M. Mulholland

RES, AN EXPERT SYSTEM FOR THE SET-UP AND INTERPRETATION OF A RUGGEDNESS TEST IN HPLC METHOD VALIDATION .1. THE RUGGEDNESS TEST IN HPLC METHOD VALIDATION

Abstract In method validation, an intralaboratory repeatability study and an interlaboratory reproducibility study can be performed as part of a precision test. In HPLC, an intralaboratory ruggedness test can be performed to detect problems that would otherwise be encountered in a reproducibility study. In a ruggedness test, variations in ambient factors that are expected to occur in practice, are simulated. Several steps determine the success of a ruggedness test. The complexity and lack of standard procedures for some of these steps is the main reason why ruggedness testing is still not widely accepted.

Investigation of the limitations of saturated fractional factorial experimental designs, with confounding effects for an HPLC ruggedness test

SummaryRecently much attention has been directed to the validation of analytical methods. The level of validation will depend on the method application. If a method is developed for general use, for instance by different analysts, instruments or laboratories, then the effect of these changes need evaluation. This is normally referred to as ruggedness testing, where the limitations of the method to changes in the specified conditions are examined.This paper examines the use of Plackett-Burman fractional factorial experiment designs for ruggedness testing in high performance liquid chromatography (HPLC). The ability of these designs to identify confounding effects is applied to the stability indicating analysis of Salbutamol and its major degradation product, AH4045. The results show that confounding effects, proving extremely pertinent to HPLC, can be identified.The assay proved rugged to most tested changes although not to the use of column packing material from different manufacturers.

An expert system for the choice of factors for a ruggedness test in liquid chromatography

Abstract Method validation is an important and costly step in the development of liquid chromatographic methods, especially for pharmaceutical samples. A ruggedness test is valuable for finding the analytical conditions which give the best performance. By varying the factors that influence method performance, it is possible to design a more rugged method before a study of reproducibility is started. The choice of the factors to test is important. An expert system is described for the selection of factors in ruggedness tests. The system proved satisfactory for 10 of the 11 cases of pharmaceutical formulations tested.

Expert systems for chemical analysis (ESPRIT Project 1570)

SummaryThis paper gives an overview of the structure and processes going on in the project Expert Systems for Chemical Analysis (ESCA), an international project within the ESPRIT research programme of the European Community. The application area, HPLC method development, is explained and broken down into four domains. The methods used for representing knowledge in the project are discussed.

An overview of contemporary method development in liquid chromatography

SummaryThis paper provides an overview of method development in liquid chromatography. It is explained why every practicing chromatographer needs to understand the process of method development. Thus, this paper is directed towards chromatographers who develop new separation methods, as well as to those who apply published methods. The method-development process is first explained in broad terms, after which the different aspects of the process are described in more detail.First, attention is paid to the initial stages of method development, which consist of the accurate definition of the separation problem and the selection of the most suitable chromatographic method. Method-development expert systems are discussed with regards to their applicability in this area.Selectivity optimization is shown to rely on three main factors,i. e. the selection of the parameter space, the experimental design and the optimization criterion. Selectivity-optimization procedures are described very briefly.System optimization concerns those factors which do not affect the chemistry of the system (mobile and stationary phase), but are essentially determining the analysis time and the sensitivity.The method-validation stage can be divided into three main parts: qualitative method validation (i.e. peak integrity and identity), calibration and quantitative method validation. The requirements of calibration procedures are briefly reviewed and an inventory of method-validation procedures is presented.

RES, an expert system for the set-up and interpretation of a ruggedness test in HPLC method validation: Part 2: The ruggedness expert system

Abstract An expert system is described for the design and diagnosis of the results of a ruggedness test in HPLC method validation. It advises on the selection of relevant factors and an appropriate experimental design and it translates the statistical results into chemically relevant results. If the test fails, the program can advise on how to improve the HPLC method. The basis of the program is a Common Data Structure which represents all objects that are important in HPLC. Linked to this Common Data Structure are modules that manipulate objects. The modules represent major steps in a ruggedness test. An expert system on factor choice and a program on solving resolution problems are integrated in this program as modules. The program is designed to advise on a complete ruggedness test, from factor choice to improvement of the method.

An expert system for designing an intelligent spreadsheet for evaluation of precision of liquid chromatographic methods

Abstract Method validation is increasing in importance as higher standards of precision and accuracy are required. The validation of liquid chromatographic methods requires the examination of selectivity, sensitivity, accuracy, precision and limitations, depending on the purpose of the method. The precision is affected by the repeatability of procedural steps (e.g., injection), within the method and by its overall reproducibility (e.g., interlaboratory reproducibility). The application of spreadsheets with an expert system to evaluate these effects is described. The spreadsheets are programmed to produce the necessary statistics. Rules are defined for the expert system to interact with these to select suitable tests for different applications, to set up spreadsheets into which the analyst inputs the data, and to interpret the data processed in the spreadsheet. The system is tested with a repeatability study of the separation of aspirin and salicylic acid. A combination of the Goldworks software for development of expert systems and the Lotus 1-2-3 spreadsheet package was used.

RES, an expert system for the set-up and interpretation of a ruggedness test in HPLC method validation: Part 3: The evaluation

Abstract Van Leeuwen, J.A., Buydens, L.M.C., Vandeginste, B.G.M., Kateman, G., Cleland, A., Mulholland, M., Jansen, C., Maris, F.A., Hoogkamer, P.H. and Van den Berg, J.H.M., 1991. RES, an expert system for the set-up and interpretation of a ruggedness test in HPLC method validation. Part 3: The evaluation. Chemometrics and Intelligent Laboratory Systems , 11: 161–174. In order to establish the confidence of target users in an expert system, it is important that it has been submitted to a thorough testing procedure. In the case of RES, an expert system on ruggedness testing in HPLC, the testing procedure is divided into two parts: a validation and an evaluation part. In the validation part, the performance of the expert system is measured against the experts performance using simulated test cases. In the evaluation part, the suitability of RES is assessed by evaluators in a real laboratory environment. RES has been evaluated in two laboratories. In one laboratory the emphasis of the evaluation was on the knowledge in RES. In the second evaluation the usability of RES with respect to users who were inexperienced in formalized testing was emphasized. The results and comments of the evaluators are discussed. RES has been found to be useful in practice.

AN EXPERT SYSTEM FOR THE VALIDATION OF HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHIC METHODS

Abstract A method validation expert system, developed as part of Esprit project ESCA, is described. The proper validation of high-performance liquid chromatography methods is an issue of rapidly growing importance. This is due to the increasing demands of good laboratory practice. Since validation involves a lot of statistical calculation and interpretation with which most analysts are not familiar, it is often neglected in the method development process. An expert system that provides this knowledge and experience is therefore very useful.

Expert system for method validation in chromatography

Abstract Validation of chromatographic methods is essential to ensure that a newly developed or implemented method is capable of performing the analysis within the required accuracy and precision. A validation programme consists of the evaluation of precision, accuracy, specificity, sensitivity and limitations such as lifetimes of re-agents and detection limits. These performance characteristics are affected by many contributions, e.g., precision is affected by repeatability and reproductivity. The validation experiments must be designed such that these contributions are tested under the conditions with which the method is likely to be used. The first results of research into the application of expert system technology for method validation are presented. The acquisition and representation of the knowledge are described. The expert system is designed to set up and interpret results from various method validation experiments. The expert system development tool used for the creation of a prototype is Goldworks.