Pharmaceutical Technology - November 2018

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22 Pharmaceutical Technology LABORATORY BEST PRACTICES 2018 P h a r mTe c h . c o m Analytical Methods With these steps, it is important to be careful in defining the range of concentrations, as this will be important in defining the method design space. If the design space is too restrictive, the method will be limited. There are many options for the experimental matrix in the DoE study. For small studies in which only two or three factors are being evaluated, a full factorial design is appropriate. For studies with five or more variables, then alternate designs should be explored, as detailed in Figure 2. Analysis of variance (ANOVA)/analysis of covari- ance (ANCOVA) and range analysis are the basis of the statistical analysis methods for response surface designs. Range analysis is frequently em- ployed to establish each factor's effect and identify the best level for the different factors. For a factor, the range of means is the difference of the maxi- mum and minimum means. In the design space of a method, the factor (or variable) with the largest range of means has the most impact on method performance. While range analysis can be used to identify the optimal value of different factors, this method can't be used to determine the significance of different factors. ANOVA, using the F-test, is then employed for more quantitative analysis. The F value for each factor is indicative of the ratio of the variance for each factor to that of the experimental error. The percentage contribution of each factor, ref lecting the factor's inf luence, is the percentage of the sum of square deviation due to that factor in the total sum of square deviation. Additionally, the determination of relationships among variables is typically performed by regression analysis. Once the method design space has been estab- lished, confirmatory studies should be conducted. The method should contain appropriate system suitability requirements to monitor and ensure consistent system functionality. Additionally, the method should include assay acceptance crite- ria in conjunction with the analysis of a suitable product reference standard or assay control. The chosen criteria should be in-line with the intended purpose of the method. Results from the analysis of the reference standard/assay control should be plotted and trended to monitor method perfor- mance over time. There should be a well-defined plan in place on how to address any assay drift; similarly, a strategy should be available for transi- tioning from an old lot of reference standard/assay control to a new one. Method qualification After completing the development and depending on the stage of clinical development, it is important to perform either a method qualification, recom- mended for methods used for analysis of products in pre-investigational new drug application (IND) evaluation up to Phase I, or a method validation, for methods used to support products in Phase II and beyond. Validation work should be performed in accordance to ICH Q2(R1) (4) and the draft guid- ance issued by FDA (5). Briefly, when validating an analytical method, it is good practice to minimally ensure that: • All systems used in the execution of the validation study be qualified or calibrated, as appropriate. • Analysts are fully trained on the method. • Method validation requirements are clearly de- fined. • Representative materials are used during the validation.

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