A qualified chromatography scale-down model is prerequisite for process characterization of manufacturing processes.  Due to wall effects, small diameter columns can be difficult to pack, especially for certain resin types.  Difficulties in achieving the bed compression specified for manufacturing scale columns can result in practically different protein loading at the particle scale when the loading is specified according to packed bed volume.  For challenging separations between product charge variants of a fusion protein studied here, IEX column loading is classified as a critical process parameter (CPP) that has significant impact on critical performance attributes (CPAs).  A correction to the column loading based only on bed compression appears inadequate to ensure equivalent column performance and to establish a representative scale-down model during characterization of the IEX step for a second generation process.  In this work, mechanistically-based column simulation is used to assess the impact of bed compression over a wide range of operating conditions with minimal experimental data.  This approach allows for efficient identification of representative operating conditions (e.g. protein loading) for scale-down studies, and once verified, can help determine appropriate operational conditions for columns of various bed compression conditions during process scale-up.

Use of chromatography simulation and fundamental measurements to determine equivalent IEX loading under different bed compression conditions for a fusion protein

251st National Meeting (2016)

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