System suitability testing

The main criterion of acceptance for results of calculations of MWD for dextran 40 is validity of system suitability test (characteristics of MWD for dextran 40 standai d for system suitability test must be in prescribed intervals). 

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. 

In this work there is proposed approach which allows using broad standar ds for calibration and system suitability test. The approach is based on main principle of using of standards i.e. maximal closeness of tested sample and standar d. It has been shoved that the approach allows achieving essential improvement of robustness of method for determination of MWD of dextrans. 

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. 

Acceptance Criteria System suitability tests are to be conducted, if necessary, every time an analysis method is installed, in order to ensure that meaningful results are generated. Criteria are in place to supply the necessary information for a go/no go decision. 

In case of reduced availability of an impurity a possible approach is to prepare a spiked sample , i.e. a known amount of impurity is added to the CRS and may serve in a system suitability test as well as for the control of the level of this impurity. An example is given in the monograph for chlorprothixene hydrochloride (Monograph 0815 1999) where the content of the E-isomer is controlled to a level of not more than 2 per cent, Figure 5.5. 

Rose U (1998) In situ degradation a new concept for system suitability tests in monographs of the European Pharmacopoeia. J Pharm Bio Anal 18 1-14. 

It is being recognized increasingly that regulation can have a positive impact on laboratory productivity.36 System suitability testing has been proposed as superior to and supplemental to calibration in the UV-VIS detector.37 Large variations in both response factor and in relative response factors were observed on different instruments. Even on the same instrument, UV-VIS spectra can be extremely dependent on solution conditions, as was observed in a separation of hypericin, the antidepressant extract of St. John s wort.38... 

A number of recommendations have been made in the development of quantitative chromatographic methods. The American Society for Testing Materials — using as a benchmark the reversed phase separation of benzyl alcohol, acetophenone, benzaldehyde, benzene, and dimethylterephthalate — discovered substantial laboratory-to-laboratory differences in quantitative analysis.53 These compounds are routinely used to test column performance or for system suitability testing. A followup study, using benzyl alcohol, acetophenone, p-tolualdehyde, and anisole, showed that measurement of... 

Wahlich JC, Carr GP (1990) Chromatographic system suitability tests - what should we be using J Pharmac Biomed Anal 8 619... 

In Phase III, the final dosage formulation has been established and the pivotal clinical trials are being conducted. Degradation products have been identified, so the method selectivity should be reevaluated to ensure that all degradants can be detected and quantitated. The analytical methods are completely validated, and appropriate for routine quality assurance and control purposes. The type and frequency of system suitable testing (SST) should be determined, and an excellent publication on SST for chromatography systems is available [47],... 

It is always recommended that OQ is carried out after a service visit. Evidence of continued satisfactory performance during use (PQ) should be obtained from everyday method-related checks (e.g. system suitability testing, calibration and analytical quality control). It is advisable to set up thresholds outside of which the performance of an instrument is no longer acceptable. Each stage of the equipment qualification needs to be fully documented so that the evidence of performance at any given time can be checked. 

Mirza T, Grady LT, Foster TS. Merits of dissolution system suitability testing response to PhRMA s proposal on mechanical calibration. Pharm Forum 2000 26(4) 1167—1169. 

There are four general steps to ensure this control and consequently to guarantee the data quality [32] quality control checks (QC), system suitability tests (SSTs), analytical methods validation (AMV), and analytical instrument qualification (AIQ) (see Figure 5). 

System suitability tests serve to define the level of electrophoretic performance necessary to ensure valid CE assay results. System suitability of the method was evaluated by analyzing the symmetry of the IB-367 peak, theoretical plates of the capillary, and resolution between IB-367 and IB-300, the closest peak to IB-367. The sample concentration of the method was selected at approximately 0.5 mg/ml to assure symmetry below 3.5 and to assume sufficient sensitivity for detecting low... 

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. 

FIGURE I Schematic diagram showing the overall validation strategy, which includes calibration, system validation, and system suitability testing. Figure adopted with ideas from Reference I. 

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