Assignment of Validation Parameters

The type and degree of validation depends on the nature of the test. In particular, methods described in pharmacopeias may not have to be validated but should be verified, if needed. Different test methods require different validation parameters. As development of the project progresses and as more analytical and product-specihc information is acquired, the analytical methods evolve and are gradually updated. The extent of validation increases and the documentation is completed. Table 9-1 outlines the validation parameters that are usually required for the early development stage, and Table 9-2 outlines the validation parameters that are usually required for the full development stage. 

The proposed acceptance criteria in Table 9-3 should be included in the validation protocol, especially for the full development stage. 

There are numerous method validation examples in the literature [9-18]. Each company has their own approach and own set of acceptance criteria for different analytical assays, but these approaches must be within the confines of their line unit QA department and be in accordance with any regulatory provisions. In the next section a description for each of the parameters to be validated (figures of merit) are described in detail and examples are given for each. 

Tor the identity test of a 0-mg formulation (placebo), it may be necessary to document the absence of drug substance, and an LOQ determination will then be required. 

TABLE 9-3. Proposed Acceptance Criteria for Drug Product (DP) and Drug Substance (DS) 

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The procedure adopted to portray the scope and utility of a linear free-energy relationship for aromatic substitution involves first a determination of the p-values for the reactions. These parameters are evaluated by plotting the values of log (k/ka) for a series of substituted benzenes against the values based on the solvolysis studies (Section IV, B). The resultant slope of the line is p, the reaction constant. The procedure is then reversed to assess the reliability and validity of the Extended Selectivity Treatment. In this approach the log ( K/ H) observations for a single substituent are plotted against p for a variety of reactions. This method assays the linear or non-linear response of each substituent to variations in the selectivity of the reagents and conditions. Unfortunately, insufficient data are available to allow the assignment of p for many reactions. It is more practical in these cases to adopt the Selectivity Factor S as a substitute for p and revert to the more empirical Selectivity Treatment for an examination of the behavior of the substituents. 

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