Jan 7, 2021 | Medical Device Testing, Regulatory, Technical Expertise
Regulations published by the International Standards Organization (ISO) provide a global structure for the medical device industry. These standards can affect development timelines for new products and, in some cases, can influence which products a company can keep on the market, depending on ongoing approvals.
Manufacturers must examine recent regulatory updates and anticipate expected changes in other standards to avoid delays in the approval process. The 2020 updates to ISO 10993-18 have altered medical device testing and timelines, and the expected role ISO 10993-17 (Part 17; updates expected to be published by 2021-2022) will play in the biological evaluation process is crucial when planning for device submissions.
Key learnings from Part 18
Before preparing for the potential impact of changing ISO 10993-17 requirements, it’s crucial to understand ISO 10993-18. Part 18 provides guidance on the required chemical information for medical device evaluations, including testing requirements for chemical characterization and the exposure dose estimation, which acts as the starting point for toxicological risk assessments.
Some of the significant updates include:
- Replicates. Manufacturers are now expected to submit multiple replicates during chemical characterization testing. This expectation follows suit with U.S. Food & Drug Administration (FDA) current thinking, making multiple replicates a standard practice unless you can justify your approach.
- The analytical evaluation threshold (AET). Part 18 defined and implemented the AET to align the work of chemists and toxicologists when designing studies. It requires that toxicological data, such as the threshold of toxicological concern (TTC), and exposure assumptions to inform chemistry study design and execution.
- Intensified extractions. Part 18 requires more extensive extraction studies for prolonged devices (i.e., those with contact with the body for more than 24 hours).
Widespread changes like those in Part 18 make it imperative for manufacturers to plan and take a proactive approach to chemical characterization and other required endpoints. For many manufacturers, this involves working with a knowledgeable testing lab to meet characterization standards. To prepare for upcoming changes to ISO 10993-17, collaborating with toxicologists that are up to date with the latest changes will be crucial.
The importance of thorough chemical characterization
Manufacturers that stress preparedness and ensure their chemical characterizations are conducted according to the current regulatory thinking have an advantage when seeking to gain or maintain regulatory approval in the coming years. Achieving this involves the identification of all compounds found above the AET. The more unknowns a device has in its characterization report, the more likely it will face setbacks or possibly rejection during the approval process.
When unknowns are present, it is challenging for the toxicologist to assess the device’s toxicological risk accurately. This situation can require additional testing and lead to an additional investment of time, resources and money. Chemical characterization, whether conducted in-house or through an external partner, is critical to the success of a device’s submission.
Part 17: Standardizing toxicological risk assessments
Potential updates to ISO 10993-17, now in the second committee drafting phase, will expand guidance on conducting toxicological risk assessments (TRAs), likely standardizing the evaluation process. Standardization should lead to more clarity regarding medical device risks and change how companies organize and support testing procedures. As a result of potential updates, companies will need to be more strategic in their planning as they face a dynamic regulatory landscape.
ISO 10993-17 will aim to provide requirements and guidance for establishing whether the toxicological risk of chemicals extracted from a medical device are without appreciable harm to health. This process considers the intended patient populations and accounts for uncertainties in the risk evaluation, such as the exposure duration, route of exposure and quality of the toxicological data. First, scientists must obtain the available toxicological information needed to derive the tolerable intake (TI) level, or the amount of a chemical constituent (per body weight, per day) without harm to health. Experts should base the TI on the lowest clinically relevant point of departure (POD), and in the absence of available toxicology data, apply an appropriate TTC.
The TI/TTC helps derive a margin of safety (MOS) value, which is an important tool in evaluating overall biological risk associated with a medical device. MOS values less than or near one may indicate the need for additional chemical information (e.g. targeted chemical analysis, or simulated use extraction studies), biological testing, and/or use of ISO 10993-1 to further assess the overall biological risk (e.g. including benefit, and clinical factors).
Planning for a more robust TRA now will help manufacturers when the standard is adopted. Without a proactive approach to these requirements, manufacturers may find gaps in their information. Then, they would be required to complete chemical characterizations at a higher level of analysis, adding cost and timeline of their project.
