In September 2024, the FDA published its draft guidance on “Chemical Analysis for Biocompatibility Assessment of Medical Devices” to improve the consistency and reliability of analytical chemistry studies.

The draft guidance provides recommendations on how to perform chemical analysis for biocompatibility assessment, with an emphasis on considering the specific characteristics and intended use of the medical device in scope of the evaluation when designing the evaluation strategy.

In our topical article below, our Senior Operations Consultant Dr Silvio Peng highlights the aspects of the draft guidance most essential to consider in your upcoming biological evaluations that include chemical characterization testing.

First, let’s establish the purpose behind chemical characterization

The purpose of a chemical characterization is to characterize chemicals that may be released from a medical device and evaluate their respective risk during the intended use of the device.

For this purpose, the evaluation usually includes a toxicological risk assessment (TRA) in accordance with ISO 10993-17. The results from chemical characterization and – if applicable – the TRA, can be used in conjunction with other relevant input for biological evaluation to assess the overall risk of the product. In parallel, the results may also help to reduce animal testing.

FDA’s draft guidance provides recommendations on how various aspects of the chemical analysis should be handled, including how the different steps of the chemical analysis must be performed, which explanations or justifications are required, and how the methods and results shall be presented, e.g., in a submission.

The general recommendation for adhering to the guidance is to provide sufficient information, explanation, and justification in your dossier that documents the chemical analysis. Complete test reports should also feature in your submission.

Let’s now review the separate steps of the chemical analysis in relation to the recommendations in the FDA’s guidance.

Meeting the requirements for extractable studies

The most common form of chemical analysis is via extractable studies – which are also a focus point in the FDA guidance. Extractable studies should be designed to identify and quantify chemicals released from the medical devices under laboratory extraction conditions which usually exceed the conditions phased during clinical use.

The first step in preparing an extractables study is to gather information on the medical device in scope. This includes general information which is also required for other aspects of the biological evaluation, such as the intended use, device category etc. and a list of device components and materials. Material-specific information should preferably include additional details such as compliance with material standards and information provided by the supplier of the material.

In-depth knowledge of the device in scope, its materials of composition, and the manufacturing processes used to manufacture the device, facilitates the anticipation of potential extractables and selection of appropriate extraction conditions and analytical methods. It also supports interpretation of the results including identification of detected chemicals.

Assessing the test article

The biological evaluation requires consideration of the final device, i.e., the interface with the patient. Consequently, the test article should mimic the clinical use as close as possible. Thus, any steps which are performed on the marketed device such as packaging, sterilization, clinical preparation etc. should also be performed on the test article to account for these potential sources of contamination.

Vice versa, any additional modifications to the test article, e.g., cutting of the device before testing, which are normally not performed, should either be avoided or be subject to the provision of additional information or justification to explain why the respective modification was required and why it is not expected to considerably impact the result of the assay.

Considering control articles & blanks

For the chemical analysis, appropriate controls require consideration. For example, the inclusion of comparative articles to demonstrate chemical equivalence between the article before and after a change in the manufacturing operations was performed, and application of negative controls, e.g., solvent blanks, which are identically extracted and analysed. If comparative articles are included, the same level of description as for the device in scope should be applied.

Extracting the test article

Selecting exhaustiveness & solvents

The extractions performed for a chemical characterization should collectively be able to quantitively extract any potential residues present on the medical device in scope. Consequently, the best practice is to select several solvents and apply exaggerated or exhaustive conditions to obtain worst-case estimates of the extractable chemicals.

By “exaggerated” we mean extraction intended to result in a greater amount of a chemical constituent being released as compared to the amount generated under the simulated conditions of use.

And in this context “exhaustive” means extraction conducted until the amount of extractable material in a subsequent extraction is less than 10% by gravimetric analysis (or that achieved by other means) of that detected in the initial extraction.

FDA recommends using polar and non-polar solvents, and for devices in long-term contact, semi-polar solvents. Notably, it is preferable to use neat solvents and not mixtures since the material might interact differently with the solvents. The selection of exhaustiveness and the solvents should be explained, and if there are any limitations from the material of the medical device such as incompatibility with certain solvents, justification must be provided, or biological testing may be required. Pre-studies to determine compatibility with commonly applied solvents might be helpful – particularly with novel materials.

Selecting temperature & duration

Furthermore, the selection of the temperature and duration used for the extractions must be explained, including justification of how the selected conditions represent worst-case exposure estimates. ISO 10993-12 is a good starting point for the selection of appropriate time and temperature conditions. It is also worth noting that both time and temperature should exceed the conditions expected during clinical use to represent an exaggerated extraction.

