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TSL/EED/MOS (TEEM) Calculator

Catalog of Regulatory Science Tools to Help Assess New Medical Devices 

 

This regulatory science tool is a method that applies the ISO 10993-17 toxicological risk assessment approach to medical device extractables screening data to assess systemic toxicity, genotoxicity, carcinogenicity, or reproductive/developmental toxicity in the biocompatibility evaluation of a medical device.

 

Technical Description

The revised International Standard Organization (ISO) FDIS 10993-17:2023 includes new toxicological risk assessment approaches, such as application of toxicological screening limits (TSL) and worst-case estimated exposure doses (EEDmax) for margin of safety (MOS) calculations. The TSL/EEDmax/MOS (TEEM) Calculator is a web-based toxicological risk assessment tool that applies these equations to chemical extractables data to facilitate consistent application of the new toxicological risk assessment approaches that are aligned with the ISO 10993-17:2023. The tool standardizes how EEDmax and MoS values are calculated and calculates thousands of EEDmax and MoS values.

The TEEM Calculator Web-App is a web portal  with links for the instructions for use (IFU), the TEEM Calculator Smart-Template Worksheet, and an application to perform EEDmax and MOS calculations for thousands of medical device extractables. 

Figure 1 illustrates the four simple steps to calculating EEDmax and MoS values for medical device extractables. In addition to the IFU, guidance is embedded in the TEEM Calculator Smart-Template Worksheet.

Figure 1. TEEM Calculator: A Simple Four Step Process for Users: Figure 1 illustrates the four simple steps to calculating EEDmax and MoS values for medical device extractables. In addition to the IFU, guidance is embedded in the TEEM Calculator Smart-Template Worksheet. 

Intended Purpose 

The TEEM Calculator Tool is intended for users (e.g., medical device manufacturers and regulators) who apply the ISO 10993-17 toxicological risk assessment approach to medical device extractables screening data to address systemic toxicity, genotoxicity, carcinogenicity, or reproductive/developmental toxicity in the biocompatibility evaluation of a medical device. 

The TEEM Calculator Tool is not applicable for users assessing the toxicological risk of volatile organic compounds released from respiratory gas pathway devices that apply the ISO 18562: 2017 “Biocompatibility evaluation of breathing gas pathways in healthcare applications” series of international standards.  Furthermore, the TEEM Calculator output is NOT a chemical toxicological risk assessment because this tool does not include all of the criteria necessary to complete the toxicological risk assessment (see ISO 10993-17:2023 for the additional criteria).

