Manufacturers producing medical devices that involve patient contact are typically required to perform biological safety evaluations, including biocompatibility tests to ensure patient safety, as specified by ISO 10993. Chemical characterization can help support the biocompatibility testing process, reduce the use of animal testing, in some cases, shrink turnaround time and cost, and, perhaps, eliminate the need to do some biocompatibility testing altogether.
Traditional biocompatibility tests involve evaluating the biological effects of compounds extracted from devices on animals (in vivo) and/or cells (in vitro). Chemical characterization of a device, in contrast, involves utilization of analytical chemistry to identify and quantify the amount of chemicals extracted from a device and an evaluation of the toxicological risk associated with the exposure level. This approach involves characterizing both the product material—typically a polymer, metal, or ceramic—and the extractable or leachable compounds that come from those materials or byproduct residuals on the device from the manufacturing process. As stated in the U.S. FDA draft guidance issued April 23, 2013, “The biocompatibility of a final device depends not only on the materials but also on the processing of the materials, manufacturing methods (including the sterilization process), and the manufacturing residuals that may be present on the final device.”
Using analytical chemistry and data from compound libraries to assess the finished device can yield more specific data about these extractable compounds than biocompatibility testing. The known properties of the compounds can then be used to create a toxicological risk or safety assessment based on the predicted biological response to the compounds.
This article will examine the various ways in which chemical characterization can augment and refine the biocompatibility testing process.
When to Use Chemical Characterization
Material/Process Changes: Medical device manufacturers trying to shepherd a device involving patient contact to market must perform biocompatibility tests. Should the device or the process used to manufacture it undergo a change after it has reached market, the manufacturer must assess the impact of the change on patient safety. However, rather than simply repeating all of the original biocompatibility tests, chemical characterization can be used to formulate a risk assessment and conduct a comparison study of materials, which can help indicate which (if any) of the original biocompatibility tests must be repeated or if the material change can be supported through analytical evaluation and a written toxicological risk assessment.
Supplementing in vivo Biocompatibility Testing: The same principle can be applied to certain new device submissions. If a manufacturer can show it has evaluated patient safety via other means—such as a toxicological risk assessment built on chemical characterization—it might not have to perform every biocompatibility test as outlined in ISO 10993, especially with regards to some of the long-term carcinogenicity or genotoxicity tests. For example, the carcinogenicity characteristics and toxicity of many compounds are known—including whether they have carcinogenic properties for humans or not—hence the data gleaned from chemical characterization can be used to assess the relative carcinogenicity risk (or lack thereof) for the device’s extractable compounds. This potentially enables the manufacturer to avoid performing these long-term and expensive biocompatibility tests.
Regulatory Reviewer Request: It has recently become more common for regulatory reviewers and notified bodies to request chemical characterization data during the review process, and manufacturers are increasingly aware of the possibility that they might be asked by the reviewer to provide this data. However, the current standards in this area are still fairly vague, as it’s a newer concept than the more tried and true area of biocompatibility testing. Reviewer expectations for written toxicological risk assessments may vary due to device type, target population, and available material safety data. It is important that manufacturers consult with a regulatory expert and a toxicologist to ensure a written assessment adequately addresses patient safety based on the intended use.
Specific Device Types: Reviewers are becoming more interested in the chemical characterization of certain specific devices that involve high-risk patient contact. For example, those that have vascular or neurological contact, indirect contact with the airway that may introduce materials to the lung, combination products that house or transfer pharmaceuticals, and those that include colorants, pigments, or plasticizers (e.g., phthalates) that are believed to have developmental, reproductive, carcinogenic, or other toxic effects. There is increased scrutiny and concern, from a regulatory perspective, about potentially harmful or toxic materials leaching from these critical devices. Chemical characterization testing offers a high level of specificity regarding the quantitative amount of a chemical and quantitation needed for safety evaluation and a toxicological risk assessment when seeking approval for such devices.
There are two categories of tests for performing chemical characterizations: direct material characterization and extractable/leachable analysis. While many options are available for assessing materials and extractable/leachable chemicals from a device, a few common tests are given below.
Direct Material Characterization: Two types of tests under this category require direct analysis of the material (no extraction):
- Fourier Transform Infrared Spectroscopy (FTIR): Characterizes the internal bonding structure of the polymers, which can be used to identify said polymers. This test is qualitative and provides a comparison of the material to a known library or reference materials.
- Differential Scanning Calorimetry (DSC): Involves identifying polymers by their thermal properties. This test is qualitative and provides a comparison of the material based on known thermal properties to a reference library.