In addition, temperature selection should consider the thermal properties of the materials of the extracted test article. If extraction cycles are applied, the recommendation is that all cycles have the same duration, e.g., if exhaustiveness shall be demonstrated, it is a common practice to apply consecutive 24hr cycles rather than an initial 72hr cycle. For determination of exhaustiveness, determination of non-volatile residues by means of gravimetry is the recommended method and thus, other methods will require justification.

The same conditions must be applied for all extracts and analyses unless justified. The prime example for an exception is the extraction of volatile organic compounds for analysis using HS-GC-MS (headspace-gas chromatography-mass spectroscopy) since immediate analysis after (exhaustive) extraction is preferred to avoid loss of extracted compounds.

Performing the extraction

The extraction is performed by minimising the extraction volume while considering the sensitivity of the chemical analysis. For more on this process see our article on how to calculate the AET for your biocompatibility assessment.

The extraction is performed such that the test article is completely covered by the solvent in a sealed container with minimal dead space. In addition, continuous mechanical agitation and temperature monitoring must be included.

FDA’s recommendation is that for each solvent the extractions shall be performed in triplicate including the follow-up analyses (unless otherwise justified) and the identification and quantification of extractables. The highest amount of each extractable would then be considered as the worst-case exposure estimate. Triplicates are recommended to support statistical comparison of data (for example, demonstrating chemical equivalence), and to compensate for potential variability between devices resulting from manufacture, shelf-life etc. Notably, if three or more devices require being pooled for extraction, e.g., to provide sufficient extract volume, triplicate extractions might not be necessary.

Managing test extract observations

Under certain circumstances, the test article or solvent can be subject to changes after extraction. Consequently, if there are any observations made on the test article such as visible changes, they might be related to thermal damage or solvent incompatibility and be an indicator that the extractables profile might have changed. As such, additional justification will be required to explain the observed change and potential impact on the extractables profile. Notably, such an observation can be an indicator that the selection conditions are not feasible for your product and require extraction repetition. Discussion of thermal or chemical properties in relation to the applied temperature or solvent respectively, will be required.

Similarly, if particulates are observed in the extract, their chemical composition and potential source must be determined (for this purpose, we recommend referring to ISO/TS 10993-19). This is especially important if the particulates might also contact the patient during device application. However, in some cases the particulates are an artifact of sample preparation (such as cutting as mentioned above) or extraction and are not deemed to interfere with the subsequent chemical analysis. If that is the case, this must be justified, which is even more important if a removal step is required. Then, explanation for why the removal step does not alter the extraction profile – if that is the case – is required. In other cases, the observed particulates might be precipitated extractables and thus, it is recommended to re-dissolute before further analysis.

Creating your chemical analysis plan

The analytical methods you select must be explained and justified in a chemical analysis plan. The general recommendation is to profile the extractables using non-targeted analysis (“screening”) coupled with subsequent targeted analysis including identification and quantification of extractables. Thereby, preferred methods would be those that can cover a wide range of analytes, and the applied methods must be optimised and / or complemented with additional detectors.

The explanation of the analytical methods must describe the sensitivity of the method, i.e., limit of detection and limit of quantification, and application of reference standards, such as an internal reference standard added at a defined concentration to facilitate quantification.

The chemical identity of the detected extractables above the AET must be determined, including confidence of identification (i.e., unknown, tentative, confident, confirmed). If the cohort of concern compounds are known or suspected to be present, additional targeted analysis regarding these compounds should be considered. Consequently, extractables with confident and confirmed identification should be toxicologically assessed or sufficient justification provided as to why this is not deemed to be required. For unknown compounds, additional analytical or biological approaches need to be considered.

In summary…

FDA’s draft guidance provides various recommendations on how to perform chemical analysis for biocompatibility assessment to improve the consistency and reliability of analytical chemistry studies. Considering the draft guidance for your studies will allow you to more effectively tailor your study for your submissions to the US market – and improve study quality in general.

The common thread through the guidance is that each step, from initial information collection – to extraction and analysis of the test articles – to the final documentation of the assay, must be explained and justified in sufficient detail. Ultimately, the central piece in the chemical characterization study is the medical device being investigated and the biological and chemical risks associated with its application. Accordingly, a well-designed chemical characterization considers the specific requirements and features of the device in connection with FDA’s recommendations and the applicable standards.

Should you have a challenge related to chemical analysis and biocompatibility for medical devices, our Operations team is ready and happy to help. Simply get in touch to start the conversation.

Further reading

• The draft guidance discussed above has been open to public comment and might be subject to changes. Therefore, we highly recommend re-visiting the final published guidance document once available.
• The general guidance on the Use of International Standard ISO 10993-1 is also relevant to this topic area.