Desenvolvimento e otimização de sistemas conservantes empregando os conceitos de Qualidade por Design (QbD) e Tecnologia Analítica de Processos (PAT) / Development and optimization of preservative systems using Quality by Design (QbD) and Process Analytical Technology (PAT) concepts

Recentemente, produtos farmacêuticos e cosméticos com concentrações mínimas de parabenos e outros conservantes ganharam e apelo comercial e de segurança, devido à controvérsia sobre a segurança dos conservantes. No entanto, o uso de conservantes é essencial para garantir a conservação microbiana de produtos cosméticos e farmacêuticos durante o seu uso. Neste trabalho, desenvolveu-se um método quimiométrico de espectroscopia no infravermelho com Fourier transform near-infrared (FTIR) para prever a eficácia de sistemas conservantes em produtos farmacêuticos e cosméticos tópicos usando os conceitos de Quality by design (QbD) e Process Analytical Technology (PAT). A abordagem de QbD foi usada para determinar a eficácia antimicrobiana frente aos microrganismos: Candida albicans (ATCC 10231), Escherichia coli (ATCC 8739) e Staphylococcus aureus (ATCC 6538), em funções das concentrações de parabenos, e determinar a região de Design Space, empregando o delineamento de compóstio central (CCD) Todas as 15 formulações preparadas foram analisadas utilizando um espectrofotômetro (FTIR) equipado com aparato de Attenuated Total Reflectance (ATR). Os modelos de regressão por Partial Least Squares (PLS) para predição dos "slopes" das curvas de morte microbiana em função dos espectros ATR/FTIR foram bem ajustados, com R2 e R2-predição de 0,9937 e 0,8921, 0,9947 e 0,8783, e 0,9957 e 0,9222 para Candida albicans (ATCC 10231), Escherichia coli (ATCC 8739) e Staphylococcus aureus (ATCC 6538), respectivamente. O método FTIR proposto aplicado em uma abordagem de PAT foi capaz de prever a eficácia do sistema conservante em tempo reduzido. Este método de predição de silício permitirá um controle lote-a-lote da eficácia do sistema conservante de produtos farmacêuticos e cosméticos

Recently, pharmaceuticals and cosmetics with minimal concentrations of parabens and other preservatives have gained and commercial and safety appeal due to controversy over the safety of preservatives. However, the use of preservatives is essential to ensure the microbial conservation of cosmetic and pharmaceutical products during use. In this work, a chemometric method of infrared spectroscopy with Fourier transform (FTIR) was developed to predict the effectiveness of preservative systems in pharmaceutical products and topical cosmetics using the concepts of Quality by design (QbD) and Process Analytical Technology (PAT). The QbD approach was used to determine antimicrobial efficacy against candida albicans (ATCC 10231), Escherichia coli (ATCC 8739) and Staphylococcus aureus (ATCC) microorganisms 6538), in functions of paraben concentrations, and determine the Design Space region, employing the design of central composite (CCD). All 15 prepared formulations were analyzed using a spectrophotometer (FTIR) equipped with Attenuated Total Reflectance (ATR). The Partial Least Squares (PLS) regression models for the prediction of the slopes of microbial death curves as a function of ATR /FTIR spectra were well adjusted, with R2 and R2-prediction 0.9937 and 0.8921, 0.9947 and 0.8783, and 0.9957 and 0.9222 for Candida albicans (ATCC 10231), Escherichia coli (ATCC 8739) and Staphylococcus aureus (ATCC 6538)respectively. The proposed FTIR method applied in a PAT approach was able to predict the effectiveness of the preservative system in reduced time. This method in silico prediction will allow a batch-to-lot control of the effectiveness of the preservative system of pharmaceuticals and cosmetics

Design of Experiments (DoE) applied to Pharmaceutical and Analytical Quality by Design (QbD)

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 (R2, R2-adj, and R2-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.