Analytical procedure validation characteristics

The guideline states that the objective of validation is to demonstrate that an analytical method is fit for its purpose and summarizes the characteristics required of tests for identification, control of impurities and assay procedures (Table 13-2). As such, it applies to chiral drug substances as to any other active ingredients. Requirements for other analytical procedures may be added in due course. 

Table 13-2. Characteristics of analytical procedures requiring validation (indicated by a tick).

Analytical methods, particularly those used by accredited laboratories, have to be validated according to official rules and regulations to characterize objectively their reliability in any special field of application (Wegscheider [1996] EURACHEM/WELAC [1993]). Validation has to control the performance characteristics of analytical procedures (see Chap. 7) such as accuracy, precision, sensitivity, selectivity, specificity, robustness, ruggedness, and limit values (e.g., limit of detection, limit of quantitation). 

Selectivity and specificity are important performance characteristics of analytical procedures, especially in connection with validation processes. Nevertheless, both terms are used mostly verbal and a quantification is avoided, as a rule (IUPAC see Vessman et al. [2001]). Moreover, the concepts of selectivity and specificity are used interchangeably and synonymously. Occasionally, specificity is regarded as an intensification of selectivity, viz. the ultimate of selectivity (den Boef and Hulanicki [1983] Persson and Vessman [1998, 2001] Prichard et al. [2001]). 

Analytical data generated in a testing laboratory are generally used for development, release, stability, or pharmacokinetic studies. Regardless of what the data are required for, the analytical method must be able to provide reliable data. Method validation (Chapter 7) is the demonstration that an analytical procedure is suitable for its intended use. During the validation, data are collected to show that the method meets requirements for accuracy, precision, specificity, detection limit, quantitation limit, linearity, range, and robustness. These characteristics are those recommended by the ICH and will be discussed first. 

Validation is the process of proving that a method is acceptable for its intended purpose. It is important to note that it is the method not the results that is validated. The most important aspect of any analytical method is the quality of the data it ultimately produces. The development and validation of a new analytical method may therefore be an iterative process. Results of validation studies may indicate that a change in the procedure is necessary, which may then require revalidation. Before a method is routinely used, it must be validated. There are a number of criteria for validating an analytical method, as different performance characteristics will require different validation criteria. Therefore, it is necessary to understand what the general definitions and schemes mean in the case of the validation of CE methods (Table 1). Validation in CE has been reviewed in references 1 and 2. The validation of calibrations for analytical separation techniques in general has been outlined in reference 3. The approach to the validation of CE method is similar to that employed for HPLC methods. Individual differences will be discussed under each validation characteristic. 

ISO defines validation as Conformation by examination and provision of objective evidence that the particular requirements for a specified intended use are fulfilled. This is decided by using a number of performance characteristics. These are specificity, linearity, range, accuracy, precision, detection limit (DL), quantitation limit (QL), and robusmess. System suitability testing (SST) is an integral part of many analytical procedures. Definitions of these terms based on the recommendations of the ICH Guideline Q2 (Rl) are given in Table... 

The USP requirements for assay validation are very close to the ICH proposal. Here, three categories are distinguished. Category I corresponds to ICH assay, category II corresponds to ICH determinations of impurities. The additional category III includes analytical methods for the determination of performance characteristics (e.g., dissolution, drug release). For this category, the ICH assay characteristics are always sufficient. The objective of the analytical procedure... 

Validation of an analytical procedure is the process by which it is established, by laboratory studies, that the performance characteristics of the procedure meet the Ill... 

Typical analytical performance characteristics that should be considered in the validation of the types of procedures described in this chapter are listed below. Each validation characteristic is defined to ensure consistency in usage of terminology and interpretation ... 

Validation is needed to demonstrate that the analytical method complies with established criteria for different performance characteristics [82]. When these different characteristics are being evaluated individually, this is generally done for the analytical method as such—where the input is the purified or isolated analyte and the output is the analytical result. However, MU covers the whole analytical procedure, starting from the original sample lot. The assessment of MU (see Section 8.2.2) is in line with the so-called modular validation approach. Modular validation refers to the modularity of an analytical procedure divided up into several sequential steps needed to analyze the material. These may be sample preparation, analyte extraction, and analyte determination (Figure 7). Each step in the procedure can be seen as an analytical system and can thus be validated separately and combined... 

Association of Official Analytical Chemists (AOAC) International (2000), Method validation programs (OMA/PVM Department), including Appendix D Guidelines for collaborative study procedures to validate characteristics of a method of analysis, available http //www.aoac.org/vmeth/devmethno.htm. 

The aim of validation of an analytical procedure is to demonstrate that the method employed in any product testing, such as the identification, control of impurities, assay, dissolution, particle size, water content, or residual solvents, is validated in the most important characteristics. Identification tests, quantitative tests for impurities content, limit tests for control of impurities, and quantitative tests of the active moiety in samples of pharmaceutical product are the most common types of analytical procedures that validation addresses [1]. 

Different approaches may be used to validate the potency method. However, it is important to understand that the objective of validation is to demonstrate that a procedure is suitable for its intended purpose. With this in mind, the scientist will need to determine the extent of validation required. It is advisable to design experimental work such that the appropriate validation characteristics be considered simultaneously to obtain overall knowledge of the capabilities of the analytical procedure. 

