Method validation introduction

As laboratory accreditation becomes more established, the requirements to demonstrate traceability and to determine uncertainty will inevitably feature as part of method validation (Christensen 1996). The fundamental role which reference materials play in these steps has already been alluded to in the Introduction. 

This chapter has considered two key aspects related to quality assurance - the use of control charts and the evaluation of measurement uncertainty. These activities, along with method validation, require some knowledge of basic statistics. The chapter therefore started with an introduction to the most important statistical terms. 

Spectral imaging is a complex and multidisciplinary field. The introduction of new FPAs is making it increasingly powerful and attractive. It has proven potential in qualitative pharmaceutical analysis and can be used when spatial information becomes relevant for an analytical application. Even if online applications and regulatory method validation require further study, the potential contribution of imaging to quality control and PAT needs no further demonstration. 

Introduction Quality of Analytical Results Role of Method Validation in Traceability and MU Guidelines on Traceability and Uncertainty of Results Concept of Traceability Concept of MU... 

Accreditation is a formal recognition that a laboratory is competent to carry out specific (types of) calibrations or tests [2]. After the use of validated and standardized methods, the introduction and use of appropriate IQC procedures and the participation in PT schemes, accreditation to ISO/IEC 17025 is the fourth basic principle related to laboratory QA in general [4]. Guidelines on the implementation of ISO/IEC 17025, including the estimation of MU (see also Section 8.2.2), are published in the literature and by official accreditation bodies such as Eurachem, CITAC, EA, Eurolab, and ILAC (see Table 1) [2,60, 80, 81,110]. It is worthwile to mention that accreditation, just like participance in PT schemes, does not necessarily indicate good performance of the laboratory [108]. 

This chapter has two aims to demonstrate the necessity of using properly validated and verified methods and to explain what constitutes a validated method, and to provide an introduction to method validation for in-house methods. There is an abundance of published material that defines, describes, and generally assists with method validation, some of which is... 

Method validation is the process of confirming that the analytical procedure employed for a specific analysis is suitable for its intended use. Analytical methods need to be validated or revalidated before their introduction into routine use, or whenever the conditions for which the methods have been validated change. 

There have been over 100 papers published in the scientific literature on validation of methods using CE, including a few review articles [55,56]. For those needing an introduction to the field, the following references are best consulted [57,58], as well as an article on validation of LC methods [59], CE methods validate in the same fashion as LC methods. 

The process for the transfer of analytical methodology is, on the surface, a relatively simple operation. In its most common form, analytical method transfer is the verification that a method or test procedure works in an equivalent fashion at two or more different sites or laboratories and meets all acceptance criteria. This process is driven by compliance and governed by a statistical treatment of the resulting data. This interlaboratory transfer aspect of the overall transfer process has been covered comprehensively by McGonigle, who stressed that successful transfers are linked to the method validation process. Method transfer was defined in this case as the introduction of a validated method into a designated laboratory so that it can be used in the same capacity for which it was originally developed. The second portion of the technology transfer... 

General sample preparation will be discussed in this chapter, but instmment-specihc sample preparation is included in the appropriate chapter on each technique. Method validation and documentation will not be covered as the focus of this text is on instrumentation. The text by Christian cited in the bibliography has an excellent introduction to validation and documentation for the interested student. 

The definition of calibration function does not specify that the measurement be made in the presence of potential interferants. This serves as an introduction to a discussion of the appropriate approach to calibration in an analytical method for veterinary drug residues, such as antibiotics. Construction of a calibration curve requires a sufficient number of standard solutions to define the response in relation to concentration, where the number of standard solutions used is a function of the concentration range. In most cases, a minimum of five concentrations (plus a blank, or zero ) is considered appropriate for characterization of the calibration curve during method validation. It is also typically recommended that the curve be statistically tested and expressed, usually through linear regression analysis. However, for LC/ESI-MS analysis of residues, the function tends to be quadratic. The analytical range for the analysis is usually defined by the minimum and maximum concentrations used in establishing the calibration curve. 

Spectroscopic methods can provide fast, non-destructive analytical measurements that can replace conventional analytical methods in many cases. The non-destructive nature of optical measurements makes them very attractive for stability testing. In the future, spectroscopic methods will be increasingly used for pharmaceutical stability analysis. This chapter will focus on quantitative analysis of pharmaceutical products. The second section of the chapter will provide an overview of basic vibrational spectroscopy and modern spectroscopic technology. The third section of this chapter is an introduction to multivariate analysis (MVA) and chemometrics. MVA is essential for the quantitative analysis of NIR and in many cases Raman spectral data. Growth in MVA has been aided by the availability of high quality software and powerful personal computers. Section 11.4 is a review of the qualification of NIR and Raman spectrometers. The criteria for NIR and Raman equipment qualification are described in USP chapters <1119> and < 1120>. The relevant highlights of the new USP chapter on analytical instrument qualification <1058> are also covered. Section 11.5 is a discussion of method validation for quantitative analytical methods based on multivariate statistics. Based on the USP chapter for NIR <1119>, the discussion of method validation for chemometric-based methods is also appropriate for Raman spectroscopy. The criteria for these MVA-based methods are the same as traditional analytical methods accuracy, precision, linearity, specificity, and robustness however, the ways they are described and evaluated can be different. 

