Monoclonal antibodies (mAbs) have become the leading drug class for cancer treatment, and over 150 anti-neoplastic mAbs are in the biopharmaceutical pipeline. Most mAb therapies must be administered in doses of 4-15 mg/kg, resulting in per patient costs of up to $100,000 per year. The high price of mAb therapy causes a significant financial burden for patients, insurance companies and the health care system. To be- come practical for the health care industry, the cost of developing and producing these drugs must be reduced. Clinical manufacturing expenses directly contribute to the overall drug development costs. Recent developments in protein expression, cell culture, and bioreactor technologies have led to substantial advancements in protein production and mAb titers. The development of downstream purification processes has not kept pace and represents a bottleneck that impedes cost-effective and robust manufacturing. Currently, downstream processing (DSP) accounts for up to 70% of the total mAb production cost. The "industry-standard" Protein A capture (PAC) is the most expensive DSP step, contributing up to 40% of the total cost per gram of product. The current PAC method still uses one large column in a sequential batch process. Continuous SMB (simulated moving bed) chromatography offers significant advantages over standard batch methods, including more efficient use of expensive adsorbent with smaller columns, reduced buffer consumption, and operation under steady-state conditions, allowing more robust process analytics. In the Phase I SBIR project (R43 CA162632-01) we investigated the feasibility of developing a continuous PAC process for the purification of clinical-grade mAbs using our lab-scale Octave(tm) SMB System. We obtained equivalent or better mAb purity when our continuous process was directly compared with the standard batch process. How- ever, the current Octave System is not designed for cGMP compliance or the scale required for clinical manufacture. In Phase II we propose to develop a large-scale continuous chromatography device for economical purification of clinical-grade antibodies, based on the Octave valve design and our Phase I findings. The Phase II device will support flow rates up to 2 L/min and processing of 500 L culture fluid containing 5-10 g/L mAb in 8-20 hours, which matches the future demand for therapeutic mAbs in the range of 200 kg/yr. The Phase II de- vice and optimized PAC process will increase productivity at least 3-fold relative to batch methods, and will feature a single-use flow path to eliminate the need for sanitation and revalidation between campaigns. This Phase II project will develop at least one prototype device that will be placed at a Beta test site. The device will be a customizable plug-and-play chromatography module compatible with future integrated continuous bioprocessing facilities. This project fits with the 2011 FDA strategic plan, which seeks development of improved product manufacturing technologies including continuous processes rather than batch approaches.
Recent developments in protein expression, cell culture, and bioreactor technologies have led to substantial improvements in protein production and increased antibody (mAb) titers. The development of downstream purification processes has not kept pace and represents a bottleneck that impedes cost-effective and robust manufacturing. Currently, downstream processing accounts for a significant percentage of the total mAb production cost. Improvements in manufacturing technologies which increase capacity and productivity are highly desired for speeding up progress through clinical trials. The device developed under this proposal will dramatically improve productivity and reduce cost of the most expensive purification step by up to 80%. Incorporation of this device into manufacturing processes will ultimately improve patient access to new anti-cancer mAb therapies at lower cost.