Analytical validation approaches

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. 

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. 

A pharmaceutical company has to adopt a proactive policy of validation for its facilities, production processes, production equipment and support systems, analytical methods, and computerized systems. A properly validated approach will help to assure drug product quality, optimize the processes, and reduce manufacturing cost. 

In Table 1, the typical validation parameters required for the different types of analytical procedures are listed. For all these analytical procedures CE might be an appropriate analytical technique. In fact numerous validated CE methods for pharmaceutical analysis have been described in literature during the last decade.In Table 2, an overview is listed of the ICH validation parameters included in several reported CE validation studies. Since chiral purity determination is an important application area of CE methods, this test is listed separately as a specific analytical procedure. In addition, the determination of drug counterions has been included as a separate application. This overview illustrates that in general the required validation parameters are addressed in reported CE validation studies. It should be noted, however, that the validation parameters included in Table 2 are not necessarily evaluated exactly according ICH requirements in the reported references. Many pharmaceutical companies apply a phase-related validation approach in which the depth of validation depends on the clinical phase of development of the product involved. 

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... 

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... 

Holst-Jensen, A., and Berdal, K. G. (2004),The modular analytical procedure and validation approach and the units of measurement for genetically modified materials in foods and feeds, J. AO AC Int., 87,1-9. 

In cases in which tliis less stringent model cannot be used, alternative validation schemes may be used (17). These include a two-laboratory validation protocol similar to the AOAC International Peer Verified Method Protocol, or a singlelaboratory validation approach. With any of tlie alternative validation schemes, the Joint FAO/IAEA Expert Consultation on Validation of Analytical Methods... 

Whether the monitoring of endoxifen plasma concentrations in breast cancer patients would constitute a valid approach to optimize individual dosage and improve treatment efficacy is under scrutiny and remains to be demonstrated. In that purpose large prospective studies relating endoxifen plasma levels to clinical outcomes are as yet needed. In this perspective, it is critical to settle analytical and selectivity discrepancies between methods and laboratories and to ensure reproducible quantification results between laboratories. These concerted harmonization efforts can be carried out within the frame of an international external quality control program, which as yet, remains to be organized. 

This appendix presents some information on the characteristics that should be considered during validation of analytical methods. Approaches other than those specified in this appendix may be followed and may be acceptable. Manufacturers should choose the validation protocol and procedures most suitable for testing of their product. 

Since the authors review on Oil Spill Identification (1,2), a number of significant occurrences have firmly established oil fingerprinting as a valid approach to the identification of spill sources. These include increased understanding of the effects of weathering on oils, continued refinement of various analytical techniques, continued refinement of computer pattern recognition techniques for comparison of oils, the adoption by ASTM of new methods of analysis of waterborne oils (3,4, 5), the establishment of a Central Oil Identification Laboratory (COIL)... 

Prospective validation should be conducted prior to the commercial distribution of an API produced by a new or substantially mocfified process. This validation approach should involve obtaining and evaluating documented processing and analytical control information for multiple batches manufactured, sampled, and tested according to a preestablished validation plan. 

Analytical methods must also be validated. The approach used for method validation is consistent with the validation of analytical methods for drug products. See USP monograph on analytical validation procedures. 

Careful understauding of the effects of each preanalytical variable on the biomarker data is complex and necessitates a staged approach conceptually similar to the fit-for-purpose analytical validation of a biomarker assay (see Chapter 41). In the early exploratory phase of biomarker investigation, standardization of procedures with a defined protocol for sample collection and handling will permit comparative interpretation and analysis of the data within study and/or between studies. Minimally, variables that should be experimentally evaluated to optimize sample collection for a specific biomarker will include matrix type, preservation... 

The advantage of reductionism is to allow a true analytical approach for dividing a system into simpler elements and being able to reconstruct it in the opposite way. Emergentism requires a rigorous definition of levels and associated properties for pretending to be a valid approach. 

The exclusive use of chemometrics alone provides a weak basis for analytical science. When performing mnltivariate calibrations, analytically valid calibration models require a relationship between X (the instrument response data or spectral data) and Y (the reference data) probability tells us only if X and Y appear to be related. If no cause-effect relationship exists between X and Y, the analytical method will have no true predictive significance. Interpretation of NIR spectra provide the knowledge basis for understanding the cause-and-effect of molecular structure as it relates to specific types of absorptions in the NIR. Interpretive spectroscopy is a key intellectual process in approaching NIR measnrements if one is to achieve an analytical understanding of these measurements. This book represents onr best effort to provide the tools necessary for the analyst to interpret NIR spectra. 

Figure 17.1 illustrates how precision may vary as a function of analyte concentration. The %RSD values of ethanol quantification by GC increased significantly as the concentration decreased from 1000 ppm to 10 ppm. Higher variability is expected as the analyte levels approach the detection limit for the method (8). The analyst must determine during the validation of the method at what concentration the imprecision becomes too great for the intended use of the method. 

Comparison with a currently accepted compendium method is another validation approach and is frequently used in industrial research laboratories. This approach uses results from a currently accepted (analytical) method as verification of the new method s results. Agreement between results initially suggests validation. However, disagreement could cast doubts on the acceptability of the new method or may suggest that the currently accepted method is invalid. Validation of compendial methods has been addressed by the USP Chapter (1225) [68]. Interlaboratory collaborative studies are discussed in Chp. 8.4.2. 

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