Analytical method validation components

These components, rigorously interconnected, enable analytical chemists to produce accurate and reproducible data when unknown samples are analysed. Especially the two basal compartments are of crucial importance analytical methods validation and analytical instrument qualification. 

While validating a production process, several steps were listed as they pertained to each of the components of manufacturing equipment, process conditions, personnel, and so forth. These key elements multiply rapidly when it comes to analytical methods validation. Take, for example, HPLC — the most commonly used method of analysis. A typical analytical method would involve use of columns, pumps, heaters, detectors, controllers, samplers, sensors, recorders, computers, reagents, standards, and operators — put together as a system. Each of these components and systems needs independent validation, followed by a validation of the system. Note that when this equipment is used to manufacture a product such a therapeutic proteins wherein HPLC techniques are used for the purification purpose, then all additional requirements of a manufacturing system also apply, including, but not limited to, the requirement that the equipment be of a sanitary kind. This limits the choice for manufacturers, and these considerations should be taken into account in the first selection of equipment. 

Analytical methods validation is a critical component of the entire company validation program. A method is not declared acceptable until a collaborative crossover study is conducted between two development laboratories and at least one quality control laboratory to ensure proper precision, accuracy, and efficiency. In the new world of outsourcing, it is imperative that an analytical crossover study be conducted between the client and supplier before any work is begun on dosage form development. 

Analytical method validation should track closely to the stages of development of the method itself However, it is not realistic to expect complete and thorough validation of the method until its development cycle is complete. An exception to this would be a situation where an accepted compendial method is applied to clinical material (such as a dissolution test or release testing of a compendial component). In these cases, companies must be prepared to demonstrate that consistent acceptable results can be obtained when using the compendial method in the company s laboratory (also known as methods verification). The obvious... 

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. 

A pharmacopoeial reference substance is intended for the determination of the main component of a substance or for the active ingredient of a pharmaceutical formulation which is usually present at a high proportion of the total. The reference substance is to be used as a primary standard in a specific method validated as prescribed in the ICH Guideline Validation of Analytical Procedure Methodology" (Technical Guide for the Elaboration of Monographs 1996 ICH Guideline 1997). the reproducibility of which is known. This is taken into account when the limits of acceptance (tolerance) for the substance or product are fixed (Daas and Miller 1997,1998). 

Here two components, the free phenol and the intact ester, are included in the residue definition. Usually, analytical methods for the determination of bromoxynil and its octanoate begin with hydrolysis during maceration of the sample. If those methods are validated, the sole fortification of the octanoate is sufficient. However, in other existing methods, hydrolysis follows a separate extraction step. In that case, the chosen solvent must be able to extract both compounds with equal efficiency. 

Komit6 for Levnedsmidler (NMKL)]. The standard presents a universal validation approach for chemical analytical methods in the food sector. This includes methods for the main constituents and also for trace components. Therefore, the NMKL procedure focuses on primary validation parameters, such as specificity, calibration, trueness, precision, LOD or LOQ and does not refer to special requirements of pesticide residue analysis. 

Method validation determined the limit of detection (LOD) to be 1 ngL (ppt) for isoxaflutole, 1 ngL for RPA 202248 and 3 ngL for RPA 203328. However, after experience with a number of surface waters with high levels of matrix components, the method LOD was increased to 3 ng L for all three analytes. RPA 202248 also proved to be particularly sticky and prone to carry over. Over time, this produced abackground level, which also prevented determinations below the 3ngL method LOD. 

Accurate, precise and sensitive analytical methods are important to the collection of data needed for regulatory decisions about pesticide registration. This article describes the various components of analytical method development, validation and implementation that affect the collection of pesticide residue distribution data for regulatory assessment of environmental fate and water quality impacts. Included in this discussion are both the technical needs of analytical methods and the attributes of study design and sample collection needed to develop data that are useful for regulatory purposes. 

Reference method, n - the analytical method that is used to estimate the reference component concentration or property value which is used in calibration and validation procedures. 

Reference values, n - the component concentrations or property values for the calibration or validation samples which are measured by the reference analytical method. 

Toxicokinetics has become a critically important component of any nonclinical program (see discussion in Section 14.10). Current ICH guidelines require the determination of animal pharmacokinetics at all dose levels administered on at least 2 days (beginning and end) during a nonclinical toxicology study.5 Similarly, this requires the development of a validated analytical method for the determination of parent drug (and possible major metabolites). 

System suitability test characteristics and limits are recommended as a component of any analytical method. This ensures that both methodology and instrumentation are performing within expectations prior to the analysis of test samples. The test characteristics are inferred from robustness studies and evaluated during the validation experiments. 

The error of an analytical result is related to the (in)accuracy of an analytical method and consists of a systematic component and a random component [14]. Precision and bias studies form the basis for evaluation of the accuracy of an analytical method [18]. The accuracy of results only relates to the fitness for purpose of an analytical system assessed by method validation. Reliability of results however has to do with more than method validation alone. MU is more than just a singlefigure expression of accuracy. It covers all sources of errors which are relevant for all analyte concentration levels. MU is a key indicator of both fitness for purpose and reliability of results, binding together the ideas of fitness for purpose and quality control (QC) and thus covering the whole QA system [4,37]. 

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. 

Chromatography is a well-known analytical method, but is also a validated industrial purification tool. However, the preparahve or produchon approach is very different from the analytical one. In analyhcal chromatography, the focus is on analyzing a mixture in order to separate the peaks of each component. The injected amount is small and peak resolution tends to be maximized. Column size is generally small in order to minimize analyhcal costs. An example of an analytical chromatogram is presented in Figure 12.1. 

Analytical testing (preformulation, stability, product release) is a core component of pharmaceutical operations from early R D through manufacturing of the commercial product. The original analytical methods are usually developed by the pioneer pharmaceutical firm and transferred to the provider. In some cases, the early methods are only preliminary methods and are not sufficiently robust to test the quality of downstream (clinical, commercial, and line extension) products and facility quality practices (cleaning validation). In those situations, the supplier is often asked to develop new methods, and in some cases those methods are transferred back to the client. In either scenario, the transfer of validated analytical methodology consists of the following four main tasks [52] ... 

It is therefore clear that a laboratory must take appropriate QA measures to ensure that it is capable of providing data of the required quality and that it actually does so. Method validation is therefore an absolutely essential component of the measures that a laboratory should introduce in order for it to produce reliable analytical data. 

Drug product Components, composition, specifications and analytical methods for inactive components, manufacturers, methods of manufacture and packaging, specifications and analytical methods for the drug product, stability. Methods validation package Environmental assessment Field copy certification... 

Method Validation is an essential component of the global harmonization of analytical methods. 

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