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Extractable Chemical Characterization and Risk Assessment: What is the Worst-Case?

While you may not want to think of the words “worst case” relating to your product, these words are critical in designing a chemical-characterization study and assessing those results in a toxicological-risk assessment. This blog post looks at general concepts for extractable study design and toxicological-risk assessment of medical devices per ISO 10993 Biological evaluation of medical devices, parts 1, 17, and 18; and ISO 21726 Biological evaluation of medical devices – Application of the threshold of toxicological concern (TTC) for assessing biocompatibility of medical device constituents.

The better understanding a medical-device manufacturer has about the intended clinical use of its product, the more clearly that information can be relayed to chemists for study design and to toxicologists for risk assessment. Rather than thinking of a device on an individual or component basis, the basic considerations for characterizing the worst-case device use should include the following:

  • How many devices will be needed per patient?
  • How long will the device(s) be in contact with a patient?
  • What are the patient populations?

This information can affect how chemistry studies are designed (size and number of devices, extraction conditions) as well as what biological endpoints must be assessed. Keeping the clinical use in mind during the whole risk-assessment process can help with the success of test design and outcomes.

To identify the types of questions to ask when determining a worst-case clinical use, let’s consider a scenario of implantable bone screws:

  • What parts of the body can the screws contact?
  • What is the age(s) of patients in which the screws can be used? If pediatrics or neonates are included, what is the youngest age or smallest weight (worst case)?
  • How many screws can be implanted into a patient at one time? What is the greatest number of implants that is feasible in the same patient even considering implantation from separate operations (worst case)? What is typical?
  • What is the largest version of the device or family of devices or the largest total patient contact (worst case) when considering the largest number of implants of different sizes that are simultaneously used?
  • How long do the screws remain implanted? The longest potential use must be considered (worst case). If additional screws can be implanted or replaced in the same patient at a later stage, then the cumulative time must be considered.

The type of contact with the patient and the duration of time the device is in contact with the patient both impact the biological endpoints that must be considered (ISO 10993-1) and which of these endpoints may be evaluated in a toxicological-risk assessment (ISO 10993-17) rather than through additional tests. Accurately representing the worst-case duration of a device’s use will allow for the correct threshold of toxicological concern (ISO 21726, TTC) to be considered for the extractable test design. The TTC applies to the daily exposure to a patient, which is why the worst-case size or number of devices a patient may use must be considered. If the worst-case number of devices or the contact duration are underrepresented, the study design may not be sensitive enough for the correct analytical-evaluation thresholds to be met (ISO 10993-18, AET). In this scenario, the toxicologists cannot be certain that all potential hazardous chemicals have been detected for evaluation.

Every device is unique, and correctly determining the worst-case conditions for study design and risk assessment can be challenging. Our experts, which include board-certified toxicologists, can help guide you from planning a testing program for your device to evaluating results that can be used for your regulatory submission.