Analytical performance requirements

Factors to consider in the choice of an analytical method for a pharmaceutical product include the chemical and physical nature of the drug and its impurities, the matrix in which it exists, the purpose of the analysis, and the analytical performance required. Different methods may be necessary to quantify impurities with different physicochemical properties. 

Laser based mass spectrometric methods, such as laser ionization (LIMS) and laser ablation in combination with inductively coupled plasma mass spectrometry (LA-ICP-MS) are powerful analytical techniques for survey analysis of solid substances. To realize the analytical performances methods for the direct trace analysis of synthetic and natural crystals modification of a traditional analytical technique was necessary and suitable standard reference materials (SRM) were required. Recent developments allowed extending the range of analytical applications of LIMS and LA-ICP-MS will be presented and discussed. For example ... 

Designing products is usually performed based on experience since most products only require a practical approach (Fig. 1-4). Experience is also used in producing new and complex shaped products usually with the required analytical evaluation that involves stress-strain characteristics of the plastic materials. Testing of prototypes and/or preliminary production products to meet performance requirements is a very viable approach used by many. 

The performance may be described in terms of a number of theoretical parameters, although the performance required for a particular analysis will depend upon the separation that is required. This, in turn, depends upon the similarity in the behaviour in the chromatographic system of the analyte(s) of interest to each other and to other compounds present in the mixture. 

The premarket notification application, 510(k), is reviewed by the FDA scientific staff. This evaluation takes into consideration tumor-associated analytes, test requirements, medical usefulness of the test system for a particular clinical claim, and its application (i.e., monitoring or treatment follow-up). The FDA determines the appropriate performance requirements for each tumor analyte category. The agency s staff considers factors, such as consequences of a false positive or false negative, and the importance or impact of an absolute versus a significant change in the results or values of the tumor marker tests. The performance criteria (parameters) of a particular tumor marker test are compared with those of previously... 

An inner filling solution and internal reference electrode are used in macro ISEs due to a very good stability of the potential at the inner membrane-solution interface in such a setup (see Fig. 4.4). However, the presence of a solution inside a sensor could be a serious limitation for development of microelectrodes and may be undesired for a variety of other reasons, including ionic fluxes in the membrane and limited temperature range of sensor operation. There are several requirements for such an inner contact. First of all, a reversible change of electricity carriers ions-electrons must take place at the membrane-substrate interface. The potential of the electrochemical reaction, ensuring this transfer, has to be constant, stable, and must not depend on the sample composition. At last, the substrate must not influence the membrane analytical performance. 

FDA device regulation is focused on the device and the device manufacturer. CLIA, on the other hand, focuses on laboratory quality, including the quality of the laboratory test results provided by the devices used, whether developed in-house or as a test kit in commercial distribution to multiple laboratories. The programs differ substantially in approaches and in data requirements. FDA requires unique submissions for each test under its purview, evaluates both performance and labeling, and requires demonstration of analytical validity and clinical validity as appropriate. CLIA inspects laboratories using a system approach based on key probes of the operating system. CLIA requires a demonstration of analytical performance and quality control but does not require a showing of either clinical validity or clinical utility. 

FDA routinely requires analytical data on tests under review to demonstrate that they measure what they claim to measure. Analytical performance is usually directed at evaluating a test s accuracy or bias compared with a predicate or reference test, precision or repeatability, and analytical specificity and analytical sensitivity. 

Sample preparation for analysis by hyphenated methods requires some additional planning when compared to nonhyphenated methods. All steps, extraction, concentration, and final solvent selection must take into consideration and be compatible with all the components of the hyphenated instrumentation. For gas chromatographic methods, all the components in the mixture must be in the gaseous state. For liquid chromatography (LC) or high-performance liquid chromatography (HPLC), the samples of the analytes of interest can be solids or liquids, neutral or charged molecules, or ions, but they must be in solution. If the follow-on analysis is by MS, then each of the analytes may require a different method of introduction into the MS. Metals and metal ions may be introduced by HPLC if they are in solution but commonly are introduced via AAS or inductively coupled plasma (ICP). Other analytes may be directly introduced from HPLC to MS [2],... 

