Robustness study

Model validation is a process that involves establishing the predictive power of a model during the study design as well as in the data analysis stages. The predictive power is estimated through simulation that considers distributions of PK, PD, and study-design variables. A robust study design will provide accurate and precise model-parameter estimations that are insensitive to model assumptions. 

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. 

Berzas Nevado, J. J., Guiberteau Cabanillas, C., Villasenor Llerena, M. J., and Rodriguez Robledo, V. (2005). Enantiomeric determination, validation and robustness studies of racemic citalopram in pharmaceutical formulations by capillary electrophoresis. /. Chromatogr. A 1072(2), 249—257. 

Le Mapihan, K., Vial, J., and Jardy, A. (2004). Reversed-phase liquid chromatography column testing robustness study of the test.. Chromatogr. A 1061, 149—158. 

Destandau, E., Vial, J., Jardy, A., Hennion, M.-C., Bonnet, D., and Lancelin, P. (2006). Robustness study of a reversed-phase liquid chromatographic method for the analysis of carboxylic acids in industrial reaction mixtures. Anal. Chim. Acta 572, 102—112. 

Review of the quality of data, identification of data gaps, preparation of SIDS Dossiers including Robust Study Summaries and SIDS Testing Plans... 

Once all the data elements of the SIDS for the sponsored chemical (a full SIDS chemical) have been obtained, the SIDS Initial Assessment Report (SIAR) is prepared based on the information in the full SIDS Dossier, including the robust study summaries (Section 2.3.1.4). The SIAR draws conclusions on the potential hazard(s) and recommendations on the need for further work. 

EC) No. 440/2008, (43)). Deviations from the standard protocols should be reported in the robust study summary. Moreover, if a study does not comply with any specific guideline, all relevant information on the study design should be included in the summary so that the regulator can make conclusions on the reliability and significance of the study. 

ECHA (2010) Practical guide 3 How to report robust study summaries. ECHA-10-B-06-EN... 

Method validation covers a number of aspects of an analytical method that have already been evaluated in the course of development and use. The values of the calibration parameters must be known to use the method to analyze a particular sample, and any serious deviations from the measurement model should have been discovered. In addition, however, every method should undergo a robustness study as the practicality of the method may ultimately depend on how rugged it is. 

In a robustness study the parameters to be investigated are systematically changed and the effects on the result of the analysis are measured. The steps in such a study are shown in table 8.5. 

Figure 8.11. A hypothetical effect of changing pH on the result of an analysis, as the subject of a robustness study, (a) Inappropriate choice of levels leading to an apparent lack of effect, (b) A more sensible choice with a significant main effect being calculated.

Intermediate Precision. Intermediate precision expresses within-laboratory variation and is generally performed on different days using different analysts, equipment, and sample preparations. This test may not be applicable if the laboratory has only one workstation. Additionally, this test may not be appropriate for automated workstations that are operating under the same environment and controls within a laboratory. This assumption is made on the basis that the automated workstations are identical (i.e., same configuration, same software and hardware) and that they have been suitably qualified and maintained to a consistent standard and operate under a similar climatic environment. The influence of the analyst is reduced to the preparation of solvents, and this should be covered by the robustness studies. 

Saturated Designs Plackett-Burman Designs. Use in Screening and Robustness Studies... 

Borkowski, J. J. and Lucas, J. M. (1997). Designs of mixed resolution for process robustness studies. Technometrics, 39, 63-70. 

Deliberate variations in the parameters of a procedure will provide an estimate of its reliability in routine use. The extent of robustness studies will depend upon the type of method but this evaluation should be considered during the development phase. 

If the robustness studies indicate that the experimental data are susceptible to variations in the method... 

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. 

Operating ranges should be defined for each method based on experience with similar methods, or they should be investigated during robustness studies. Availabihty of such operating ranges makes it easier to decide when a method should be revalidated. Part or full revalidation may also be considered if SST or the results of quality control sample analysis are out of preset acceptance criteria and the source of the error cannot be tracked back to instruments or anything else. 

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