What is Biocompatibility?
According to the FDA, biocompatibility “is the ability of a device material to perform with an appropriate host response in a specific situation” (Source: FDA Use of International Standard ISO-10993-1). Put more simply, this means the materials (or their degradants, leachables, or residuals) that make up a medical device which is intended for contact with or in the human body should not have a negative impact on a patient’s health. This can include delivery systems and combination products.
International Organization for Standards (ISO) describes biocompatibility testing in great detail in their well-established guidance ISO 10993: Biological evaluation of medical devices. ISO 10993 is subdivided into twenty parts, with Part 1 defining and describing the applicability of the following parts.
How is Biocompatibility Testing Changing?
With the 2018 update of ISO 10993-1 (“Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process”), the focus of ISO 10993 continues to shift toward consideration of preexisting information and reduction of repetitious biocompatibility testing. Internationally, assessment of medical devices is moving towards an evaluation based upon review of relevant established scientific data and upon chemical characterization and in vitro testing, with in vivo testing only being carried out if absolutely necessary. ISO 10993-1 now states that its focus is on minimizing the “number and exposure of test animals by giving preference to chemical constituent testing and in vitro models, in situations where these methods yield equally relevant information to that obtained from in vivo models”.
Not only does ISO 10993 suggest that not all possible biocompatibility tests need to be executed, the guidance actually specifically states that additional in vivo testing would be unethical and shall not be carried where:
- presence of leachable chemicals has been excluded
- chemicals have a known and acceptable toxicity profile
- results are available from relevant studies that have been carried out previously
- existing non-clinical and clinical data, including history of safe use, meet the requirements of biological evaluation
In some cases, there may even already be sufficient information available to perform a thorough risk assessment of the material and/or medical device without in vitro testing. The case for neglecting biological testing is particularly strong if material characterization can demonstrate equivalence to an established safe material and/or medical device.
The 2020 update of ISO 10993-18, “Biological evaluation of medical devices – Part 18: Chemical characterization of medical device materials within a risk management process” continues to shift the focus of biocompatibility testing toward chemical characterization.
The Ever-Increasing Importance of Extractables Studies
In light of these changes, chemical characterization and extractables studies are now more important than ever. Because chemical analysis using exhaustive extraction techniques can evaluate long-term toxicity endpoints, ISO and the FDA assert that these studies may eliminate the need for biological testing in many cases. ISO 10993-1 specifically states, “Description of medical device chemical constituents and consideration of material characterization including chemical characterization shall precede any biological testing. Chemical characterization with an appropriate toxicological threshold can be used to determine if further testing is needed.”
Extractables studies, in conjunction with sufficient toxicological data relevant to the nature and duration of the expected exposure of the medical device, may now be sufficient to justify the omission of any further biological testing (including animal testing).
Conducting an ISO 10993 Risk Analysis
Before beginning an ISO 10993 risk analysis, it is important to have a thorough understanding of the intended use of the medical device in question. This includes the nature, degree, duration, frequency and conditions of exposure to or contact with humans. Both ISO 10993 and subsequent FDA guidance emphasize that the risk assessment should evaluate the final medical device whenever possible, and if not possible must utilize representative samples accounting for all materials and processing steps (manufacturing, sterilization, storage, etc.). Components of medical devices requiring biological evaluation include, but are not limited to:
- the material(s) of construction
- intended additives, process contaminants, and residues
- packaging materials
- leachable substances
- degradation products
Risk analysis requires identification and characterization of all materials potentially present in final form of the medical device, taking into account the presence of any manufacturing additives and examining the impact of processing, from production to storage, on material composition and chemistry. This is an extremely complicated step in risk analysis, as it can include assessment of:
- chemical interactions between materials
- impact of physical degradation (wear, load, fatigue, friction, etc.)
- environmental interactions (heat and thermal degradation, UV light and light-catalyzed degradation)
- manufacturing processes
- intended additives or processing aids, such as catalysts, antioxidants, pigments, and surface treatments
- potential process contaminants (etching agents, lubricants, etc.)
