Analytical validation process steps

Step 5 Off-line method or analyzer development and validation This step is simply standard analytical chemistry method development. For an analyzer that is to be used off-line, the method development work is generally done in an R D or analytical lab and then the analyzer is moved to where it will be used (QA/ QC lab, at-line manufacturing lab, etc.). For an analyzer that is to be used on-line, it may be possible to calibrate the analyzer off-line in a lab, or in situ in a lab reactor or a semiworks unit, and then move the analyzer to its on-line process location. Often, however, the on-line analyzer will need to be calibrated (or recalibrated) once it is in place (see Step 7). Off-line method development and validation generally includes method development and optimization, identification of appropriate check samples, method validation, and written documentation. Again, the form of the documentation (often called the method or the procedure ) is company-specific, but it typically includes principles behind the method, equipment needed, safety precautions, procedure steps, and validation results (method accuracy, precision, etc.). It is also useful to document here which approaches did not work, for the benefit of future workers. 

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. 

Regulatory professionals too often assume that any analytical method can undergo the steps necessary to validate its use in marketing a pharmaceutical product. In many cases the need for validation of a particular analytical method is often revealed late in the drug development process by corporate regulatory and quality assurance (QA) professionals who are responsible for compliance with the regulatory requirements associated with product registration. Commonly these individuals view the requirements and parameters of the validation processes as independent of the actual analytical chemistry and technical objective of the method itself. 

Developing the validation protocol is a crucial step in the validation process. It is the culmination of the regulatory and technical accomplishments to this point in the development of the method. The protocol must define which validation parameters are needed and the specific experiments necessary to demonstrate the validity of the analytical method. The protocol must contain all of the acceptance criteria for each of the relevant validation parameters. Additionally, the protocol must define the number of replicates, the reporting format, and the number of significant figures. In short, the validation protocol instructs the analyst on how to validate the analytical method. 

The ultimate objective of the method validation process is to produce the best analytical results possible. To obtain such results, all of the variables of the method should be considered, including sampling procedure, sample preparation steps, type of chromatographic sorbent, mobile phase, and detection. The extent of the validation rigor depends on the purpose of the method. The primary focus of this section will be the validation of chromatographic methods. 

Table 19.1 lists in chronological order the steps that a user of computerized analytical equipment can follow for the entire validation process. 

The original manufacturing formula (HV) and five variations are performed in the first step of the synthesis. Six samples are analysed. The results of these six analyses are used to assess the validation of this process step. In this case validation of the analytical method is a prerequisite for any decision that is made about the validity of the process. This information is needed before the process research chemist can start variations of the process otherwise it is possible that the data received cannot be assessed. The difficulty of assessing the data of the process validation results from the fact that the data is influenced by the analytical method and the uncertainty of the chemical process. If the uncertainty of the analytical method is larger or in the same range as the variations of the chemical process, assessment of the data is not possible. 

The validation of data also is an important step in the process. Validation begins at the station with standard operating procedures for self-consistency of operations and maintenance and with systematic calibration of instruments. Air quality instruments are not particularly reliable so that frequent, careful calibration is required for useful data acquisition. Validation of data is continued after transmission before archiving. To maximize reliability, validation involves a dedicated scientist and engineer whose experience permits identification of possible errors or inconsistencies in reported observations. Finally, the validation process is cross-checked with station performance audits and laboratory intercomparisons to identify discrepancies in analytical procedures. This chain of activity generally makes air quality a rather expensive commodity, a fact that is not appreciated by many users. 

All of these manipulations have in common that the validity of the representation with respect to its analytical value, its reliability and truth can easily be lost. It is therefore of major importance that image-processing steps are performed under controlled and traceable conditions by the software. Already, at the level of grayscale transformation of mass spectral intensities, data processing methods must be scrutinized in detail. A visuaUzed representation of a 2-D array of mass spectra is, by definition, a quantitative statement, even if the individual mass... 

Step 3 In this step, the validity of the classification is determined by various criteria, rj, where 0Other method is analytical hierarchy process (AHP) well presented, e.g., by Saaty (2008). 

After all the validation criteria are established, the application of the method to the analysis of real samples constitutes the ultimate step of the validation process. Up to now, all procedures have been conducted from samples constituted from blank matrices spiked with analytes. The goal now is to verify that the method is applicable to real samples. It is indeed possible for the extraction of the analytes from real samples to be less efficient than extraction of samples from a spiked matrix. 

All aspects in the analytical process are equally important, and each step should be isolated in method development experiments and/or validation to ensure acceptable quality of results. A good way to evaluate robustness of a method is to alter parameters (e.g., solvent volumes, temperature, pH, sources of reagents) of each step to determine... 

Retrospective validation uses historical information gathered in actual process runs to evaluate the process. For example, batch records can provide extensive data on column performance and analytical data of fractions and final product can provide valuable information on the efficiency of the chromatographic steps in removing contaminants. Chapman67 cautions that while retrospective validation is a valid and valuable approach, it is not meant to be retroactive — validation must be done before product is released to market. 

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