississippi for providing the SEM analysis and T. J. Nash of Davis and Geck for generously supplying polyglucolic acid surgical mesh.

REFERENCES

1. Storey RF, Wiggins JS, Mauritz KA, et al., "Synthesis and Fabrication of Completely Absorbable Composites for Biomaterials," ACS Div Polym, Chem Polym Preprs, 30(2):492­493, 1990.

2. Vacanti JP, Morse MA, Saltzman WM, et al., J Ped Surg, 23(1):3­9, 1988.

3. Gogolewski S, and Pennings AJ, "Biodegradable Materials of Polyactides, Porous Biomedical Materials Based on Mixtures of Polyactides and Polyurethanes," Makromol Chem, Rapid Commun, 3:839­845, 1990.

4. Daniels AU, Chang MKO, Andriano KP, et al., J Appl Biomat, 1(1):57­78, 1990.

5. Pitt CG, Hendren RW, Schindler A, et al., "The Enzymatic Surface Erosion of Aliphatic Polyesters," J Controlled Rel, 1:3­14, 1984.

6. Han YK, Edelman PG, and Huang SJ, "Synthesis and Characterization of Crosslinked Polymers for Biomedical Composites," J Macromol Sci-Chem, A25(5­7):847­869, 1988.

Robson F. Storey, PhD, is professor of polymer science at the University of Southern Mississippi (Hattiesburg), where he has taught since 1983. His research interests include living polymerizations, block and star-branched polymers, ionomers, reactive oligomers, bioabsorbable polymers, and polymer coatings. Jeffrey S. Wiggins, PhD, is manager of new product development for thermoplastic polyurethanes at Bayer Corp. (Pittsburgh).

Supreme Court May Resolve Liability Preemption Dilemma

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published March 1996

Product Liability

The most important court case in the recent history of the medical device industry is scheduled to begin this spring. "There are a lot of medical device manufacturers, particularly small ones, that are in danger of being driven into bankruptcy by the ballooning number of lawsuits against device manufacturers," says Richard Samp, chief counsel for the Washington Legal Foundation (WLF; Washington, DC). "Many of them look upon this case as their only hope for salvation."

The case is Medtronic, Inc. v. Lohr, which is set to be argued before the U.S. Supreme Court in April. For the individuals involved, the case involves simply the recovery of damages for an allegedly defective pacemaker. But for the medical device industry, there is much more at stake, namely the protection--or lack of it--afforded by the preemption provision written into the Medical Device Amendments of 1976.

In recent tort cases pursued in state courts, medical device companies have tried to use the amendments as a shield from liability, contending that successfully navigating either the premarket notification (510(k)) or premarket approval (PMA) process means they have met rigorous safety standards established by FDA--standards that preempt any that the individual states may set as part of tort law. But that argument has met with varied and limited success.

"It has been widely held that some of FDA's labeling regulations and good manufacturing practices (GMP) regulations may preempt failure-to-warn claims and claims regarding failure to manufacture properly," says Donald R. Stone, a partner in the food and drug department of McKenna & Cuneo (Washington, DC), the law firm retained by Medtronic. "But fewer courts have held that design claims are preempted."

This variability extends to opinions rendered in several appeals courts. Stone cites four design-related cases involving 510(k)-cleared devices. Two of the cases were decided in favor of the medical device companies, two against. "That is the kind of issue that interests the Supreme Court, when the lower courts are clearly not of the same mind and the high court needs to straighten out the conflict," Stone says.

The case being heard by the Supreme Court this spring could do just that. The opportunity is to establish a precedent of uniformity by which the Medical Device Amendments can be interpreted. The upcoming legal battle, which could set the tone for innovation well into the next century, is being driven by a specific action brought in a specific state, Florida, where plaintiff Lora Lohr has charged Medtronic with negligent design, negligent manufacture, and failure to warn, and has issued liability claims against the company for an allegedly defective pacemaker. "Our position is that the preemption provision should operate to prohibit three of those actions--defective design, manufacture, and failure to warn," Stone says.

