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.