Chemical Characterization of Medical Devices: ISO 10993-18

In medical devices, chemical substances are routinely used in the composition of critical materials or components. Chemicals are also used in the device manufacturing process and may be affected post sterilization, often leaving residual traces on device surfaces. Since many medical devices perform their functions through contact with the body, understanding the potential effects associated with exposure to compositional or residual chemicals can help ensure that the benefits of a given medical device are not outweighed by the potential health and safety risks.

Chemical characterization is a critical aspect of the overall biocompatibility assessment process of a medical device. Specifically, chemical characterization analytically identifies and quantifies the constituent chemicals of a specific material or component to identify potentially unsafe or unsafe levels of chemical substances. In general, chemical characterization does not involve the use of animals to assess the specific impact of exposure to a given chemical, a costly and time-consuming process that also creates ethical concerns for many medical practitioners and patients. Instead, it relies on laboratory testing and in vitro analysis to develop a toxicology risk profile for a given device.

Chemical characterization can also be used during the product development process to evaluate the biocompatibility profiles of alternative material compositions. Used in this way, chemical characterization can make the device development process more efficient, and help to reduce the likelihood of delays or outright rejection in the regulatory approval process.

ISO 10993-18, “Biological Evaluation of Medical Devices – Part 18: Chemical Characterization of Materials,” defines chemical characterization as “…a process of obtaining chemical information, accomplished either by information gathering or by information generation, for example, by literature review or chemical testing.”

Typically, chemical characterization begins with investigating the nature and composition of the materials used in a medical device. This initial effort can generate useful information about chemicals and chemical compounds found in device materials and components. Research into available published literature on similar medical device types can provide additional context regarding the type of chemicals typically used in such devices. Together, these efforts can serve as a foundation for the development of a testing plan to help further characterize a device’s chemical makeup.

The chemical characterization process also relies on a variety of evaluation technologies and methods, such as microscopic and spectroscopic analysis, x-ray diffraction, and chromatography. These and other techniques can provide detailed information regarding a material’s chemical formulation, the purity of chemical composition, or the presence of impurities or degradants. They can also provide critical information about the nature and extent of potential health, safety, or environmental risks that may occur with the use of such materials over their entire lifecycle, including systemic toxicity, genotoxicity, carcinogenicity, and reproductive/developmental toxicity.

The biological evaluation of medical devices, including the chemical characterization process, is the focus of the ISO 10993 series of standards. Consisting of more than 20 individual documents, the ISO 10993 series provides detailed information on every aspect of the biological evaluation process and serves as a basis for medical device biocompatibility requirements in most jurisdictions.

ISO 10993-1, “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management system,” is the general standard in the ISO 10993 series. Published in 2018, the 5th Edition of the standard establishes the overall framework for planning and executing a biological evaluation process to assess the safety of a medical device. Figure 1 in ISO 10993-1, “Summary of the systematic approach to a biological evaluation of medical devices as part of a risk management process,” presents a detailed decision analysis flowchart of that process.

Annex B of ISO 10993-1, “Guidance on the conduct of biological evaluation within a risk management process,” expressly references the role of chemical characterization as a method for accounting for the safety of “intended additives, process contaminants, residues and leachable substances” in the overall biological evaluation. Specifically, chemical characterization “can be useful in selecting appropriate biological evaluation tests,” as well as for estimating the anticipated risk associated with exposure to individual chemicals.

Individual standards in the ISO 10993 series that specifically apply to the chemical characterization process include:

• ISO 10993-12:  “Biological evaluation of medical devices – Part 12: Sample preparation and reference materials,” specifies requirements for the selection of reference materials and the preparation of samples for biological and chemical characterization testing.
• ISO 10993-17:  “Biological evaluation of medical devices – Part 17: Establishment of allowable limits for leachable substances,” details the process for determining allowing limits for substances leachable from medical devices in cases where such limits do not exist.
• ISO 10993-18:  “Biological evaluation of medical devices – Part 18: Chemical characterization of medical device materials within a risk management process,” provides a framework for identifying and quantifying material composition of a medical device, including chemicals and other ingredients.

