The use of platform technology in the biopharmaceutical industry facilitates a holistic approach to process development that avoids looking at each process unit operation individually but instead allows development of consecutive purification strategies. By considering different combinations of consecutive steps, such as the polishing chromatography order after product capture, conditioning between unit operations can be minimized and holding times are reduced. Moreover, the overall process can be optimized instead of optimizing each unit operation individually.

It becomes apparent that the development of combined chromatography steps cannot easily be performed experimentally because the number of variables increases with each additional purification step.

Mechanistic modeling is capable of solving this challenge by performing thousands of simulations to optimize consecutive chromatography steps, which can revolutionize biopharmaceutical process development.

In our study, we compared the individual optimization of three unit operations (capture and polishing steps) to holistic multistep optimization. First, load density and buffer conditions were optimized with respect to yield and purity for each unit operation. Then capture and polishing were optimized with a holistic multistep mechanistic modeling approach to achieve a higher process performance.

We also investigated how mechanistic modeling can be used for robustness testing to tremendously reduce the experimental workload. The robustness of each step is determined by, for example, quantifying the impact of variability in ionic capacity or of wash conditions on yield and purity.

In summary, we demonstrated how combined mechanistic modeling of consecutive steps enables the holistic optimization of the whole process at once. With the multistep model, we can not only optimize and investigate the robustness of each step but can also evaluate the impact of variation in one chromatography step on the subsequent steps and the overall process performance.

Lena Enghauser

Appearances