Manufacturers producing medical devices that involve patient contact are typically required to perform biological safety evaluations, including biocompatibility tests to ensure patient safety, as specified by ISO 10993. Chemical characterization can help support the biocompatibility testing process, reduce the use of animal testing, in some cases, shrink turnaround time and cost, and, perhaps, eliminate the need to do some biocompatibility testing altogether.

Traditional biocompatibility tests involve evaluating the biological effects of compounds extracted from devices on animals (in vivo) and/or cells (in vitro). Chemical characterization of a device, in contrast, involves utilization of analytical chemistry to identify and quantify the amount of chemicals extracted from a device and an evaluation of the toxicological risk associated with the exposure level. This approach involves characterizing both the product material—typically a polymer, metal, or ceramic—and the extractable or leachable compounds that come from those materials or byproduct residuals on the device from the manufacturing process. As stated in the U.S. FDA draft guidance issued April 23, 2013, “The biocompatibility of a final device depends not only on the materials but also on the processing of the materials, manufacturing methods (including the sterilization process), and the manufacturing residuals that may be present on the final device.”

Using analytical chemistry and data from compound libraries to assess the finished device can yield more specific data about these extractable compounds than biocompatibility testing. The known properties of the compounds can then be used to create a toxicological risk or safety assessment based on the predicted biological response to the compounds.

This article will examine the various ways in which chemical characterization can augment and refine the biocompatibility testing process.

When to Use Chemical Characterization

Material/Process Changes: Medical device manufacturers trying to shepherd a device involving patient contact to market must perform biocompatibility tests. Should the device or the process used to manufacture it undergo a change after it has reached market, the manufacturer must assess the impact of the change on patient safety. However, rather than simply repeating all of the original biocompatibility tests, chemical characterization can be used to formulate a risk assessment and conduct a comparison study of materials, which can help indicate which (if any) of the original biocompatibility tests must be repeated or if the material change can be supported through analytical evaluation and a written toxicological risk assessment.

Supplementing in vivo Biocompatibility Testing: The same principle can be applied to certain new device submissions. If a manufacturer can show it has evaluated patient safety via other means—such as a toxicological risk assessment built on chemical characterization—it might not have to perform every biocompatibility test as outlined in ISO 10993, especially with regards to some of the long-term carcinogenicity or genotoxicity tests. For example, the carcinogenicity characteristics and toxicity of many compounds are known—including whether they have carcinogenic properties for humans or not—hence the data gleaned from chemical characterization can be used to assess the relative carcinogenicity risk (or lack thereof) for the device’s extractable compounds. This potentially enables the manufacturer to avoid performing these long-term and expensive biocompatibility tests.

Regulatory Reviewer Request: It has recently become more common for regulatory reviewers and notified bodies to request chemical characterization data during the review process, and manufacturers are increasingly aware of the possibility that they might be asked by the reviewer to provide this data. However, the current standards in this area are still fairly vague, as it’s a newer concept than the more tried and true area of biocompatibility testing. Reviewer expectations for written toxicological risk assessments may vary due to device type, target population, and available material safety data. It is important that manufacturers consult with a regulatory expert and a toxicologist to ensure a written assessment adequately addresses patient safety based on the intended use.

Specific Device Types: Reviewers are becoming more interested in the chemical characterization of certain specific devices that involve high-risk patient contact. For example, those that have vascular or neurological contact, indirect contact with the airway that may introduce materials to the lung, combination products that house or transfer pharmaceuticals, and those that include colorants, pigments, or plasticizers (e.g., phthalates) that are believed to have developmental, reproductive, carcinogenic, or other toxic effects. There is increased scrutiny and concern, from a regulatory perspective, about potentially harmful or toxic materials leaching from these critical devices. Chemical characterization testing offers a high level of specificity regarding the quantitative amount of a chemical and quantitation needed for safety evaluation and a toxicological risk assessment when seeking approval for such devices.

Test Methods

There are two categories of tests for performing chemical characterizations: direct material characterization and extractable/leachable analysis. While many options are available for assessing materials and extractable/leachable chemicals from a device, a few common tests are given below.

Direct Material Characterization: Two types of tests under this category require direct analysis of the material (no extraction):

  • Fourier Transform Infrared Spectroscopy (FTIR): Characterizes the internal bonding structure of the polymers, which can be used to identify said polymers. This test is qualitative and provides a comparison of the material to a known library or reference materials.
  • Differential Scanning Calorimetry (DSC): Involves identifying polymers by their thermal properties. This test is qualitative and provides a comparison of the material based on known thermal properties to a reference library.

Extractable/Leachable Analysis: All of the test methods that fall under this category begin with an extraction that simulates clinical or exaggerated clinical conditions. A device is submerged in a polar and non-polar solvent—like water, hexane, or alcohol—and kept there for the appropriate time and temperature (e.g., human body temperature or greater) for extraction. The extract is then analyzed, which yields quantitative, semi-quantitative, and/or qualitative data, depending on the test method. Four common types of ex tractable and leachable analyses are as follows:

Gas Chromatography-Mass Spectrometry (GC-MS): Provides quantitative data for volatile and semi-volatile organic compounds of small molecular weight.

