There are a few circumstances in which biocompatibility testing is likely not required:

• If the same product is already on the market and has historical use data.
• If the product, device, or materials do not involve patient contact.

Although we would agree that your orthopedic brace is a low-risk device, biocompatibility testing, or at least some type of material characterization demonstrating equivalence to a product already on the market, would be required. The type of testing required for this type of device would be:

• Cytotoxicity testing; agar overlay test. This is a test for skin-contacting devices. If your device could potentially contact breached skin, we would suggest that you perform an MEM elution cytotoxicity test.
• Primary skin irritation test for skin-contacting products.
• Buehler sensitization test for skin-contacting products.

If the stent is metal or has metal in it, I would prefer gamma radiation because the E-beam method can cause ‘shadowing.’ By ‘shadowing,’ I mean that the E-beam bounces off metal objects and does not penetrate to the other side well if they are not sterilized from both sides. E-beam sterilization also needs additional samples to dose-map the sterilization process. Gamma is a better sterilization method, in my opinion. It ‘radiates’ from all sides and provides very good sterilization assurance.

Because the stent would most likely have a very low bioburden, a low-dose sterilization process could be performed if the bioburden is consistent. However, according to TIR17, polylactides are poor to good with regard to radiation stability. The best option may be to irradiate using both sources and see how the functionality testing comes out.

According to the ISO 10993 standard, you should perform biocompatibility testing only on material that directly or indirectly contacts the patient. Thus, if the material does not contact the patient, testing is not necessary.

My experience is that silicone does very well dimensionally with respect to most forms of sterilization. I have never seen a percentage shrink published, however. Usually, what is required is that the company perform feasibility studies using the different forms of sterilization followed by dimensional analysis. We can assist with applying the sterilization methods, if needed.

The indirect contact method is an extraction procedure in which the device or material is extracted in physiological saline for a given time and at a given temperature depending on the intended use of the product (for example, 37°C for 72 hours, 50°C for 72 hours, 70°C for 24 hours, or 121°C for 60 minutes). The extract fluid is then exposed to serum or plasma for a given period of time, and the complement levels are determined using ELISA assays specific for C3a and SC5b-9. This method determines the complement activation levels of leachables extracted from the device or material in saline. One of the problems with this method is that the saline must be diluted significantly (1:10) when exposed to the serum in order to perform the test, thereby potentially diluting the effects of the extracted leachables during complement activation.

The direct contact method directly exposes the device or material to serum or plasma, and the complement levels are determined using ELISA assays specific for C3a and SC5b-9. This method determines the direct material interactions with the serum or plasma and possible chemical leachables that may come off of the device or material during exposure. This method is typically more sensitive than the indirect method, and it shows the direct effect of the device or material in contact with the serum or plasma.

As a general rule, FDA accepts only the direct contact method because of its sensitivity and the direct material interaction with the serum or plasma. Moreover, because there is no industry standard acceptance criteria or pass/fail criteria for this test, Nelson Laboratories Inc. strongly recommends that when you perform this assay, you should include a predicate device or material (a comparative device or material already on the market similar in function and patient contact duration to the device you are testing). Typically the test device or material protein concentrations are compared statistically with negative control protein concentrations, and complement activation is determined based on the statistical similarities or differences. When a predicate device is included in the assay, the test device protein concentrations are statistically compared with the predicate device protein concentrations to determine statistical similarities or differences between the product you’re testing and a product already on the market.

If your sample is processed in the identical way as an existing sample and the materials used are the same, you don’t have to repeat biocompatibility testing. The only warning I would give is that the percentages of the materials in the new device should be comparable to those in the previous device. Since these tests use extracts and these extracts are based on surface area to volume, if your new device has a higher percentage of a certain material than the predicate, retesting might be needed.

Both Teflon and Kevlar have been used in medical devices and are generally considered to be safe. However, biocompatibility does not just investigate materials but also processing residuals that could be toxic. Therefore, such residuals should be considered, too

According to ISO 10993 guidelines, devices that make either direct or indirect contact with the patient should be tested in their final configuration and through all of their processes. Because of residuals, the processing of a device can impact its biocompatibility. Thus, mold, cleaning agents, oil, or other processing substances on the device can have a negative impact on it.

Silicone rubber is routinely sterilized with steam and occasionally with dry heat. While all the silicone that I am familiar with does well with steam sterilization, there are some potential problems that you need to ensure do not occur. I would suggest you do performance tests before buying much of the material.

You can also look up silicone rubber in AAMI TIR 17, a great reference that describes a wide range of materials, modes of sterilization, and their associated effects. AAMI TIR 17:2008 is good for this kind of information for those who are not polymer scientists. It states that silicone can range widely from poor to excellent in its ability to withstand steam sterilization (autoclaving). Resterilization up to more than 10 cycles is likely acceptable. Autoclavability depends largely on the grade of silicone you have. The best thing to do at this point is to try a cycle and see how it works.

The Parenteral Drug Association (PDA) has a technical monograph (#27) on Pharmaceutical Packaging Integrity that cites helium mass spectrometry methods. There are dozens of published articles that compare helium leak methodology to microbial ingress for testing container closure integrity and for pharmaceutical packaging. Most of the published articles are in the PDA Journal of Pharmaceutical Science and date from the 1980s to the present. Other standards that could be referenced include the following:

• ASTM E493-06—Standard Test Methods for Leaks Using the Mass Spectrometer Leak Detector in the Inside-Out Testing Mode

• ASTM E499-95 (2006)—Standard Test Methods for Leaks Using the Mass Spectrometer Leak Detector in the Detector Probe Mode

• ASTM E908-98 (2004)—Standard Practice for Calibrating Gaseous Reference Leaks

• ASTM E1603-99 (2006)—Standard Test Methods for Leakage Measurement Using the Mass Spectrometer Leak Detector or Residual Gas Analyzer in the Hood Mode