(138b) An Integrated Quality by Design (QbD) Approach towards Prediction of Protein Degradation In Heated Mixing Vessels by Computational Fluid Dynamics

Combined heating and mixing of protein solutions is a process often found in the pharmaceutical industry during the manufacture of biopharmaceutics. In the case of proteins or enzymes, the local anisotropy of temperature and the exposure time to such temperature may have a major effect on the degradation of the API(s) in the processed solution or emulsion and consequently, the quality of the biopharmaceutical medicinal product could be jeopardized. Hence, in order to assure patient safety and efficacy of the product and to avoid out-of-specification results leading to rejection of large amounts of costly compounds, optimal combinations of mixing operational parameters have to be evaluated.

In our study, a combined QbD and computer simulation approach is employed to (1) define a representative critical quality attribute of a biopharmaceutical manufacturing process (i.e., thermal degradation of the active pharmaceutical ingredient), (2) identify potentially critical input factors that may affect this critical quality attribute and (3) define and perform activities for computer simulation based process characterization. Data are then used to map out a knowledge space, providing parameters to define a design space as its subset to set up an appropriate control strategy.

In our work rotational speed and solution viscosity have been considered as potentially critical input factors leading to inhomogeneous temperature distribution resulting in increased degradation of the mixture components. Simulations have been performed according to statistically designed experiments. The degradation laws, which apply to particular enzymes and proteins, are well known from literature and have been directly integrated in the simulation model. The effects have been represented by means of a degradation index.

Results show that some region of the processed solution could present stagnation points or recirculation zones where energy cannot be exchanged by convective motions. On the contrary, in other regions higher velocity gradients, hence stronger convective motions can be detected. These fields are the main causes of the inhomogeneous temperature distribution (hot and cold spots) resulting in increased degradation of the mixture components. It is shown that the combination of lower rotational speed and higher viscosity provides the highest degradation index for the biological solution.

Data and knowledge generated in our study can be used as a generic approach to design efficient heated mixing processes for different API-excipients mixtures providing optimal performance and quality output. Moreover, the developed correlations between degradation of mixture components as one major critical quality attribute of biopharmaceutical manufacturing processes and critical process parameters can result in better quality assurance and validation strategies, taking into account more efficient in-process-controls and continued process verification throughout the life cycle of the (bio-)pharmaceutical product.