Reference standards are used ubiquitously within a Quality Control laboratory and are integral to many test procedures. A laboratory should have defined controls for the use, handling, inventory management, and characterization of these standards, as well as consulting the WHO’s Annex 3 for “General guidelines for the establishment, maintenance, and distribution of chemical reference substances,” which provides excellent guidance and can form the basis for such laboratory’s procedure.
The recent issuance of ICH Q2(R2) and the draft ICH Q14 Analytical Procedure Development highlights the virtues of implementing a lifecycle management model for a firm’s analytical procedures, which include defining a method’s Analytical Target Profile (ATP), which forms the basis of the analytical method development. It is critical that, via method development, one understands the impact the reference standard has on achieving the ATP; thus, defining the required attributes of that standard is critical. A specification should be set for that reference standard where there is consideration of the type of reference standard (i.e., Primary Reference Standard, Working Reference Standard) and the purpose as it relates to the test procedure: confirming identity, determining sample assay, analytical control strategy.
Method development should also determine the chemical and physical attributes of the reference standard, resulting in understanding the defined storage requirements. The goal is to minimize the risk that, upon retesting of the reference standard, the specification requirements are not met, whereby there is a need for an investigation to determine the impact to historical testing. With that in mind, the frequency of retesting should be riskbased and should consider the known stability of the material in the defined storage conditions, the criticality of the test data, and the criticality of the purity of the standard on the method’s ATP (which, in turn, is reflected in the standard specification criteria). For example, it is common for hygroscopic reference standards, where the assigned potency has a critical impact on the afforded sample data, that the analytical method will require that the moisture content of the reference standard is measured at the time of use, resulting in “real time” adjustment of the reference standard’s potency to afford the most accurate sample data.
It is recommended that, for those reference standards where the assigned potency/purity has a critical impact on the accuracy of the reported result, this is not only reflected in the frequency of retesting but, as an additional control, there is ongoing monitoring of the reference standard’s purity profile/result (as generated by the method) where there is, for example, an understanding of any marker of degradation and where the level of that marker is recorded and tracked for each usage. Such guidance can also be reflected in the test method where a requirement includes a system suitability upper criterion for that marker that, when exceeded, prevents the acquisition of sample data. This can be critical as any change in the purity of the reference standard (that is not reflective in the assigned potency) can result in the generation of inaccurate sample data.
If you have any questions relating to reference standard controls, Lachman Consultants can help you! Please contact Paul Mason at p.mason@lachmanconsultants.com for support with this critical undertaking.
