Complete chemical characterization is critical for not only the submission of your medical device but also – and most importantly – patient safety. This primer covers the most important things you need to know about performing a complete chemical characterization under ISO 10993-18.
ISO 10993 is a series of standards published by the International Organization for Standardization (ISO) that covers the process for evaluating the biocompatibility of medical devices to manage biological risk. Chemical characterization is the first step of the biological evaluation process, but it’s covered by Part 18 of the series.
Regulatory expectations for medical devices are higher than ever, and interpretations are in flux. ISO 10993-1, which sets the stage for the rest of the series, was updated in 2018 with an increased emphasis on chemical characterization. ISO 10993-18 was then updated in 2020 to reflect new expectations for replicates, intensified extractions and the analytical evaluation threshold (AET) – all to drive more robust toxicological risk assessments (which are covered in ISO 10993-17).
Simply put, there’s a lot to unpack. Here’s what manufacturers need to know about ISO 10993-18.
What is ISO 10993-18?
As a recap from ISO 10993-1, there are generally three critical elements evaluating biological risks:
- Complete chemical characterization
- Toxicological risk assessment
- Biocompatibility testing
Chemical characterization is the starting point that feeds into toxicological risk assessments, as the combination of these two steps often addresses several biocompatibility endpoints. Biocompatibility testing should be used to help meet the necessary endpoints that cannot or could not be addressed in the chemistry and risk assessment.
Part 18, provides specific guidance on chemical characterization testing requirements and exposure dose estimation, ultimately helping the chemist gather the information necessary to design a study that will be appropriate for the toxicological risk assessment.
Why is ISO 10993-18 (and Chemical Characterization) Important?
Hazardous chemicals may be introduced into a medical device during routine activity such as manufacturing, sterilization, and storage as well as impurities in the raw materials. The purpose of ISO 10993-18 – and the goal of chemical characterization – is to identify all of the chemical constituents in a medical device so that those chemicals can be assessed as part of a toxicological risk assessment.
The data collected from chemical characterization helps toxicologists calculate the potential risk to patients. To effectively do this, it’s critical to identify all chemicals present above the analytical threshold that is determined in partnership between chemistry experts and toxicologists, with justification of the AET expected by regulatory bodies. This is one of the key reasons why ISO 10993-18 introduced the AET in the 2020 update, better aligning the work of chemists and toxicologists when designing studies. In short, the AET sets the baseline at which chemicals should be identified, reported, and evaluated for potential toxicological concern in the risk assessment.
When chemicals are left unidentified, they must be considered carcinogenic or genotoxic, and toxicologists won’t be able to accurately assess the medical device’s toxicological risk. Thus, the more unknowns a device has, the more likely it is to face additional scrutiny from regulators.
When Should Medical Device Manufacturers Consider ISO 10993-18?
As mentioned, chemical characterization of a medical device is the first step in the biological evaluation process, which means you should care about ISO 10993-18 early on in the preclinical testing process. But it must be completed on the finished medical device as part of the regulatory submission package. This gives chemists and toxicologists the full picture, including manufacturing and sterilization methods that might impact the extractables profile of the product.
Bottom line: Chemical characterization should be considered a journey, not a check-box exercise.
How Do Regulatory Authorities Approach ISO 10993-18?
Regulatory bodies in the US and EU have incrementally interpreted, adopted, and implemented ISO 10993-18:2020.
The U.S. Food and Drug Administration (FDA)
While the FDA stopped short of full recognition, it does expect manufacturers submitting products for use in the U.S. to address the requirements of the standard.
The FDA accepts most of ISO 10993-18:2020, with a few notable exceptions related to:
- Applying the limit of quantification (LOQ) when the AET is unachievable.
- Grouping chemicals into classes to assist with toxicological risk assessment.
- Selecting surrogate extraction vehicles correlating chemical to biological testing.
- Issues related to determination of uncertainty factors in the AET calculation.
The FDA argues that the portions of the standard that are not recognized are in conflict with published literature or other recognized standards, or include technical errors that will be corrected in subsequent versions of the standard.
As acknowledged in their guidance document on the use of ISO 10993-1, published in September of 2020, the FDA clearly recognizes the importance of chemical characterization as part of an overall biocompatibility evaluation and that characterization data may be used to address several biocompatibility endpoints (e.g., genotoxicity, carcinogenicity, developmental toxicity). As a general rule, the FDA expects the chemical characterization studies to be conducted in accordance with ISO 10993-18:2020, especially with respect to solvent selection, extraction conditions, and inclusion of the AET.
The EU Medical Device Regulation (MDR)
In 2021, the MDR provided a new, more comprehensive regulatory framework for medical devices, changing how devices are classified and introducing stringent requirements that prioritize patient risk.
When it comes to ISO 10993-18:2020, the MDR has accepted the standard as “state of the art” and generally holds manufacturers to it. However, the EU has yet to harmonize the standard across member states. It’s up to notified bodies to interpret the meaning of state of the art and work with medical device manufacturers to ensure a smooth submission process.
