Analytical Characterisation of Biotherapeutic Process Residuals and Critical Quality Attributes

Downstream processing is an integral part of the manufacturing process of biotherapeutics. The downstream process plays a crucial part in determining the final product purity by removing process impurities, clearing viruses, and ensuring evaluating critical quality attributes are within the defined process specifications. The monitoring of process impurities and critical quality attributes is a fundamental task that manufacturers must perform to ensure both patient safety and compliance with global regulatory agencies. Traditionally, product quality attributes are determined and monitored via analytical characterisation assays with the final product specification testing being performed on the drug substance and subsequent drug product in quality control laboratories. Biotherapeutics are required to be fully characterised prior to market authorisation and submission of a biologic licencing application, however the use of characterisation strategies do not end there and continue throughout a molecule’s lifecycle for further optimisation and refinement, such as in the case of product reformulation. Mass spectrometry is a key analytical technology employed in the characterisation of biotherapeutics, however in recent years, the technology platform has become more robust and available, resulting in its increased use in the current Good Manufacturing Practices environment. The findings described in this work describe novel approaches for the utilisation of mass spectrometry in the batch release quality environment. The methodology and workflows developed have been directly applied to the characterisation of biotherapeutics during downstream purification, not only in an industry environment but also a current Good Manufacturing Environment. The novel approaches offer rapid and robust profiling of process residuals and critical quality attributes while also ensuring compliance with ICH and FDA guidelines. In addition to these compliant workflow and methods detailed in chapter 2 through 4, chapter 5 describes a novel approach of evaluating host cell proteins in continuous manufacturing during the Protein A purification unit operation. The findings described demonstrate the applications of a lab scale study for optimisation of the downstream process to ultimately shorten cycles times while increasing product yield.