Medical Device Extractables and Leachables Testing
The goal of medical device chemical characterization is to evaluate potential biological hazards to a patient during end-use conditions. As described in the key biocompatibility standard ISO 10993-1 and the associated FDA 2016 guidance document, chemical characterization is a critical first step in evaluating a device's biocompatibility.
Chemical characterization can be a daunting process for a medical device manufacturer. Both extraction in highly aggressive conditions and subsequent analysis by extremely sensitive analytical techniques seem capable of identifying seemingly endless chemicals at trace concentrations. However, a well-designed chemical analysis program can streamline this process, and provide reasonable justification for chemical identification thresholds.
Benefits of Chemical Characterization
If conducted carefully and grounded in an understanding of material science and manufacturing processes, chemical characterization yields accurate, actionable data and can be an invaluable tool throughout the product life cycle.
Beyond creating a detailed, defensible report suitable for regulatory submission, the chemical characterization process may be used:
- To screen for the impact of a raw material change (e.g. resin “equivalency”).
- To evaluate the impact of a process change such as the addition of a new cleaning step or change in polishing compound.
- As part of a supplier qualification—such as in a diversified supply chain—that product materials or sub-assemblies from different suppliers are of equivalent toxicological risk.
- To evaluate for potential degradation products as a function of product shelf life, sterilization, or high temperature processing steps like welding, molding, or laser cutting.
- To facilitate development and regulatory filings of future medical devices that use similar materials as already cleared and marketed devices.
Why Choose CPG for Your Chemical Characterization?
Cambridge Polymer Group scientists recognize that chemical characterization is not a once-size-fits-all approach, nor is it generally amenable to turn-key solutions. Every medical device represents a unique combination of materials, manufacturing steps, and end use conditions. Each must be fully considered to provide adequate justification for analytical method selection and crucial context for confidence in extractable identifications.
In addition to leveraging our state-of-the-art lab instrumentation and deep knowledge of polymer science, CPG scientists work closely with you to ensure that your workflow is grounded in the context of your product.
CPG's procedures mitigate the typical pitfalls of chemical characterization projects:
- non-compliance with most current regulatory guidance
- incomplete analytical methods
- unclear confidence in identification
- unknown extractables
- inaccurate measurements of extractable concentrations
Chemical Risk Assessment Workflow
The chemical risk assessment workflow may be viewed as a three-tiered structure composed of:
1. Information gathering
2. Extractables analysis
3. Leachables analysis
The need to perform each successive tier of characterization depends on the nature of the device and the results of the previous stage.
Information Gathering
The critical first step of the chemical risk assessment is information gathering. This step involves collecting all available data on the medical device’s materials of construction, additive packages, surface treatments/coatings, etc. In addition to information on the compositional level, the information gathering step also includes collection of the manufacturing processing aids and processing conditions: e.g. machine oils, spin finishes, polishing compounds, sterilization modes, etc. Some laboratory work may be needed to fill in knowledge gaps of the composition.
Extractables
For devices of greater risk or more uncertainty in materials/manufacturing, an extractables study is likely to be required, at minimum. Extractables are compounds that may conceivably be released from the medical device under exaggerated conditions, typically far in excess of what would be anticipated under clinical use. Depending on the device and application area, the extraction conditions may be standard, aggressive, or exhaustive.
Leachables
If an extractables study finds chemicals presenting a potential toxicological risk, a targeted leachable study may be necessary. Leachables are compounds that migrate from a product into a surrounding media under simulated end-use conditions more closely aligned to the physiological environment.
For both extractables and leachables studies, extreme care must be paid to sample preparation details such as selection of appropriate solvents and extraction conditions. One must ensure that compounds are efficiently extracted, but without causing damage or change products to the device that would result in a non-representative extractable profile. This requires a particular understanding of the chemical properties of expected extractable compounds as well as the medical device materials of construction. Sample preparation conditions must also be suitably qualified and compatible with downstream analytical techniques. CPG’s knowledge of polymeric materials and their behavior in different solvents is often used in designing leaching conditions.
