We left part 8 discussing the ISO take on uncertainty, and the criteria that fall in that category. We now turn to the second of the two key parts in determining fitness for purpose, specificity/selectivity.
Confirmation of Identity
A concept related to “selectivity” is “specificity”. “Specificity” is a desired state of selectivity. “Specificity” is one of those terms that is defined differently depending on where you look: specificity is either 100% selectivity (see Eurachem Guide paragraph 6.13) or a high degree of selectivity (see http://en.wikipedia.org/wiki/Selectivity).
As we’ve seen in earlier discussions on TBV, “specificity” is part of the ISL criteria for method validation (see ISL Rules 18.104.22.168.1 and 22.214.171.124.2). As per usual with rules written by WADA, it’s not clear exactly what the ISL means when it refers to specificity. The ISL contains separate rules for the validation of methods for threshold substances (ISL rule 126.96.36.199.2) and non-threshold substances (ISL rule 188.8.131.52.1). Both of these rules require validation of all WADA lab methods, and list “specificity” as an “[e]xample of factors relevant to determining if the method is fit for the purpose.” Given that specificity is described as an example of a criterion relevant to method validation, it’s not clear whether specificity is a required or an optional criterion. Later, rules 184.108.40.206.1 and 220.127.116.11.2 contain a bullet point for “Specificity” stating the following:
Specificity. The ability of the assay to detect only the substance of interest must be determined and documented. The assay must be able to discriminate between compounds of closely related structures.
The specificity bullet point makes it sound as if specificity is both a required criterion for method validation under the ISL, and that the ISL defines specificity as 100% selectivity. However, to confuse matters further, ISL rules 18.104.22.168.1 and 22.214.171.124.2 contain a second bullet point for “Matrix interferences”, and there are differences in the way each rule describes “Matrix interferences”. The bullet point for matrix interferences under ISL rule 126.96.36.199.1 (for non-threshold substances) reads as follows:
Matrix interferences. The method should avoid interference in the detection of Prohibited Substances or their Metabolites or Markers by components of the sample matrix.
And the bullet point for matrix interferences under ISL rule 188.8.131.52.2 (for threshold substances) reads as follows:
Matrix interferences. The method must limit interference in the measurement of the amount of Prohibited Substances or their Metabolites or Markers by components of the sample matrix.
In short, the ISL language governing specificity and matrix interference wanders all over the place: permissive language (specificity and matrix interferences are merely examples of criteria for method validation), mandatory language (specificity must be determined and documented), and language somewhere in-between (some methods should avoid matrix interference; other methods must limit matrix interference). How, then, should we understand the ISL rules regarding specificity?
Up to the Introduction; back to part 8; on to part 10.