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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