Method validation aspects

Method Validation The signal path from detector up to the hard copy output of the final results must be perceived as a chain of error-prone components there are errors due to conception, construction, installation, calibration, and (mis-)use. Method validation checks into these aspects. 

Within CEN TC 275, a distinct protocol for the conduct of inter-laboratory method validation trials is not selected or required, but it is recommended to apply ISO 5725 or the ISO/International Union for Pure and Applied Chemistry (lUPAC) harmonized protocol. " In the past, results of several national and international interlaboratory trials had been accepted. Nevertheless, the following fundamental aspects of the harmonized protocol for the design of method-performance studies should be fulfilled ... 

Practical aspects of TLC method development comprise (i) searching for a suitable developing solvent (ii) optimising the visualisation and evaluation process and (iii) method validation. Table 4.34 lists the main features of HPTLC. 

Precision estimates are key method performance parameters and are also required in order to carry out other aspects of method validation, such as bias and ruggedness studies. Precision is also a component of measurement uncertainty, as detailed in Chapter 6. The statistics that are applied refer to random variation and therefore it is important that the measurements are made to comply with this requirement, e.g. if change of precision with concentration is being investigated, the samples should be measured in a random order. 

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. 

XRPD as a stability-indicating assay method When the phase identity, or degree of crystallinity (or lack thereof), of a drug substance is important to its performance in a drug product, XRPD can serve as a vital stability-indicating assay method. There is no doubt that XRPD can be validated to the status of any other stability-indicating assay, and that one can use the usual criteria of method validation to establish the performance parameters of the method. This aspect would... 

It is beneficial to develop generic methods, this means methods that are already validated for some aspects, e.g., EOF stability and freedom of matrix interferences. Generic methods that are suitable to separate a number of analytes can be found in CE, especially due to the high separation efficiency. Some aspects, like specificity and repeatability, are still analyte specific, but the entire method validation is substantially speeded up when a generic method already exists. 

Once an application has been accepted for evaluation, the Pharmaceutical Chemistry Evaluation Section, Toxicology Section and Clinical Evaluation Units evaluate the Module 3, 4 and 5 data, respectively. For applications relating to products of biological origin, a second copy of the Module 3 data is also evaluated by the TGA Laboratories (TGAL) Branch, which evaluates aspects such as laboratory methodology, method validation and shelf-life. 

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. 

Analytical method validation forms the first level of QA in the laboratory. Analytical quality assurance (AQA) is the complete set of measures a laboratory must undertake to ensure that it is able to achieve high-quality data continuously. Besides the use of validation and/or standardized methods, these measures are effective IQC procedures (use of reference materials, control charts, etc.), with participation in proficiency testing schemes and accreditation to an international standard, normally ISO/IEC 17025 [4]. Method validation and the different aspects of QA form the subject of Section 8.2.3. 

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 ... 

If a method must be developed from scratch, or if an established method is changed radically from its original published form, then before the method is validated, the main task is simply to get the method to work. This means that the analyst is sure that the method can be used to yield results with acceptable trueness and measurement uncertainty (accuracy). When the analyst is satisfied that the method does work, then the essentials of method validation will also have been done, and now just need to be documented. If there is an aspect of the method that does not meet requirements, then further development will needed. Discovering and documenting that the method now does satisfy all requirements is the culmination of method validation. 

An important aspect of a full method validation is estimating bias components attributable to the method itself and to the laboratory carrying out the analysis. This step is required to estimate measurement uncertainty with a reasonable range that covers results that would be obtained in another laboratory of similar experience and standing. In chapter 5 I discussed these approaches at length. ISO (1994b) has a procedure for such interlaboratory... 

How analytical methods deal with interferences is one of the more ad hoc aspects of method validation. There is a variety of approaches to studying interference, from adding arbitrary amounts of a single interferent in the absence of the analyte to establish the response of the instrument to that species, to multivariate methods in which several interferents are added in a statistical protocol to reveal both main and interaction effects. The first question that needs to be answered is to what extent interferences are expected and how likely they are to affect the measurement. In testing blood for glucose by an enzyme electrode, other electroactive species that may be present are ascorbic acid (vitamin C), uric acid, and paracetamol (if this drug has been taken). However, electroactive metals (e.g., copper and silver) are unlikely to be present in blood in great quantities. Potentiometric membrane electrode sensors (ion selective electrodes), of which the pH electrode is the... 

All sources of uncertainty that are not quantified by the standard deviation of repeated measurements fall in the category of Type components. These were fully dealt with in chapter 6. For method validation, it is important to document the reasoning behind the use of Type components because Type components have the most subjective and arbitrary aspects. Which components are chosen and the rationale behind the inclusion or exclusion of components should documented. The value of the standard uncertainty and the distribution chosen (e.g., uniform, triangular, or normal) should be made available, as should the final method used to combine all sources. 

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. 

The validation requirements are discussed as they apply to both the sample preparation and sample analysis aspects of a dissolution method. The focus of the discussion in this chapter is on the validation considerations that are unique to a dissolution method. Validation is the assessment of the performance of a defined test method. The result of any successful validation exercise is a comprehensive set of data that will support the suitability of the test method for its intended use. To this end, execution of a validation exercise without a clearly defined plan can lead to many difficulties, including an incomplete or flawed set of validation data. Planning for the validation exercise must include the following determination of what performance characteristics to assess (i.e., strategy), how to assess each characteristic (i.e., experimental), and what minimum standard of performance is expected (i.e., criteria). The preparation of a validation protocol is highly recommended to clearly define the experiments and associated criteria. Validation of a test method must include experiments to assess both the sample preparation (i.e., sample dissolution) and the sample analysis. ICH Q2A [1] provides guidance for the validation characteristics of the dissolution test and is summarized in Table 4.1. 

Different approaches may be used to validate the sample preparation component of the dissolution test. However, it is important to understand that the objective of validation is to demonstrate that the procedure is suitable for its intended purpose. For example, one of the strategies will demonstrate the validity of different aspects of sample preparation during method development (prior to the formal method validation exercise). As a result, the final validation experiments will confirm the work done during method development. The strategy that will be followed for the method development and validation process will depend on the culture, expertise, and strategy of the analytical laboratory. 

Huber has published two validation reference books for the analytical laboratory [7,8]. The first one covers all validation aspects of an analytical laboratory, including equipment, analytical methods, reference compounds, and personnel qualification. The second covers the validation of computerized and networked systems. 

Analytical method validation—Aprerequisite for any validation involving the analysis of the microbiological, physical, or chemical aspects of materials is the use of analytical methods that have been demonstrated to be reliable and reproducible. No meaningful assessment of product or material quality can be made without the... 

Although swab assays are different conceptually than both the impurity and the potency assay, the same scientific rationale governs the development of these assays. Many of the references listed in Table 15.4 outline different validation approaches. Seno outlined validation practices in the Japanese pharmaceutical industry for cleaning verification,23 and Kirsch outlined an approach for swab method validation that is consistent with ICH guidelines for method development.24 An important aspect of any cleaning-verification assay begins with swabbing the... 

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. 

Abstract Although the validation process necessary to ensure that an analytical method is fit for purpose is universal, the emphasis placed on different aspects of that process will vary according to the end use for which the analytical procedure is designed. It therefore becomes difficult to produce a standard method validation protocol which will be totally applicable to all analytical methods. It is probable that far more than 30% of the methods... 

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