Quality by design for the downstream processing of biopharmaceuticals

Abstract

This thesis explores the concept of “Quality by Design” (QbD) as proposed by the FDA and demonstrates how this concept can be used and applied to the manufacture of biopharmaceutical proteins. QbD principles and approaches have been adopted in carrying out the development of unit operations that are typical for most biopharmaceutical products and to carry out studies that are required for the successful filing of a biopharmaceutical application. The introduction defines Quality by Design and discusses why this is an important topic. To better understand and define QbD, the history of the concept is reviewed with emphasis on how it came to be applied in the area of Pharmaceutical development, how it should be defined in practice and how it has been applied to the manufacture of biopharmaceuticals. Protein A chromatography is the most commonly used technique for the manufacture of monoclonal antibodies today. To make the results of this work widely applicable a QbD approach is developed to compare the suitability of different Protein A resins for the manufacture of a monoclonal antibody product with the aim of selecting an optimal or preferred Protein A resin for the purification of a monoclonal antibody at industrial scale. Resins identified for closer scrutiny are used to purify a biopharmaceutical monoclonal antibody and the product of the resins is compared to identify a Protein A resin to act as the basis of a manufacturing platform. Experimental work is also directed at determining how well the standard models used to explain the equilibrium binding of Protein A to an IgG molecule represent the binding behaviour seen in practice using an industrially-relevant IgG feedstock. As a result of this research a preferred equilibrium model for use with Protein A and IgG-conditioned medium is identified. Isothermal titration calorimetry (ITC) is used to determine the mechanistic reasons why one Protein A resin (Mab Select SuRe™) was superior to other protein A resins in its performance. It is shown that Mab Select SuRe™ has a markedly higher Ka compared to native Protein A and the ability to bind the monoclonal antibody under pH conditions much lower than native Protein A. Further, the affinity of native Protein A for IgG is shown to be increased by increasing salt concentration whereas Mab Select SuRe™ is shown to be insensitive to the salt concentration during binding. QbD concepts and techniques are then applied to a chromatography resin lifetime study, a unique and specific requirement for biopharmaceutical manufacture, to improve the efficiency of the study and gain more knowledge from limited experimentation. A resin lifetime study is carried out using a model biopharmaceutical protein feedstock and the data analysed using statistical quality control techniques to understand how these techniques, an important part of QbD, can be used to improve understanding and control of the manufacturing system. While chromatography is the most commonly used technology for downstream purification of biopharmaceuticals, tangential flow filtration (TFF) is probably the second most common unit operation in the manufacture of these products. To determine how QbD can be applied to TFF a case study is developed in applying QbD techniques and mechanistic understanding to the development of a TFF unit operation for a biopharmaceutical protein. Multiple membrane types and operating modes are compared for use with the protein. QbD techniques are used to optimize the manufacturing settings using the most preferred filter membrane to produce a robust and reliable manufacturing process at commercial manufacturing scale. The results of scaling up and using the developed process at full commercial manufacturing scale are also reported and compared to the laboratory scale development to confirm the effectiveness of the QbD development approach.