Analytical Quality By Design (AQbD) como ferramenta no desenvolvimento e validação de método analítico por cromatografia gasosa

Abstract

The U.S. Department of Health, through their ICH guides, describes Quality by Design (QbD) as "a systematic approach to pharmaceutical development that begins with predefined objectives and emphasizes product, process understanding and control, based on sound scientific data and quality risk management." The concept of QbD can and should be applied to analytical methods, since they are an integral part of pharmaceutical development. Thus, arises Analytical Quality by Design (AQbD), a justifiable and recommended procedure to reduce out-of-specification results, achieve a high degree of robustness, and a cost-effective analytical method and regulatory flexibility. Design of Experiments (DoE) is an important tool set that includes screening and optimization designs to study variation in factors and determine their effects on responses, thus identifying which factors are most significant. This work aimed to apply the concepts of AQbD tools in the development and validation of an analytical method for the residual solvents acetone, methanol, dichloromethane and chloroform in the raw material Bisoprolol Hemifumarate by gas chromatography with flame ionization detection (FID) and headspace transferline (HS) injection mode. In the first step of the study, a factor screening was performed using the Plackett-Burman design to define the best response conditions with maximization of signals and recovery of analytes. With the variables filling pressure and incubation temperature being the most significant, the central composite design (CCD) was used as an optimization experiment in 5 levels and 11 trials, 4 in cube, 4 in axial and 3 central points, with α=√2 where, at the end, a tendency to better results was obtained. A robustness study, a parameter typically performed in method development, followed with the best condition of the parameters fill pressure and incubation temperature, in addition to others typically used in robustness. Then, the analytical validation step was performed according to RDC 166/2017 demonstrating that the method is selective, linear, precise and accurate method. The application of the AQbD tools allowed a better understanding of the variables, leading to the development of an analytical method by gas chromatography in a rational way and achieving all the criteria required.