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978-3-8439-0818-4, Reihe Ingenieurwissenschaften

Sonja Wolfrum
Physical Degradation of Proteins in Well-defined Flow Fields

149 Seiten, Dissertation Universität Erlangen-Nürnberg (2013), Softcover, A5

Zusammenfassung / Abstract

In recent years, the interest in biopharmaceuticals such as recombinant proteins and monoclonal antibodies has risen sharply as these molecules can be used to treat various human diseases. During their manufacturing the formation of sub-visible and visible aggregates due to external stress is a common issue. The presence of aggregates in a liquid protein formulation is critical as there exists the risk of causing an immune response after the injection in the human body. Thus, strict specifications are given for the market admission of a protein-based product.

For this reason, during the development of biopharmaceuticals a large number of pre-tests (screening tests) are performed in the lab-scale. Within these studies the proteins are exposed to extreme stress conditions (high temperatures, high shear stress, pH gradients, etc.) and the physical degradation inculding aggregation, denaturation and adsorption is analyzed. By testing different formulation conditions the right mixture of co-solutes which stabilize the protein against degradation is developed. For successful screening experiments, the right experimental setup and parameter set has to be found which simulates the conditions the protein molecules will experience during the manufacturing process. Furthermore, well-defined stress conditions allow to derive a clear relation between the applied stress and the response of the molecules and thus, lead to a better understanding of the underlying degradation mechanism.

The present work addresses the physical degradation of proteins due to applied fluid stress.

A flow apparatus was developed for lab-scale studies to stress protein solutions in well-defined flow fields that contain both, shear and elongation. Integrated analytical methods allow monitoring the formation of aggregates and the perturbation of the native protein structure directly in the flow field. Due to the real-time measurements novel insights in the mechanism of protein aggregation in the flow fields are provided. Susceptibility tests of various proteins were performed under defined flow conditions and the aggregation behavior is related to individual structure properties of the native proteins. This enables to identify structure elements that are linked to an increased resistance of proteins against fluid stress.

In addition to different proteins, the physical degradation behavior of two monoclonal antibodies (mAbs) in flow fields was investigated.