Each ISO 10993 standard expressly encourages device manufacturers to review and use existing biological safety data from all available sources, such as prior scientific research and studies, to determine what additional testing might be required, if any, and to eliminate unnecessary testing.

Because the range of biological hazards associated with a medical device depends on a number of factors, the ISO 10993 standards are not prescriptive. Instead, they require device manufacturers to adopt a risk management approach, in which every potential biological risk is identified, and then thoroughly analyzed and evaluated to determine the likelihood and the potential severity of the risk. With that information, the manufacturer can then take necessary steps to eliminate or mitigate that risk in their device.

ISO 10993-18 details the requirements for conducting a chemical characterization of a medical device to support claims regarding its overall biological safety. According to the standard, the goal of chemical characterization is to provide detailed information on the identities and quantities of:

• The materials used in constructing a medical device;
• The chemical constituents in each material;
• The chemical substances used in the device’s manufacturing process; and
• The potential of the device as constructed and manufactured to release chemical substances to which patients and device uses might be exposed.

Section 5 of the standard, “Characterization procedure,” details each of the steps in the characterization process, as follows:

• Establish medical device configuration and material composition (5.2)—Describe the configuration, intended purpose, and clinical use of a medical device, including the individual materials used in the construction of a device, the proportion of those materials used (either by surface area or weight), and its physical structure. Address any gaps in the configuration and composition data.
• Assess material/chemical equivalence to a clinically established material or medical device (5.3)—Use the information compiled in Section 5.2 to determine whether a device is equivalent to a previously approved medical device. If equivalence is verified, no further analysis or testing is required. 
• Assess the hypothetical worst-case chemical release based on total exposure to the medical device’s chemical constituents (5.4)—Again, using the information compiled in Section 5.2, establish the hypothetical worst-case chemical release and determine the potential health impact of such a release on a patient. If total exposure is determined to be acceptable, no further testing or analysis is required. 
• Establish an analytical evaluation threshold (5.5)—Calculate and verify the analytical evaluation threshold (AET) for the device. The process for AET is detailed in Annex E of the standard.
• Estimate the chemical release; perform extraction study (5.6)—Conduct an extraction study to identify and quantify chemical extractables for toxicological risk. ISO 10993-17 details the process for conducting an extraction study.
• Assess the estimated chemical release (extractables profile) (5.7)—Summarize and report the results of the extraction study in order to assess the risk attributable to each identified extractible.
• Determine the actual chemical release; perform leachables study (5.8)—In some cases, potentially unsafe quantities of an extractable released from a medical device may be attributable the exaggerated extraction conditions in an extractables study. If applicable, a leachables assessment using actual or accelerated extraction conditions, such as elevated temperature, etc., may be more clinically relevant.
• Assess the actual chemical release (leachables profile) (5.9)—Summarize and report the results of the leachables study in order to assess the risk attributable to each identified leachable. 
  
  Figure 1 in ISO 10993-18, “General chemical characterization process,” provides a high-level visual, step-by-step representation of this chemical characterization process within the overall biological evaluation assessment described in the standard.

(Insert Figure 1 from ISO 10993-18 here)

The chemical characterization process is deemed completed when its findings support claims of equivalence with a previously approved medical device, or when the toxicological risk assessment verifies that any extractables or leachables identified present an acceptable health risk. Otherwise, further biological testing may be required to assess and verify device biological safety. 

Chemical characterization takes advantage of today’s advanced testing technologies and sophisticated analytical methods including to assess the overall safety and biocompatibility of a given medical device. In many cases, the chemical characterization process can provide critical safety and biocompatibility information more quickly and with less financial investment than other forms of assessment. And, as previously noted, chemical characterization does not involve the use of animals to measure the impact of specific instances of chemical exposure.

However, despite these benefits, chemical characterization also has several significant limitations that can complicate the biological evaluation of a medical device. While applicable standards describe approaches for conducting chemical characterization, they do not detail specific methods to identify and quantify chemical extractables. This leads to variations in the methodologies applied in the characterization process which impacts the findings that are produced.

