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While the chemistry of biopolymers and the source of these materials' building blocks are very diverse, there is a commonality among them when it comes to potential patient risk: there is always concern over side products and manufacturing residuals. While it is accepted that biopolymers have an inherent advantage from being similar chemically to substances naturally found in the body, they also have the same disadvantage facing all medical device materials from being processed. For that reason, the chemical evaluation strategy used for medical devices made from biopolymers is very similar to what is used for devices made from fully synthetic materials. The heart of the strategy is acknowledging that the manufacturer of the device does not know what they do not know, and the only way to safeguard against unpleasant surprises is to screen for everything that might reasonably be in or on the device.
1.3.2 Chemistry Screening of Biopolymers
It is important to start the design of a chemistry testing strategy with the end goal in mind. In the case of chemistry for biocompatibility, the end goal is to be able to screen for unexpected contaminants with enough sensitivity and with enough accuracy that toxicological conclusions can be made based on the data produced (Figure 1.3). Determining the proper sensitivity can be a matter of debate but should be low enough so that any chemicals that are present – but not reported because they are below the sensitivity – are known to not be toxicologically concerning. In other words, a threshold of toxicological concern (TTC) is needed.
Figure 1.3 Important aspects for setting up a chemical characterization study.
The TTC concept was developed to define an acceptable intake for any unstudied/understudied chemical that, if below the TTC, would pose a negligible risk of carcinogenicity, systemic toxicity, and reproductive toxicity. The concept was developed for chemicals present in the human diet and is accepted by the US Food and Drug Administration (FDA), International Conference on Harmonization (ICH), and the European Medicines Agency (EMA) for the evaluation of impurities in pharmaceuticals. It has also been used for assessing contaminants in consumer products and environmental contaminants. The methods upon which the TTC is based are generally considered very conservative since they involve data for the most sensitive species and most sensitive site induction (several “worst‐case” assumptions). The TTC concept provides an estimate of safe exposures values for any compound not on the TTC exclusion list (i.e. metals, nitrosamines, and polycyclic aromatic hydrocarbons). The most conservative TTC value has been set at 1.5 μg/d and is assigned for greater than 10 years to a lifetime of exposure. A TTC of 120 μg/d has been proposed for genotoxic exposures limited to one month or less [12]. Exceeding the TTC is not necessarily associated with an increased risk given the conservative assumptions employed in the derivation of the TTC value [13,17]. When adequate evidence exists that a constituent is non‐carcinogenic, a non‐carcinogenic TTC value may be used to address the constituent (e.g. Cramer classification) [18,19].
The TTC concept for medical devices was formalized in ISO 21726 published in February 2019. This brief international standard outlines the appropriate strategy for using the Cramer class and TTC. When adequate toxicological data is not available in the literature, the Cramer classification should be used for non‐cancer effects; for cancer‐based effects, the ICH M7 TTC values should be used based on the contact duration of the device. Cramer classification stratifies compounds into three groups (I, II, and III, with III being the highest risk); the acceptable daily exposures are 1800 μg/d for class I, 540 μg/d for class II, and 90 μg/d for class III compounds. The TTC values from ISO 21726 for carcinogenic endpoints depend on contact duration and are shown in Table 1.3.
Table 1.3 Recommended TTC values from ISO 21726.
| Medical device contact category | Limited (<24 h) | Prolonged (24 h to 30 d) | Long terma (>30 d) | ||
| Duration of body contact | ≤1 mo | >1–12 mo | >1–10 yr | >10 yr to lifetime | |
| TTC for any one compound (μg/d) | 120 | 20 | 10 | 1.5b | |
a Considered permanent according to ISO 10993‐1.
b This value incorporates a 10−5 cancer risk for a 60 kg adult.
In addition to the sensitivity, the breadth of the analysis is critical. ISO 10993‐12, ISO 10993‐17, and ISO 10993‐18 provide guidance on the sample preparation and scope of analysis to give the required breadth. The device should be extracted in multiple solvents covering a range of polarities to be representative of the range of matrices that are found in the body. Extraction conditions should be selected to appropriately exaggerate the amount of chemicals found. For example, extraction of the device at 50 °C for 72 hours is prescribed by ISO 10993‐12 and is the most commonly used extraction condition. Typical extraction solvents are purified water, isopropyl alcohol, and hexane. Following extraction, the extracts must be analyzed for volatile organic compounds (VOCs), semi‐volatile organic compounds (SVOCs), non‐volatile organic compounds (NVOCs), and metals using a suite of techniques that are both qualitative and quantitative; these are almost always chromatography with mass spectroscopy (MS) for organic compounds and inductively coupled plasma for metals.
VOCs are typically analyzed for only in aqueous extracts, as semipolar and nonpolar solvents are often VOCs themselves. Two main techniques are available for VOCs: headspace gas chromatography with mass spectroscopy (HS‐GC/MS) and purge and trap GC/MS. HS‐GC/MS measures the volatiles present in the gas above a water sample in a closed vial; the vial might be slightly heated to encourage volatiles to enter the gas phase above the liquid. The gas is directed through a gas chromatograph, which separates molecules in the gaseous mixture by polarity. Different molecular polarities are retained in the instrument for different amounts of time; how long a molecule remains in the instrument is referred to as the retention time. After separation, the molecules are identified using mass spectroscopy. Briefly, mass spectroscopy works by fragmenting molecules into electrically charged pieces and then measuring the weight of those pieces very precisely. With knowledge of both the retention time and mass fragmentation patterns, VOCs can almost always be positively identified by comparison with large public or commercial databases. Purge and trap measurements differ from headspace only in the way compounds are sampled; first volatile organics are purged from the water by bubbling inert gas through the liquid and trapped in an adsorbent tube. VOCs are released from the tube into the GC/MS for analysis as with HS‐GC/MS.
SVOC measurement methods provide the single broadest source of information regarding the content of extracts and are amenable to both aqueous and nonaqueous extraction matrices. The term SVOC is ill defined in the medical device community but generally is considered to be those compounds most well suited for analysis by direct injection GC/MS. The distinction of this definition is important, as there are many molecules amenable to direct injection GC/MS that are considered to be NVOCs by every other definition. The methods used for SVOCs by GC/MS are mostly characterized by the details of their sample preparation and rigor of data analysis; instrumental details of the GC/MS remain largely harmonized. Water extracts are