By Thor Rollins, Nelson Laboratories
Convening recently to review medical device biocompatibility standards, the ISO 10993 working group assessed the standards related to chemical characterization and the evaluation of leachables, and how they can affect the body. Both of these areas currently require animal testing; however, alternatives to current test procedures are being considered as standard changes among the ISO body.
In Vitro Irritation and Sensitization Testing. Today in the United States, sensitization and irritation evaluations for medical devices, cosmetics, and chemicals are performed using animal tests. In vitro irritation and sensitization testing is an alternative method, however, that utilizes a cell matrix mimicking a dermal layer. The chemical, cosmetic, or device extract is applied to the top of the dermal layer. Then, an evaluation of the cells on the bottom layer is performed to look for signs of irritation.
Seeking such alternatives to controversial animal testing, when possible, the working group is considering performing validation tests with medical device extracts to explore whether the in vitro irritation and sensitization test can be performed in lieu of animal tests, provided that enough data can be obtained for FDA to accept the test. But at this point, it is still unclear whether this test can be conducted for medical devices that have not been spiked with known irritations; current studies are insufficient and inconclusive. The next step for the committee is to collect sufficient data for FDA and other regulatory agencies in order to pursue acceptance of this test in place of animal testing.
Chemical Characterization. FDA currently requires two in vitro tests and one animal test in order to validate genotoxicity. One possible in vitro alternative discussed by the ISO 10993 working group is a chemical analysis of leachables off of a medical device. The first thing to look for among the leachable chemicals is the Cramer classification—a classification of compounds grouped into three toxicity classes:
- Class 1 consists of substances containing chemical structures with efficient modes of metabolism suggesting a low order of oral toxicity. These compounds are of low concern.
- Class 2 consists of compounds that have higher order of toxicity but do not contain significant toxicity or reactive functional groups.
- Class 3 consists of substances that cannot be presumed as safe. These substances may even suggest significant toxicity or have reactive functional groups.
In the test, the chemicals leaching off of the device are compared with a searchable database that provides background on toxicity and the Cramer classification. The proposed change in the standard would set a threshold of possibly 1.5 ug/person/day, for instance. If the compound is below this level, it is not considered genotoxic. This method is an evaluation that needs to be conducted by a toxicologist or other knowledgeable individual, however. If this approach doesn’t become the standard, it may become a technical draft.
There are a few compelling motivations for these proposed changes to the ISO 10993 biocompatibility testing standard for medical devices. Obviously, it is becoming increasingly desirable for ethical reasons to reduce the need for animal testing, when possible. But alternatives to animal testing can also present substantial savings in both cost and time. Animal testing, for example, can currently take as long as 22 weeks. However, these testing alternatives could effectively eliminate that time spent, resulting in significant overall savings. In turn, this expedited testing phase could dramatically reduce time to market for medical device manufacturers. It also creates economies of scale when testing to meet both European and U.S. regulations.
Moving forward, the ISO 10993 working committee will finish writing its standard drafts and will meet next year to work towards finalizing the verbiage. For now, it may be wise for medical device manufacturers to perform chemical analysis on their final medical devices and on the materials as well. This tactic will allow them to have leachables data ready when they must provide justification to changes of future biocompatibility work.
Thor Rollins, RM(NRCM), is a biocompatibility specialist at Nelson Laboratories.