Validation studies, analytical methods

In analytical practice, they are best recognized by the determination of xtest as a function of the true value xtrue, and thus, by analysis of certified reference materials (CRMs). If such standards are not available the use of an independent analytical method or a balancing study may provide information on systematic errors (Doerffel et al. [1994] Kaiser [1971]). In simple cases, it may be possible, to estimate the parameters a, / , and y, in Eq. (4.5) by eliminating the unknown true value through appropriate variation of the weight of the test portions or standard additions to the test sample. But in the framework of quality assurance, the use of reference materials is indispensable for validation of analytical methods. 

In the early stages of new product development, it may not be necessary to perform all of the various validation studies. However, the process of validating a method cannot be separated from the actual development of the method conditions, because the developer will not know whether the method conditions are acceptable until validation studies are performed. The development and validation of a new analytical method may therefore be an iterative process. Results of validation studies may indicate that a change in the procedure is necessary, which may then require revalidation. During each validation study, key method parameters are determined and then used for all subsequent validation steps. 

Performance characteristics of residue methods are often only determined for major food animal species. The Joint FAO/IAEA Expert Consultation on Validation of Analytical Methods for Food Control (17) has discussed the issue of the availability of suitable analytical methods for determining compliance of residues in tissues of the so-called minor species with established MRLs. The Consultation has concluded that if metabolism and related pharmacokinetic data are similar in minor species to those in major species, only the recovery of the analytes in the minor species needs to be determined. If the recovery remains stable, there is no need to study the method performance any further. If the recovery is not stable the full set of performance data should be determined. 

Prior to a field study, enough untreated control material should be provided to allow the lab to develop and validate adequate analytical methods. The control material should match the test samples as closely as possible to minimize the matrix variations which might affect the performance of the method. Development and validation of a method using a matrix which does not closely resemble the actual test matrix frequently results in a method which is not adequate for the actual study samples. The method revisions required in such a case represent a clear waste of... 

Exposure Levels in Humans. Studies have been conducted measuring chlorobenzene levels in drinking water and air (including indoor air). Conflicting data on chlorobenzene air levels point to a need for confirmation and, possibly, validation of analytical methods. Less conflicting estimates of environmental emissions are the prerequisite for any attempt to prioritize control measures. 

Preventive Strategy. The firm should have an SOP for the validation of analytical methods that contains specificity requirements. If so, the firm would have shown in the specificity portion of the validation that X and Y indeed form the critical resolution pair. If this were proven in the specificity section with confirmation of the resolution of unknown impurities during a purposeful degradation study, this FDA-483 citation would have been avoided. 

Several LC-MS and LC-MS/MS methods were developed in plasma for only one antidepressant and, sometimes, its major metabolite(s) to perform pharmacokinetic, bioavailability, or bioequivalence studies. Analytical methods developed for these purposes require very low LLOQ values and, usually, narrow linear ranges covering the low range of the therapeutic concentrations are validated. In this context, several methodologies were described for the determination of fluoxetine [94, 95, 98-100], paroxetine [44, 71, 85, 101, 102], venlafaxine [48, 61, 64, 86, 103,104], sertraline [62, 68, 83], citalopram [46, 89] and escitalopram [105], mianserine [106, 107], mirtazapine [42], trazodone [84], nefazodone [51, 81], duloxetine [47, 50, 73], and bupropion [43], Deuterated analogues of the analyte of interest or of other drugs were employed by few authors as IS [43, 61, 73, 81, 85, 99] however, in most of these methods, another antidepressant or other therapeutic drug was used for this purpose. 

To avoid or limit problems in this area after submission of the NDA, the validation of analytical methods and the conduct of stability studies should be planned from the initial phases of clinical research. This will provide the type of data approvable by FDA. The reader is directed to the Guideline for Stability Studies for Human Drugs and Biologies and the final ICH Guideline for the Stability of Drug Substance and Drug Product for assistance in fulfilling this essential requirement. 

Zhang et al. [43] developed and validated a stability indicating HPLC method for the determination of lornoxicam in pharmaceutical formulation. The isocratic procedure was performed in Shimadzu ODS (4.6 mm x 15 cm, 5 pm) column maintained at 25 °C. The mobile phase was degassed mixture of sodium acetate (0.05 mol/L, pH 5.8) and methanol (55 45). The flow rate was 1 ml/min and detection at 290 nm. Selectivity, specificity, linearity, precision, accuracy, and robustness were evaluated to validate the analytical method. Forced degradation studies were performed to provide an indication of the stability-indicating capacity. The stability indicating method for lornoxicam in the injectable dosage was developed and validated. The method can be considered for routine analysis and quality control of lornoxicam in injectable formulation. 

Since its beginning in 1884, AOAC INTERNATIONAL has been truly dedicated to the validation of analytical methods through trials in multiple laboratories. An early undertaking of AOAC is still its most important business supporting the use of analytical methods used in multiple laboratories through validation by interlaboratory studies. 

Under forcing conditions, decomposition products may be observed that are unlikely to be formed under the conditions used for confirmatory studies. This information may be useful in developing and validating suitable analytical methods. If in practice it has been demonstrated they are not formed in the confirmatory studies, these degradation products need not be further examined. 

Aprea, C Betta, A., Cacenacci, G, Lotii, A, Magnaghi, S., Barisano, A, Pas.sini, V., Pavan, L, Sciarra, G, Vitalone. V., and Mitioia, C. (1999), Reference value.s of urinary 3,.5,6-trictiloro-2-pyridinol in the Italian population—Validation of analytical method and preliminary results (muiticentric study), J. AOACfni. 82(2). 305-312. 

CCRVDF, and also evaluating the suitability of analytical methods for these residues. Two aspects are considered by JECFA with respect to the performance of analytical methods (1) JECFA must ensure that methods used in the pharmacokinetic and residue depletion studies considered in the establishment of an ADI or recommendation of MRLs are suitably validated to support the quality of the data reported in these studies, and (2) JECFA has been asked by CCRVDF to recommend when a suitably validated analytical method is available for regulatory use to support the recommended MRLs. JECFA has published a guidance document that states the requirements for validation of analytical methods submitted for JECFA consideration. " ... 

Eor the validation of analytical methods, an international guideline applies [61] that has been elaborated by EDQM, see Sect. 32.16.2. Eor stability studies on pharmacy preparations, where there may be neither the equipment nor the time available to develop and validate an analytical method, as an alternative approach [62-64] can be used. 

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