The review of PSI s activities within the framework of the fast reactor physics R D has clearly shown that the main thrust for this work was to contribute to the understanding of the neutron physics characteristics of plutonium burning fast cores. The removal of the fertile blanket zones, the increase in plutonium content and the introduction of a considerable amount of steel surrounding the fissile zones alter both the operational and safety characteristics of such cores, making this data and calulational methods validation effort necessary. 

Method validation and method transfer are distinct processes. Method validation certifies that the method performs in the manner for which it was developed and is the responsibility of the method development laboratory. Method transfer, on the other hand, is the introduction of a validated method into a designated laboratory so that it can be used in the same capacity for which it was originally developed. Accordingly, method transfer criteria should be based on the SOPs which are unique to the designated laboratory. For the essential principles of method transfer, cfr. ref. [69]. Interlaboratory transfer of HPLC methods has been reported [70]. Inter technique validation is equally important. Both in R D and in a production environment, the change from one technology to another must be totally transparent. A sample concentration obtained by a method in one laboratory must be the same as that obtained by another method in another laboratory. 

With the introduction of the first commercial UHPLC system in 2005, pharmaceutical laboratories rushed to investigate whether these high-pressure systems would truly offer efficiencies that would result in a greater ability to resolve difflcult-to-separate matrices. The systems were introduced because of their enhanced separation efficiencies, not solely for a reduction in mobile phase usage or analysis times. These benefits were welcome bonuses. Scientists looked to develop straightforward ways to convert existing methods validated on 3 pm, 4.6 mm i.d. columns to the new UHPLC standard. The use of UHPLC enabled improved efficiencies in pharma (2-13) as well as in environmental (14-16) applications. 

A sin that is casually committed under routine conditions is to once and for all validate an analytical method at its introduction, and then to assume a s 0 thus, X( y ) would be calculated from the measurement of a reference. 

Apart from innovative work, RMs are essential during exerdses such as the introduction to a laboratory of a method from elsewhere or the transfer of an established method onto new instrumentation. Even where the conditions for the analysis have been standardized by the manufacturer of a reagent kit, some validation work should still be undertaken so as to have documented data for quality assurance purposes, e.g. accreditation, as a basis for IQC, for later reference when problems which may be related to equipment, reagents or staff etc. need to be investigated. 

In this paper a method [11], which allows for an a priori BSSE removal at the SCF level, is for the first time applied to interaction densities studies. This computational protocol which has been called SCF-MI (Self-Consistent Field for Molecular Interactions) to highlight its relationship to the standard Roothaan equations and its special usefulness in the evaluation of molecular interactions, has recently been successfully used [11-13] for evaluating Eint in a number of intermolecular complexes. Comparison of standard SCF interaction densities with those obtained from the SCF-MI approach should shed light on the effects of BSSE removal. Such effects may then be compared with those deriving from the introduction of Coulomb correlation corrections. To this aim, we adopt a variational perturbative valence bond (VB) approach that uses orbitals derived from the SCF-MI step and thus maintains a BSSE-free picture. Finally, no bias should be introduced in our study by the particular approach chosen to analyze the observed charge density rearrangements. Therefore, not a model but a theory which is firmly rooted in Quantum Mechanics, applied directly to the electron density p and giving quantitative answers, is to be adopted. Bader s Quantum Theory of Atoms in Molecules (QTAM) [14, 15] meets nicely all these requirements. Such a theory has also been recently applied to molecular crystals as a valid tool to rationalize and quantitatively detect crystal field effects on the molecular densities [16-18]. 

In vitro tools could be used alone or in test batteries with increased potency of the description of cellular events and changes. The chapter provides a brief introduction on the components of an in vitro system, the main differences between models for research and models for testing and a list of validated alternative methods according to the European Centre for the Validation of Alternative Methods (ECVAM) (http // ecvam.jrc.it/, http //ecvam.jrc.ec.europa.eu/) evaluation. 

Member States shall ensure that the validation of methods of analysis used within the context of official control of foodstuffs by the laboratories referred to in Article 7 of Directive 89/397/EEC comply whenever possible with the provisions of paragraphs 1 and 2 of the Annex to Council Directive 85/591/EEC of 23 December 1985 concerning the introduction of Community methods of sampling and analysis for the monitoring of foodstuffs intended for human consumption.7... 

This book is the result of a cooperation between a chemometrician and a statistician. Usually, both sides have quite a different approach to describing statistical methods and applications—the former having a more practical approach and the latter being more formally oriented. The compromise as reflected in this book is hopefully useful for chemometricians, but it may also be useful for scientists and practitioners working in other disciplines—even for statisticians. The principles of multivariate statistical methods are valid, independent of the subject where the data come from. Of course, the focus here is on methods typically used in chemometrics, including techniques that can deal with a large number of variables. Since this book is an introduction, it was necessary to make a selection of the methods and applications that are used nowadays in chemometrics. 

Note Sample introduction systems such as reservoir inlets, chromatographs, and various types of direct probes (Chap. 5.3) are of equal importance to other ionization methods. The same holds valid for the concepts of sensitivity, detection limit, and signal-to-noise ratio (Chap. 5.2.4) and finally to all sorts of ion chromatograms (Chap. 5.4). 

Francl et al. (1996) examined the conditioning of the least squares matrix in the fitting procedure, and conclude that the method cannot be used to assign statistically valid charges to all atoms in a given molecule. This problem cannot be alleviated by the selection of more sampling points, and thus may require the introduction of chemical constraints to reduce the number of charges to be determined. 

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