The objective of this work is to develop new manufacturing technology for large-scale production of recombinant proteins. Purification technology for large biomolecules such as monoclonal antibodies is an important component of biological research and for the production of therapeutic proteins that are used in a growing number of cancer therapies and other applications in medicine. Conventional sorbents for these applications are in the form of beads which characteristically have large pores and a large particle size. The large pores are needed to accommodate the proteins;the particle size needs to be large to minimize the compressive pressure drops produced by buffer flow. The large particle size and small diffusion coefficients of large biomolecules within the particle pores reduces efficiency of the separation process. As a result of the large pore size, these materials are fragile and compressive making their use in preparative chromatography difficult. On a preparative scale, in order to minimize pressure drop and its consequences, ion exchange columns with this type of media are typically large diameter, shallow beds that are difficult to pack and maintain. Innovations from this research will address these inherent problems in the existing technology. These studies will focus on new technology for large scale application of Macro-IPN substrates which are monolithic, macroporous, sheet-form materials consisting of a high capacity hydrogel and an inert nonwoven material which were developed by the PI in a related NIH project. New systems and devices developed as part of this project will enable large scale applications of the Macro-IPN media and will allow the technology to capitalize on the body of knowledge that has already been established for large-scale pharmaceutical filter products and applications.
The specific aims of this project are, (1) Design and build ion exchange devices based on Macro-IPN substrates, (2) Develop materials, equipment, and methods based on Macro-IPN substrates that will lead to linearly scalable, larger scale applications (3) Characterize performance for applications to immunoglobulins and smaller proteins in terms of capacities, kinetics, diffusivities, and comparisons to existing technology. The broad, long term objectives for this technology are to enable (a) one- time-use or disposable chromatographic systems for therapeutic proteins and (b) systems that will improve and simplify the manufacture of single or multiple products in a bio-processing facility. The avoidance of possible cross contamination and the need to validate systems after cleaning protocols promises to improve compliance with Good Manufacturing Process (GMP) standards and speed up the FDA approval process. Potential commercial products are (a) devices for anion and cation exchange chromatography, (b) devices for affinity chromatography, (c) low cost, disposable devices for large scale capture and release chromatography, and (d) application specific licenses to companies involved in membrane products for bio-processing applications.
The relevance of the proposed research to public health is to provide new technology for accelerated and improved manufacturing methods for therapeutic drugs that are being developed to eliminate suffering and death due to cancer. The technology from this project is needed to ensure delivery and reduce the cost of new, anti-cancer therapeutics such as recombinant proteins which are needed in large quantities