System suitability limit

Vander Heyden, Y, Jimidar, M., Hund, R., Niemeijer, N., Peeters, R., Smeyers-Verbeke, J., Massart, D. L., and Hoogmartens, J. (1999). Determination of system suitability limits with a robustness test. J. Chromatogr. A 845, 145-154. 

In addition to validation of the automation, full validation of the chromatographic procedure, as described in Chapter 12, should be conducted for late-phase methods. This should include specification of system suitability parameters to ensure that the performance obtained during method development and validation is maintained during routine use. The system suitability parameters may include specification of acceptable injection repeatability, criteria for resolution between critical pairs, maximum allowable tailing factors, and a means of verifying that the requisite sensitivity is obtained. As recommended by Vander Heyden et al., system suitability limits are best set following robustness tests. 

It is found that the validity of system suitability test depends on loading of dextran standai d. Chai acteristics for loading 3 was close to the middle of prescribed interval, for loading 2 it is close to the upper limit, for loading 1 it is outside of the limit. 

Methods which ai e described in Phamiacopoeias (American, British, and European) ai e based on using narrow standai ds for calibration and broad standai d for system suitability test. Prescribed limits of system suitability ar e broad and therefore it may cause large uncertainty of results. But on the other side results ar e strongly influenced by par ameters of chromatographic system. 

A system suitability test prescribes a relative standard deviation of not more than 1% for the procedure to be valid with Xmean = 173.5 this translates into Vr - (1.735)2 because the limit is imposed, this is equivalent to having no uncertainty about the numerical value, or in other words,/r = Since Si was determined to be 2.43 for n, = 1 ... 

Assuming the 1% limit was set down in full cognizance of the statistics involved, the system suitability test must be regarded as failed because 2.43 > 1.74. This would be the legalistic interpretation under GMP rules. Statistically it would have made more sense to select the criterion as St <0.01 Xmean VFc 0.05,ft, °°) for acceptance and demanding, say, u > 5 in this particular case, s, could have been as large as 3.6. 

Factors of importance in preventing such thermal runaway reactions are mainly related to the control of reaction velocity and temperature within suitable limits. These may involve such considerations as adequate heating and particularly cooling capacity in both liquid and vapour phases of a reaction system proportions of reactants and rates of addition (allowing for an induction period) use of solvents as diluents and to reduce viscosity of the reaction medium adequate agitation and mixing in the reactor control of reaction or distillation pressure use of an inert atmosphere. 

It is desirable to be able to continuously monitor all the reactants and products so that a time resolved response curve is obtained for the separate components in the pulse. The sequence in which the products appear and the shape of each individual peak can, in principle, give information on the reaction sequence and on adsorption properties that cannot easily be obtained in any other way. Infrared spectroscopy has been used with good results, but the number of systems suitable is limited and at best only a small number of components can be analyzed for, Figure 1. The... 

LIMB [Lime/limestone injection into a multi-stage burner] A flue-gas desulfurization process used in Germany and Finland. Dry, ground limestone is injected directly into the combustion chamber. This reacts with the sulfur dioxide, and the dry particulate product is collected downstream together with the ash. The process is suitable only for those systems which limit the maximum combustion temperature by staging, in order to minimize the production of oxides of nitrogen. 

The performance of a chemical reactor can be described, in general, with a system of conservation equations for mass, energy, and momentum. To solve this system we must have a model for the reaction on the basis of which we can derive the intrinsic rate equation on one side, and a model of the reactor in which we want to run the reaction on the other side. Both tasks are, of course, interconnected and difficult to solve without reduction of more general equations to a suitable limiting reactor type to be used for each particular reaction system [4,26],... 

Where the safety device consists of an additional regulator that is associated with or functions in combination with one or more regulators in a series arrangement to control or limit the pressure in a piping system, suitable checks shall be made. These checks shall be conducted to determine that the equipment will operate in a satisfactory manner to prevent any pressure in excess of the established MAOP of the system, should any one of the associated regulators malfunction or remain in the wide-open position. 

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. 

To validate the suitability of methods, experiments to establish specificity, accuracy, precision, limits of detection, limits of quantitation, linearity, range, and robustness should be conducted. Furthermore, appropriate system suitability criteria should be developed to assure that the method is performing to pre-established criteria at the time of use. 

Further discussion of method validation can be found in Chapter 7. However, it should be noted from Table 11 that it is frequently desirable to perform validation experiments beyond ICH requirements. While ICH addresses specificity, accuracy, precision, detection limit, quantitation limit, linearity, and range, we have found it useful to additionally examine stability of solutions, reporting threshold, robustness (as detailed above), filtration, relative response factors (RRF), system suitability tests, and where applicable method comparison tests. 

System suitability test characteristics and limits are recommended as a component of any analytical method. This ensures that both methodology and instrumentation are performing within expectations prior to the analysis of test samples. The test characteristics are inferred from robustness studies and evaluated during the validation experiments. 

Repeatability can be divided into two areas injection repeatability and analysis repeatability. Injection repeatability is measured by analyzing multiple injections of the same solution preparation. It is an indicator of the performance of the HPLC system under the specified conditions and at the time of the analyses. This information is included as part of the validation package and is also used during routine analysis in the form of a system suitability. During the validation the specification for % RSD will be set, which will determine the variation limit for the analysis. If the value is low... 

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... 

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