In today's biopharmaceutical pipeline, monoclonal antibodies (mAbs) are a predominant modality for a broad range of clinical indications including oncology and inflammatory diseases. Most antibody therapies have to be administered to the patients in large doses of 4-15 mg/kg, resulting in extremely high cost for patients (~$2,000-$5,000 per dose;up to $100,000 per year). Therefore, manufacturing capacity and cost per purification campaign are two critical factors for making these therapies more affordable. In recent years, new developments in protein expression, cell culture, and fermentation technologies have led to significant advancements in protein production and antibody titers. The development of the subsequent downstream purification steps, however, has not kept a similar pace and can become a bottleneck that impedes achieving a cost-effective and robust manufacturing process. Currently, the downstream processing accounts for up to 70% of mAb production cost. As such, scalable technologies that create manufacturing equipment with in- creased capacity through downstream process productivity improvements and cost reduction are highly de- sired. In mAb purification, the "industry-standard" Protein A capture step is the most expensive step, contributing 51% to the overall purification cost [and up to 40% of the total cost per grammAb]. We propose to demonstrate the purification of a mAb using a highly efficient Protein A capture step with a novel continuous chromatography process and instrument and to demonstrate up to 10-fold savings in Protein A chromatography media and buffers as compared to the traditional single-column batch method. Our novel chromatography instrument is a bench top multicolumn system capable of simulated moving bed (SMB) chromatography proto- cols that increase productivity up to 10-fold vs. conventional single-column methods. In Phase I, we will purify a model mAb using our instrument and the Step-SMB Protein A capture process. We will compare the efficacy of this process in terms of yield and purity to that of the traditional single-column process purified mAb. We will also identify instrument hardware and software design changes to insure the optimized SMB process would achieve FDA-recommended purity specifications. In Phase II, we will extend this demonstration to a prototype manufacturing process supporting up to eight-step cGMP Protein A capture step of mAb, implement in-process controls, such as UV absorbance, pH and conductivity, and evaluate the effect of process throughput on mAb purity. We will also work with a commercial partner to integrate our continuous mAb Protein A capture step into a complete purification process.
In recent years, new developments in protein expression, cell culture, and fermentation technologies have led to significant advancements in protein production and antibody titers. The development of the subsequent downstream purification steps has not kept a similar pace and is becoming a bottleneck that impedes achieving a cost-effective and robust manufacturing process. Currently, the downstream processing accounts for a significant percentage of mAb production cost, and improvements in manufacturing technologies which increase capacity and productivity are highly desired for speeding up progress through trials and, ultimately, improving patient health and access to lower cost therapeutic mAbs. Protein A capture is the "industry-standard", most efficient yet expensive step in mAb purification, and increasing productivity while reducing cost of this step would lead to more affordable biological drugs for patients.