The continued movement toward testing standardization supports the prioritization of patient safety and positive device outcomes. When preparing for the updates to Part 17 and testing impacts, lessons from Part 18 may heed critical advice. Medical device manufacturers need to take proactive steps to plan for changes in the varying regulatory landscape.
To learn more about how regulatory updates may impact your medical device testing and submission, contact a WuXi AppTec Medical Device Testing expert today.
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WuXi AppTec provides a broad portfolio of R&D and manufacturing services that enable companies in the pharmaceutical, biotech and medical device industries worldwide to advance discoveries and deliver groundbreaking treatments to patients. As an innovation-driven and customer-focused company, WuXi AppTec helps our partners improve the productivity of advancing healthcare products through cost-effective and efficient, socially responsible and sustainable solutions. With industry-leading capabilities such as R&D and manufacturing for small molecule drugs, cell and gene therapies, and testing for medical devices, WuXi AppTec’s open-access platform is enabling more than 4,100 collaborators from over 30 countries to improve the health of those in need – and to realize our vision that “every drug can be made and every disease can be treated.
Nov 2, 2020 | ISO10993-17, Medical Device Testing, Toxicological Risk Assessment
Around the world, various regulatory factors are driving the evolution of medical device risk evaluation. The industry is beginning to recognize the limitations of biocompatibility testing. While the data it can provide still have a pivotal role in the assessment process, it may not be able to measure other factors that are becoming increasingly important to consider, such as carcinogenicity or reproductive and developmental toxicological concerns. When it comes to patient and practitioner safety, you must address these risks.
Chemistry, toxicological risk assessment (TRA) and biocompatibility are necessary components of a biological evaluation. A biological evaluation provides evidence-based data focused on device nature and duration of patient contact which ultimately supports the safety of a device. With the additional expectations regarding chemistry were provided in 10993-18:2020, it is natural that the expectations of toxicological risk assessments also need to be further harmonized. ISO 10993-17 is under revision to provide guidance on toxicological risk assessments.
Driving Forces
The toxicological risk assessment and biological testing are conducted to address the biological endpoints appropriate for the device duration and nature of body contact, to support the biological safety of the device. Regulations are the main driver behind the growing role of TRAs, including the EU Medical Device Regulation (MDR) and 2020 guidance from the U.S. FDA. These documents not only help to set expectations, such as the analytical evaluation threshold (AET) but also support the methodologies and approaches to performing this analysis.
ISO 10993 Biological Evaluation of Medical Devices
The ISO 10993 series of standards highlight the importance of biological evaluations as a part of the overall medical device risk management program. Part 1 demonstrates a need for detailed physical and chemical information, and if manufacturers do not provide sufficient data, additional testing, such as E/L studies, will be necessary before designing a biocompatibility testing plan.
In addition, Part 18, updated in 2020, faced an overhaul in its latest revision. This update increased the requirements for characterization of medical device chemical constituents in a final finished form of a medical device. This section has made it challenging for some to achieve characterization to the levels required by regulators. However, as the industry adjusts, the role of this data will become more evident as appropriate TRAs will rely on this information.
FDA Guidance on use of ISO 10993-1
For manufacturers seeking approval in the United States, it is important to consider that the U.S. FDA does not recognize all clauses of all parts of ISO 10993. The FDA Guidance on the Use of ISO 10993-1 most recently published in 2020, which is almost identical to the 2016 version, provides FDA recommendations that may differ from the ISO 10993 requirements.
ISO 14971 Application of Risk Management to Medical Devices
This document requires risk management, including biological evaluation, to continue throughout a product’s lifecycle.
ISO/TS 21726 Biological Evaluation of Medical Devices
When conducting chemical characterization and TRAs, applying the threshold of toxicological concern (TTC) will often reference this technical specification.
Medical Device Regulation
The EU MDR currently recognizes the most current versions of ISO 10993 standards as “state of the art,” meaning notified bodies expect applications to meet current ISO 10993 requirements.
Collating this information and staying updated is a complicated task. Fortunately, lab testing partners not only have an extensive background on regulatory standards but often play a part in shaping what the future of these standards will be.
