An enzymatic modification of a therapeutic protein coupled to size-exclusion chromatography for separation and recycling of unreacted protein was studied. A risk based approach needs to consider both process steps together to capture all important interactions. This was achieved by developing mechanistic models for the reaction and SEC steps, establishing the causal links between process conditions and product quality. Model analysis was used as a complement to the qualitative risk assessment, and design space and critical process parameters were identified. The simulation results gave an experimental plan focusing on the �worst case regions� in terms of product quality and yield. This way the experiments were used to verify both the suggested process and the model results. This work shows all steps necessary for a model assisted process analysis; from model development through experimental verification. The methodology is well suited for a quality by design approach to process development.

Risk analysis of integrated process steps – a model assisted approach

243rd National Meeting (2012)

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