Focus on AET and TSL

Among the changes introduced by the 2023 version of ISO 10993-17 (Biological evaluation of medical devices – Toxicological risk assessment of medical device constituents)^[1] is the introduction of a new concept, the TSL (Toxicological Screening Limit).

The standard defines the TSL as “the cumulative exposure dose to an identified constituent over a specified time period that is without appreciable harm to health”. This is a crucial threshold for assessing the risks associated with potential patient exposure to toxic substances. The TSL concept is already applied in a variety of contexts to guide laboratory analysis in public health surveillance and environmental risk assessment. Now applicable to the toxicological evaluation of medical devices, the TSL does not replace the AET (Analytical Evaluation Threshold), but can be used to complement the AET. 

What is TSL? How is it used? And how does it differ from AET?

AET (Analytical Evaluation Threshold)

Defined by ISO 10993-18:2020 (Annex E), the AET is used an analytical threshold for toxicological assessment purposes related to extractable and leachable substances and to define a threshold below which the detected substance is considered in insufficient quantity to induce a potential toxic effect in clinical use. This threshold indicates whether the analytical method is capable of producing sufficiently reliable and accurate analytical responses in terms of substance identification and quantification, including potentially genotoxic or carcinogenic substances.

To achieve this, the AET must be well above the LOD (Limit Of Detection) and LOQ (Limit Of Quantification) for each analytical method. Calculation of the AET is therefore an important step, which must be carried out in conjunction with the analysis laboratory, prior to launching the analyses. It should be noted that AET does not apply to inorganic elements and anions.

AET is a concentration-based threshold, derived from the DBT (Dose Base Threshold), and takes into account the use of the medical device and its extraction conditions applied by the laboratory. It is calculated as follows:

Where:

• DBT: is expressed in µg/day (also called TTC^[2] or SCT^[3])
• A : is the number or quantity (cm², g or ml) of devices used to generate the extract,
• B : is the volume of solvent used to generate the extract, in mL,
• C: is the clinical exposure of the device, i.e. the number of devices or the quantity (cm², g or ml) to which a patient may be exposed per day under normal clinical conditions of use,
• D : is the concentration factor,
• UF : is the uncertainty factor of the analytical method, defined by the laboratory (according to Amendment 1 of ISO 10993-18:2020).

The TTC (Thresholds of Toxicological Concern) are exposure threshold values, below which appreciable risks to human health are very low (including carcinogenic risks). The choice of TTC for calculating AET is made in accordance with ISO/TS 21726, depending on the duration of contact between the device and the patient’s body.

The AET value is closely related to the extraction ratio (A/B), corresponding to the number or quantity of devices extracted (A) divided by the volume of extraction solvent (B). ISO 10993-12 defines standard extraction ratios to be applied to chemical and biological assays. These ratios should be applied whenever possible. However, in the case of chemical characterizations, they are indicative and must be adapted to the following recommendations of ISO 10993-18 for immersion extractions:

• The AET value must be above the detection and quantification limits of the analytical methods, and
• The device must be completely immersed in the solvent.

To meet the first condition, it may be necessary to reduce the solvent volume (B) to a minimum. Indeed, this is the only factor, along with concentration factor (D), upon which the laboratory can act or intervene to increase an AET value that is too low to obtain sufficiently reliable and accurate results. However, in order to also meet the second condition, this volume must be sufficient enough to allow complete immersion of the device in the solvent. Consequently, when defining extraction ratios, the aim is to find the right balance between fully immersing the device and using a minimum volume of solvent. To achieve this, several strategies can be put in place, defined and agreed upon together with the laboratory, prior to the launch of the study. This may involve, for example, increasing the concentration of the non-polar extract, or adding glass beads to the non-aqueous solvents, depending on the laboratory’s capabilities.

In the specific case of device filling extractions (often when only the inner part of the device is in contact with the patient, a tube or an injection syringe, for example), the difficulty lies in bringing all concerned surfaces into contact with the extraction solvent. Once again, the extraction volume needs to be high enough to allow this contact, but small enough to obtain an AET value above the detection and quantification limits of the methods applied. Depending on the laboratory’s capabilities, solvent circulation methods can also be  considered.

TSL (Toxicological Screening Limit)

The TSL is a toxicological threshold that establishes whether the Total Quantity (TQ) of an identified constituent (in µg), is too low to cause a risk of genotoxicity, cancer, systemic toxicity or reproductive or developmental toxicity, for oral and parenteral applications only.

Thus, for a device with a long-term patient contact (> 30 days), two TSL values must be applied: 

• A TSL of 600 µg: all substances released at a concentration > 600 µg are considered as potentially posing a long-term risk,
• A TSL of 120 µg: all substances released at a concentration > 120 µg are considered likely to induce a short- or medium-term risk.

Therefore, in case of a long-term contact device, if a substance is detected at a concentration of between 120 and 600 µg, only the MoS (Margins of Safety) for sub-chronic or chronic exposure need to be calculated. The risks of systemic toxicity, genotoxicity, carcinogenicity and reproductive toxicity from acute and sub-acute exposure are considered low.

Note that TSL does not apply to: 

• Local risks;
• Single-use devices whose repeated exposure leads to long-term exposure (>30 days);
• Substances in the cohort of concern, for which TTC values are not protective, as described in ISO/TS 21726:2019;
• Compounds not identified by chemical characterization, i.e. whose chemical identity is unknown or incomplete;
• Inorganic and anionic compounds;
• Volatile compounds from gas pathways used in a medical device (for these, specific TTC thresholds are given in ISO 18562-1);
• Devices intended for premature babies and infants under 6 months of age.

The following flow-chart summarizes the use of these two thresholds:

Efor Group’s biocompatibility and toxicology experts can accompany you in your toxicological analyses, the drafting of your TRA (Toxicological Risk Assessments) and the implementation of version 2023 of ISO 10993-17. Our team’s expertise is constantly updated by keeping abreast of the state of the art, new approaches and regulatory developments.

Contact our technical department at onedt@efor-group.com for assistance with your projects and specific requirements.

^[1] See our technical article on the subject here

^[2] TTC : Threshold of Toxicological Concern

^[3] SCT : Safety Concern Threshold