When it comes to medical devices, regulatory standards are never set in stone. The guidance offered by authorities is ever evolving, as technology advances, new data becomes available and old interpretations become obsolete. As medical device manufacturers innovate, they encourage regulators to interpret existing standards in new ways, too.
The International Organization for Standardization (ISO) tries to review standards every five years to decide if any revisions are necessary. A crucial standard recently underwent a big change, and device manufacturers need to be aware of these changes. After a lengthy process of updating verbiage and public voting, ISO 10993-17 (the standard guiding medical device toxicological risk assessments) has been updated.
Prior to its revision, the standard’s complete title was “ISO 10993-17: Biological evaluation of medical devices – Part 17: Methods for the establishment of allowable limits for leachable substances.” The new title is “ISO 10993-17: Biological evaluation of medical devices – Part 17: Toxicological risk assessment of medical device constituents.”
Read more for the rationale behind the name change and other insights medical device manufacturers will encounter in the revised standard.
The Name Change
The change of title is significant for many reasons. The revised name more accurately reflects the intent of the standard, which is to estimate toxicological risk based on a compound’s tolerable intake (TI) or tolerable contact level (TCL), and worst-case estimated exposure (EEDmax).
The phrase “allowable limit” has been removed from the title, which is worth noting. The updated standard also extends the previous version by clarifying when a toxicological risk assessment is recommended, how to calculate worst-case estimated exposure, and when potential harm should be addressed by other means.
ISO 10993-17’s Systematic Approach
The standard introduces many new concepts and eliminates some older ones. One of the major themes included is the idea of a “systematic approach” to toxicological risk assessment. This means identifying hazards and estimating the risk based on TI, TCL, EEDmax and Margin of Safety (MOS). These terms are addressed in greater detail below.
Tolerable intake (TI): An estimate of the daily exposure of an identified constituent over a specified time period, based on body weight, that is without appreciable harm to health. To establish the TI value, toxicologists conduct a toxicological review of the identified constituent and then select the most conservative point of departure (POD) for the intended use. Once the POD is selected, uncertainty factors are applied to account for variability. The updated standard provides more guidance on deriving a TI, the application of uncertainty factors, and data quality and reliability considerations.
Tolerable contact level (TCL): An estimate of the surface-contact exposure to an identified constituent that is without appreciable irritation. ISO 10993-17 guides manufacturers in the application of uncertainty factors that need to be considered.
Worst-case estimated exposure dose (EEDmax): An exposure dose that is the maximum value for a specific clinical-use scenario. The EEDmax considers the worst-case assumptions of chemical release and device use.
Margin of safety (MOS): The ratio of the tolerable intake to the worst-case estimated exposure dose. If the EEDmax is greater than the TI, the margin of safety will be less than 1, which means the exposure could be harmful. If the MOS value is less than 1 additional risk analysis, risk control, or risk evaluation is required. Only expert analysis can determine if there are uncertainties within the chemical characterization or risk assessment approach that may affect MOS interpretation.
Major Additions to the Standard
There are other additions to the standard, but here are four major differences and what they mean:
Identified constituent: A constituent with a complete set of molecular structure information. The identity can be obtained through non-targeted or targeted analytical means. Any chemistry report that has too little structural information about a compound can’t be used to support a toxicological risk assessment. In these cases, the chemical may be considered an “unknown.”
Total quantity (TQ): The amount of a constituent present in or extracted from a medical device. The standard explains how to generate an acceptable total quantity and document the comparison between the total quantity and the toxicological screening limit.
Toxicological screening limit (TSL): The cumulative exposure dose of an identified constituent over a specified period which will not cause appreciable harm to health. Chemical characterization studies can often lead to large sets of data that need to be evaluated in the toxicological risk assessment and in a lot of cases the constituents are present in very low levels. The TSL provides an option for screening constituents when the TQ falls below a short-term or long-term TSL.
Release kinetics: The quantity of a constituent that is released from a medical device over time. Experimental release kinetics are most often generated in leachables or simulated use chemical characterization studies with multiple time points. The updated ISO 10993-17 standard provides guidance around calculating assumed release kinetics based on the TQ of a constituent.
A Handful of Subtractions
Several old or outdated concepts have also been removed from the standard. Device manufacturers and lab testing partners still using these concepts should update both terminology and their approach, if necessary. These concepts include:
- Allowable limit
- Benefit factor
- Proportional exposure factor
- Tolerable exposure
- Utilization factor
A Final Word
Updates to ISO 10993-17 have been anticipated for a long time. The first whispers of an impending update started several years ago but, given the standard’s importance to medical devices and patient safety, it makes sense that it has taken a while to arrive. The standard provides extensive guidance around risk assessment for medical devices, which should improve consistency. It also introduces new tools to streamline the toxicological risk assessment process without additional testing—something which will save both time and money.