Characterization of a Monoclonal Antibody Cell Culture Production Process Using a Quality by Design Approach |
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Authors: | Brian Horvath Melissa Mun Michael W Laird |
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Institution: | (1) Late Stage Cell Culture, BioProcess Development US, Genentech—a member of the Roche Group, San Francisco, CA, USA |
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Abstract: | The goal of quality by design (QbD) in cell culture manufacturing is to develop manufacturing processes which deliver products
with consistent critical quality attributes (CQAs). QbD approaches can lead to better process understanding through the use
of process parameter risk ranking and statistical design of experiments (DOE). The QbD process starts with an analysis of
process parameter risk with respect to CQAs and key performance indicators (KPIs). Initial DOE study designs and their factor
test ranges are based on the outcomes of the process parameter risk ranking exercises. Initial DOE studies screen factors
for significant influences on CQAs as well as characterize responses for process KPIs. In the case study provided here, multifactor
process characterization studies using a scale-down model resulted in significant variation in charge heterogeneity of a monoclonal
antibody (MAb) as measured by ion-exchange chromatography (IEC). Iterative DOE studies, using both screening and response
surface designs, were used to narrow the operating parameter ranges so that charge heterogeneity could be controlled to an
acceptable level. The data from the DOE studies were used to predict worst-case conditions, which were then verified by testing
at those conditions. Using the approach described here, multivariate process parameter ranges were identified that yield acceptable
CQA levels and that still provide operational flexibility for manufacturing. |
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