Method validation accuracy improvements

Rozet, E., Wascotte, V., Lecouturier, N., Preat, V., Dewe, W., Boulanger, B., Hubert, P. Improvement of the decision efficiency of the accuracy profile by means of a desirability function for analytical methods validation application to a diacetyl-monoxime colorimetric assay used for the... 

Acceptance criteria for accuracy and precision of standards and QCs must be determined during method validation, and are analogous to acceptance criteria for chromatographic methods. IAs may not be as inherently precise as chemical methods, because IAs measure a reaction rather than a physicochemical property of the analyte. In cases where internal standards are not used for recovery correction, two to three replicate assays may be conducted on a single sample to improve precision. Despite all of the available mathematical transformations, it is important to remember that this is not a linear system and caution must be used as the concentrations approach either the upper or lower end of the standard curve. For example, variability becomes too large to be acceptable as the B/B0 value goes beyond <0.1 or >0.9 for most limited reagent assays. 

The first point to remark is that methods that are to be incorporated in MD, and thus require frequent updates, must be both accurate and efficient. It is likely that only semi-empirical and density functional (DFT) methods are suitable for embedding. Semi-empirical methods include MO (molecular orbital) [90] and valence-bond methods [89], both being dependent on suitable parametrizations that can be validated by high-level ab initio QM. The quality of DFT has improved recently by refinements of the exchange density functional to such an extent that its accuracy rivals that of the best ab initio calculations [91]. DFT is quite suitable for embedding into a classical environment [92]. Therefore DFT is expected to have the best potential for future incorporation in embedded QM/MD. 

While venting technology and methods are improving, considerable uncertainty remains as to the validity of various assumptions and accuracy of the correlations. Nearly all of the experimental data to verify calculations to-date are with air-water-steam systems. 

For the first time in the history of chemical sciences, theoretical predictions have achieved the level of reliability that allows them to rival experimental measurements in accuracy on a routine basis. Only a decade ago, such a statement would be valid only with severe qualifications as high-level quantum-chemical calculations were feasible only for molecules composed of a few atoms. Improvements in both hardware performance and the level of sophistication of electronic structure methods have contributed equally to this impressive progress that has taken place only recently. 

The CE method was validated in terms of accuracy, precision, linearity, range, limit of detection, limit of quantitation, specificity, system suitability, and robustness. Improved reproducibility of the CZE method was obtained using area normalization to determine the purity and levels of potential impurities and degradation products of IB-367 drug substance. The internal standard compensated mainly for injection variability. Through the use of the internal standard, selected for its close mobility to IB-367, the method achieved reproducibility in relative migration time of 0.13% relative standard deviation (RSD), and relative peak area of 2.75% RSD. 

The strengths of the factor-based methods lie in the fact that they are multivariate. The diagnostics are excellent in both the calibration and prediction phases. Improved precision and accuracy over univariate methods can often be realized because of the multivariate advantage. Ultimately, PLS and PCR are able to model complex data and identify when the models are no longer valid. This is an extremely powerful combination. 

It is very important to evaluate the accuracy and the regions of applicability of the methods developed for the effective study of the structure and properties of many-body systems, to demonstrate their utility on selected problems of genuine physical and chemical interest, to improve understanding of the fundamentals on which these methods are based, and to perform mutual checking and validation of results obtained by various... 

In a nutshell (DFT methods) Electron density description of chemical phenomena, straightforward interpretation Large molecular systems can be treated Variable accuracy, validation necessary Little basis set dependence No systematic improvements. 

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