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| <h1 style="text-align:center">CHRIS: <font color="#0070C0">CH</font>emical <font color="#0070C0">RIS</font>k calculator - Bulk leachables</h1> |
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| <h2 id="context-of-use-cou">Context of Use (COU)</h2> |
| <p>The bulk leachable module of the CHemical RISk calculator (CHRIS) is |
| intended to conduct screening level risk assessments to aid in the |
| biocompatibility evaluation of bulk additives and impurities in |
| polymeric medical device components. These assessments can assist device |
| manufacturers by providing instantaneous feedback on whether the |
| presence of the bulk chemical would require additional justification |
| and/or testing to demonstrate acceptable biological risk. The output of |
| CHRIS is a conservative margin of safety (MOS = toxicological safety |
| limit ÷ exposure dose) value for a bulk chemical contained within a |
| polymeric medical device component. Based on the MOS value, the |
| calculator determines if further assessment of one or more |
| biocompatibility endpoints is necessary for the specific chemical.</p> |
| <p>Because CHRIS only addresses compounds with a distribution that is |
| macroscopically homogeneous within the matrix, the tool can only be used |
| to assess bulk additives and impurities. Therefore, only compounds that |
| are introduced either intentionally or unintentionally during synthesis |
| (e.g., residual monomers and oligomers, catalysts, initiators) or |
| compounding (e.g., stabilizers, antioxidants, plasticizers) are within |
| scope. Surface residuals from processing, cleaning, and sterilization |
| are excluded. Also, CHRIS requires the total amount of the chemical to |
| be established in advance, e.g., based on a certificate of analysis. |
| Further CHRIS only addresses individual chemicals; therefore, a |
| favorable outcome by CHRIS does not imply acceptable biological risk for |
| the final finished form of a medical device. CHRIS is also not intended |
| to establish device classification or identify biocompatibility |
| requirements.</p> |
| <p>CHRIS provides clinically relevant, yet still conservative, exposure |
| dose estimates using a physics-based transport model for polymeric |
| systems where transport data are available to support the use of the |
| model. The model applies worst-case boundary conditions for release of a |
| substance from the polymer matrix and is based on five (5) primary |
| assumptions:</p> |
| <ol type="1"> |
| <li>The clinical use environment does not cause the polymer matrix to |
| swell or degrade.</li> |
| <li>Manufacturing processes do not impact the stability of the |
| polymer.</li> |
| <li>The chemical is homogeneously distributed throughout the |
| polymer.</li> |
| <li>The total amount of the chemical is present in dilute concentrations |
| (<= 2 m/v %).</li> |
| <li>Any particles/aggregates of the chemical present in the polymer are |
| much smaller than the smallest component dimension (<= 50x).</li> |
| </ol> |
| <p>While these assumptions are typically valid for bulk additives and |
| impurities in biostable polymers, users of CHRIS must confirm |
| conformance to the underlying assumptions or provide supporting |
| justification to ensure compliance for a given system. Further, CHRIS |
| only enables system specific exposure estimates for fifty-three (53) |
| polymeric systems that are generally biostable (non-swelling and |
| non-degrading). To estimate chemical release based on the model, the |
| diffusion coefficient of the chemical in the polymer matrix must be |
| specified. For the fifty-three (53) listed polymeric systems, a |
| worst-case (upper bound) diffusion coefficient, as a function of |
| molecular weight, has been established based on data from the |
| literature. For polymer matrices that are not included in this list |
| (“Other polymer”), CHRIS has two approaches. If the polymer glass |
| transition temperature is not specified, an ultra-conservative diffusion |
| coefficient that assumes the polymer has the properties of water is |
| used. If the glass transition temperature is specified, a |
| less-conservative upper bound diffusion coefficient is estimated using a |
| machine learning method. For the listed polymeric systems and the |
| ultra-conservative assumption, note that the worst-case diffusion |
| coefficient is only defined over a molecular weight range of up to 1100 |
| g/mol. Therefore, for substances with a molecular weight > 1100 |
| g/mol, the value of the diffusion coefficient assuming a molecular |
| weight of 1100 g/mol is used as a conservative value. When the machine |
| learning method is used, a check is conducted to verify that the |
| polymer/solute combination falls inside the applicability domain of the |
| model. If it falls outside that domain, CHRIS instead uses the |
| ultra-conservative assumption. Additionally, note that polymers with |
| high fractional free volume (FFV) should not be used with the machine |
| learning method because diffusivity may be underestimated. Instead, the |
| ultra-conservative assumption should be used.</p> |
| <p>In the absence of adequate toxicological and exposure data for a |
| chemical in a polymeric matrix, a toxicological risk assessment can be |
| conducted for systemic biocompatibility endpoints by comparing the |
| exposure estimate to an appropriate threshold of toxicological concern |
| (TTC). This is the approach used by CHRIS in this module. The TTC values |
| are based on systemic toxicity, thus CHRIS can address acute systemic |
| toxicity, subacute/subchronic toxicity, genotoxicity, carcinogenicity, |
| and reproductive and developmental toxicity. It does not, however, |
| address cytotoxicity, sensitization, irritation, hemocompatibility, |
| material mediated pyrogenicity, or implantation. Therefore, an MOS >= |
| 1 implies the chemical will not raise a safety concern with respect to |
| only the systemic biocompatibility endpoints, provided the chemical is |
| not within the cohort of concern, which is reflected in the output of |
| CHRIS.</p> |
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