Accelerating process development for biologics on an automated, pharmacy-scale manufacturing system

Abstract

The conventional large-scale, centralized, single-product manufacturing model for biologic drugs does not allow for the economical production of drugs for small patient populations or for the distribution of these drugs in developing countries. A decentralized model featuring small-scale, fully automated, multi-product manufacturing of biologics at the point-of-care could address some of these issues. To truly realize the benefits of such a manufacturing paradigm, it must also be paired with rapid process development methods for the production of new molecules. In this thesis, we describe the development of a bench-scale, automated, multi-product manufacturing system for the end-to-end production of hundreds to thousands of doses of clinical quality protein medicines in about three days. We then demonstrate the application of this platform to the manufacture of a trivalent vaccine in a single campaign through co-expression and co-purification.

We further demonstrate new methodologies for the accelerated development of manufacturing processes to produce new molecules on the system including a strategy for the development and optimization of fully integrated, multi-column processes for straight-through chromatographic purification, and the development of a platform process for the production and purification of single-domain antibodies. We then propose a workflow for the collection of a dataset relating the chromatographic behavior of host-cell proteins to their biophysical characteristics with the goal of building an in silico tool for the prediction of purification processes for any new molecule. Finally, we propose a platform approach, as opposed to a platform process, for the development of manufacturing processes for new biologics which is based on gaining a deeper understanding of process development challenges with regard to the host and to the molecule itself.

Ultimately, we believe that the combination of a small-scale, automated manufacturing platform and accelerated strategies for developing processes to manufacture new products on the platform could enable time- and cost-efficient manufacturing of a wide variety of biologic drugs, increasing access to medicines throughout the world.