The Protein A capture step used in monoclonal antibody manufacturing is seen as a process bottleneck, as well as being one of the most expensive unit operations to perform within downstream purification. The characterization of such processes is an arduous task that requires significant experimental effort. Through the use of a model assisted methodology to process characterization for continuous processes, the experimental burden may be alleviated allowing for resources to be reallocated to other development areas. In this study we introduce three process characterization approaches toward validation of continuous twin-column capture chromatography (CaptureSMB), referred to as “standard”, “model assisted” and “hybrid”. All are based on a traditional risk-based approach, using process description, risk analysis, Design-of-Experiments (DoE), and statistical analysis as essential elements. The “standard” approach uses a traditional experimental DoE to explore the design space of the high-ranked process parameters for the continuous process. Due to the larger number of process parameters in the continuous process, the DoE is extensive and includes a larger number of experiments than an equivalent DoE of a single column batch capture process. In the investigated case, many of the operating conditions were practically infeasible, indicating that the design space boundaries had been chosen inappropriately. To reduce experimental burden and at the same time enhance process understanding, an alternative “model assisted” approach was developed in parallel, employing a chromatographic process model to substitute experimental runs by computer simulations. Using the “model assisted” approach, only experimental conditions that were feasible in terms of process yield constraints (&gt; 90%) were considered for statistical analysis. The “model assisted” approach included an optimization that identified potential boundaries of the design space automatically and contributed to increased process understanding compared to the “standard” approach. In this work, a “hybrid” approach was also used containing the general concepts of the “standard” approach but substituting a number of its experiments by computer simulations. The presented approaches contain essential elements of the FDA’s process validation guidelines.

Model assisted process characterization and validation for a continuous two-column protein A capture process

2019 Spring National Meeting

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