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Quality by Design

Quality cannot be tested into products. Quality should be built in by design.


As of 2013, all new drug registrations at the FDA require the Quality by Design (QbD) approach, which changes the way we develop pharmaceutical products.


Fresenius Kabi has integrated the QbD concept into its routine development of new innovative formulations and generic drugs. Using both internal expertise and advice from outside consultants, we have successfully completed the QbD-based development process for several formulations and are now able to offer the expertise we have gained to our customers. We can offer QbD support for your next pharmaceutical project, providing you with the full range of formulation technologies, including aqueous formulations (terminally sterilized or aseptic manufacturing), emulsions, liposomal formulations, suspensions and lyophilisates.


The QbD concept goes back to 2002, when the FDA launched a new GMP initiative titled “Pharmaceutical cGMPs for the 21st Century – a Risk-Based Approach”. The goal of this strategic action was an improvement of the registration processes, minimizing drug risks to patients, as well as fostering innovation within the pharmaceutical industry, encouraging continuous improvements and utilizing new manufacturing processes and technologies.


Whereas the “traditional” approach was to limit all potentially critical parameters in a very narrow range, QbD aims to introduce a scientific understanding in the choice of the parameters. Since the actual ranges of critical parameters were often not known or at least not thoroughly understood, parameters were often chosen in a very limited range regardless of their scientific basis. By tightening up all process parameters through different quality systems (e.g. SOPs, IPC, etc.), drug quality and reproducibility were proven through three validation batches. These procedures and fixed process parameters are part of the registration, resulting in a legal restriction of deviations and freezing of the manufacturing process. As a consequence, the data collected during manufacturing (IPC, quality) provide only limited information on the chemical and physical reactions during the manufacturing process, and hinder continuous accumulation of knowledge and improvements.


In contrast, QbD aims to bring in a detailed understanding about the manufacturing process and a fundamental knowledge about parameters that eventually should also result in improved product quality. An essential part of the QbD concept is to understand all variations during the manufacturing process. These variable parameters are to be controlled by appropriate measurements in the form of in-process controls.


QbD starts with a risk analysis for identifying all potential parameters that might cause deviations of the process and have consequences for the product quality. By bringing together our experts dealing with galenic development, scaling-up process and commercial manufacturing, we can efficiently identify critical parameters relevant for both registering the product and guaranteeing a smooth scale-up and commercial manufacturing process. By having sophisticated pharmaceutical development procedures in place for determining the parameter space of a range of factors (e.g. oxygen sensitivity, photostability, influence of pH range, homogenization parameters for emulsions etc.), we can determine the critical parameters relevant for product quality.


In order to achieve this goal, one can choose a multidimensional approach during pharmaceutical development, testing the influence of two or more parameters systematically. Through specific statistical test plans, so called DoE (Design of Experiments), one can identify the parameter space with the help of software supported statistical tools in which product quality stays within specifications. Once these parameters can be measured in real time during manufacturing, it is no longer necessary to freeze them, because the manufacturing can occur within the investigated parameter space, resulting in a product with consistent quality with very small deviations.


Overall, the QbD approach puts a focus on the development phase, easing the consequent scale-up and manufacturing process and improving drug quality in the long run.