ISO 10993-1 & 10993-18 Testing Services
In accordance with ISO 10993-1:2018, every medical device must be evaluated and tested as part of a risk management strategy; and Chemical Characterization is the starting point. Our team of chemists and toxicologists will meet with you to develop an appropriate test plan that aligns with current regulatory expectations.
ISO 10993-1 & 10993-18 Chemical Characterization
Chemical Characterization along with Toxicological Risk Assessment (ISO 10993-17) inform the biological test plan. All data is then combined into an expert-written weight of evidence argument known as the Biological Evaluation. In order to assess the risk of chemicals to patients for many products, Chemical Characterization will require analytical chemistry programs to identify and quantify the chemical constituents of the device. Typically, an extractables or exhaustive extractables study will include a range of analytical methods to uncover compounds that are inorganic and organic and are semi-volatile, non-volatile and volatile in nature. The most common analytical equipment used to gather this information includes:
- Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) to identify inorganic constituents such as metals and other elements;
- Gas Chromatography-Mass Spectrometry (GC-MS) and Headspace Gas Chromatography-Mass Spectrometry (HS-GC-MS) to identify volatile and semi- volatile compounds;
- Liquid Chromatography- High Resolution Mass Spectrometry (LC-MS) to identify semi-volatile compounds to non-volatile compounds.
Identification of compounds is extremely important for a toxicologist to accurately assess risk. While identification using some analytical methods is relatively straight-forward, identification of compounds from LC-MS can be challenging, as no commercial databases exist. With today’s devices that include polymers and plastics, LC-MS is an analytical method that tends to yield more chemicals – which means the laboratories must tap into their experts to make the identification; a significant resource commitment. WuXi AppTec’s Chemical Characterization lab is the only lab committed to complete characterization as part of our standard service—a commitment we refer to as “Unknowns are Unacceptable.”
Square feet of dedicated E/L testing space
Toxicological risk assessments
ISO 10993 Part 18
Designing an extractables/leachables study for your device requires an understanding of the materials and manufacturing process. Even commonly used materials can have different extractables/leachables results based on impurities and processing. Our team of chemists and toxicologists will meet with customers to develop an appropriate test plan that aligns with current regulatory expectations.
Analytical Equipment Commonly Used for Extractables/Leachables Studies Include:
- Inductively Coupled Plasma-Mass Spectrometry to identify metals and other elements [ICPMS]
- Gas Chromatography-Mass Spectrometry and Headspace Gas Chromatography-Mass Spectrometry to identify volatile and semi-volatile compounds [GCMS & HS-GC-MS]
- Liquid Chromatography-High Resolution Mass Spectrometry, such as LCMS QToF, to identify semi-volatile compounds to non-volatile compounds [LCMS]
- Ion Chromatography (IC) is sometimes required for the evaluation of ionic contaminants
Multiple analytical techniques aid in uncovering the full range of extracted chemicals associated with your product. Regulatory bodies are looking for this as part of the assessment of risk associated with your product.
Full identification of the chemicals is required, and unknowns must be treated as worst-case scenarios. WuXi AppTec Medical Device Testing is the industry leader in identification, and our chemistry program was built knowing that chemistry data alone—without a toxicological risk assessment—is not enough to support product safety.
Full characterization of all chemicals is required for an accurate assessment of risk, and it is our goal to identify all of the potential chemicals that could come out of your product. Utilizing multiple analytical methods, our team of chemistry experts works tirelessly to understand your materials, process and product to detect a full range of organic, semi-volatile and volatile chemicals, providing you with the data you need to make informed decisions and meet current regulatory requirements.
Fourier Transform Infrared (FTIR) Scan
This test is a type of infrared spectroscopy in which the sample is subjected to all the wavelengths in the region of interest at all times, instead of only a small portion at a time.
Trace Metals – Elemental Analysis
This method is used to determine the presence of trace metals by atomic absorption spectroscopy or inductively coupled plasma spectroscopy.
