Systems Suitability

The procedure known as system suitability test consists in testing an instrumental analytical system against documented performance specifications for a given analytical method. System suitability tests are based on the concept that the equipment, electronics, analytical operations and samples constitute an integral system that can be evaluated as a whole. These tests are used to make sure that the resolution and reproducibility of the system are adequate for 

Validation requires analytical method instructions comprising a system suitability test in order to verify identical starting conditions. Part or full revalidation may be considered if system suitability tests, or the results of quality control sample analysis, are out of pre-set acceptance criteria and the source of the error cannot be tracked back to instrumental factors or anything else. 

RATIONAL STEP-BY-STEP METHOD DEVELOPMENT AND VALIDATION FOR POLYMER/ADDITIVE ANALYSIS 

As yet, there are no generally accepted formats for the overall method development of in-polymer additive analysis. However, one may take a lead from the work of Swartz et al. [6], and various other sources [20,80,87,128], who have presented a rationale for the process of successful development of (HPLC-based) analytical methods, their optimisation, and eventually validation. A sequence of steps is necessary in the development of a fully validated method for the analysis of additives in polymeric matrices, in which the user has specified validation parameters and limits, as follows  

Aims at collecting relevant chemical and physical information about the analyte determines the availability of standards (including degradation products) and evaluates only methods which are compatible with the sample stability. 

Very recently (Briscoe 2007) the question of system suitability testing for LC-MS/MS applications in biomedical analysis was addressed in detail, and a generic test that monitors instrument performance throughout an analytical run was described. This procedure includes tests for signal stability, carryover and instrument response in a fashion that is integrated throughout an analytical run of multiple samples. The importance of this work is illustrated by 

Thus the SSTS analyses in principle can not check for the various sample preparation effects that the QCs monitor. On the other hand, variations in the quantitative data obtained by the QCs will reflect all the steps of the analytical method combined, so that instrument performance can not be unambiguously determined from the combined effects that lead to variability in the QC data. Indeed, it is possible that some of these effects can partially cancel one another out, e.g., a poor extraction efficiency might be cancelled by an upward drift in the instrument sensitivity. 

In both of the examples described (Briscoe 2007) as examples where something of this sort must have occurred, the use of QC samples followed the FDA guidelines, i.e. a minimum of three concentrations (one within 3x of the LLOQ, one in the midrange and one approaching the high end of the range), with a minimum number of QC samples that should be at least 5 % of the number of unknown samples or six in total, whichever is greater. Moreover, the data obtained for the QCs met or exceeded the FDA acceptance criteria, i.e. at least 67 % ( ) of the QC samples should be within 15 % of their respective nominal (theoretical) values (the 33 % of the QC samples that can be outside the 15 % of 

The take-home message from this work (Briscoe 2007) appears to arise from two aspects that, when combined, can potentially cause problems, namely the role of QC samples in monitoring the integrated variability of the entire analytical method and the potential for instrumental drift in response of LC-MS/MS instruments for a variety of reasons (e.g. accumulation of contamination). Thus system suitabihty checks conducted only before an analytical run is started may not suffice to guarantee validity of data obtained and should be designed to monitor instrument performance regularly in the course of an analytical run. 

A method that has been proven to be both robust and rugged will produce sound statistically supported results by anyone properly trained in the field when coupled with the final topic of this chapter system suitability. 

All of the validation parameters above deal with method performance during the critical phases of validation and method review. Unfortunately, no matter how rigorous the validation protocol is for a method, validation cannot preclude or anticipate the effect of instrumentation that is not wofijing properly or analyst error. It is for this reason that an on-going method-specific test (or set of tests) is needed. This is the reasoning behind the use of system suitability parameters. 

System suitability refers to a unique set of performance specifications that is directly linked to a method. These specifications are not accuracy, precision, linearity, etc., which are measures of method performance and are used to support product release. These data are generated after the analysis set is complete. Conversely, a system suitability parameter directly ties the immediate performance of the method for a specific portion of an analytical sequence. Some parameters that are commonly used as system suitability parameters include theoretical plates aaA/oc peak symmetry for the analyte peak Ifl), resolution or a for multiple analyte peaks in a determination), or check sample results (analysis of a previously analyzed sample). 

These parameters can be ranges (both upper and lower control limits) as in the case of an analyte level in a check standard maximum values (upper control limit only) as in the case of peak asymmetry or minimum values (lower control limit only) as is the case of resolution or plate number. Parameters that do not directly monitor the actual performance of the method (e.g., mobile phase pH, flow rate determination), although functionally important, are inadequate and inappropriate for system suitability determinations. 

Alcohols are a frequently used class of LC solvents. They are used both as major constituents in reversed-phase (RP) mobile phases and as low-volume constituents in normal-phase (NP) separations. They offer the following set of unique properties  

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Table 1.5 Trivial Names of Heterocyclic Systems Suitable for Use in Fusion...

Owing to governmental regulations, considerable research has been expended to develop systems suitable for substitution of solvent-based systems, particularly for automobile and container appHcations. In the switch from solvent-based to waterborne systems, epoxies are successfully bridging the gap largely by adaptation of conventional resins. 

In this work the results of seai eh of sensor systems suitable for analysis of liquid and solid media for eontent of volatile aliphatie amines ai e presented. The most suitable proeedure of analysis is gas extraetion - deteetion . 

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. 

To obtain a strong busbar mounting system, suitable to withstand the electrodynamic forces arising out of a system fault, modern practice is to make use of thermosetting plastics, such as DMC (Dough Moulding Compounds)... 

In the Intoduction to ISO 9001 it states that the quality assurance models represent three distinct forms of quality system suitable for the purpose of a supplier demonstrating its capability and for the assessment of such capability by external parties. In other words, the standard is suitable for contractual as well as for assessment purposes, but it does not actually require demonstration of capability to the assessor or purchaser unless required by the contract. 

Optical fiber cables and fiber optic devices approved as an intrinsically safe system suitable for the hazardous (classified) location involved shall be installed in accordance with Sections 504-20 and 770-52. 

Purification of the activation products (PMs). The methylamine activation product dissolved in methanol is purified by chromatography, first on a column of silica gel using a mixed solvent of chloroform/ethanol, followed by reversed-phase HPLC on a column of divinylbenzene resin (such as Jordi Reversed-Phase and Hamilton PRP-1) using various solvent systems suitable for the target substance (for example, acetonitrile/water containing 0.15% acetic acid). 

Reproducibility of experiments indicates whether measurements are reliable or not under GMP regulations this is used in the systems suitability and the method validation settings. 

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. 

Of all the requirements that have to be fulfilled by a manufacturer, starting with responsibilities and reporting relationships, warehousing practices, service contract policies, airhandUng equipment, etc., only a few of those will be touched upon here that directly relate to the analytical laboratory. Key phrases are underlined or are in italics Acceptance Criteria, Accuracy, Baseline, Calibration, Concentration range. Control samples. Data Clean-Up, Deviation, Error propagation. Error recovery. Interference, Linearity, Noise, Numerical artifact. Precision, Recovery, Reliability, Repeatability, Reproducibility, Ruggedness, Selectivity, Specifications, System Suitability, Validation. 

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. 

The monographs of the European Pharmacopoeia describe a so-called test for related substances which is intended to control the level of impurities. Reference substances may be used in this test in order to ensure the system suitability and/or to control the content of related substances. 

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. 

System suitability information. Minimum requirements for instrument acceptability and any critical operating parameters should be identified. 

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