The case stems from the implantation in 1987 of a Medtronic pacemaker in Lohr. The pacemaker, which had been cleared for sale by FDA in 1982, allegedly malfunctioned some three years later due to a defect in the lead that carried electrical impulses from the device to the heart. Emergency surgery was necessary to replace the device.

Medtronic won the initial round, when a federal judge dismissed the lawsuit on the grounds that Florida courts had no jurisdiction over the issue because of the 1976 law that governed FDA's regulation of medical devices. The company lost ground in the U.S. appeals court, however, which found that Lohr could pursue her case on two counts--negligent design and liability claims arising from an unreasonably dangerous design. Two other counts, negligent manufacture and failure to warn, were disallowed. The decision made neither side happy and both appealed.

On January 19, the Supreme Court decided to hear the case. The high court will actually rule on two motions: the appeal by Medtronic that neither claim allowed by the appeals court is permissible in the context of the Medical Device Amendments; and the appeal by Lohr that federal law does not preempt liability claims made under state law to recover damages due to injury as the result of a defective medical device. "So the issue before the Court is whether the preemption provision in the Medical Device Amendments was intended to preempt state tort claims regarding product warranty liability," Stone says.

But there is also the possibility that this case will not yield as uniform a precedent as industry would like. Medtronic, Inc. v. Lohr specifically raises the question of whether clearance of a medical device through FDA's 510(k) process insulates the manufacturer from product liability suits. Whether the decision will be extended to cover devices approved through the PMA process is not certain. "Generally, the courts have supported the broadest preemption for those devices that underwent PMA review, and there have been lesser degrees of protection afforded to those devices that were 510(k) cleared," Stone says. But the decision rendered in this case might be tightly applied only to devices that have been cleared through the 510(k) process, since that's how the pacemaker that spurred the action was cleared.

It is also possible that the high court will find totally in favor of the plaintiff. That outcome would seem unlikely, in that 9 of the 10 circuit appeals courts that have ruled on the issue of medical device liability have come out in favor of some type of preemption. But there is a wild card in this game, and that wild card is FDA.

In connection with recent preemption decisions, the agency has offered an opinion only once, in a federal appeals case involving C. R. Bard that took place in Boston about a year ago. In that case, the agency opined that there should be no preemption. WLF's Samp points out that the case was unusual because there was strong evidence of criminal activity by the device company. But it also indicates, he says, that "when the federal government is asked for its position on preemption, it files in support of the plaintiff."

In Medtronic, Inc. v. Lohr, Samp expects that the Supreme Court will ask the United States government, in this case FDA, to provide an opinion--and he expects that opinion to favor the plaintiff. If that happens, he says, it could have serious consequences for the medical device industry. "Generally, what government agencies have to say gets a fair amount of deference from the Supreme Court," says Samp. "If FDA comes out strongly against preemption, it would be supporting not only FDA regulation, but al-so whatever regulation the states want to impose."

These and other uncertainties may be cleared up in short order. Unlike lower court trials, cases brought before the U.S. Supreme Court do not involve witnesses or the presentation of evidence directly related to the claims involved in the case. Rather, court presentations focus entirely on legal arguments in support of or against opposing motions. As a result, cases are often presented expeditiously and decisions rendered quickly. In the Medtronic case, briefs are scheduled to be filed in March and oral arguments are set to follow in April. "We would expect the Court to decide the case before it adjourns for the summer at the beginning of July," Stone says.

Even so, the Supreme Court's decision may be only the beginning for Medtronic and plaintiff Lohr, since it will determine only whether a suit can be brought in the Florida courts. If Medtronic does not win total victory, it will soon find itself back in the lower courts and on the defensive again. --Greg Freiherr

Device Manufacturers Say Yes to EDI

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published March 1996

Manufacturing

If electronic data interchange (EDI) is the destination of the future, U.S. device manufacturers are halfway there--sort of.

Responding to an informal straw poll of MD&DI's editorial advisory board and reader board members, exactly half of the 23 respondents indicated that some form of EDI is currently in use at their companies. But their responses also suggest that exploring the full potential of EDI may take a while to develop.

Of the seven common applications of EDI identified in MD&DI's recent article on "The Promise of Electronic Data Interchange for Device Manufacturers" (November 1995), the one most frequently in use at respondents' companies is design-manufacturing transfer (65%). Other categories making a strong showing were design and sales/customer service (both with 57%), and packaging/labeling (52%).

