Imprecision analytical method

A reference method is an analytical method with thoroughly documented accuracy, precision and low susceptibility to interferences. The accuracy and precision shall be demonstrated by direct comparison with the definitive method and primary reference material or, where not available, with other well-characterized and documented analytical approaches) (Boutwell, 1977). As long as accuracy and imprecision are within the limits, each technique or method is acceptable as a reference method. However, for reference methods one always looks for a method easily applicable in the laboratory. Therefore, the expensive instrumentation and the relatively low sample capacity make IDMS suitable as a definitive method rather than as a reference method. For some applications, however, IDMS is the method of choice, allowing a more specific detection than the existing methods in the laboratory. 

An indication of the rate of drug absorption can be obtained from the peak (maximum) plasma concentration (Cmax) and the time taken to reach the peak concentration (fmjx), based on the measured plasma concentration-time data. However, the blood sampling times determine how well the peak is defined and, in particular, fmax. Both Cmax and tm3LX may be influenced by the rate of drug elimination, while Cmax is also affected by the extent of absorption. The term Cmax/ AUC, where AUC is area under the curve from time zero to infinity or to the limit of quantification (LOQ) of the analytical method, provides additional information on the rate of absorption. This term, which is expressed in units of reciprocal time (h ), can easily be calculated. In spite of the imprecision of the estimation provided by Cmax, it generally suffices for clinical purposes. 

Abstract Validation of analytical methods of well-characterised systems, such as are found in the pharmaceutical industry, is based on a series of experimental procedures to establish selectivity, sensitivity, repeatability, reproducibility, linearity of calibration, detection limit and limit of determination, and robustness. It is argued that these headings become more difficult to apply as the complexity of the analysis increases. Analysis of environmental samples is given as an example. Modern methods of analysis that use arrays of sensors challenge validation. The output may be a classification rather than a concentration of analyte, it may have been established by imprecise methods such as the responses of human taste panels, and the state space of possible responses is too large to cover in any experimental-design procedure. Moreover the process of data analysis may be done by non-linear methods such as neural networks. Validation of systems that rely on computer software is well established. 

It is often claimed that the analytical quality should be better when determining reference values than when producing routine values. This may be true for accuracy aU measures should be taken to eliminate bias. The question of imprecision is more difficult because it depends partly on the intended use of the reference values. Increases in analytical random variation result in widening of the reference intervals For some special uses of reference values, the narrower reference interval obtained by a more precise analytical method may be appropriate. However, this is usually not true... 

The term probability for false rejection (p ) is used to describe the first situation, where there are no analytical errors present except for the inherent imprecision or inherent random error of the analytical method. (There is always some random error associated with an analytical method, even when it is working properly. This is the random error that is estimated by the replication experiment during method evaluation studies.) When only this inherent random error is present, without any additional errors, the probability for false rejection should be zero. The frequency of false rejections is critical, because false rejections are like false alarms. Too many false alarms cause the analyst to disregard the alarm system, even when the alarm is occurring as a result of real errors that should be corrected. 

Most manufacturers provide some indication of the performance of their analyzers with preferred reagents in terms of imprecision, linearity, and reportable ranges. All analytical methods should be assessed by the user for imprecision, accuracy, linearity, limits of detection, and carryover between samples. 

In recent years the proximate analysis procedure has been severely criticised by many nutritionists as being archaic and imprecise, and in the majority of laboratories it has been partially replaced by other analytical procedures. Most criticism has been focused on the crude fibre, ash and nitrogen-free extractives fractions for the reasons described above. The newer methods have been developed to characterise foods in terms of the methods used to express nutrient requirements. In this way, an attempt is made to use the analytical techniques to quantify the potential supply of nutrients from the food. For example, for ruminants, analytical methods are being developed that describe the supply of nutrients for the rumen microbes and the host digestive enzyme system (Fig. 1.1). 

Automation is an essential part of the sample preparation procedures. The added imprecision that results from the increased manipulation of the sample during extraction can be minimized by the use of robotics and automated sample preparation systems. For these reasons, it is essential that the validation of analytical methods include sample preparation. The validation process defines the method parameters and the impact that each parameter has on the effectiveness of the extraction method. In addition, the use of manual techniques is not practical... 

Standard deviations from two to five or more. This means that the upper seventeenth percentile may be as much as from two to five times the mean. This variabihty is compounded by the problem of estimating the exposure of a group of workers having differing exposures to find the most exposed workers. Compared to this environmental variabihty, the variabihty introduced by the sampling and analytical error is smah, even for those methods such as asbestos counting, which are relatively imprecise. 

Theoretically IQC should be the front-line approach to quality. If a method has been adequately validated and shown to meet the requirements of the user and kept in analytical control with IQC to detect intrusion of bias or imprecision, then the EQA needs to provide the occasional, independent, objective reassurance. In practice however, the EQA is likely to play an equal role with IQC, both in confirming problems brought to the attention of the analyst by the IQC and in stimulating further action. 

Among the methods used, the determination of selected of analytes in vitreous humor (and of potassium in particular, based on the observation that its concentration progressively increases in this substrate after death) has been often adopted in the attempt to reduce imprecision of the estimate. Recently, for example, Munoz et al. [142] have developed an HPLC method for the determination of hypoxanthine, another substance whose concentration has been found to increase after death in vitreous humor. Separation was carried out under RP conditions using a mobile phase of KH2PO4 0.05M (pH 3) containing 1% (v/v) methanol at a flow rate of 1.5mL/min. UV spectra were recorded in the range 200-400 nm. Based on the analysis of samples collected at different PMIs, the authors found that about 53% of the variation in the data is explained by PMI. 

The isotope ratios for the six analyzed curse tablets plus the results from Pintozzi s analysis of curse tablet 90.3—260 are summarized in Table III. These results will supersede those of Pintozzi in all future work due to the imprecision of her 206Pb/204Pb ratios. An estimate of her error in this ratio is approximately 0.6% per amu based on her four analysis of the SRM981 standard. This precision is not within the error limits of the current database. This is in no way a criticism of Pintozzi s analytical ability it is just that the instrument and methods used at that time do not meet the requirements of a modem lead isotope study. 

Accuracy. The more accurate the sampling method the better. Given the very large environmental variability, however, sampling and analytical imprecision is rardy a significant contribution to overall error, or width of confidence limits, of the final result. Even highly imprecise methods, such as dust count methods, do not add much to overall variability when the variability between workers and overtime is considered. An undetected bias, however, is more serious because such bias is not considered by the statistical analysis and can, therefore, result in gross unknown error. 

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