The FSA undertakes surveillance exercises, the data for which are acquired from analytical determinations. The Agency will take measures to ensure that the analytical data produced by contractors are sufficient with respect to analytical quality, i.e. that the results obtained meet predetermined analytical quality requirements such as fitness-for-purpose, accuracy and reliability. Thus when inviting tenders FSA will ask potential contractors to provide information regarding the performance requirements of the methods to be used in the exercise, e.g. limit of detection, accuracy, precision etc., and the quality assurance measures used in their laboratories. When presenting tenders, laboratories should confirm how they comply with these specifications and give the principles of the methods to be used. These requirements extend both to the laboratory as a whole and to the specific analytical determinations being required in the surveillance exercise. The requirements are described in three parts, namely ... 

The increased availability of kits has greatly reduced the necessity for individual laboratories to develop their own methods. It is a requirement that all kits are validated before they can be sold and that details of the expected analytical performance are included with the product. Nevertheless, each laboratory is responsible for its own results and staff should ensure that the manufacturer s instructions are followed and that they are satisfied with all aspects of any kit that they use. This may necessitate checks on the quoted analytical performance being made. 

The development and use of appropriate analytical models require not only knowledge of the kinetic parameters involved but also of the mechanisms of the participating reactions. As such, the studies performed addressed both these aspects. 

As with any process analytical application, instrument selection is based on the required analytical merits (sensitivity, dynamic range, precision and accuracy, etc.), process and enviromnental conditions, integration complexities (mechanical and controls automation) and operational and maintenance requirements. Because of the wide disparity in analytical performance and functionalities among photometric and spectroscopic LIE process instruments, selection should be carefully weighed on the basis of the technical problem, instrumental cost, implementation complexities, ease of use, conunercial and legacy maturity, level of vendor support and cost of ownership. 

Task Analysis— An analytical process for determining the specific behaviors required of the human components in a man-machine system. It involves determining the detailed performance required of people and equipment and the effects of environmental conditions, malfunctions, and other unexpected events on both. Within each task to be performed by people, behavioral steps are analyzed in terms of (i) the sensory signals and related perceptions, (ii) the decisions, memory storage, and other mental processes, and (iii) the required responses. 

While methods validation and accuracy testing considerations presented here have been frequently discussed in the literature, they have been included here to emphasize their importance in the design of a total quality control protocol. The Youden two sample quality control scheme has been adapted for continuous analytical performance surveillance. Methods for graphical display of systematic and random error patterns have been presented with simulated performance data. Daily examination of the T, D, and Q quality control plots may be used to assess analytical performance. Once identified, patterns in the quality control plots can be used to assist in the diagnosis of a problem. Patterns of behavior in the systematic error contribution are more frequent and easy to diagnose. However, pattern complications in both error domains are observed and simultaneous events in both T and D plots can help to isolate the problems. Point-by-point comparisons of T and D plots should be made daily (immediately after the data are generated). Early detection of abnormal behavior reduces the possibility that large numbers of samples will require reanalysis. 

Flow Rate Accuracy. One of the key performance requirements for the pump module is the ability to maintain accurate and consistent flow of the mobile phase. This is necessary to provide stable and repeatable interactions between the analytes and the stationary phase [8,9]. Poor flow rate accuracy will affect the retention time and resolution of the separation. The flow-rate accuracy of the pump can be evaluated simply by calculating the time required to collect a predetermined volume of mobile phase at different flow rate settings. For example, the flow-rate accuracy at 2 mL/min can be verified by using a calibrated stopwatch to measure the time it takes to collect 25 mL of effluent from the pump into a 25-mL volumetric flask. A calibrated flow meter can be used to determine the flow rate as well. The typical acceptance of the flow rate accuracy is listed in Table 11.1. A steady backpressure may be required, depending on the requirement of the system. 

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