RESUMEN
Modern drug product development is expected to follow quality-by-design (QbD) paradigm. At the same time, although there are several issue-specific examples in the literature that demonstrate the application of QbD principles, a holistic demonstration of the application of QbD principles to drug product development and control strategy, is lacking. This article provides an integrated case study on the systematic application of QbD to product development and demonstrates the implementation of QbD concepts in the different aspects of product and process design for brivanib alaninate film-coated tablets. Using a risk-based approach, the strategy for development entailed identification of product critical quality attributes (CQAs), assessment of risks to the CQAs, and performing experiments to understand and mitigate identified risks. Quality risk assessments and design of experiments were performed to understand the quality of the input raw materials required for a robust formulation and the impact of manufacturing process parameters on CQAs. In addition to the material property and process parameter controls, the proposed control strategy includes use of process analytical technology and conventional analytical tests to control in-process material attributes and ensure quality of the final product.
Asunto(s)
Alanina/análogos & derivados , Tecnología Farmacéutica/métodos , Tecnología Farmacéutica/normas , Triazinas/química , Adhesividad , Alanina/química , Alanina/normas , Química Farmacéutica , Cromatografía Líquida de Alta Presión , Composición de Medicamentos , Liberación de Fármacos , Embalaje de Medicamentos , Estabilidad de Medicamentos , Tamaño de la Partícula , Control de Calidad , Solubilidad , Espectroscopía Infrarroja Corta , Comprimidos Recubiertos , Triazinas/normasRESUMEN
A quality by design approach was applied to the development of brivanib alaninate tablets. Brivanib alaninate, an ester pro-drug, undergoes hydrolysis to its parent compound, BMS-540215. The shelf-life of the tablets is determined by the rate of the hydrolysis reaction. Hydrolysis kinetics in the tablets was studied to understand its dependence on temperature and humidity. The BMS-540215 amount versus time profile was simulated using a kinetic model for the formation of BMS-540215 as function of relative humidity in the environment and a sorption-desorptiom moisture transfer model for the relative humidity inside the package. The combined model was used to study the effect of initial tablet water content on the rate of degradation and to identify a limit for initial tablet water content that results in acceptable level of the degradant at the end of shelf-life. A strategy was established for the moisture and degradant control in the tablet based on the understanding of its stability behavior and mathematical models. The control strategy includes a specification limit on the tablet water content and manufacturing process controls that achieve this limit at the time of tablet release testing.
Asunto(s)
Alanina/análogos & derivados , Inhibidores de la Angiogénesis/química , Profármacos/química , Triazinas/química , Agua/química , Alanina/química , Alanina/normas , Inhibidores de la Angiogénesis/normas , Química Farmacéutica , Simulación por Computador , Estabilidad de Medicamentos , Humedad , Hidrólisis , Cinética , Modelos Químicos , Profármacos/normas , Control de Calidad , Solubilidad , Comprimidos , Tecnología Farmacéutica/métodos , Temperatura , Triazinas/normas , Agua/normasRESUMEN
Many industries mix granular materials of different sizes and shapes. Product quality and consistency are often compromised by demixing of constituent components. Not only is this practically problematic but it is also philosophically unsettling, for on smaller colloidal scales, systems consisting of particles differing by size and shape display quantitatively predictable transitions between mixed and separated phases. We report here that patterns and segregation transitions analogous to those seen in colloidal systems can be found in granular blends differing in shape, concentration, and temperature. This provides insights into the mechanisms of granular segregation.