Further, some chemical characterization methods may not account for all of the physico-chemical factors that can affect biocompatibility. For example, data collected through the chemical characterization process may not be sufficient to accurately assess objective endpoints related to irritation, sensitization, and other critical factors. Again, a lack of standardized approaches for evaluating and assessing endpoints results in potential variations in characterization findings, potentially undermining confidence in the reliability of the results.

The U.S. FDA requires the submission of chemical characterization data as part of its review of Premarket Applications (PMAs), Premarket Notifications (510(k)s), De Novo applications, and other types of medical device review requests submitted to the agency. Chemical characterization data is then used by the agency to determine the potential for an unacceptable adverse biological response in a patient resulting from contact between medical device component and the body.

A 2020 FDA Guidance offers additional clarification on its requirements for the chemical assessment of medical devices:

“(The) FDA evaluates the safety of medical devices based on duration of exposure and nature of contact. Inherent in the review of medical devices is an understanding of the body’s entire exposure to the medical device, including all chemical entities contained within the device. For devices where the patient-contacting portions may contain potentially toxic chemicals, the evaluation of safety should include both chemical risk (i.e., the level of toxicological concern) and the type and duration of exposure.”

In reviewing some medical devices, including those made from new materials that have never been previously used in a medical device, the FDA may also require data from toxicity testing to better understand and evaluate the toxicological risk presented by a given device. The FDA may also seek additional chemical testing data for medical devices that incorporate materials that can change over time, such as absorbable or degradable materials.

However, as we noted previously, current chemical characterization processes include some important limitations, including the lack of specified methods to characterize chemical extractables and the inability to accurately assess objective endpoints for some critical safety factors. These issues can place reviewers at the FDA and other regulatory agencies in the difficult position of having to make case-by-case assessments of the thoroughness and applicability of chemical characterization data supplied by a device manufacturer.

Chemical characterization remains a foundational element of a manufacturer’s overall effort to verify the safety and biocompatibility of their medical devices. Chemical characterization conducted early in the new product development process allows developers to address potential safety considerations up front and reduces the chances of discovering unanticipated issues late in the development process when they can derail market entry plans. Chemical characterization can also help confirm chemical equivalence of device materials and components coming from new suppliers or in situations in which manufacturing or processing systems have been modified or changed.

Despite the regulatory challenges previously mentioned, conducting a chemical characterization consistent with the rigorous process detailed in ISO 10993-18 remains the best way to verify the chemical safety of new and existing medical devices and to meet the expectations of regulators. At the same time, manufacturers can benefit from soliciting FDA input on their proposed characterization protocols before beginning the chemical assessment of their medical device, via the FDA Pre-Submission Program. Early input from regulators can validate the intended scope and process of the planned assessment or offer useful suggestions or proposed modifications that will better align the process with the agency’s expectations.

Finally, to successfully navigate the challenges of chemical characterization assessment and regulatory review, it is highly advisable to seek the assistance of a third-party testing laboratory with extensive knowledge of medical devices and broad experience in device testing in accordance with applicable biocompatibility standards, including ISO 10993-18. Working with a trusted third-party testing partner can make all the difference in achieving an efficient and timely regulatory review and approval for new medical devices.

TÜV SÜD is actively working with the FDA to understand the agency’s position regarding the chemical characterization of medical devices and to foster greater transparency regarding its expectations. We believe that these ongoing efforts will ultimately result in the formulation of uniform, objective, and scientifically based criteria for assessing chemical characterization data submitted to the agency as part of its pre-market review of new medical devices.

Concurrently, TÜV SÜD offers medical device manufacturers chemical testing services and product evaluation solutions to meet the FDA’s expectations, as well as the regulations and directives applicable in the European Union (EU) and other jurisdictions around the world. These include chemical testing services consistent with the requirements of the ISO 10993-18 on the chemical characterization of materials, as well as the toxicological risk assessment requirements set forth in ISO 10993-17.

Our global team of medical device experts bring decades of technical knowledge and practical experience to their work and stays current on the ever-changing regulatory landscape through their active involvement in relevant standards development efforts. These qualifications allow TÜV SÜD to bring unmatched technical expertise to chemical characterization processes, and to provide our clients with the highest quality medical device safety solutions while supporting their efforts to achieve global market access.