Biocompatibility Guidelines, Using EtO with Parylene

Medical Device & Diagnostic Industry Magazine
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An MD&DI  January 1998 Column

HELP DESK

Richard F. Wallin, PhD, president and CEO of NAMSA (Northwood, OH), explains why complying with biocompatibility guidelines is important when constructing medical devices.

What are the consequences of failing to comply with biocompatibility guidelines in the manufacturing of a medical device? For example, if an adhesive is used in the assembly of a device, but the adhesive does not come into contact with the patient, why must it still meet biocompatibility guidelines?

Any medical device that comes into direct or indirect contact with a patient must be tested for biocompatibility. Even if a device doesn't physically touch the patient, in some cases it may release chemical constituents that could be harmful. The degree of concern about a material depends on its composition and the nature and duration of its contact with the patient. Failing to comply with biocompatibility requirements could result in patient harm, regulatory difficulties (e.g., rejection of a 510(k)), and product liability claims.

Current FDA biocompatibility guidelines are contained in blue book memorandum #G95-1, a document based on the international standard ISO 10993, Biological Evaluation of Medical Devices, Part 1: Evaluation and Testing. The FDA memo and the ISO standard describe means of addressing the potential toxicity resulting from contact with the component materials of a device. As mentioned, device materials may contact the body directly or indirectly through the release of chemical constituents.

Attachment C to the blue book memorandum is a flowchart to be used in selecting toxicity tests for 510(k)s. The flowchart makes it clear that if the device does not contact the body either directly or indirectly, there is no need for testing and biocompatibility requirements are met by default. For example, the biocompatibility of materials used in a medical device control console that remains remote from the patient is not of concern. Although an adhesive might be used in the assembly of the console, testing is not required because it has no contact with patients.

Biocompatibility becomes an issue when devices have direct or indirect contact with the patient. For example, extractable chemicals may find their way from the adhesive or other materials into circulating blood and then into the patient. Because of its complex composition, blood can extract both water-soluble and lipid-soluble chemicals. If adhesives were used to bond the lines of an extracorporeal circuit, the patient's blood could potentially pull chemicals from the adhesive as it flows through the circuit. The amount of chemicals extracted would vary depending on the amount of adhesive exposed, its composition and the extent to which it had been cured, the solubility of its chemical constituents in blood, and other variables.

There are a number of ways to determine the biocompatibility of adhesives. The device manufacturer may have used the adhesive in a device for which biocompatibility data were already collected; such data may support similar use.

Alternatively, the adhesive manufacturer may have data addressing the adhesive's extractability and biocompatibility in a defined, cured state. In some cases, adhesive samples can be cured on an inert substrate and handled as a solid device material for testing purposes. Generally, only selected test results, such as cytotoxicity and one or more components of the USP Class tests, are available from the adhesive's supplier.

If sufficient supporting biocompatibility data are not available, the manufacturer must evaluate the adhesive prospectively against current guidelines and standards, based on the device's end use.

The guidelines place an emphasis on characterizing device materials as part of the safety evaluation for two reasons. First, the physicochemical profile of a material defines that material and provides information about the quantities and identities of any extractables it may contain. Materials that possess large amounts of extractables are not necessarily toxic to a patient under clinical-use conditions. Much depends on the nature of the extractables and the amount of the material used in the device. However, extractable-rich materials should be considered suspect until shown to be biocompatible.

Second, the characterization profile of a material identifies the material at the time samples were subjected to biocompatibility testing and thus provides the basis for specifications used to control the material's uniformity throughout a device's lifetime.

Adhesives require special consideration. In their liquid or semiliquid form, many adhesives are relatively toxic. They often contain low-molecular-weight, extractable, reactive chemicals that are not compatible with biological systems. This usually changes for the better once they are polymerized. However, incompletely or improperly cured adhesives may contain residual quantities of starting materials, which can alter biocompatibility even from batch to batch. In this case, characterization is of particular importance to ensure that curing occurs as it was intended and as it did when samples were evaluated for biocompatibility.

David W. Eaker, PhD, manager of biological sciences, corporate medical affairs, toxicology and product support for Becton Dickinson and Co. (Research Triangle Park, NC), discusses how to find a biocompatible adhesive.

I am currently searching for a documented Class IV—biocompatible, electrically conductive adhesive. Is there a source for known biocompatible and nonbiocompatible materials?

A variety of manufacturers offer electrically conductive adhesives with a range of applications and intended uses. Many such adhesives are intended for electronic products and specialty engineering uses; for example, the attachment of components to printed circuit boards, electron microscopy, replacement of metal solders, and so forth. Base compositions include heat-curable epoxies, two-component epoxies, acrylics, silicones, and ultraviolet-curable resins. Electrical performance is typically achieved by including in the adhesive a significant weight percent metallic/conductive component (e.g., silver flake, carbon, nickel) to provide particle-to-particle conduction. Consideration of the conductor type would be critical to selecting such an adhesive for a medical device application.

A single source for documented Class IV—compliant materials may not exist, but manufacturers in this field may be found by referring to industry supplier directories. One such directory, available on Medical Device Link's suppliers directory, lists 27 adhesive product suppliers in response to a request for electrically conductive adhesives. This list includes both large, well-known companies and smaller specialty manufacturers. Several companies advertise adhesives compliant with Class IV requirements and high-performance, electrically conductive materials.

In addition to commercial directories, universities with electrical engineering programs are a good source of information. However, obtaining a list of suitable materials would depend largely on the specifics of the application and would probably require consultation with companies marketing these products.

Robert R. Reich, president of Pharmaceutical Systems, Inc. (Mundelein, IL), discusses whether ethylene oxide sterilization is compatible with parylene-coated devices.

I am designing a device that will require a load cell as one of its components. The company that makes the load cell I am considering has not used ethylene oxide (EtO) to sterilize its devices. I need to know whether EtO can penetrate or will react with paraxylylene, also called parylene (the coating used to make the device moisture resistant), and whether EtO has adverse effects on electronic components.

It seems to me that EtO should be compatible with the device because EtO is used to sterilize pacemakers and the electrical components are coated with paraxylylene. However, I need proof. I would appreciate it if you would list a few references.

Parylene is the generic name for members of a thermoplastic-polymer series developed by Union Carbide. These plastics are unique because they are produced as thin films by vapor-phase polymerization and the deposition of paraxylylene. The polymers are highly crystalline, straight-chain compounds that are extremely resistant to chemical attack due to their excellent dielectric characteristics—they are often used as dielectric film coatings on electrical components and devices. Parylenes exhibit low gas permeability, moisture-vapor transmission rates, and temperature ductility.

Based on the chemical properties of parylenes, they should be compatible with EtO sterilization. An excellent reference to the chemistry of parylenes can be found in the Handbook of Plastics and Elastomers published by McGraw-Hill.

I have experience successfully validating EtO sterilization for the routine processing of many electrical components as well as the reprocessing of several reusable electrical devices. An important point to remember is that a critical aspect of any device validation is an assessment of its postprocess functionality. Based on my experience, I would anticipate that the reader's device would be compatible with EtO processing. However, even before manufacturers initiate cycle validation, they should assess and document the EtO compatibility of their device as part of their design control system.

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

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

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

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