A clear mandate has emerged throughout the industry to improve the timelines from candidate identification to phase 1 clinical trials. The goal of reducing the time to phase 1, combined with increasing titers and regulatory requirements, presents novel challenges to downstream development. To meet these challenges, Boehringer Ingelheim has developed the BI-Purification Excellence (BI-PurEx) strategy to shorten the development time to clinical trials while improving process understanding during early development phases to ensure a safe, effective, and competitive process for each novel therapeutic protein. BI-PurEx is an innovative downstream development strategy that maximizes efficiency and flexibility to specifically focus on the most critical aspects of each project. Through the development and application of this modular and flexible technology platform, Boehringer Ingelheim can deliver a robust, efficient, and scalable process with significant process understanding within the timeline of a platform process.

Integrated Decision Tree and Analytical Toolbox for Lean Development

The BI-PurEx strategy is based on an integrated decision tree that is designed to streamline the development of each process step and balance development efforts with results. The decision tree is based on extensive experience with purification technologies and analytical methods to build understanding of both the process and the therapeutic molecule to provide scientific data to drive development decisions. BI-PurEx is a technology platform rather than a platform process. The strategy is designed around preferred process steps and takes advantage of a set of highly sensitive analytical tools and automated screening technologies to efficiently develop each unit operation in a downstream process.

An example of improving efficiency is the high-throughput Thermofluor assay designed to screen molecular stability under various buffer and process conditions. Protein stability data from this assay allow a developer to define conditions for purification columns within 60 minutes, with very small material requirements. These buffer stability data are used to focus the screening efforts using the Rapid Automated Protein Purification Technology (RAPPTor®) to efficiently optimize chromatography steps. RAPPTor® integrates both a highly flexible and automated purification screening platform with automated analytical assays to produce a complete data set for an optimization screen in a single 24-hour experiment. The automated plate set-up protocols within RAPPTor® gives a developer the flexibility to screen any combination of resins to cover a large parameter space. The implementation of design of experiments with RAPPTor® screening improves the understanding of the parameter space and results in the identification of optimized and scaleable purification conditions in addition to providing information on the robustness of each customized purification step.

Summary

The result of the BI-PurEx strategy is a more efficient and effective, lean development process to reduce timelines in early development. In addition, through the integration of novel analytical assays and RAPPTor® high-throughput screening into this technology platform, process knowledge is gained throughout process development to maintain a critical focus on future market supply. Through the integration of design of experiments and the application of quality by design, the design space of each unit operation within a process is understood from the early stages of development. The increased process understanding gained through BI-PurEx significantly reduces comparability risks and streamlines scale-up for later clinical phases and market. In all, the BI-PurEx Strategy delivers an optimized and robust purification process for each novel therapeutic protein with significant process understanding and lower risk resulting in the same or better timeline than a platform process.

About the Author

Author Details
Dr. Joey M. Studts is an associate director of purification development at Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Strasse 173, 55216 Ingelheim am Rhein, Germany; www.boehringer-ingelheim.com.