Commenting on the progress of device companies toward use of EDI, Larry Kupeli, marketing manager for Bio-Rad Laboratories (Hercules, CA), noted that "with increased documentation and regulations, paper is no longer a convenient medium of exchange."

But others indicated that making full use of EDI was more a dream than a reality. "Many companies (mine included) are struggling to implement the EDI systems that will make them successful," wrote Stephen Hamilton, senior engineer at the USCI Division of C. R. Bard, Inc. (Billerica, MA).

Fewer than half of the responding readers (48%) indicated that their companies are currently using EDI systems for marketing feedback. Even fewer said that their companies are using EDI as part of a manufacturing execution system (30%) or for communicating with outside vendors (26%).

But the key to expanded use of EDI by device companies may lie in its potential for "doing business with government," an area of interest identified by Gordon Hodgson, materials manager for Vident, Inc. (Brea, CA). With FDA interest in electronic submissions growing, more and more device companies may soon find that EDI is not only a business convenience, but an essential regulatory tool. And when that happens, you can be sure the future has arrived. --Steven Halasey

First FDA Reform, Then a New Agenda

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published March 1996

Henry A. McKinnell, PhD

Chairman, Health Industry Manufacturers Association (HIMA)

Executive Vice President, Pfizer, Inc.

Few people in the medical device industry could have said it better than Senator Nancy Kassebaum. When introducing comprehensive legislation (S. 1477) to reform FDA, the head of the Senate committee with legislative jurisdiction over the agency declared, "Increasing FDA demands on new product development and delays in new product reviews are reducing incentives for research and development, encouraging American companies to locate abroad, delaying Americans' access to new pharmaceuticals and medical devices, and costing American jobs."

In the House of Representatives, Congressman Tom Bliley, a Virginia Republican, chairs the committee that oversees FDA. On reforming FDA, his words are equally forthright: "I am not interested in reinventing the FDA, and neither are my colleagues. What's called for is fundamental reform, and it's up to Congress to deliver."

Judging by Congressman Bliley's past words on the subject, a House bill to reform the agency is likely to contain even stronger medicine than the measures that Senator Kassebaum has prescribed. Even so, the Kassebaum bill is an encouraging development that aims Congress in the direction that industry has long advocated. It is an important first step.

The Kassebaum bill would expedite the development and review process for medical devices, drugs, biologics and certain food additives, and it includes several basic changes that HIMA and the medical device industry have long sought. It does fall short, however, in some critical areas. Most notably, it fails to compel FDA to complete its review processes in the time periods set by current U.S. law. In addition, although the bill includes incentives for FDA to expedite device reviews, those rules wouldn't take effect immediately. HIMA's own reform proposal calls for the immediate establishment of independent third parties to review device applications, especially those for break-through devices.

In other areas, the Kassebaum bill tracks closely with industry's recommendations for reform, particularly with respect to the definition of device effectiveness. Language in the bill would have the effect of allowing doctors, rather than FDA, to determine those treatments that are most effective and in the best interests of patients.

Politically, the cause of FDA reform is light-years ahead of where it was two years ago. The momentum toward medical device reform began in 1993, when Congressman John Dingell's oversight subcommittee issued a report on the FDA device program. That report, "Less Than the Sum of Its Parts," planted the first seeds of doubt about the program--seeds that took root with the 1994 congressional elections. In the new political environment, the Republican Congress made FDA reform a primary issue. Largely in response, the administration has also made some efforts, although they fall short, toward reforming the agency. Although the near-term goal of FDA reform is critical to the industry's sustainability and U.S. competitiveness, I believe it is in the best interest of industry to focus special attention on long-term strategies.

Too much is at stake for patients and companies to sit back and "let the other guy do it." It's time for everyone in the device industry to realize that the future of each company and each individual is tied to how well the industry performs in the next few critical years. In my view, the medical device industry is at a major crossroads. Getting to the other side should not be our only goal.

