Prior to marketing a device, the FDA requires biological evaluation to determine potential toxicity resulting from contact of component materials with the body. The intention of such testing is to ensure device materials do not produce adverse local or systemic effects; are not carcinogenic; or, do not produce adverse reproductive and developmental effects.
The specific biological tests required are based on chemical characteristics of device materials; and, the nature, degree, frequency and duration of exposure to the body. These tests may include: in vitro cytotoxicity; acute, sub-chronic and chronic toxicity; irritation; sensitization; hemocompatibility; implantation; genotoxicity; carcinogenicity; and effects on reproduction, including developmental effects. Additional tests for specific target organ toxicity may be required based on material composition and characteristics, intended use, target population and nature of contact with the body.
Some devices are made of materials that have been well characterized in published literature, both chemically and physically, and have a long history of safe use. For these materials, it may not be necessary to conduct all FDA suggested tests in order to demonstrate substantial equivalence of these devices to other products in the market. Ultimately, FDA reviewers are advised to use their scientific judgment in determining which tests are needed for the demonstration of substantial equivalence in a 510(k) submission.
ISO 10993 Overview
Since 1995, the testing protocol FDA reviewers use as a guide for required biological tests on device materials is described in the International Standards Organization standard 10993 (i.e., ISO 10993). This is a multi-part standard. The first part, “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process,” provides a framework for planning biological evaluation of device components, and selection of biological tests if needed. Most of the other parts deal with appropriate methods to conduct biological tests that may be identified when following Part 1 of the standard.
The ISO 10993 Part 1 uses an approach to biological test selection for device materials that includes seven principles:
1. The selection of device materials to be tested and the toxicological evaluations should take into account full characterization of all materials of manufacture. For proprietary materials, device master files (MAF) can be submitted to FDA to assist in determining the formulation of some components of the final device.
2. The materials of manufacture, the final product and possible leachable chemicals or degradation products should be considered for their relevance to the overall toxicological evaluation of the device.
3. Tests to be utilized in the toxicological evaluation should take into account the bioavailability of the material (i.e., nature, degree, frequency, duration and conditions of exposure of the device to the body).
4. Any in vitro or in vivo experiments or tests should be conducted in accordance with recognized Good Laboratory Practice (GLP).
5. Full experimental data should be submitted to the reviewing authority unless testing is conducted according to a recognized standard that does not require data submission.
6. Any change in chemical composition, manufacturing process, physical configuration or intended use of the device should be evaluated with respect to possible changes in toxicological effects and the need for additional toxicity testing.
7. The toxicological evaluation performed in accordance with this guidance should be considered in conjunction with other information from other non-clinical tests, clinical studies and post-market experiences for an overall safety assessment.
Biological Testing Matrix
ISO 10993 uses a tabular format (matrix) to outline the recommendations for biological testing of medical device materials. This matrix consists of two tables:
- Initial Evaluation Tests for Consideration
- Supplementary Evaluation Tests for Consideration.
In addition, ISO 10993 provides a biocompatibility flow chart for the selection of toxicity tests. If novel materials or manufacturing processes are used, additional testing may be requested to fully characterize the toxicology profile. (Please use the link below for more details, including the specific matrix tables described above)
In the 2009 revision of ISO 10993 Part 1, the focus changed from how to determine which biocompatibility tests to conduct, to an approach that considers existing information prior to determining if biocompatibility testing is needed. This revision to this standard attempted to minimize the number and exposure of test animals by giving preference to chemical constituent testing and in vitro models. However, the FDA still requires submission of a scientifically-based rationale for omission of any recommended tests within the matrix. In some cases, no testing may be required if the material has a demonstrable safe history of use in a specified role and physical form that is equivalent to that of the device under design.