Upcoming: ISO 10993-17
While not expected to publish until at least 2021, ISO 10993-17 is currently in the revision process and will provide additional guidance on conducting a TRA. The majority of the standard is expected to change, from defining terminology to summarizing recommended steps in the process. Performing these assessments will likely become more standardized, but this does not indicate process simplicity.
Because TRAs consider device risk as a combination of hazard and the level of exposure, detailed background on the device and its use are critical. Manufacturers need to provide as much contextual understanding of a device’s materials, production process and potential exposure parameters (e.g. maximum clinical use, and patient populations). These considerations are important in the design of chemical characterization and the conduct of a valid toxicological risk assessment. Without this information, the result may be under or over-predicting patient risk; both may lead to undesirable outcomes for different reasons.
Partnering with an informed, reliable testing partner can help prevent potential issues with changing guidance. Qualified, expert judgment will be necessary for many parts of this process, such as when scientists evaluate the results for the margin of safety for medical device chemical constituents. It can be an added benefit if the lab performing your device’s TRA has an inside look at what standards are coming.
An Evolving Outlook
As medical devices continue to evolve, so will the standards. Our industry continues to drive innovation, which is something to celebrate. While there are still opportunities for improvement, chemical characterization plays a critical role in modernizing the biological evaluation of medical devices.
For a more in-depth review of the TRA process, watch our webinar “Toxicological risk assessment of medical devices and proposed updates to 10993-17, including the application of TTC values.”
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Established in December 2000, WuXi AppTec provides a broad portfolio of R&D and manufacturing services that enable companies in the pharmaceutical, biotech and medical device industries worldwide to advance discoveries and deliver groundbreaking treatments to patients. With industry-leading capabilities such as R&D and manufacturing for small molecule drugs, cell and gene therapies, and testing for medical devices, WuXi AppTec’s open-access platform is enabling more than 4,100 collaborators from over 30 countries to improve the health of those in need – and to realize our vision that “every drug can be made and every disease can be treated”.
Oct 7, 2020 | MDR, Medical Device Testing, Technical Expertise
In cases where biocompatibility testing may not entirely mitigate medical device risk, chemical characterization data has become increasingly important. The updates to ISO 10993-18:2020 are applying pressure to supply sufficient chemistry data, meaning the industry must apply the concept of the analytical evaluation threshold (AET) to support the advancing methodology of toxicological risk assessments (TRA).
In her latest webinar, Sherry Parker, Senior Director of Regulatory Toxicology at WuXi AppTec Medical Device Testing and international committee member of Technical Committee 194, discusses what medical device manufacturers and regulators need to know to conduct quality toxicological risk assessments (TRA) and shares insights on the upcoming changes to ISO 10993-17. As this guidance development continues, Sherry provides background on the proposed changes, perspective in how the standard continues to define “toxicological risk assessment” and the application of threshold of toxicological concern (TTC).
The industry currently faces a learning curve in what this developing guidance means for medical device testing. Especially with the more exaggerated and exhaustive chemical characterization conditions recommended in ISO 10993-18:2020, and larger extractable chemical profiles, including data-poor substances as a result, testing methodologies are increasingly intricate and complex. Toxicologists, chemists and manufacturers will need to come together to ensure understanding of the potential for patient exposure and develop an appropriate chemical characterization program.
Join Sherry Parker in the webinar, “Toxicological risk assessment of medical devices and proposed updates to 10993-17, including the application of TTC values.”
Established in December 2000, WuXi AppTec provides a broad portfolio of R&D and manufacturing services that enable companies in the pharmaceutical, biotech and medical device industries worldwide to advance discoveries and deliver groundbreaking treatments to patients. As an innovation-driven and customer-focused company, WuXi AppTec helps our partners improve the productivity of advancing healthcare products through cost-effective and efficient solutions. With industry-leading capabilities such as R&D and manufacturing for small molecule drugs, cell and gene therapies, and testing for medical devices, WuXi AppTec’s open-access platform is enabling more than 4,000 collaborators from over 30 countries to improve the health of those in need – and to realize our vision that “every drug can be made and every disease can be treated”.
For more information, please visit: http://medicaldevice.wuxiapptec.com/
