According to Quality by Design (QbD) concept, quality should be built into product/method during pharmaceutical/analytical development. Usually, there are many input factors that may affect quality of product and methods. Recently, Design of Experiments (DoE) have been widely used to understand the effects of multidimensional and interactions of input factors on the output responses of pharmaceutical products and analytical methods. This paper provides theoretical and practical considerations for implementation of Design of Experiments (DoE) in pharmaceutical and/or analytical Quality by Design (QbD). This review illustrates the principles and applications of the most common screening designs, such as two-level full factorial, fractionate factorial, and Plackett-Burman designs; and optimization designs, such as three-level full factorial, central composite designs (CCD), and Box-Behnken designs. In addition, the main aspects related to multiple regression model adjustment were discussed, including the analysis of variance (ANOVA), regression significance, residuals analysis, determination coefficients (R 2 , R 2-adj, and R 2-pred), and lack-of-fit of regression model. Therefore, DoE was presented in detail since it is the main component of pharmaceutical and analytical QbD.

The aim of this work was to develop and validate a new microbiological assay to determine potency of linezolid in injectable solution. 2(4) factorial and central composite designs were used to optimize the microbiological assay conditions. In addition, we estimated the measurement uncertainty based on residual error of analysis of variance of inhibition zone diameters. Optimized conditions employed 4 mL of antibiotic 1 medium inoculated with 1% of Staphylococcus aureus suspension, and linezolid in concentrations from 25 to 100 µg mL(-1). The method was specific, linear (Y=10.03X+5.00 and Y=9.20X+6.53, r(2)=0.9950 and 0.9987, for standard and sample curves, respectively), accurate (mean recovery=102.7%), precise (repeatability=2.0% and intermediate precision=1.9%) and robust. Microbiological assay׳s overall uncertainty (3.1%) was comparable to those obtained for other microbiological assays (1.7-7.1%) and for determination of linezolid by spectrophotometry (2.1%) and reverse-phase ultra-performance liquid chromatography (RP-UPLC) (2.5%). Therefore, it is an acceptable alternative method for the routine quality control of linezolid in injectable solution.

Microbiological agar diffusion methods are widely employed for clinical, pharmacological and industrial purposes.

No abstract