Evaluation of multi-column chromatography processes for the industrial manufacturing of monoclonal antibodies

Abstract : The biopharma industry sees most of the therapeutics based on monoclonal antibodies shifting from the blockbuster status to a niche and personalized market, in a globalized world. To continue the development of new drugs, existing and future production facilities have to increase in flexibility and productivity. Multi-column chromatography is one of the potential tools to make that happen, as the technology did in the last decades for the petro and for the food industries. In parallel, the protein A capture step remains a must for all purification trains of the industrial manufacturing capacities due to its specificity and capability to easily reach a high level of purity in a single step. This research work is an evaluation of the multi-column chromatography processes combined with the protein A capture step to increase the productivity and the applicability of current purification platforms for clinical and commercial manufacturing activities. In every part of the work, prepacked chromatography columns have been evaluated as an enabler of multi-column processes, freeing the operational teams from the packing activities burden and associated infrastructures. A first chapter describes the traditional literature review and current state-of-the-art in the relevant field, together with a theoretical description of chromatography in general, and multi-column processes in particular. In a second chapter, several recent, commercially-available protein A resins have been compared when involved in 2 multi-column processes: the Sequential Multi-Column Chromatography (SMCC) process and the Parallel Batch process, and compared to a traditional mono-column process. Based on a simulation and optimization software, both processes proposed have been compared in terms of gains and performance. Recommendations on the resin and the type of process to be selected have been proposed. In a third chapter, the impact of multi-column processes on the resulting quality and purity has been addressed through several sets of experiments. The impact of the sequential organization of an SMCC process has been evaluated. The impact of the residence time on the washing and the elution steps has also been evaluated, in order to potentially speed-up the capture step. Third, the impact of the resin saturation on the design of the washing step has been assessed. Eventually, cycling studies have been performed to detect if the different multi-column processes were impacting differently the resin’s lifetime and performance. In a fourth chapter, a simplified calculation tool has been designed to propose simple sizing of multi-column processes, accounting more accurately for Merck’s production constraints. This tool has been used to evaluate the performance of Parallel Batch processes for 2 case-studies. Eventually, in a more exploratory chapter, the simplified tool previously developed has been adapted to evaluate the feasibility and the primary constraints of continuous capture steps, characterized by either a continuous loading step or a continuous elution step.
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Submitted on : Thursday, May 16, 2019 - 12:21:45 PM
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Nicolas-Julian Hilbold. Evaluation of multi-column chromatography processes for the industrial manufacturing of monoclonal antibodies. Chemical and Process Engineering. Université de Lorraine, 2018. English. ⟨NNT : 2018LORR0253⟩. ⟨tel-02131440⟩

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