So, what does meeting regulatory expectations really look like, especially today when those expectations are higher than ever? It depends on where you plan to submit, but there are some general tips you can follow to set your product up for success.
What Do Medical Device Manufacturers Need to Do to Meet Regulatory Expectations?
To follow ISO 10993-18 and meet current FDA and/or MDR expectations, the key is planning and preparation. Taking a proactive approach to these requirements will help you prevent gaps in your information that may lead regulators to question your data and your methods. It is not out of the ordinary to have regulators request repeat testing, adding cost and timeline to your project.
Here are some key takeaways for meeting current regulatory expectations and a smoother path to regulatory clearance for your medical device:
#1. Stay Current with Regulatory Updates
It sounds obvious, but it can’t be understated: The best way to meet expectations is to stay current with regulatory updates.
Those that stress preparedness and ensure their chemical characterizations are conducted according to the current regulatory thinking have an advantage in the submission process. Be sure to carefully read recent regulatory updates and anticipate expected changes in other standards to avoid delays in the process.
One advantage of outsourcing your chemical characterization testing is to leverage the lab’s experience with similar products and their knowledge of regulators’ expectations. Labs that maintain a database of regulators questions will be valuable in addressing any requests for additional information.
#2. Provide Complete Chemical Characterization with No Unknowns
A chemical characterization report that includes unknowns will likely face additional regulatory scrutiny and may jeopardize your submission.
That’s why it’s critical to identify all chemicals associated with your device above the AET. However, identifying all compounds above a certain level depends on your testing lab’s capabilities and resources.
#3. Anticipate Risk-Mitigation
ISO 10993-18:2020 recommends more exaggerated and exhaustive chemical characterization conditions – and regulators expect them. Because of this, more chemicals are identified and the chances of having chemicals of concern increases.
So, medical device manufacturers should enter into these studies anticipating risk-mitigation, including:
- Simulated use extractables study
- Targeted study
- Additional biological testing
When you plan timelines, budget, and test articles for risk-mitigation, you won’t be thrown off if you do need to conduct additional testing.
Can Device Manufacturers Manage 10993-18 Testing In-House?
To move towards a successful submission, medical device manufacturers must complete:
- Preliminary chemistry testing
- Extractables/leachables (E/L) testing
- Toxicological risk assessment
- Risk mitigation, if necessary
It’s a lot to manage, but it can be done in-house or outsourced to a specialized lab.
Ultimately, outsourcing testing makes sense for some manufacturers but not for others. One of the main considerations you must weigh is whether the data generated from testing will be complete enough to meet regulators’ expectations.
Here are the pros of testing in-house:
- You own the medical device testing process and have control over the whole project, from technical insights and costs through timing and submission decisions.
- You don’t have to compete with other manufacturers for priority.
- You don’t have to deal with delays outside of your control.
If your manufacturing company does decide to test in-house, ensure that your internal team:
- Is aware of the latest testing standards and regulatory expectations.
- Has experience with E/L studies and elucidation.
- Has written risk assessments on medical device products before.
However, testing in-house is not always the best option, especially if you don’t already have infrastructure up and running. Building a facility, hiring expert chemists and toxicologists and purchasing highly sensitive lab equipment alone will take a lot of time and cost millions of dollars. A lot needs to happen before testing can even begin, so bringing it in-house may not be feasible.
So, what other options are available to a device manufacturer?
Working with a Medical Device Testing Partner for ISO 10993:18
Outsourcing testing to a specialized lab comes with a number of benefits that address the above challenges and more. Here’s what you can expect:
#1. Unbiased Evaluation
When analytical techniques are biased towards expected analytes, unexpected analytes could be missed in the evaluation. Using a third-party lab ensures that the analytical techniques are not biased toward expected analytes.
#2. Access to Experts to Identify More Compounds
You are the expert in your medical device, but identifying compounds requires an entirely different set of skills and knowledge. When you outsource to the right lab, you gain access to experts who are capable of complex elucidation to identify compounds and you have access to their chemical database.
Although commercially available libraries to help identify chemicals exist for gas chromatography, the LC-MS method does not have a commercially available library. Partnering with a lab dedicated to complete chemical characterization with no unknowns alleviates some of the burden of identification.
#3. More Visibility Into Regulatory Agencies
Specialized labs often have visibility into types of products, regulations, new standards, and questions or requests that may come from regulatory agencies. This visibility will help you address Additional Information (AIs) requests quickly. Also, the ability to anticipate questions helps with the initial design of studies to proactively address potential concerns.
Chemical characterizations and toxicological risk assessments require specific tools, methods, and expertise to know when and how to use different analytical methods. You wouldn’t want a general practitioner to attempt open-heart surgery. Specialization in the field of medical device testing works the same way.
WuXi AppTec has seasoned chemistry and toxicology experts that are well versed in E/L testing and identifying unknown chemicals. Over the past 11 years conducting E/L programs on medical devices, we have built an extensive LC-MS chemical database allowing our experts to leave no compound unidentified.
Talk to an expert about your upcoming project to see how we can help.
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