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.
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.
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.