Linear dynamic range, LDR

For all practical purposes, the upper limit of quantitation is the point where the calibration curve becomes nonlinear. This point is called the limit of linearity (LOL). These can be seen from the calibration curve presented in Figure 1.3. Analytical methods are expected to have a linear dynamic range (LDR) of at least two orders of magnitude, although shorter ranges are also acceptable. 

The fundamental parameters for this validation include accuracy, precision, selectivity, sensitivity, reproducibility, and stability [58], Other parameters are limits of detection (LODs) and quantification (LOQs), linear dynamic range (LDR) [56], In the case of LC-MS/MS based procedures, appropriate steps should be taken to ensure the lack of matrix effects throughout the application of the method, as outlined by several authors [55, 60-64]. 

HPLC provides reliable quantitative precision and accuracy, along with a linear dynamic range (LDR) sufficient to allow for the determination of the API and related substances in the same run using a variety of detectors, and can be performed on fully automated instrumentation. HPLC provides excellent reproducibility and is applicable to a wide array of compound types by judicious choice of HPLC column chemistry. Major modes of HPLC include reversed phase and normal phase for the analysis of small (<2000 Da) organic molecules, ion chromatography for the analysis of ions, size exclusion chromatography for the separation of polymers, and chiral HPLC for the determination of enantiomeric purity. Numerous chemically different columns are available within each broad classification, to further aid method development. 

In addition to choosing separation conditions, both the injection volume and the sample concentration must be chosen during method development. These must be considered with respect to the detection used. For the simultaneous detection of API and related substances, the detector should minimally be able to quantify compounds from 0.1% (limit of quantitation) to 130% of the concentration of the API for compliance with ICH guidelines.This requires the detector to have a minimum linear dynamic range (LDR) of 1300, assuming equal responses of the API and related substances. For samples where... 

Linear dynamic range (LDR) The concentration range over which the analytical working calibration curve remains linear. 

Method 200.8 describes a protocol for determining the method detection limit (MDL) as well as the linear dynamic range (LDR). For the MDL, the analyst sets up the instrument hardware and method as intended for the analysis, and then analyses a reagent blank solution spiked at 2-5 times the estimated detection limit. Seven repeats are required over three non-consecutive days. The standard deviation is determined for each of the sets and multiplied by 3.14 to arrive at the MDL. The data for the MDL calculation must have all the required calculations included, e.g. interference correction equations, as these can have a substantial influence on the MDL. Table 9.4 lists some typical MDL values obtained as per the method for a standard quadrupole ICP-MS instrument. 

For reversible interactions, the linear dynamic range is determined by that portion of the coating-analyte sorption isotherm (discussed in Section 5.4) that lies between the LOD and the saturation limit. For irreversible interactions, the LDR will depend on the sorption/reaction kinetics and the coating capacity. For practical reasons, it is desirable to have the widest LDR possible, although inexpensive microprocessors and associated memory make correction for minor nonlinearities straightforward. For an example of a wide linear dynamic range, refer to Figure 5.13. 

Table 26 MAS methods for determination of non-metals (1%-abs. — characteristic concentration or mass, LDR = upper limit of linear dynamic range, USD = relative standard deviation, HCL — hollow cathode lamp)...

Linear dynamic range The concaitrationiang over which a calibration curve demonstrates linear response with concentration. LDR is usually reported in terms of orders of magnitude... 

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