As vitally important as it is, reforming FDA is not going to solve all of industry's problems. Those who regard comprehensive FDA reform as a cure-all are mistaken. Research and development, clinical trials, and jobs that have been displaced to Europe will not return overnight. Unobstructed by FDA, a wave of innovative, miraculous new products will not suddenly burst forth. Major questions important to the future of the industry will still be unresolved.

INDUSTRY'S ISSUES

Quite simply, all health care is moving into a new era, one in which fee-for-service medicine is largely supplanted by managed-care systems that range from those applying refined case-management techniques to fee-for-service care to those directly employing their own staff. Driven by concerns to improve patient care and to reduce costs, many employers and most managed-care systems are focusing on outcomes measures, cost containment, and technology assessment. Today approximately 7 out of 10 American workers are covered by managed-care plans. That change has come swiftly. As recently as 1993, half still had fee-for-service coverage. At the same time, the changing demographics in most industrialized nations mean that fewer workers will be paying taxes in the future to support government-sponsored health-care systems for the elderly. That's significant because people over 65 require four times as much health care as people under 65, according to estimates.

Meeting the needs of the new cost- conscious marketplace and the unmet medical needs of patients everywhere should be industry's top priority in coming years. That means developing new products that can be demonstrated to improve the quality of care and reduce the cost of care through well-conducted outcomes trials. It also means working with managed-care customers to implement cost-effective solutions, whether those are disease management strategies or treatment criteria for certain technologies.

Advances in medical technology can save hundreds of thousands of lives and also billions of dollars in health-care costs each year--and industry can prove it. Just one example from HIMA's 1995 industry study by The Wilkerson Group illustrates the point. According to the study, implantable pumps--currently in use in Europe--are helping improve the control of diabetes; if such devices were available in the United States, they could save an estimated 3000 lives and as much as $9 billion in health-care costs over three years. For its own good, industry must get facts such as these to the public, to purchasers, and to policymakers. If the industry doesn't make the case for technology and its benefits for patients and for controlling costs for health-care providers, no one else will.

Making the case for technology will mean working with Congress to remove obstacles to innovation and to research and development efforts wherever they may sprout. Calculations based on Wilkerson's financial model for a typical medical device show that today's regulatory requirements have added $9.5 million to the cost of a premarket approval over just a decade ago, and two years to the time it takes a product to generate a positive cash flow. Similarly, for a product involving a 510(k) application, the cost has more than doubled from 1985 levels to $19.9 million, while the time to positive cash flow has increased by two years.

These numbers indicate how crucial it is for industry to educate lawmakers and regulatory officials about the fragile, financially risky process of innovation. Society and industry both benefit in recognizing the special needs of small, high-technology companies where much of the innovative work for lifesaving medical devices takes place, step-by-step, in tiny increments. Legislatively, we must work with Congress to ensure that government regulators act as partners to the industry, not as its adversaries.

As all levels of government are increasingly focused on developing more appropriate and cost-effective regulations, industry must also continue to take steps to enhance its own performance and standards. The medical device industry must begin to conduct itself so effectively that lawmakers have no legitimate reason for stricter regulation in the future.

Companies must strengthen their scientific and self-regulatory functions. Standards for basic science must be raised, and companies must willingly embrace the discipline of appropriate well-conducted, well-controlled clinical trials. To continue to advocate that, in effect, the most efficient form of regulation is self-policing, industry must be able to demonstrate that it can consistently produce good science.

With or without FDA reform, government also has a role to play in the new marketplace as a purchaser. That means industry must continue to participate actively in the legislative process to ensure that governmental health-care programs take into account current market realities and thereby benefit from market efficiency instead of constraining it. Consumers, who inevitably will pay a larger share of the health-care bill, must also be educated about the value of medical technology. Industry must make the facts about products available and therefore help physicians and consumers make responsible choices about their treatment options.

Technology can save money as well as lives. Technological innovation, appropriately utilized, is a key ingredient in cost containment and in maintaining top-quality health care. The facts are on our side. The industry, however, must do what is necessary to make certain that lawmakers, regulators, providers, and patients get these facts. Their decisions--and what we do to shape them--will determine the opportunities and limits to future progress in medical technology and, thus, to the shape of our industry as well.