Testing

  1. The testing conducted by the TEEM Calculator Tool Development Team is summarized below. Initial TEEM Tool Testing– The goal of initial testing was to:
    • Test the TEEM Calculator Tool user interface functionality and verify application of the ISO 10993-17: 2023 formulas that are used in the calculation of applicable EEDmax and MoS values using a mock dataset.
    • Identify parts of the program code that require debugging and revision.
    • Prepare mock test datasets to be used for beta-testing.
    • Documentation:
      • Test datasets 
      • Results from test datasets
  2. TEEM Calculator Tool Beta Test– The goal of the beta-test was to evaluate the user interface functionality of the TEEM Calculator Tool and to further verify accuracy of user data entry. 
    • The beta-testers were given three documents containing mock TEEM Calculator Tool input datasets comprised of device-specific information chemical extractables data, including quantities and summary toxicity information. 
    • The beta-testers were asked to use the TEEM Calculator to calculate the Toxicological Screening Limits (TSL), Estimated Exposure Doses (EEDmax) and Margins of Safety (MOS) for the three different mock test data sets by following the Instructions for Use and the WebApp steps.
    • The beta-testers were asked to:
      • Fill out and upload the TEEM Calculator Smart-Template Tool Output .csv worksheet file that they generated for each mock dataset as well as the Web App Output file and send them to the TEEM Calculator development team for assessment and as the foundation for further refinement of the tool.
      • Provide qualitative feedback on how to improve the TEEM Calculator by answering the following questions:
        • Were there difficulties or inefficiencies experienced using the WebApp?
        • Was the interface intuitive and easy to use?
        • Was the Instructions for Use document helpful?
        • How much time was spent on the beta-test?
        • Did beta-testers have other feedback/suggestions to improve WebApp? 
      • Documentation
        • Instructional Webinar
        • Email Communications (recruitment)
        • Mock test datasets
        • Responses from beta-testers
        • TEEM Beta-Test Analyses
        • Follow-Up Actions Summary
  3. Follow-up Beta Testers Discussion– The goal of this discussion was to request confirmation from the beta-testers that their feedback was addressed by the post beta-test changes made to TEEM Calculator Tool.
    • Six of the seven beta-testers were given two documents containing mock TEEM Calculator Tool input datasets comprised of device-specific information chemical extractables data, including quantities and summary toxicity information. 
    • A survey was provided to the beta-testers to answer three questions regarding the utility of the TEEM Calculator Tool and whether we addressed their feedback.
    • Documentation:
      • Email Communication 
      • Meeting slide deck
      • Mock test datasets
  4. Survey Responses from beta-testers 
    • Follow-up Internal Testing (Confirmatory Testing)– The goal of this testing was to confirm functionality of a modified/revised TEEM Calculator Tool that had undergone changes based on beta-testing results and internal testing.
    • Comprehensive datasets were created to evaluate the functionality and performance of the TEEM Calculator Tool features.
    • The outputs were compared to independent calculations conducted by TEEM Calculator Development Team.
    • Documentation:
      • A panel of SMART-Templates filled with mock datasets for select device submission scenarios and corresponding ‘.csv.’ output files generated from the TEEM Calculator WebAppS.
      • Analysis worksheet identifying bugs/technical issues that were addressed with subsequent revisions to the WebApp code.
  5. Independent WebApp Code Verification– The goal of this testing was to carry out independent testing of the Webapp code to confirm that the code is free of syntax errors, which can lead to compiling issues.
    • Code verification was completed through the Visual Studio Code software used to develop and write the WebApp code.
    • Documentation – Screenshots from the Visual Studio Code software and GitHub (online repository of the programming code) that the WebApp code is free of syntax errors and compiling issues.
  6. Final Internal Testing (Confirmatory Testing)– The goal of this testing was to confirm that any change to the TEEM Calculator WebApp did not adversely impact the functionality and performance of the tool. 
    • Comprehensive datasets for 18 device use scenarios that included up to 48 calculated values per scenario were used to assess accuracy of WebApp outputs.
    • Three internal tests were completed until testing resulted in zero errors.
    • The outputs were compared to correct calculated values conducted by TEEM Calculator Development Team.
    • Documentation:
      • Tracked bugs/technical issues that were addressed with subsequent revisions to the WebApp code.
      • No calculation errors identified in final testing.
      • Worksheets summarizing errors reported from our testing.

Limitations

  • The TEEM Calculator output file is not a toxicological risk assessment.
  • The TEEM Calculator SMART-Template Worksheet has been tested for use with Microsoft Excel and LibreOffice Calc. Issues with other spreadsheet applications have not been tested.
  • The TEEM Calculator WebApp requires javascript enabled web browsers (e.g., Chrome, Microsoft Edge, Safari (MacOS), and Firefox).
  • The TEEM Calculator tool is not for supporting toxicological risk assessment of volatile organic compounds (VOCs) from respiratory gas pathway devices evaluated using approaches described in the ISO 18562 series of ISO standards.

Supporting Documentation

  1. A downloadable Instructions for Use (IFU) document that contains the purpose of the tool, how to use it, and frequently asked questions about the tool. 
  2. A downloadable TEEM Calculator Smart-Template Worksheet that contains what inputs are needed to complete the calculations. 
  3. A web browser independent javascript.js file, which performs instant calculations, that is embedded in the html code of the web page.

Contact

Tool Reference

  • In addition to citing relevant publications please reference the use of this tool using RST24BT04.01