Common moiety methods validation

If the relevant residue cannot be properly determined using a routine multi-method, an alternative method must be proposed. In the case of residues consisting of a variety of structurally related compounds, a common moiety method may be acceptable in order to avoid the use of an excessive number of methods for individual substances. For example, the relevant residue of isoproturon in plant material is defined as the sum of isoproturon and all metabolites containing the 4-isopropylaniline group. Therefore, residues are determined following hydrolysis as 4-isopropylaniline and are expressed as 4-isopropylaniline equivalents. It is not necessary to validate the method individually for all possible metabolites which are covered by the residue definition (e.g., all metabolites which contain the 4-isopropylaniline group), provided that it is demonstrated that in the first step, the conversion to the common moiety is complete. However, common moiety methods often lack sufficient specificity, and should therefore be avoided if possible. If need be, their use must be justified. 

The use of common moiety methods acceptable in exceptional circumstances where there is no other practical means of determining the target analyte, and in these cases, full justification is required. This should include an explanation of why the compound cannot be determined by a specific analytical technique. For existing a.i., common moiety methods are also acceptable, in cases where the residue definition includes a common moiety. Moreover, validation data must be presented separately for all relevant components. 

A final special case may occur during the validation of common moiety methods. Based on the normal set of recovery experiments (two control samples, five samples fortified at the LOQ and five samples fortified at 10 times the LOQ), in total 12 samples have to be analyzed per matrix and analyte. A typical intention of common moiety methods is their suitability for the parallel determination of residues of the parent compound and a broad spectrum of metabolites. In the common moiety method discussed above for residues of spiroxamine, validation experiments were performed with four compounds. This results in at least 48 experiments per matrix. Assuming a normal... 

On the other hand, some sensible reduction may be acceptable. In the spiroxamine example, an appropriate reduced validation protocol may be as follows a full set of recovery experiments at both levels performed with the intact spiroxamine (which has the longest reaction pathway to the common moiety) and separately with one primary metabolite. Such two complete validations should be an acceptable test of the working range of the common moiety method. 

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. 

The aim of validation of an analytical procedure is to demonstrate that the method employed in any product testing, such as the identification, control of impurities, assay, dissolution, particle size, water content, or residual solvents, is validated in the most important characteristics. Identification tests, quantitative tests for impurities content, limit tests for control of impurities, and quantitative tests of the active moiety in samples of pharmaceutical product are the most common types of analytical procedures that validation addresses [1]. 

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