How the New FDA Biocompatibility Testing Guidance Could Affect You (Part 2)

The new draft guidance document is the most expansive presentation of testing standards for the medical device industry in more than 18 years.

Good Laboratory Practices for In Vivo and In Vitro Testing. If a company is willing to spend large amounts of time and money on biocompatibility testing, it should go the extra mile and ensure that good laboratory practices are employed. Audited by an independent quality group, biocompatibility testing performed according to good laboratory practices is preferred by FDA.

Chronic Toxicity and Carcinogenicity Testing for Permanent Devices. When G95 was issued, most devices did not undergo carcinogenicity testing. In fact, the use of genotoxicity testing was used to help justify the decision to forego carcinogenicity testing. But now, extractable leachables testing enables manufacturers and testing facilities to evaluate both the chronic toxicity and carcinogenicity effects of chemical compounds. Thus, genotoxicity testing, as well as some subacute and subchronic toxicity testing, enables companies to justify foregoing chronic toxicity and carcinogenicity tests.

Guidance on Representative Coupon Devices. In the past, companies used G95 as a checklist. When a reviewer or company ascertained the types of biocompatibility testing that a device required, it performed the tests that appeared on a list. This is not the intent of guidance documents, however. Guidance documents indicate which categories of issues can affect a device’s lifespan or its suitability for patient contact.

Consequently, biocompatibility testing does not address device functionality or internal components such as electronics or wires that do not make contact with the patient. The sole objects of concern in biocompatibility testing are the device materials and how they are processed. Thus, the new document provides guidance on how to develop coupons—test devices that are processed the same way as the final devices, that are made from the same materials in the same proportions, but that do not incorporate functional internal components.

Failure Options. While the internal components of such medical devices as balloons are not supposed to make contact with the patient, these components can fail, exposing the patient. Thus, such components may have to undergo biocompatibility testing. Two methods for testing such internal parts include either examining the differences between the inside and outside of the device or comparing the surface area to the device as a whole.

Sample Preparation. To assess a device’s biocompatibility, two types of ratios are used to get the device into a solution or to extract it. Typically, these ratios have been based on either the surface area or the weight of the device. The larger the surface area or the heavier the device, the more volume the device has. While the previous standard was ambiguous about which method was preferable, FDA now stipulates that the surface-area test should be used.

Take the case of partial knee implants, for example. Weighing 93.9 g, such implants can be made from a range of metals, including titanium and stainless steel. Using the weight-to-volume ratio test, the device would be extracted in 468 ml—or a half-liter—of solution. However, because its surface area measures approximately 115 cm2 with a material thickness greater than 0.5 mm, its surface-area-to volume ratio is only 3 cm2/ml, requiring 38.6 ml of extraction fluid. The use of the weight-to-volume ratio requires 12 times more solution than the surface-to-volume ratio, leading to a twelvefold increase in the dilution rate of the chemical substances being extracted. Thus, this ratio is much less sensitive than the surface-area ratio. While the weight-ratio test requires less material than the surface-area test, this is not a good justification for using it.

Prolonged-Contact Devices. The new guidance document states that traditional biocompatibility extraction methods—37°C for 72 hours, 50°C for 72 hours, 70°C for 24 hours, or 121°C for one hour—are acceptable for many biocompatibility tests. It also notes that while testing at 37°C may not be sufficient for prolonged-contact devices and permanent implants to obtain an extract that represents the chemicals that may leach out over the use life of the device, temperatures above 37°C can result in degradants that may not occur in clinical use and may result in toxicities not representative of the final product.

The standard extraction parameter for prolonged-contact devices has been 37°C for 72 hours. If a device undergoes extraction for longer than 72 hours, it cannot mimic the prolonged exposure it will experience in the patient at body temperature. Thus, FDA has requested that extraction be performed at an elevated temperature to mimic prolonged exposure. FDA also advises that unless the device changes chemically at 37°C, extraction should be conducted at 50°C regardless of duration in order to simulate the worst-case scenario. Most devices can endure exposure at 50°C.

Cytotoxicity. Medical devices can fail biocompatibility testing as a result of cytotoxicity. The first step in evaluating cytotoxicity-related device failures is to confirm that the test procedure was performed correctly and that the protocols were followed properly. Then, the results must be confirmed. It is also advisable to ensure that substance tests are failsafe. Once it has been found that the device contains toxic material, two options are possible: either eliminate the material or accept it based on performing a risk assessment. The new document provides guidance on performing this assessment based on projecting how the device will impact the patient’s health and whether the lack of the device will harm the patient more than the cytotoxicity.

When testing for cytotoxicity, the extract should not be manipulated. In other words, it should not be filtered or centrifuged in order to rid it of particulates or chemicals. Furthermore, the guidance document states that extractions should be conducted using a vehicle that allows for extraction of both polar and nonpolar constituents from the test sample, such as mammalian cell culture media (MEM) and 5% calf serum. This is important because some labs occasionally perform extractions and tests using saline. But because saline causes cellular death, they must mix the saline into MEM fluid at the back end, resulting in the dilution of the 100% pure extract. Thus, cytotoxicity testing should be performed using 5% calf serum.

Hemocompatibility. For blood-contacting devices, regardless of contact duration, the new guidance document recommends that testing facilities should consider performing hemolysis, immunology (complement activation), and thrombogenicity testing. However, if testing is not conducted, FDA recommends that the facility provide a scientific justification for omitting the test. For example, complement activation and in vivo thrombogenicity testing are not generally needed for devices that contact the blood only indirectly.

Implantation Criteria. For many types of materials, tests involving intramuscular implantation are often more sensitive than tests involving subcutaneous implantation, according to the guidance document. Intramuscular implantation testing is performed on rabbits by inserting the device in the muscle tissue along the spine. While the implant can also be inserted in a subcutaneous space, this method provides less sensitivity than intramuscular implantation.

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