How the Updated ISO 10993-18 Standard Improves Medical Device Testing

The British Standard has implemented the EN ISO10993-18:2020 +A1:2023. This version is identical to ISO10993-18:2020 incorporating the amendment 1:2022 and it supersedes BS EN ISO 10993-18:2023 which is now withdrawn. 

The quantification of extractables is determined by screening methods, which need to be able to detect a large variety of possible extractables. Some compounds ionise more readily than others, which can lead to inaccurate results when quantifying if a similar reference standard is not used. The variation in response factors of extractables and internal standards is accounted for in the calculation of the analytical evaluation threshold (AET). The AET is the threshold used to determine whether a chemical detected in the test sample is of a high enough concentration to be reported. The AET is only applicable to screening methods such as GC-MS and HPLC-MS. The AET should not be used for methods designed to identify and quantify highly toxic extractables in a cohort of concern. The formula below from ISO 10993-18 Annex E is used to calculate the AET. 

 
Where: 

A is the number of medical devices extracted to generate the extract; 
B is the volume of the extract in ml; 
C is the number of devices a patient would be exposed to in a day under normal clinical practice; 
DBT is the dose-based threshold (e.g. (TTC) or (SCT)) in µg/day; 
UF is an uncertainty factor that accounts for the analytical uncertainty of the screening methods used to estimate the concentration of extractables in an extract. 
 
Each of the variables that make up the formula for calculating the AET are easily known, when preparing the extraction, apart from the UF, which must be calculated or justified beforehand. As shown by the formula for the AET, the UF and the AET are inversely proportional to each other i.e. a larger UF will give a smaller AET and vice versa. A small UF is desired, because it shows that the variation in response factors is low and therefore suitable for reporting data, which is the basis of a toxicological risk assessment (TRA). 

Protecting Patients, Ensuring Safety

For analytical methods, where the variation in response factors of expected extractables, applied internal standards and targeted extractables using qualified methods are known to be acceptably low, an UF of 1 can be justified. An UF of 2 can also be justified for screening methods that use GC-FID or GC-MS, as the response factors of extractables detected by these methods are deemed to be somewhat consistent. For other screening methods, such as HPLC-MS, no guidance is given by the standard for a specific UF. However, rather than assuming and justifying the value of the UF to be 1, 2 or another number, the UF can be calculated for a specific method, which gives a more accurate value of the AET, and therefore a more reliable threshold to exclude or include peaks when reporting data. The standard details how to determine the UF. The UF is calculated by using the formula, below, which assumes a Gaussian distribution of response factors, which is not the case for all chromatographic detection methods. 

Where, the RSD is the relative standard deviation of the responses or response factors from the reference database. The reference database is an internal record of response factors specific to the analytical method that the UF is being calculated for. These response factors are the peak areas or heights of each compound at the same concentration. One analytical method for an extractables and leachables study should have many compounds in the reference database as they are screening methods. 
 
The size of the UF must not be too large or too small, as this indicates that the method being used is unsuitable. A large UF e.g. greater than 10, shows that the method is inaccurate and gives an AET that is so small, that it would not be detected by the analytical method, because it is smaller than the method’s limit of detection (LOD). When the RSD is greater than or equal to 1 (this occurs when the standard deviation is greater than or equal to the mean), the UF will equal infinity or a negative number. If either of these situations occur the method should be improved before it is used as the foundation of a toxicological risk assessment.