This refers to absorption spectroscopy or reflectance spectroscopy in the ultraviolet-visible spectral region or light in the visible and adjacent ranges. The absorption or reflectance in the visible range directly affects the perceived color of the chemicals involved.
Particulate Matter Light Obscuration Method – Medical Device Extraction
This involves extraction of the medical device in water followed by analysis of subvisible particulates using a light obscuration particle counting method.
Chemical Characterization Equipment
Our comprehensive selection of state-of-the-art testing equipment and analytical instrumentation allows us to support the broadest possible range of device testing needs.
- HS-GC-FID/MS and DI-GC-FID/MS
- Direct Inject GCMS
- Microscope FTIR
- Particle Count
ISO 10993 Testing FAQ
What is ISO 10993?
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.
What is ISO 10993 Part 18?
The official title: ISO 10993-18:2020: “Biological evaluation of medical devices — Part 18: Chemical characterization of medical device materials within a risk management process”
There are generally three critical elements evaluating biological risks; 1) complete chemical information/chemical characterization, 2) toxicological risk assessment, and 3) 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 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. Regulatory bodies in the US and EU have incrementally interpreted, adopted, and implemented ISO 10993-18:2020. 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. MDR has accepted the standard as “state of the art” and generally holds manufacturers to it.
The best way to meet expectations is to stay current with regulatory updates. Our technical and regulatory experts serve as active participants and hold leadership positions within international regulatory standards committees. This allows us to better anticipate regulatory changes ahead of the published standards and guidance and track regulatory trends. We guide our clients’ test plans based on our industry knowledge, regulatory collaboration, and the extensive number of products we have assisted through product clearance.
What kind of testing is required?
Chemical characterization, also referred to as materials characterization, should be designed with the nature and duration of clinical exposure in mind. Chemical information can be a paper-based review of all materials or chemical data can be generated in a screen for all potential extractables/leachables or a targeted study focusing on a single compound of concern. However, extractables/leachables (E/L) testing is often necessary due to the risk of impurities in the raw materials and hazardous chemicals being introduced into the medical device during routine activity such as manufacturing, sterilization, and storage.
What do device manufacturers need to do?
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.
Chemical characterization should be considered a journey, not a check-box exercise.
For many medical devices, exhaustive and exaggerated extractions are recommended by ISO 10993-18:2020 and are expected by regulators.
Extractables study designs challenge devices under extreme conditions to maximize the extraction of chemicals from the devices and provide information for estimating potential hazards. Exhaustive extraction studies involve extracting devices in solvents with ranges of polarity and repeating the extractions until the amount of extractable material in subsequent extractions is less than 10 percent by gravimetric analysis of that detected in the initial extractions. The intent of extractables studies is to determine the cumulative amounts of each chemical that could potentially extract from devices over time. Exaggerated extractions may be the appropriate method to maximize extractable chemicals that could be released from limited and some prolonged duration devices. Exaggerated extractions also use aggressive solvents and elevated temperatures to yield extractions.
Leachables/simulated-use study designs may be conducted to evaluate the potential for chemicals to extract or leach from devices under clinically relevant conditions. These studies incorporate the actual clinical matrix (leachable study) or a solvent that simulates the environment of clinical use (simulated-use studies).
Because TRAs based on exhaustive extractions often require additional chemical characterization studies (e.g., leachables or simulated-use) to further refine exposure assessments and mitigate risk, it may be helpful from a timeline perspective to conduct both studies concurrently. Otherwise, the studies can be conducted sequentially with the understanding that longer timelines may be necessary to conduct a complete toxicological assessment of the device.
This process of chemical identification is laborious and requires investment in equipment, expert personnel, and the time commitment to complete identification.
What is the benefit of working with a testing partner?
Outsourcing testing to a specialized lab comes with a number of benefits, including access to experts to identify all the compounds and more visibility into regulatory requirements.
You are the expert in your medical device, but identifying compounds (expected and unexpected) 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.
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.