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The biopharmaceutical industry is transitioning from currently deployed batch‐mode bioprocessing to a highly efficient and agile next‐generation bioprocessing with the adaptation of continuous bioprocessing, which reduces capital investment and operational costs. Continuous bioprocessing, aligned with FDA's quality‐by‐design platform, is designed to develop robust processes to deliver safe and effective drugs. With the deployment of knowledge‐based operations, product quality can be built into the process to achieve desired critical quality attributes (CQAs) with reduced variability. To facilitate next‐generation continuous bioprocessing, it is essential to embrace a fundamental shift‐in‐paradigm from "quality‐by‐testing" to "quality‐by‐design," which requires the deployment of process analytical technologies (PAT). With the adaptation of PAT, a systematic approach of process and product understanding and timely process control are feasible. Deployment of PAT tools for real‐time monitoring of CQAs and feedback control is critical for continuous bioprocessing. Given the current deficiency in PAT tools to support continuous bioprocessing, we have integrated Infinity 2D‐LC with a post‐flow‐splitter in conjunction with the SegFlow autosampler to the bioreactors. With this integrated system, we have established a platform for online measurements of titer and CQAs of monoclonal antibodies as well as amino acid analysis of bioreactor cell culture. [ABSTRACT FROM AUTHOR]

Process analytical technology (PAT) is a fast‐growing field within bioprocessing that enables innovation in biological drug manufacturing. This study demonstrates novel PAT methods for monitoring multiple quality attributes simultaneously during the ultrafiltration and diafiltration (UF/DF) process operation, the final step of monoclonal antibody (mAb) purification. Size exclusion chromatography (SEC) methods were developed to measure excipients arginine, histidine, and high molecular weight (HMW) species using a liquid chromatography (LC) system with autosampler for both on‐line and at‐line PAT modes. The methods were applied in UF/DF studies for the comparison of single‐use tangential flow filtration (TFF) cassettes to standard reusable cassettes to achieve very high concentration mAb drug substance (DS) in the order of 100–200 g/L. These case studies demonstrated that single‐use TFF cassettes are a functionally equivalent, low‐cost alternative to standard reusable cassettes, and that the on‐line PAT measurement of purity and excipient concentration was comparable to orthogonal offline methods. These PAT applications using an on‐line LC system equipped with onboard sample dilution can become a platform system for monitoring of multiple attributes over a wide dynamic range, a potentially valuable tool for biological drug development and manufacturing. [ABSTRACT FROM AUTHOR]

Technologies capable of monitoring product quality attributes and process parameters in real time are becoming popular due to the endorsement of regulatory agencies and also to support the agile development of biotherapeutic pipelines. The utility of vibrational spectroscopic techniques such as Fourier transform mid‐infrared (Mid‐IR) and multivariate data analysis (MVDA) models allows the prediction of multiple critical attributes simultaneously in real time. This study reports the use of Mid‐IR and MVDA model sensors for monitoring of multiple attributes (excipients and protein concentrations) in real time (measurement frequency of every 40 s) at ultrafiltration and diafiltration (UF/DF) unit operation of biologics manufacturing. The platform features integration of fiber optic Mid‐IR probe sensors to UF/DF set up at the bulk solution and through a flow cell at the retentate line followed by automated Mid‐IR data piping into a process monitoring software platform with pre‐loaded partial least square regression (PLS) chemometric models. Data visualization infrastructure is also built‐in to the platform so that upon automated PLS prediction of excipients and protein concentrations, the results were projected in a graphical or numerical format in real time. The Mid‐IR predicted concentrations of excipients and protein show excellent correlation with the offline measurements by traditional analytical methods. Absolute percent difference values between Mid‐IR predicted results and offline reference assay results were ≤5% across all the excipients and the protein of interest; which shows a great promise as a reliable process analytical technology tool. [ABSTRACT FROM AUTHOR]