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How the New FDA Biocompatibility TestingGuidance Could Affect You

Posted in Testing Services by bmichaels on March 18, 2014

The new ISO 10993 draft guidance document is the most expansive presentation of testing standards for themedical device industry in more than 18 years.

By Thor Rollins

In April 2013, FDA released draft guidance for industry and FDA administrationstaff titled “Use of International Standard ISO 10993, ‘Biological Evaluation of Medical Devices Part 1: Evaluation andTesting.’” Meant to replace FDA’s 1995 G95 document, the new draft guidance document is the most expansivepresentation of testing standards affecting the medical device industry in more than 18 years.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 howmedical device manufacturers or testing facilities can justify their decisions to perform specific tests or to foregotesting altogether. The third part explains the overall impact of the guidance document on device makers and theirtesting partners.

The New Guidance—Step by Step

While the ideas contained in the new guidancedocument have appeared in FDA responseletters over the last two years and more, theyhave not been presented in summary form untilnow. By codifying them in a single document,FDA has enabled medical devicemanufacturers and testing facilities toreference them in order to perform such tasksas setting up a test design or evaluating theimpact of a failure. While these ideas arefamiliar to many biocompatibility testingexperts, their appearance in the draft guidanceincreases their impact.

The ideas in the draft guidance documentcover colorants and other chemicalcompounds, test plans, final device approvals,organ-specific devices, master files, goodlaboratory practices for in vivo and in vitrotesting, chronic toxicity and carcinogenicity testing for permanent devices, representative coupon devices, failureoptions, sample preparation, prolonged-contact devices, cytotoxicity, hemocompatibility, and implantation criteria.

Colorants and other Chemical Compounds. In a discussion of toxic chemicals, the document specifically addressescolors and colorants—a topic that was not addressed in the G95 document. Relying on the ISO 10993-17 and ISO10993-18 chemical characterization standards, the new guidance focuses on safety concerns associated withchemicals 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 howmuch colorant leaches off of devices, how much it interacts with the body, and how it impacts safety from atoxicological standpoint. To answer these questions, the agency adopted two different approaches. First, to determinecolorant leachable levels, it requested that companies perform leachables studies that mimic devices’ actual clinicaluse. Second, it limited the scope of leachables studies, focusing instead on the total amount of colorant in the deviceand the toxicological effect of releasing all the color at once. While both types of tests have been successful, the newdraft 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 measuringthe quantity of a chemical that leaches from the medical device—a procedure known as extractable leachablestesting. The effects of a chemical on patient safety are determined using a measure known as human dailyexposure—the dose of the chemical per body weight. For male adults, body weight is assumed to be 70 kg, while forwomen, 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 to0.0000033 mg of chloroform daily. To determine the toxicological effects of this level of chloroform on the body, testingexperts can consult resources such as Toxnet, Toxline, or the Environmental Protection Agency, which containno-observed-adverse-effect levels (NOAELs) or lowest-observed-adverse-effect levels (LOAELs) for a host ofchemical compounds. By multiplying NOAELs or LOAELs by the human daily level of chloroform—and by modifyingfactors, depending on the quality and type of data generated—it is possible to calculate the effect of chloroform on thebody.

Containing a wealth of data on chloroform, Toxline indicates that NOAELs for this chemical compound range between15 and 125 mg per kilogram of body weight. To determine which of these levels is most representative of the medicaldevice in question, it is necessary to know how the device makes contact with patient, its route of administration, andits dwell time. In the real-life case of a medical device containing chloroform, the NOAEL of 15 mg/kg was the mostrealistic value. Thus, assuming a human daily exposure of 0.0000033 mg/kg, a NOAEL of 15 mg/kg, a safety factor of100 based on interspecies and intraspecies differentiation, and possible quality of data, the margin of safety is

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45,000. In other words, the device could leach 45,000 times more chloroform than the NOAEL and still be consideredsafe.

This type of mathematical research can help medical device manufacturers to justify the chemicals that leach off of adevice. As with chloroform, this method can also be used to determine the toxicological impact of colorants on thebody. In place of chloroform, the colorant’s CAS number can be entered in the database, providing a good method forperforming risk assessment on devices.

Discussing a Test Plan with FDA.Biocompatibility tests are so long and expensivethat it is important to discuss them with FDA inorder 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 IndividualMaterials. Often, medical device manufacturerstest raw materials for biocompatibility, assumingthat they can apply the results directly to the finaldevice. While this approach can be successful,manufacturers must also evaluate the impact ofthe production process on the materials. Forexample, how do mold-release agents orsterilization methods such as gamma radiationaffect the biocompatibility of the final device? Justbecause a raw material is biocompatible does notnecessarily 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 howthe device will be used. For example, if a device is meant to go into the brain, it must be tested for neurotoxicity. Inmost 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 masterfiles, 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 differentmedical devices. In addition, materials with master files or the devices from which they are made may not haveundergone 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.

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