The primary point of control for many critical quality attributes is the production bioreactor. The purification steps are designed to ensure the purity of the final drug substance through the removal of process- and product-related impurities such as host cell protein, host cell DNA, cell culture media components and high molecular weight (HMW) species. Other aspects of the protein, such as glycosylation and charge profile, are not typically modified via chromatography steps, although there are exceptions. The in-process hold points can also alter product quality (e.g. charge profile) depending on the conditions during the hold, such as pH and temperature. Each unit operation is characterized independently using scale-down models of the bioreactor, centrifuge and chromatography columns. Mathematical models are generated to predict the effects of input parameters on product quality at each step. The final control strategy, however, must encompass the combined impact of the entire process including raw material, bioreactor, chromatography, filtration, in-process hold and drug substance handling effects. This paper will present case studies from Bristol-Myers Squibb highlighting the integrated approach we have utilized to develop control strategies for biologics manufacturing processes.After defining the acceptable ranges for the input/operating parameters in the production bioreactor and primary recovery steps, the expected variation in CQAs at harvest can be predicted from the process characterization models. These worst-case outputs in the harvest are evaluated for their predicted impact to the performance of the capture chromatography step and so on through subsequent steps of the process. Once the worst-case region of the design space is identified for a CQA, studies are conducted at laboratory or pilot scale linking upstream and downstream steps to demonstrate adequate control of the CQA.  Several examples of integrated design space mapping and process improvements for better control of host cell protein, HMW and charge profile will be presented.

Quality by design case studies: Integration of cell culture, primary recovery and purification process characterization

243rd National Meeting (2012)

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