Robustness, of analytical method

In analytical chemistry, validation of the analytical methods is of utmost importance [4,5]. One of the aspects of this validation is the robustness of analytical methods against variations in experimental circumstances. The term experimental circumstances is very broad it might even include inter-laboratory variation. In this book, only intra-laboratory experimental conditions are considered. No explicit attention is given to inter-laboratory variations, although some of the presented methodology might be useful in that area. 

Y. Vander Heyden and D.L. Massart. in Robustness of Analytical Methods and Pharmaceutical Technological Products, Elsevier. 1996, p. 79. 

Volume 18 Signal Treatment and Signal Analysis in NMR, edited by D.N. Rutledge Volume 19 Robustness of Analytical Chemical Methods and Pharmaceutical Technological Products, edited by M.W.B. Hendriks, J.H. de Boer and A.K. Smilde Volume 20A Handbook of Chemometrics and Qualimetrics Part A, by D.L. Massart, B.G.M. 

It should be noted that all requirements listed in Table 10 apply to an individual analyte-matrix combination. There are no specific demands or proposals for investigations of the infiuence of various sample materials. This procedure does propose the study of other matrices together with further parameters infiuencing robustness of the method. 

All aspects in the analytical process are equally important, and each step should be isolated in method development experiments and/or validation to ensure acceptable quality of results. A good way to evaluate robustness of a method is to alter parameters (e.g., solvent volumes, temperature, pH, sources of reagents) of each step to determine... 

Hendricks MMWB, de Boer AH, Smilde AK (1996) Robustness of analytical chemical methods and pharmaceutical technological products. Elsevier, Amsterdam... 

Some important parameters for testing the robustness of TLC methods include the stability of analyte in the solution being analyzed and on the plate before and... 

When performing dissolution testing, there are many ways that the test may generate erroneous results. The testing equipment and its environment, handling of the sample, formulation, in situ reactions, automation and analytical techniques can all be the cause of errors and variability. The physical dissolution of the dosage form should be unencumbered at all times. Certain aspects of the equipment calibration process may show these errors as well as close visual observation of the test. The essentials of the test are accuracy of results and robustness of the method. Aberrant and unexpected results do occur, however, and the analyst should be well trained to examine all aspects of the dissolution test and observe the equipment in operation. 

Test methods used in the laboratory are generally derived from pharmacopoeias such as the US Pharmacopoeia, British Pharmacopoeia, or European Pharmacopoeia. For test methods that are not from recognized pharmacopoeias, validation of the analytical methods is required. The validation includes testing for accuracy, specificity, ruggedness, robustness, precision, detection limit, quantitation hmit, and range. A discussion of analytical methods vahda-tion is presented in Section 9.6.5. 

The ICH guidelines define robustness as The robusmess of an analytical procedure is a measure of its capacity to remain unaffected by small, but deliberate variations in method parameters and provides an indication of its reliability during normal usage.Thus, the robustness of a method is a measure of its capacity to be transferred to another laboratory without affecting the analytical result. A robustness test is the experimental setup applied to evaluate the robustness of the method. The ICH guidelines also state that One consequence... 

Mulholland, M. (1996). Ruggedness tests for analytical chemistry. In Robustness of Analytical Chemical Methods and Pharmaceutical Technological Products (M. W. B. Hendriks, J. H. de Boer, and A. K. Smilde, Eds), pp. 191-232, Elsevier, Amsterdam. 

The fact that the EP wants to replace old TEC methods with more selective, efficient, and sensitive separation methods provides the chance for the introduction of more CE methods. The continuous development of analytical methods is reflected in the national and international pharmacopoeias. This might be demonstrated for atropine sulfate. Whereas the Deutsches Arzneibuch, 7th Edition (DAB 7) only limits the tropic acid by extraction and titration with NaOH and phenolphthalein indication, the 4th edition of the EP looked for foreign alkaloids and decomposition products by means of TEC with a potassium iodobismuthate for detection. By intensity comparison of the obtained spots, it was possible to limit these impurities to 0.5%. The EP 5 utilizes an ion-pair HPLC method that is able to limit most of the impurities to less than 0.2%. To make the method more robust, an HPLC method using a polar embedded was applied, which might be the next step for the EP. However, recently the same authors have reported on a MEEKC method being as robust and precise as the latter HPLC method (see Eigure 6) but far more sensitive and, therefore, a future perspective for the EP. 

The first two points are best dealt with as part of the process for developing vahdated analytical methods. Vafidation should include testing the robustness of a method in repeated use over a period of time determining the precision and accuracy and study of potential interferences. As an example, it would be expected that in the capillary GC—TEA method for organic explosives, a peak should be at least three times the basefine noise to be counted as a real signal, and that the relative retention time should be within 1.0% of the standard for volatile compounds and within 0.5% for the rest. The relative retention time is simply the ratio of the analyte s retention time compared with that of an internal standard. Use of relative retention times significantly improves the repeatabdity of GC analysis... 

Robustness of analytical chemical methods and pharmaceutical technological products... 

Typical parameters that are generally considered most important for validation of analytical methods are specificity, selectivity, precision, accuracy, extraction recovery, calibration curve, linearity, working range, detection limit, quantification limit, sensitivity, and robustness. 

The evaluation of robustness should be considered during the developmental phase of a method and depends on the type of procedure under study. If measurements are susceptible to variations in analytical conditions, the analytical conditions should be suitably controlled or a precautionary statement should be included in the procedure. Once tire robustness of a method has been established,... 

Jones SP. Stability and response surface methodolgy. In Hendriks MMWB, DeBoer JH, Smilde AK, eds. Robustness of Analytical Chemical Methods and Pharmaceutical Technological Products. Amsterdam Elsevier, 1996 11-77. 

In the article of Kaarls and Quinn [34] primary methods are carefully defined as methods for the determination of the amount of substance in pure or simple compound systems, i.e. in samples which do not contain impurities acting as potential interferences. It is explicitly stated that it is a future task of the CCQM to investigate the applicability and robustness of these methods for complex mixtures encountered in practical analytical chemistry. Many other papers (e.g. [36]), however, tend to identify primary methods already as methods of analysis (to be used on complex samples of unknown overall composition). This over-optimistic (and unwarranted) enlargement of the definition implies that all titrimetric methods of analysis would be considered as primary methods putting aside any interference that occurs in complex samples. Considering all possible sources of error that may occur in both the stoichiometry of the reaction and with the determination of the equivalence point of a titration, this cannot be possible. Neither was this the intention of the CCQM. 

Analytical methods are validated by investigating the specificity, sensitivity, detection limits, quantification limits, accuracy (of the individual result), precision (variation between different tests), applicability and practicability under laboratory conditions and the robustness (susceptibility to interference) of the method. This enables the organization itself to employ these tests much more consciously and with better results, but it also serves the purpose of enabling the registration authorities to use these tests for the regular batch control tests. Official guidelines by the regulatory authorities for the validation of analytical methods and processes are available for consultation. 

Zbinden, P., Audrey, D. Determination of trace element contaminants in food matrixes using a robust, routine analytical method for ICP-MS. At. Spectrosc. 19, 214—219 (1998)... 

Bosque-Sendra, J.M. Nechar, M. Cuadros Redriguez, L. Decision protocol for checking robustness with previous outlier detection in the validation of analytical methods. Fresenius J. Anal Chemie 1999, 365, 480-488. 

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