Analytical Validation

The principle of insignificancy , enabling use of the given principle for any level of probability is substantiated. The systematic application of the given principle results in developing metrological criteria for pharmaceutical reference substance, analytical validation, evaluation of results of interlaboratory testing and suitability of the analytical equipment for the phamiaceutical analysis. 

Guidance on specifications is divided into universal tests/criteria which are considered generally applicable to all new substances/products and specific tests/criteria which may need to be addressed on a case-by-case basis when they have an impact on the quality for batch control. Tests are expected to follow the ICH guideline on analytical validation (Section 13.5.4). Identification of the drug substance is included in the universal category, and such a test must be able discriminate between compounds of closely related structure which are likely to be present. It is acknowledged here that optically active substances may need specific identification testing or performance of a chiral assay in addition to this requirement. 

Stability Data Package for Registration Applications in Climatic Zones III and IV Analytical Validation... 

The analytic validity of an abstract parallel elastic component rests on an assumption. On the basis of its presumed separate physical basis, it is ordinarily taken that the resistance to stretch present at rest is still there during activation. In short, it is in parallel with the filaments which generate active force. This assumption is especially attractive since the actin-myosin system has no demonstrable resistance to stretch in skeletal muscle. However, one should keep in mind, for example, that in smooth muscle cells there is an intracellular filament system which runs in parallel with the actin-myosin system, the intermediate filament system composed of an entirely different set of proteins, (vimentin, desmin, etc.), whose mechanical properties are essentially unknown. Moreover, as already mentioned, different smooth muscles have different extracellular volumes and different kinds of filaments between the cells. 

Urinary alkaline phosphatase activity. II. An analytical validation of the assay method. JAMA (1963), 185, 953-957. 

B. Richter, J. EzzeU, and D. Felix, Single Laboratory Method Validation Report Extraction of Organo-phosphorus Agrochemicals, Chlorinated Herbicides and Polychlorinated Biphenyls Using Accelerated Solvent Extraction (ASE) with Analytical Validation by GC/NPD and GC/ECD, Document 101124, Dionex Sunnyvale, CA (1994). 

There is one additional general requirement included in Directive 75/318/EEC as amended, which affects all parts of the pharmaceutical section of the dossier. This is a blanket requirement that all analytical methods are to have been adequately validated and the validation data included in the submission. This applies to all analytical methods including those used in connection with preclinical and clinical parts of the dossier. Additional guidance on how to meet these requirements is included in the two notes for guidance developed on the topic of analytical validation through the ICH process, available at the EMEA web site or at the Commission s web site, mentioned earlier. 

Single-site IVD "Home brew" or "in-house" IVD made with an analyte specific reagent FDA requires labeling disclosing the "in-house" nature of the test but has no premarket review requirement CLIA requires analytical validation and quality control systems... 

FDA device regulation is focused on the device and the device manufacturer. CLIA, on the other hand, focuses on laboratory quality, including the quality of the laboratory test results provided by the devices used, whether developed in-house or as a test kit in commercial distribution to multiple laboratories. The programs differ substantially in approaches and in data requirements. FDA requires unique submissions for each test under its purview, evaluates both performance and labeling, and requires demonstration of analytical validity and clinical validity as appropriate. CLIA inspects laboratories using a system approach based on key probes of the operating system. CLIA requires a demonstration of analytical performance and quality control but does not require a showing of either clinical validity or clinical utility. 

An analytically sensitive test always detects analytes when they are present in specimens. An analytically specific test does not detect analytes when they are absent. The Task Force also recommended that laboratories providing a test for routine clinical use (after it had been developed) demonstrate their ability to provide analytically valid tests. These laboratories are regulated under the Clinical Laboratories Improvement Amendments of 1988 (Holtzman, 2000). 

Most analytical methods involve several preparative steps before the final measurement can be made and it is possible to produce a flow diagram representing a generalized method of analysis (Table 1.2). Not all the steps may be necessary in any particular method and it may be possible to combine two or more by careful choice of instrumentation. It is important when selecting a particular method to consider not only its analytical validity but also the cost of the analysis in terms of the instrumentation and reagents required and the time taken. 

Quality Ten topic headings—Stability, Analytical Validation, Impurities, Pharmacopoeias, Quality of Biotechnological Products, Specifications, GMP, Pharmaceutical Development, Quality Risk Management, Pharmaceutical Quality System total of 24 guidelines... 

Kirsch, R. B., Validation of Analytical Methods Used In Pharmaceutical Cleaning Assessment and Validation Analytical Validation in the Pharmaceutical Industry, Supplement to Pharmaceutical Technology pp. 40 6, 1998. 

Define Quality Control, Quality Assurance, sample, analyte, validation study, accuracy, precision, bias, calibration, calibration curve, systematic error, determinate error, random error, indeterminate error, and outlier. 

An analytically validated assay needs to be available in the clinic. 

The ICH also provides guidelines in analytical validation [Q2(R1), impurities (Q3 series), pharmacopeias (Q4 series), quality of biotechnological products (Q5... 

Analytical methods validation is one of the most regulated validation processes in the pharmaceutical industry. Analytical validations are required to demonstrate that the methods employed are the most indicated for each product and that the results obtained are reliably correct. All methods employed in raw and finished product materials analysis are required to be validated. 

The validation protocol and report may also include the product stability data or a summary and documentation concerning cleaning and analytical validation. 

It is assumed that before the analyst has considered using the assay for patient samples, it has been analytically validated (i.e. the recovery, sensitivity, linearity and reproducibility have been determined) and that the method is able to reproduce results, under ideal conditions, so that its variation is sufficiently predictable to apply statistical quality control. 

Apart from establishing analytical validation parameters, other activities should include experimental optimization of each procedural step or method manipulation to determine the critical control steps that have a substantial impact on method performance. The ruggedness or process variability that may be employed in any particular method step, without reducing method performance, should be determined. It should be identified, for example, whether an analytical method may be stopped without adversely affecting the result. 

Validation is one method of assuring that the product manufactured satisfies the design required, the specification established, and the reproducibility of the results. Validation may include the items described in Figure 1, although individual validation may include IQ, OQ, process validation, and analytical validation. 

In practical terms, the verification, qualification, analytical validation, cleaning validation, and process validation need to satisfy certain requirements. 

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