Model based control of downstream purification in continuous processing of biotherapeutics
13th, March 2019, Thursday, 4:30‐5:00 pm, ChE Seminar hall
Abstract:- Due to low tolerance of risk and complex regulatory implications, the biotech industry has long been following the conventional batch model for the manufacturing of biotech therapeutics. A typical manufacturing facility uses large volume batch bioreactors with downstream processing consisting of a chain of chromatographic steps of large column sizes. In recent years, there has been increasing interest towards exploring continuous processing among the bioprocessing community due to aided advantages like increase in productivity (10-20X), consistent product quality, low cycle time, reduction in cost of consumables, and significantly improved process economics. Major regulators such as FDA have expressed their faith in continuous processing since it aligns with principle of building quality directly into process design. The continuous platform can consist of high cell density bioreactor along with integrated downstream processing involving continuous multi-column chromatography necessary to fully automate a wide range of different chromatographic processes.
Process modeling (mechanistic and/or empirical) is required for enabling predictive control schemes, a prerequisite for continuous processing and for ensuring consistent product quality. To predict process behavior, use of modeling is becoming increasingly common. It is more practical and economical approach than the traditional trial and error method for predicting process dynamics. In case of continuous manufacturing, combining the predicting modeling approach with the aid of on-line analyzers will not only lower manufacturing cost but also ensure more consistent product quality. In the case of monoclonal antibodies (mAbs), due to their inherent complexity, it is very difficult to monitor the critical quality attributes (CQAs) in presence of other media components and protein prior to purification. High resolution chromatography separation with on-line analyzers combined with predictive modeling can enable the monitoring of the CQAs during continuous manufacturing thereby ensuring product with consistent quality.
On-line (high-performance liquid chromatography) HPLC with its high resolution and speed of analysis has been shown to act as an enabler for continuous production of biologics. In the present work, on-line HPLC has been established for real time monitoring of product quality attributes. However, requirement of liquid handling system capable of online sampling and fractionation and interfacing it with preparative scale chromatography appends to the cost and complexity of the design module of commercially available online HPLC. In the present work, we propose a cost-effective approach for using a traditional offline HPLC for online analysis using a 2 way/6 port valve to facilitate simultaneous automated sampling of product stream eluting from a process column and fractionation. No sample dilution is required in the proposed approach. The versatility of the proposed online configuration was verified by demonstrating its use for two of the most common separations required during production of monoclonal antibody therapeutics: separation of aggregates and separation of charge variants. Process modeling was performed to allow interpolation of HPLC data and facilitate pooling to achieve the desired purity (model predicted purity 99.1% vs achieved purity of 99.3% for removal of aggregates, model predicted main species yield of 62.4% vs achieved main species of 62.9% for pooling of charge variants). The study thus demonstrates that the proposed online HPLC configuration can be used for PAT applications in preparative chromatography.