The Food and Drug Administration (FDA) has published detailed guidance dedicated to the use of International Standard ISO 10993-1 “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process”.

International Standard ISO 10993-1

The document is intended to provide all the parties involved in operations with medical devices with the additional clarifications and recommendations regarding the way the aforementioned standard should be applied. The present FDA guidance replaces the previous version published earlier in June 2016. It is also important to mention that due to its legal nature, the document does not establish any obligations the parties should follow, but describes the possible ways instead. Thus, the Agency allows us to choose the particular approach to use, providing that such an approach complies with the general requirements set forth under the applicable regulations. 

Regulatory Background 

The present FDA guidance describes the way the International Standard ISO 10993-1 should be used in the context of Premarket Applications, Humanitarian Device Exceptions, Investigational Device Exemption Applications, 510(k) Premarket Notifications, and De Novo requests for medical devices containing patient-contacting components. In particular, the standard establishes the approach to be applied to evaluate the biological response resulting from the use of the device and risks associated thereto. According to the standard, all patient-contacting materials should be subject to special assessment in order to verify compliance with the safety requirements. The Agency emphasizes that the present guidance also employs the principles of a risk-based approach and chemical assessment. One of the novel elements incorporated in the present version of the FDA guidance relates to the biocompatibility test method to be applied in the case of medical devices with submicron or nanotechnology components usually manufactured with the use of in situ polymerizing and/or absorbable materials. The Agency states that actually the aforementioned aspects were not covered by the previous guidelines. 

According to the general rule, the sponsor (the entity applying for the registration of a medical device – the manufacturer or its authorized representative, importer, or supplier) shall indicate whether the device contains patient-contacting materials in order to determine whether the additional biocompatibility assessment is required. The same information should be provided in case of any modifications made to the device – in particular, the sponsor shall indicate whether such changes are related to the patient-contacting materials the device contains. In case if the changes could potentially affect the safety of the patient-contacting materials, an additional biocompatibility assessment would be required even if such changes are not directly related to the tissue-contacting materials themselves.

International Standard ISO 10993-1: Key Points

As it was mentioned before, the scope of the present FDA guidance covers both sterile and non-sterile medical devices containing patient-contacting materials. First of all, the document describes the application of the International Standard ISO 10993-1. However, the scope of the guidance also covers other standards dedicated to biocompatibility matters. The aspects covered by the scope of the FDA guidance include, inter alia, the following ones:

  • Risk assessment to be applied for medical devices,
  • Biocompatibility evaluation based on the International Standard ISO 10993-1,
  • Basics of biocompatibility testing,
  • Key points associated with cytotoxicity, sensitization, hemocompatibility, and other types of special testing,
  • Recommendations related to the chemical assessment,
  • Clarifications regarding the labeling of medical devices in the context of biocompatibility and safety of patient-contacting materials. 

The Agency also mentions that in case if any of the aspects highlighted in the guidance actually falls within the scope of another, a more specific standard, the latter should be applied. 

The present FDA guidance also covers combination products containing medical devices as constituent parts. However, the Agency states that combination products require special attention and thus, the applications related to such products should be additionally discussed with the appropriate center responsible for the particular product in question. 

The Agency also mentions that ISO 10993-1, like any other international standard, could be subject to changes. So, the applicant intended to use the standard should consider the points associated with the standard updating. The FDA also reserves the right to amend the present guidance in order to reflect the changes made to the standard itself. 

In case of any doubts regarding the testing methods to be applied, the sponsors shall discuss them with the appropriate Center responsible for the particular medicinal product in question.

Risk Management for Biocompatibility Evaluation 

According to the International Standard ISO 10993-1, the biological evaluation of a medical device should be conducted in accordance with the risk-based approach. The whole process commences with the assessment of the medical device in question. Such an assessment shall cover, inter alia, the following points: 

  • The materials and components the device subject to review is composed of, 
  • The manufacturing process,
  • The intended use, including the intended application site (anatomical location), as well as the frequency and duration of use. 

The risk associated with biocompatibility matters should be based on the points listed hereabove. In particular, the risks subject to the evaluation should include ones associated with the adverse biological response caused by patient-contacting materials. 

Upon identification of the aforementioned risks, the sponsor shall dully collect all the information available, and also to identify existing knowledge gaps. The plan of testing to be developed shall cover all identified gaps. 

The FDA explicitly states that it is the final finished device to be subject to the risk assessment. Actually, the FDA approval would not cover separate materials the medical device is composed of, but the device itself as a whole. Hence, the assessment should cover not only the materials but also the manufacturing methods. 

According to the FDA guidance, the approach to biocompatibility evaluation should be also based on the intended use of the device. In particular, such important aspects as the application site (the anatomical locations the device should be used at), the duration of application/exposure, and the population the device is intended to be used for should be taken into consideration. In the context of exposure duration, such aspects as the type of contact (direct or indirect) should be considered.

The Agency emphasizes that the evaluation should cover the risk associated not only with chemical but also with physical features of the materials and components. The same approach should be used in case of any changes to the device itself, the materials used, or the manufacturing process. 

The potential sources of information to be considered in the course of biocompatibility evaluation include, inter alia, the following ones:

  • The manufacturer’s previous experience with the same materials,
  • The reported experience of other manufacturers,
  • The information provided by the supplier of materials used,
  • The information collected in the course of analysis of the device, 
  • The scientific literature covering related aspects. 

Summarizing the information provided hereabove, the present FDA guidance dedicated to the way the international standard ISO 10993-1 should be applied. In particular, the document describes the most important aspects associated with the biocompatibility evaluation of patient-contacting materials the medical device is composed of.

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