Method validation definition

Independent reference methods - one organization Two or more independent reference methods, each based on an entirely conceptually different principle of measurement, independent in theory and experimental procedure, applied in replicate, within a single organization, of the highest reputational quality, by two or more expert analysts, working independently. The methods used can, naturally, include definitive methods, and the results should be corroborated by a third or additional, independently different, accurately characterized, well established, thoroughly validated, definitive, reference, or other methods. 

The integration of analytical methods in European standards requires their acceptance by several national experts within special working groups and in a final weighted vote of National Standards Bodies. Therefore, there needs to be very high confidence in the performance of methods. Consequently, methods should be tested in inter-laboratory method validation studies, with the exception of those multiresidue methods which are widely used throughout Europe. In the case of CEN methods there is no doubt about residue definition but detailed requirements about the number of matrices and concentration levels in validation experiments do not exist. Eor this reason it may be that CEN methods are validated for important crops only. 

ECVAM is the leading international center for alternative test method validation. Hartung et al. (29) summarized the modular steps necessary to accomplish stage 3 (test validation). The seven modular steps are (I) test definition, (2) within-laboratory variability, (3) transferability, (4) between-laboratory variability, (5) predictive capacity, (6) applicability domain, and (7) performance standards (29). Steps 2-4 evaluate the test s reliability steps 5 and 6 evaluate the relevance of the test. Successful completion of all seven steps is necessary to proceed to stage 4 (independent assessment or peer review). This modular approach allows flexibility for the validation process where information on the test method can be gathered either prospectively or retrospectively. The approach is applicable not only to in vitro test methods but also to in silico approaches (e.g., computer-based approaches such as quantitative structure-activity relationships or QSAR) and pattern-based systems (e.g., genomics and proteomics). 

A ruggedness test is a part of method validation (Table 3.1) and can be considered as a part of the precision evaluation [2,4,5]. Ruggedness is related to repeatability and reproducibility. Some definitions for ruggedness come very close to those for reproducibility. Certain interpretation methods to identify the significant factors in a ruggedness test use criteria based on results for repeatability or reproducibility. These two items will be considered in Section 3.4.7. 

It is important to issue a common understanding on the topics of method validation, traceability, and uncertainty of measurements. Here, the interrelationships between method validation, traceability, and MU of results will be elucidated. Throughout the landscape of guidelines and standards, the most relevant information is selected, compiled, and summarized. Great importance is attached to the different method performance parameters and their definitions, ways of expression, and approaches for practical assessment. We discuss the role of method validation within QA as well as the topics of standardization, internal and external quality control (IQC and EQC, respectively), and accreditation and the links between these different aspects. 

Traceability and MU both form parts of the purpose of an analytical method. Validation plays an important role here, in the sense that it confirms the fitness-for-purpose of a particular analytical method [4]. The ISO definition of validation is confirmation by examination and provision of objective evidence that the particular requirements of a specified intended use are fulfilled [7]. Validation is the tool used to demonstrate that a specific analytical method actually measures what it is intended to measure and thus is suitable for its intended purpose [2,11]. In Section 8.2.3, the classical method validation approach is described based on the evaluation of a number of method performance parameters. Summarized, the cri-teria-based validation process consists of precision and bias studies, a check for... 

Method validation is a term used for the suite of procedures to which an analytical method is subjected to provide objective evidence that the method, if used in the manner specified, will produce results that conform to the statement of the method validation parameters. Like many aspects quality assurance, method validation is of a relative nature. As with the concept of fitness for purpose, a method is validated for a particular use under particular circumstances. If those circumstances vary, then the method would need to be re-validated at least for the differences. Common sense should be used, and the analysts should use his or her skill and experience to decide what aspects of a method require validation and to what extent. The goal of satisfying client requirements is prominent in most published definitions of method validation, some of which are listed below ... 

Bioanalytical method validation and definition of the acceptance criteria for the analytical run and/or batch... 

Analytical methods validation—As mentioned earlier, a good CVMP should allow the analytical method to develop concurrently with the product formulation, thus in the early stages of development, an analytical method may not be fully validated but may still be used for cleaning tests as the best available method. At the time of the PAI, however, and definitely by the time the formal cleaning validation occurs, a fully validated analytical method should be developed. This methods validation package should include all the standard parameters, with special attention to the sensitivity of the analytical method as expressed by the limit of detection (LOD) and... 

By one convention, illustrated in Fig. 3, the validation of a measurement method, as replicated in the field, succeeds if the certified value of an appropriate RM falls within the estimated measurement uncertainty when the RM is measured using the method. That definition of validation does not require a mutual conformance condition in which the two values (that deter-... 