Liquid Chromatography-Mass Spectrometry (LC-MS): Provides quantitative data by analyzing extracts for nonvolatile molecules. This is very similar to high-performance liquid chromatography (HPLC), though the mass spectrometer enables the detection of lower concentrations (better sensitivity which is important for critical devices, e.g. neonatal, neurological or other sensitive device categories where small quantities of compounds can be problematic).

Inductively Coupled Plasma-Mass Spectrometry (ICP-MS): Specific to detection of metals. This method can specifically

Fig. 1 – Autosampler for an Inductively Coupled Plasma Mass Spectrometer (ICP-MS) instrument.
identify and quantify metallic compounds, such as heavy metals, that generally do not get metabolized in the body and may lead to a toxic build up or carcinogenicity. (See Figure 1)

Gravimetric Assays: Quant itative method that is non-specific as to the compound(s) found on a device after extraction. This test detects two types of gross contaminant non-volatile residue: surface and leachable. While comparable in purpose to the non-volatile LCMS analysis, it has a faster turnaround time, but does not identify specific compounds. Therefore, it may not be adequate for Class II critical and Class III critical devices with certain target populations where specificity of compounds is needed.

There are other methods for performing chemical characterization related to material structure and compounds, including scanning electron microscope/elemental diffraction spectroscopy (SEM/EDS), nuclear magnetic resonance (NMR), X-ray fluorescence (XRF), and ion chromatography (IC). These methods are typically used for specific investigations or product property assessments.

Once the test data has been collected, a toxicological review of the extractable/leachable compounds is performed for toxicological risk and patient safety. In these dry-lab experiments, each compound is examined one at a time, using existing literature and the standards established by ISO 10993-17 to formulate a toxicological risk assessment. For most devices, the compounds that fall below toxic levels based on Benchmark Dosing (BMD) data or No-Observed-Adverse-Effect-Level (NOAELs) will be safe for patients. BMD is preferred as it incorporates multiple NOAEL values deemed to be safe. If large quantities of compounds or toxic compounds are discovered, additional testing may be required to support the toxicological risk assessment.

Case Studies

There are a number of examples of how chemical characterization can be beneficial. Here are some considerations.

Supplier Change: Most medical device manufacturers will have to evaluate the impact of a change to their product or manufacturing process at some point. Chemical characterization can be a good method to use when approaching this issue and documenting the risk for the device history file.

Consider a manufacturer that relies on a specific supplier to provide a component or raw material, such as polypropylene. If that supplier stops supplying polypropylene, or goes out of business, the manufacturer must find a new supplier. Performing a chemical characterization assessment can show the impact of the material change on device safety and can help the manufacturer determine if any biocompatibility tests need to be repeated.

Process Changes: Changes to the manufacturing process can also be accounted for via chemical characterization. Consider a manufacturer that begins using a new, detergent-free cleaning process. Performing a chemical characterization can demonstrate no new harmful materials are being added to the device as part of this new process. This can show that the device coming off the manufacturing line is unchanged by the new cleaning process.

In Lieu of Biocompatibility: It is sometimes possible to use chemical characterization data to justify out of biocompatibility testing requirements. Consider a manufacturer that wants to justify out of performing a genotoxicity test on a metallic material. A full chemical characterization profile of the product can be performed, with leachable/extractable compounds being evaluated for their toxicity. The resulting toxicological risk assessment makes it possible to justify out of performing the genotoxicity test based on the extractable/leachable chemicals and literature research of chemicals. Of course, every scenario is unique, depending on the device, the materials involved, and whether or not there are predicate devices on the market.

Manufacturers should perform a chemical characterization in the course of getting their devices to market, especially Class II or Class III. For example, it would benefit those making devices that include a colorant, as the FDA frequently requests chemical characterization data on colorants, especially regarding their leachability/extractability. The same is true of devices that involve airway contact or repeat exposures through multiple uses.

Conclusion

Fig. 2 – Analyst placing samples in a liquid chromatography-mass spectrometer (LC-MS) for analysis.
Rather than continuing to take a checkbox approach to biocompatibility testing following ISO 10993, it is becoming increasingly common for manufacturers to pair thoughtful toxicological risk assessments with chemical characterization data to evaluate devices to ensure patient safety. Chemical characterization enables manufacturers to move away from a one-size-fitsall approach to biocompatibility testing and toward a smarter, more deliberate approach to fully understand the materials and chemicals that may come off the device in clinical use. (See Figure 2)

There are many benefits to using chemical characterization, from reducing the testing burden, saving time and money for the manufacturer, and reducing the amount of animal testing required. From an ethical standpoint, the latter benefit can be especially attractive.

A recent meeting of the ISO committee that governs biocompatibility testing standards indicated that chemical characterization will be a driving force of future standards for device safety assessments. Looking ahead, standards committees and regulatory bodies will likely put more emphasis on performing chemical characterization first, then turning to biocompatibility testing to fill in the gaps for their device safety assessments.

In short, chemical characterization—which already brings many benefits to the process—will become an even more important part of toxicological risk assessments and biological safety evaluations in the crucial task of ensuring patient safety.

This article was written by Thor Rollins, Senior Scientist; Sarah Campbell, Toxicologist; and Audrey Turley, Technical Consultant, Nelson Laboratories, Salt Lake City, UT. For more information, Click Here .

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Medical Design Briefs Magazine

This article first appeared in the April, 2016 issue of Medical Design Briefs Magazine.

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