Analytical procedure quantitation limit

The detection limit of an individual analytical procedure is the lowest amount of analyte in a sample, which can be detected but not necessarily quantitated as an exact value. 

Because of the special regulatory position occupied by foods and beverages, a great deal of attention has been given to development and application of analytical procedures for them. Improved procedures have resulted in quantitation and confirmation levels in the range of 1 to 10 ppb with sample amounts of 10 to 250 g. Detection limits for foods are in the 0.1 to 1 ppb range. Detection limits of 0.1 to 1 ppm appear adequate for pesticide formulations (1, > while sensitivity of 0.01,... 

For the high accuracy needed in the quantitative measmement of the species, quality assurance of the analytical procedures is of prime importance. This can only be achieved by using representative RMs, certified for the relevant species. Up to now the number of existing certified reference materials is very limited. This section will give a survey of the main species that are presently determined routinely or for research purposes. 

Residue study protocols typically either include quality specifications for analytical procedures or refer to a written analytical method that includes such specifications. The protocol for an LSMBS should also include analytical quality specifications, either directly or by reference to a method. Analytical specifications usually include minimum and maximum recovery of analyte from fortified control samples, minimum number of such fortifications per set of samples, minimum linearity in calibration, minimum stability of response to injection of calibration solutions, and limits of quantitation and of detection. 

Analytical methods, particularly those used by accredited laboratories, have to be validated according to official rules and regulations to characterize objectively their reliability in any special field of application (Wegscheider [1996] EURACHEM/WELAC [1993]). Validation has to control the performance characteristics of analytical procedures (see Chap. 7) such as accuracy, precision, sensitivity, selectivity, specificity, robustness, ruggedness, and limit values (e.g., limit of detection, limit of quantitation). 

For non-compendial procedures, the performance parameters that should be determined in validation studies include specificity/selectivity, linearity, accuracy, precision (repeatability and intermediate precision), detection limit (DL), quantitation limit (QL), range, ruggedness, and robustness [6]. Other method validation information, such as the stability of analytical sample preparations, degradation/ stress studies, legible reproductions of representative instrumental output, identification and characterization of possible impurities, should be included [7], The parameters that are required to be validated depend on the type of analyses, so therefore different test methods require different validation schemes. 

Type of analytical procedure Assay Impurity testing Quantitative Limit tests Performance characteristics Identification ... 

In some cases, a limit of quantitation (quantification) may need to be considered where it is necessary not only to detect the presence of an analyte but also to determine the amount present with a reasonable statistical certainty. The limit of quantitation of an individual analytical procedure is the smallest amount of an analyte in a sample, which can be quantitatively determined with acceptable uncertainty. More detail can be found in Section 4.6.4. 

Once the type of limiting function has been selected, the parameters a, and P, which quantitatively define the nonlinearity i/y (0) in Eq. (11.31), have to be chosen to give the desired efficiency at the nominal Gaussian model. An analytical procedure was developed by Chen et al. (1998) for choosing each set of tuning parameters, based on the conditional probability of the measurements. 

Of the analytical procedures used for the determination of LAS in soils (Table 6.7.1), most methods rely on (Soxhlet) extraction with methanol, followed by clean-up on SPE cartridges (RP-C18 and/or SAX) and final quantitative measurements by HPLC—UV/FL. Applying this protocol, detection limits were achieved ranging between 0.05 and 5 mg kg-1 depending on the matrix, the enrichment factor and the optical detection system employed. 

Analytical data generated in a testing laboratory are generally used for development, release, stability, or pharmacokinetic studies. Regardless of what the data are required for, the analytical method must be able to provide reliable data. Method validation (Chapter 7) is the demonstration that an analytical procedure is suitable for its intended use. During the validation, data are collected to show that the method meets requirements for accuracy, precision, specificity, detection limit, quantitation limit, linearity, range, and robustness. These characteristics are those recommended by the ICH and will be discussed first. 

Analytical procedure Accuracy Repeatability Intermediate precision Specificity Detection limit Quantitation limit Linearity Range Compound(s) Reference(s)... 

ISO defines validation as Conformation by examination and provision of objective evidence that the particular requirements for a specified intended use are fulfilled. This is decided by using a number of performance characteristics. These are specificity, linearity, range, accuracy, precision, detection limit (DL), quantitation limit (QL), and robusmess. System suitability testing (SST) is an integral part of many analytical procedures. Definitions of these terms based on the recommendations of the ICH Guideline Q2 (Rl) are given in Table... 

The aim of validation of an analytical procedure is to demonstrate that the method employed in any product testing, such as the identification, control of impurities, assay, dissolution, particle size, water content, or residual solvents, is validated in the most important characteristics. Identification tests, quantitative tests for impurities content, limit tests for control of impurities, and quantitative tests of the active moiety in samples of pharmaceutical product are the most common types of analytical procedures that validation addresses [1]. 

Impurities in API. Treatment of the impurities in the API is similar to that for the new drug product. Impurities in the API include organic impurities (process and drug related), inorganic impurities, and residual solvents. Quality control analytical procedures are developed and validated to ensure appropriate detection and quantitation of the impurities. Specification limits for impurities are set based on data from stability studies and chemical development studies. A rationale for the inclusion or exclusion of impurities is set at this stage. The limits set should not be above the safety level or below the limit of the manufacturing process and analytical capability. 

ICH definition The quantitation limit of an individual analytical procedure is the lowest amount of analyte in a sample that can be determined quantitatively with suitable precision and accuracy. The detection limit of an individual analytical procedure is the lowest amount of analyte in a sample that can be detected but not necessarily quantitated as an exact value. 

Several methods are available in the literature for the measurement of aliphatic amines in biological samples [28]. Problems with specificity and separation and cumbersome derivatisation and/or extraction procedures have limited the use of these techniques on a larger scale in clinical practice. The lack of a simple analytical method may have led to an underestimation of the incidence of the fish odour syndrome. For diagnosing the syndrome, an analytical technique should be used that is able to simultaneously and quantitatively measure TMA and its N-oxide in the complex matrix of human urine. Two such methods are currently available for this purpose proton nuclear magnetic resonance (NMR) spectroscopy and head-space gas analysis with gas chromatography or direct mass spectrometry (see below). 

Similar to the analytical procedure for trace analysis in high purity GaAs wafers after matrix separation, discussed previously,52 the volatilization of Ga and As has been performed via their chlorides in a stream of aqua regia vapours (at 210 °C) using nitrogen as the carrier gas for trace/matrix separation.58 The recoveries of Cr, Mn, Fe, Ni, Co, Cu, Zn, Ag, Cd, Ba and Pb determined after a nearly quantitative volatilization of matrix elements (99.8 %) were found to be between 94 and 101 % (except for Ag and Cr with 80 %). The concentrations of impurities measured by ICP-DRC-MS (Elan 6100 DRC, PerkinElmer Sciex) after matrix separation were compared with ICP-SFMS (Element 2, Thermo Fisher Scientific) and total reflection X-ray fluorescence analysis (TXRF Phillips). The limits of detection obtained for trace elements in GaAs were in the low ngg-1 range and below.58... 

---