- potential process residuals of chemicals and additives
- decontamination and sterilization processes (detergents, disinfection agents)
- interactions with or introduction of contaminants from packaging materials
- transportation, storage, and aging
FDA Guidance on ISO 10993-1
While ISO 10993-1 through 10993-20 must be purchased and licensed individually, the FDA has a readily-available guidance on the use of 10993, which can obtained here (FDA Use of International Standard ISO-10993-1).
The document was specifically developed to assist in evaluations of biological compatibility for Premarket Applications (PMAs), Investigational Device Applications (IDEs), Premarket Notifications (510(k)s), and de novo requests for medical devices that come into direct or indirect contact with the human body. The document contains helpful attachments such as biocompatibility evaluation flow charts, example biocompatibility submission documentation, and thorough charts recommending which biocompatibility tests to carry out, organized by device type, contact, and duration of contact. It also contains example justifications of material components, processing/sterilization changes, and formulation changes.
ISO 10993 Chemical Characterization Testing at EKG Labs
At EKG Labs we specialize in chemical characterization of medical device materials to provide ISO 10993 biocompatibility data for regulatory filings. Our team has years of experience working with diverse pharmaceutical products and a variety of medical device materials including polymers, metals, ceramics, and composites. In addition to these raw materials, we understand how to characterize ancillary chemicals associated with device production such as plasticizers, fillers, additives, cleaning agents, and release agents. We are prepared to flag any materials which need further toxicological evaluation or analysis.
EKG is particularly proud of our extractables/leachables program. Our extractables and leachables program is constructed around ISO 10993-12 (sample preparation) and ISO 10993-18 (chemical characterization). We routinely carry out exhaustive extractions (assessed by gravimetric analysis), simulated-use extractions, accelerated aging studies, and leachable studies—all per ISO 10993 guidance. Extraction solutions are typically evaluated, depending on solvent utilized, by LC-MS, GC-MS, and ICP-MS. The end report of an extractable study will list all compounds found and their in-sample concentrations. You can delve into EKG case studies here.
The ISO 10993 parts EKG Labs distinctly assesses are:
- ISO 10993-1: Evaluation and testing in the risk management process
- ISO 10993-7: Ethylene oxide sterilization residuals
- ISO 10993-9: Framework for identification and quantification of potential degradation products
- ISO 10993-12: Sample preparation and reference materials
- ISO 10993-13: Identification and quantification of degradation products from polymeric medical devices
- ISO 10993-14: Identification and quantification of degradation products from ceramics
- ISO 10993-15: Identification and quantification of degradation products from metals and alloys
- ISO 10993-18: Chemical characterization of materials
Please note that EKG Labs does not perform in vivo biological testing.
EKG Labs further supports medical device and combination drug device analysis by offering regulatory consulting services to help you navigate the complex FDA regulatory process.
Combination Product Chemical Characterization at EKG Labs
The drug component of combination products and devices adds additional chemical variables to the medical profile which need evaluation. These drug/device combinations are among the most challenging products to submit to the FDA for review. As such, they require extensive forethought and planning for testing and analysis. EKG Labs leverages its knowledge of extractables, leachables, and chemical characterization to help companies develop combination products and devices for FDA approval. We have experience with many novel medical device and drug-device combination products like drug-eluting stents, bioabsorbable implants, and intraocular lenses.
Learn more about our combination product and device experience.
EKG Labs Analytical Techniques
- Chromatographic Characterization – HPLC, LC/MS, UHPLC/ToF, GC/MS, GC/FID, GC/TCD, GPC/SEC
- Spectroscopy Characterization – ICP-MS, NMR, MS, PXRD, TF-XRD, UV-Vis, FTIR, Raman
- Microscopy – SEM, TEM, AFM, STM, LSCM
- Other- TGA, DSC, TOC, BET Surface Area/Pore Size Analyzer
- Learn more about our instrumentation here