By Thor Rollins
In April 2013, FDA released draft guidance for industry and FDA administration
staff titled “Use of International Standard ISO 10993, ‘Biological Evaluation of Medical Devices Part 1: Evaluation and Testing.’” Meant to replace FDA’s 1995 G95 document, the new draft guidance document is the most expansive presentation of testing standards affecting the medical device industry in more than 18 years.
The first part of the article summarizes the new guidance document step by step. The second part discusses how medical device manufacturers or testing facilities can justify their decisions to perform specific tests or to forego testing altogether. The third part explains the overall impact of the guidance document on device makers and their testing partners.
The New Guidance—Step by Step
While the ideas contained in the new guidance document have appeared in FDA response letters over the last two years and more, they have not been presented in summary form until now. By codifying them in a single document, FDA has enabled medical device manufacturers and testing facilities to reference them in order to perform such tasks as setting up a test design or evaluating the impact of a failure. While these ideas are familiar to many biocompatibility testing experts, their appearance in the draft guidance increases their impact.
The ideas in the draft guidance document cover colorants and other chemical compounds, test plans, final device approvals, organ-specific devices, master files, good laboratory practices for in vivo and in vitro testing, chronic toxicity and carcinogenicity testing for permanent devices, representative coupon devices, failure options, sample preparation, prolonged-contact devices, cytotoxicity, hemocompatibility, and implantation criteria.
Colorants and other Chemical Compounds. In a discussion of toxic chemicals, the document specifically addresses colors and colorants—a topic that was not addressed in the G95 document. Relying on the ISO 10993-17 and ISO 10993-18 chemical characterization standards, the new guidance focuses on safety concerns associated with chemicals that can leach from medical devices and impact patient safety.
Previously, FDA recognized that color additives are potentially carcinogenic or genotoxic, prompting it to question how much colorant leaches off of devices, how much it interacts with the body, and how it impacts safety from a toxicological standpoint. To answer these questions, the agency adopted two different approaches. First, to determine colorant leachable levels, it requested that companies perform leachables studies that mimic devices’ actual clinical use. Second, it limited the scope of leachables studies, focusing instead on the total amount of colorant in the device and the toxicological effect of releasing all the color at once. While both types of tests have been successful, the new draft guidance document represents the first time that the question of colorant leaching has been addressed.
The impact of colorants and other chemical compounds on device biocompatibility can be determined by measuring the quantity of a chemical that leaches from the medical device—a procedure known as extractable leachables testing. The effects of a chemical on patient safety are determined using a measure known as human daily exposure—the dose of the chemical per body weight. For male adults, body weight is assumed to be 70 kg, while for women, children, or infants, it is assumed to be less.
For example, if 0.00023 mg of chloroform leaches off of a device, each kilogram of body weight would be exposed to 0.0000033 mg of chloroform daily. To determine the toxicological effects of this level of chloroform on the body, testing experts can consult resources such as Toxnet, Toxline, or the Environmental Protection Agency, which contain no-observed-adverse-effect levels (NOAELs) or lowest-observed-adverse-effect levels (LOAELs) for a host of chemical compounds. By multiplying NOAELs or LOAELs by the human daily level of chloroform—and by modifying factors, depending on the quality and type of data generated—it is possible to calculate the effect of chloroform on the body.
Containing a wealth of data on chloroform, Toxline indicates that NOAELs for this chemical compound range between 15 and 125 mg per kilogram of body weight. To determine which of these levels is most representative of the medical device in question, it is necessary to know how the device makes contact with patient, its route of administration, and its dwell time. In the real-life case of a medical device containing chloroform, the NOAEL of 15 mg/kg was the most realistic value. Thus, assuming a human daily exposure of 0.0000033 mg/kg, a NOAEL of 15 mg/kg, a safety factor of 100 based on interspecies and intraspecies differentiation, and possible quality of data, the margin of safety is 45,000. In other words, the device could leach 45,000 times more chloroform than the NOAEL and still be considered safe.
This type of mathematical research can help medical device manufacturers to justify the chemicals that leach off of a device. As with chloroform, this method can also be used to determine the toxicological impact of colorants on the body. In place of chloroform, the colorant’s CAS number can be entered in the database, providing a good method for performing risk assessment on devices.
Discussing a Test Plan with FDA. Biocompatibility tests are so long and expensive that it is important to discuss them with FDA in order to be confident that the test plan is correct. By getting feedback from FDA in advance, surprises at the back end can be avoided.
FDA Approves Final Devices, Not Individual Materials. Often, medical device manufacturers test raw materials for biocompatibility, assuming that they can apply the results directly to the final device. While this approach can be successful, manufacturers must also evaluate the impact of the production process on the materials. For example, how do mold-release agents or sterilization methods such as gamma radiation affect the biocompatibility of the final device? Just because a raw material is biocompatible does not necessarily mean that the device itself will also be biocompatible.
Organ-Specific Devices. The type of testing required to achieve FDA approval for a device also depends on the how the device will be used. For example, if a device is meant to go into the brain, it must be tested for neurotoxicity. In most cases, however, medical devices do not target a specific organ.
Master Files: Insufficient Basis for Submissions. Clients say frequently that since all of their materials have master files, they do not have to perform biocompatibility testing. Indeed, master files can help greatly in risk assessments, but they cannot replace biocompatibility testing because the same materials may be processed differently in different medical devices. In addition, materials with master files or the devices from which they are made may not have undergone sterilization. Thus, before performing risk assessment to determine a device’s biocompatibility, manufacturers must evaluate the impact of their processing methods on the materials they use.