Improvement schemes can be defined as a succession of individual interlaboratory studies in which several laboratories analyse the same test samples for the same characteristics (usually the content of an analyte), following a similar protocol to validate each individual step of their own analytical method (Quevauviller, 1999a). They enable laboratories to develop and validate all steps of new or existing analytical procedure(s) in adequately organised successive exercises which may be considered as preliminary studies for laboratory or method performance studies or certification of RMs (Griepink and Stoeppler, 1992 Quevauviller, 1998b). Such programmes are particularly valuable in the case of speciation studies since the analytical procedures include several complex and critical steps. 

Validation of the analytical procedure is regarded as one of the most important issues of QA. Before selecting the measurement procedure (analytical method) for a particular purpose, the laboratory should consider its experience, the technical infrastructure at its disposal, and the expected time frame and financial outlay. Validation of the analytical procedure provides necessary information on its performance characteristics and raises the confidence of users in the results.8... 

Table 3 ICH Analytical Methods and Validation Characteristics Type of analytical procedure...

It is generally recognized and accepted that analytical methods must be suitable for the intended use. Furthermore, EU Directives 85/591/EEC, 89/397/EEC and 93/99/ EEC state that analytical procedures for compliance testing with food laws are to be carried out on the basis of validated methods. Method validation is known as the process used to confirm that a procedure is fit for a particular analytical purpose. This process, an essential part of analytical quality assurance, can be described as the set of tests used to establish and document performance characteristics of a method. The performance characteristics of a method are experimentally derived values for the fundamental parameters of importance in assessing the suitability of the method (Horwitz 1988, 1995 Thompson and Wood 1993, 1995 Eurachem 1996 FAO 1998 US EPA 1995 US FDA 1993a). These parameters include ... 

The ICH was very valuable in harmonizing terms and definitions as well as basic requirements for analytical validation. Of course, due to the nature of the harmonization process, there are some compromises and inconsistencies, but the importance of a proper validation is currently widely known and accepted. In Table 1, the required validation characteristics for the various types of analytical procedures are shown. In the following, the main ICH requirements for the validation characteristics are summarized. However, the ICH guidelines must not be regarded as a checklist. It is the responsibility of the applicant to choose the validation procedure and protocol most suitable for their product. ... 

Validation characteristics Minimum number Identity Analytical procedure Impurities Quantitative Limit Assay ... 

There has been some controversy regarding the technical term for this validation characteristic, i.e., specificity vs. selectivity. This may be partly attributed to the fact that in contrast to an isolated test procedure in analytical chemistry, in pharmaceutical analysis, the sum of various control tests and hence their combined specificity is used for the overall evaluation. 

Validation of Analytical Procedures/Methodology. This text is complementary to the peirent document which presents a discussion of the characteristics that should be considered during the validation of ancilytical procedures. This text indicates some guidcince cind recommendations on how to consider the veu-ious validation characteristics. It cilso provides em indication of the data which should be presented in the application for approval. 

In 1996 and 1997 the International Conference on Harmonization (ICH) published guidelines for analytical method validation [8]. These documents present a discussion of the characteristics for consideration during the validation of the analytical procedures included as part of registration applications submitted within the European Union, Japan, and the United States. 

Analytical method validation has developed within the pharmaceutical industry over the years in order to produce an assurance of the capabilities of an analytical method. A recent text on validation of analytical techniques has been published by the international Conference on Harmonisation (ICH) [19]. This discusses the four most common analytical procedures (1) identification test, (2) quantitative measurements for content of impurities, (3) limit test for the control of impurities and (4) quantitative measurement of the active moiety in samples of drug substance or drug product or other selected components of the drug product. As in any analytical method, the characteristics of the assay are determined and used to provide quantitative data which demonstrate the analytical validation. The reported validation data for CE are identical to those produced by an LC or GC method [11] and are derived from the same parameters, i.e. peak time and response. Those validation parameters featured by the ICH (Table 1) are derived from the peak data generated by the method. Table 1 also indicates those aspects of a CE method (instrumentation and chemistry), peculiar to the technique, which can affect the peak data and highlights factors which can assist the user in demonstrating the validation parameters. 

Features of the sample and availability of reference materials are also key factors in determining an analytical procedure and detection method, which then relate to various analytical validation characteristics and parameters. 

This nomenclature is however not always adhered to. In many cases, i.e. scientific publications, codes of practice, or official directives, an analytical procedure is virtually implied when an analytical method is spoken about. Commonly used expressions such as validation of analytical methods or performance characteristics of analytical methods are typical examples of incorrect usage. Such confusion appears even in the definition suggested by Wilson in 1970 for the term analytical method [9]. As he then put it, an analytical method is to be regarded as the set of written instructions completely defining the procedure to be adopted by the analyst in order to obtain the required analytical result . It is actually difficult to make a distinction between the two notions when one of them is defined in terms of the other. 

It follows that the common criteria of validation should be made more specific in terms of measurement assurance. It is (the index of) accuracy that requires overriding consideration among the characteristics of analytical performance if quality of the results is primarily kept in mind. Other performance characteristics are desirable to ensure that a methodology is well-established and fully understood, but validation of an analytical procedure on those criteria seems impractical also in view of the lack of corresponding requirements as is commonly the case. (Strictly speaking, there is no validation unless a particular requirement has been set.)... 

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