Some chemists feel that the mole is an unnecessary SI unit as they make measurements in mass/mass or mass/ volume units, using ratio methods. The definition and the importance of the mole has been discussed elsewhere [8], and the distinction has been made between its importance as a concept, the importance of the related atomic mass values, and the lesser role of the mole as a unit for actually reporting results. A distinctive feature of the mole is the need to define the entity . This is an extra dimension compared with other SI units. For example, it is not necessary to ask, is this a mass when measuring the mass of an object, in the way that it is critical to ask, is this lead before attempting to measure the amount of lead. A mole measurement thus requires two issues to be addressed, namely identity and amount. It follows therefore that traceability claims must show unbroken chains covering both of these issues. It is because of the existence of a vast number of chemical species that it is necessary to clearly specify and separate the specified chemical entities from all other possible chemical entities prior to measurement. This leads to complex chemical measurement processes, with considerable attention to validation of the measurement method being required. 

Shah VP, Midha KK, Findlay JW et aL (2000) Bioanalytical Method Validation - A Revisit with a Decade of Progress. Pharmaceutical Research 17 1551-1557 CPMP/ICH/381/95 (1994) EEC Note for Guidance on Validation of Analytical Procedures Definitions and Terminology. London UK... 

For analytical method validation during full development (after final synthesis has been set for drug substance and after final market formulation has been set for drug product) corresponding to the definitive control procedure for new drug application (NDA), a specific validation protocol has to be written. Before start of the experimental work, the protocols must be written... 

The main characterizing strategies are the multivariate approach to the problem, searching for relevant information, model validation to build models with predictive power, comparison of the results obtained by using different methods, and definition and use of indices capable of measuring the quality of extracted information and the obtained models. 

There are no detailed recommendations for analytical procedures in the field of biotechnological production of drugs, in contrast to the recommendations made by the FDA for bioanalytical methods [16], The absence of detailed guidelines for analytical method validation in this field is surprising. It is important to validate the quantification of both substrate and product during the process, at definite time intervals, to ensure proper calculation of the kinetics of the process i.e., the coefficients of substrate conversion, and production rates must be adequately calculated. The aim of the study in pa-... 

The first problem encountered when studying literature on method validation are the different sets of terminology employed by different authors. A detailed discussion of this problem can be found in the review of Hartmann et al. [9], Therein, it was proposed to adhere, in principle, to the terminology established by the ICH [13], except for accuracy, for which the use of a more detailed definition was recommended (cf. Accuracy). However, the ICH terminology lacked a definition for stability, which is an important parameter in bioanalytical method validation. Furthermore, the ICH definition of selectivity did not take into account interferences that might occur in bioanalysis (e.g. from metabolites). For both parameters, however, reasonable definitions were provided by Conference Report II [10]. 

Analysts and end users of the measurement results should be aware of the new dimension of the procedure validation definition given in ISO/IEC 17025, which requires that a procedure s performance parameters are fit for a specific intended use. In other words this means that the work of an analyst is not finished when performance capabilities of a specific method (or preferably procedure ) are evaluated, but he/she has to go a step further and check whether these characteristics are in compliance with the client s needs. Of course, it is up to the client to specify his/her re-quirements/properties the result should have. Furthermore, ISO/IEC 17025 is introducing evaluation of measurement uncertainty as a mean of performing validation through systematic assessment of all quantities influencing the result. 

In the validation process an estimate is made of the representativeness, repeatability and reproducibility of the test method. The definitions are given in annex 1. 

This article deals with legal requirements in the European Union on basic principles of laboratory quality assurance for official notification to the EC Commission and on method validation concerning official laboratories. Widespread discussions and activities on measurement uncertainty are in progress, and the European validation standards for official purposes may serve as a basis for world-wide efforts on quality harmonization of analytical results. Although much time has already been spent, definitions and require-... 

The practical meaning of this measurement structure has been discussed by Tietz. The highest quality methods, the definitive methods, are to be used to validate reference methods and primary reference materials. The highest quality reference materials, namely primary reference materials, should be used in the development and validation of reference methods, the calibration of definitive and reference methods, and the production of secondary reference materials. Reference methods should be used to validate field methods. Secondary reference materials should be used to provide working calibrators for field methods and to assign values to control materials. Control materials are used only to monitor field methods. 

It is important to define the terms used in regulatory guidelines when discussing method validation. In the following definitions, the italic portions are quoted directly from the ICH guideline. ... 

Method transfer is loosely defined as a process that qualifies a laboratory to use a test procedure or analytical method. According to this definition, any and all means of having a laboratory qualified would meet the criteria for transfer. The most common variations of method transfer are comparative testing, covalidation between two laboratories or sites, complete or partial method validation or revalidation, and the omission of formal transfer processes, sometimes termed the transfer waiver. ... 

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