Extractable and Leachable Testing Methods
No analytical technique can see “everything” and even techniques such as “GC-MS” can be configured in a multitude of different ways affecting the range of compounds they can detect. Analytical method selection is therefore a crucial component of chemical characterization study design.
Generally, the goal is to choose methods that are grounded in the expected organic and inorganic extractables while also sufficiently flexible to detect unexpected impurities as well. Careful justification and qualification of test methods requires a deep understanding of the base material chemistry (e.g. common additives) as well as an appreciation of the limitations each analytical technique.
Common complementary techniques used for chemical characterization include the following. Many of these techniques rely on gas chromatography or liquid chromatography separations coupled to mass spectrometry for identification of individual chemicals in the sample’s extractable fingerprint.
- HS-GC-MS for highly volatile organic compounds
- GC-MS for semivolatile organic compounds (SVOC)
- UHPLC-UV-ELSD-QTOF-MS for nontargeted nonvolatile organic compounds (NVOC)
- LC-MS for targeted nonvolatile organic compounds (NVOC)
- ICP-MS for inorganic/elemental impurities
- IC for inorganic ions
Once data is generated, not all detected compounds should be identified. Doing so may generate a list of chemicals many pages long and lead to unnecessary cost and effort in toxicological risk assessments.
The latest revision of ISO 10993 part 18 (2020 revision) formalizes the concept of an analytical evaluation threshold (AET), defining the limit above which compounds must be identified and evaluated for potential patient risk. Careful justification of the AET is necessary as this directly impacts the scope of analysis required and places limits on the required sensitivity of the selected analytical techniques.
Because chemical risk assessment workflows depend in large part on non-targeted analytical methods, a key consideration in reporting results is accounting for potential uncertainty in the analytical process. Uncertainty in both identification as well as uncertainty in quantitation of extractables must both be considered and carefully justified. Quantitation is performed at one of three levels (estimate, semi-quantitation, or full quantitation), each with different levels of uncertainty. For targeted leaching studies, full quantitation is typically performed.
For identification tasks in particular, expert judgement is often required in synthesizing different data points toward assigning an extractable identity with a clear degree of confidence. In some cases, obtaining a suitably confident identification requires more than a little detective work, up to and including in-house synthesis of reference standards for a water-tight conclusion of extractable ID.
What Does the ISO 10993-18:20 Update Mean for Medical Device Manufacturers?
Given the recent dramatic changes in the regulatory landscape, medical device manufacturers are encouraged to:
1. Review standards carefully.
2. Consult with expert practitioners.
3. If possible, present a detailed experimental protocol to the FDA ahead of study initiation.
4. Start chemical characterization activities as early as possible. For example, preliminary testing during medical device development before design freeze or verification/validation activities can save substantial time and cost downstream.
How CPG Can Help
CPG is experienced in designing chemical risk assessment studies and has a full, in-house analytical chemistry laboratory under ISO 9001/17025 quality management systems. We have a successful track record in helping our clients perform chemical characterizations and extractables and leachables E&L testing as part of their broader biocompatibility risk assessments. Our experience includes the most stringent medical device cases up to and including permanent implant devices submitted through the premarket approval (PMA) pathway. Please contact us for more information about how we can assist your team.
Key Standards for E&L Medical Device Testing
- ISO 10993-1:2018 Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk management process
- ISO 10993-12:2012 Biological evaluation of medical devices — Part 12: Sample preparation and reference materials
- ISO 10993-17:2002 Biological evaluation of medical devices — Part 17: Establishment of allowable limits for leachable substances
- ISO 10993-18:2020 Biological evaluation of medical devices — Part 18: Chemical characterization of medical device materials within a risk management process
- FDA 2016 Biocompatibility Guidance: Use of International Standard ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process"