System suitability test parameters

TABLE 2 System Suitability Test Parameters Typically Applied in Testing of Drug Substance and Drug Product Materials... 

System suitability test parameters Reporting data Sample eontinuity... 

The validation of an analytical procedure produces performance parameters of a well-behaved and well-conditioned system/instrument (including defined variations) which are more or less snapshots of the combination procedure/system. In order to routinely confirm the suitability of the integrated measurement instrumentation used with a given procedure, system suitability test parameters should be defined on the basis of the validation results and robustness studies. Larger variations under routine conditions or multiple laboratories should also be taken into consideration. 

System suitability testing is an integral part of many analytical procedures. The tests are based on the concept that the equipment, electronics, analytical operations and samples to be analysed constitute an integral system that can be evaluated as such. System suitability test parameters that need to be established for a particular procedure depend on the type of procedure being evaluated, for instance, a resolution test for an HPLC procedure. 

Each analytical procedure should include the appropriate system suitability tests defining the critical characteristics of that system. Other parameters may be included at the discretion of the applicant. 

In Table 4, an overview is presented of the different experimental parameters of the CE analyses that are included in the analytical instructions part of the specific monographs mentioned above. Notice that the first 13 parameters (from capillary dimensions up to system suitability tests ) are those described in the FDA draft guidance for industry described in paragraph II From this overview it can be concluded that most experimental parameters required by the draft guidance are included in the specific monographs, currently published in the Ph.Eur. and USP. In the monograph for erythropoietin concentrated solution the injection parameters are not included. Only the injection mode (pressure or vacuum) is defined. Instead,... 

Those parameters that are not directly evaluated by system suitability testing during routine analysis must be checked periodically or the risk mitigated in some other way to ensure that the instrument is maintained in a qualified state. However for some critical parameters evaluation as part of the system suitability testing may not be sufficient and specific periodic testing may also be required. 

The system suitability tests are performed to verify that the analytical system meets predefined acceptance criteria at the time of performance. System suitability parameters should be established based on the type of method being considered and before the validation of the method actually starts. A common method of system suitability will request bracketing reference injections, with measurable quantitative acceptance criteria, such a migration time and/or a range on the main peak area. The peak of interest can be the major peak but it can also be a secondary peak, which may give more control over the sample preparation (e.g., the HMW peaks in non-reduced CE-SDS or incomplete reduced in the case of reduced CE-SDS LIE). 

Having optimised the efficiency of a chromatographic separation the quality of the chromatography can be controlled by applying certain system suitability tests. One of these is the calculation of theoretical plates for a column and there are two other main parameters for assessing performance peak symmetry and the resolution between critical pairs of peaks. A third performance test, the peak purity parameter, can be applied where two-dimensional detectors such as diode or coulometric array or mass spectrometry detectors are being used. The reproducibility of peak retention times is also an important parameter for controlling performance. 

System suitability allows the determination of system performance by analysis of a defined solution prior to running the analytical batch. System suitability should test the entire analytical system, chromatographic performance as well as the sensitivity of the mass spectrometer for the compounds of interest. Some LC-MS SOPs reference analytical methods as the source of operating details for a given analysis. This works particularly well for quantitative analysis, where analytical methods include critical details on instrument parameters and special calibrations that might be required for a particular analyte. Thus, system suitability testing provides the daily [3] checking of the system. 

Fit the purpose calibration. It is common sense to check instrument performance each day, and GLP requirements simply formalize the performance and documentation of these checks. On the other hand, it is also important to use the right test (full calibration, verification, system suitability test, or instrument and method validation) to verify the performance and to avoid needlessly lengthy procedures. As already discussed (see Sections 13.2.3 and 13.3.1), it is not always necessary to perform a MS full calibration every day. For example, if a particular MS is used only to record complete full-scan mass spectra, a daily calibration or verification of the calibration of the m/z ratio scale is required. However, in the case where a MS is coupled with an LC and utilized primarily for the analysis of one or more analytes in the selected ion monitoring (SIM) mode, it does not always require a daily verification of the calibration. In this specific case it is quite common in LC-MS and LC-MS/MS applications to test only the following performance parameters (a) sensitivity, (b) system precision,... 

A frequently discussed question is whether either system suitability testing or the analysis of QC samples are sufficient to prove ongoing system performance, or whether additional checks should be performed. The answer to this question depends very much on the conditions under which the control samples are analyzed. For example, if the system is used for trace analysis and the amounts of the control sample do not include trace-level amounts, the capability of the system to measure low amounts should be verified. In HPLC, this could be a routine check of the wavelength accuracy, the baseline noise, and the intensity of the UV lamp. System suitability checks and control sample analysis are sufficient as PQ checks if all critical system parameters are checked as part of tests and evaluations. 

During method validation the parameters, acceptance limits, and frequency of ongoing system suitability tests or quality control checks should be defined. Criteria should be defined to indicate when the method and system are out of statistical control. The goal is to optimize these experiments in such a way that with a minimum number of control analyses the method and the complete analytical system will provide long-term results that will meet the objectives defined in the scope of the method. 

Suggested Analytical Method Use this section to present a complete description of the analytical method sufficiently detailed to enable persons skilled in the art to replicate it. Include all important operational parameters and specific instructions such as reagent preparation, systems suitability tests performance, description of blanks used, precautions, and explicit formulas for calculating test results. 

The extent of the system suitability testing is dependent on, for example, the stage of drug development, the objective of the analytical procedure, the availability of reference substances, etc. The following parameters may be considered " " ... 

TABLE I System Suitability Testing to Continuously Monitor Validation Parameters... 

Additional System Suitability Parameters. Other parameters for system suitability testing can be considered (e.g., capacity factor, number of theoretical plates, etc.). 

The responses of main interest also are different in method development and robustness testing. In development, the considered responses are related to the quality of the separation (l),such as, for electrophoretic methods, migration times, peak shapes, and the resolutions between neighboring peaks. When the separation is optimized and the method is validated, thus also in robustness testing, the responses of main interest are related to the quantitative aspects of the method, such as contents, concentrations, or recoveries. The responses considered during development occasionally are considered in a second instance, for example, as system suitability test (SST) parameters. 

Figure 5.12. A summary report for system suitability testing documenting result i.d., precision, and other system suitability parameters (S/N ratio, tailing factors, plate count, and resolution). Note that means and precision of each table column can be automatically calculated.

System suitability does not assess whether any mistakes have been made in sample preparation. The Centre for Drug Evaluation and Research (CDER) document entitled Validation of Chromatographic Methods defines the parameters associated with system suitability testing as discussed in the following sections. 

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