Application of Quality by Design Principles to Legacy Drug Products

The concept of Quality by Design (QbD) is of paramount importance in designing and developing reproducible and robust drug products, processes and analytical methods, thus enabling regulatory compliance and ensuring manufacturability. Risk assessment, design space, and control strategy constitute the key elements of the QbD framework. In this paper, a data-based approach to developing robust pharmaceutical processes is presented and illustrated with an application to a drug product during a site transfer process. The key objective in applying QbD principles is to ensure that the product is designed and manufactured to consistently meet quality requirements. The approach presented simultaneously considers the variability in raw materials, quality critical process parameters and critical quality attributes. By nature, large historical databases of raw material (active ingredients and excipients) and process data exists for legacy products. Multivariate statistical models were employed to extract knowledge on critical variables. Furthermore, a number of design of experiments (DOE) were performed in the joint space of the raw materials and the manipulated process variables to develop the design space and control strategy with feedback control. The result was a joint space that combines the interaction of all the input variables such as raw materials and process parameters that have been proven to provide high quality. Throughout this paper, the use of multivariate statistical analysis and DOE and how they are applied to define meaningful raw materials specification and design space to achieve QbD are discussed.