Technology outlook for real‐time quality attribute and process parameter monitoring in biopharmaceutical development—A review

Abstract

Real‐time monitoring of bioprocesses by the integration of analytics at critical unit operations is one of the paramount necessities for quality by design manufacturing and real‐time release (RTR) of biopharmaceuticals. A well‐defined process analytical technology (PAT) roadmap enables the monitoring of critical process parameters and quality attributes at appropriate unit operations to develop an analytical paradigm that is capable of providing real‐time data. We believe a comprehensive PAT roadmap should entail not only integration of analytical tools into the bioprocess but also should address automated‐data piping, analysis, aggregation, visualization, and smart utility of data for advanced‐data analytics such as machine and deep learning for holistic process understanding. In this review, we discuss a broad spectrum of PAT technologies spanning from vibrational spectroscopy, multivariate data analysis, multiattribute chromatography, mass spectrometry, sensors, and automated‐sampling technologies. We also provide insights, based on our experience in clinical and commercial manufacturing, into data automation, data visualization, and smart utility of data for advanced‐analytics in PAT. This review is catered for a broad audience, including those new to the field to those well versed in applying these technologies. The article is also intended to give some insight into the strategies we have undertaken to implement PAT tools in biologics process development with the vision of realizing RTR testing in biomanufacturing and to meet regulatory expectations.

Real‐time monitoring of quality attributes by in‐line Fourier transform infrared spectroscopic sensors at ultrafiltration and diafiltration of bioprocess

“…Real‐time monitoring and visualization are some of the key aspects of any PAT technology, where the acquired data are processed automatically and final results are displayed in real time (Wasalathanthri et al, 2020). This involves automated piping of data from process instruments such as chromatography or spectroscopy instruments to a platform where preprocessing and analysis can be performed systematically, followed by visual projection of results and tends (Wasalathanthri et al, 2020). SynTQ® from Optimal Industrial Automation, CMET® from Bruker Optics, SIPAT® from Siemens, BioPAT SIMCA® from Sartorius and Unscrambler Process Pulse II® from Camo are some of the common platforms (Wasalathanthri et al, 2020).…”

“…This involves automated piping of data from process instruments such as chromatography or spectroscopy instruments to a platform where preprocessing and analysis can be performed systematically, followed by visual projection of results and tends (Wasalathanthri et al, 2020). SynTQ® from Optimal Industrial Automation, CMET® from Bruker Optics, SIPAT® from Siemens, BioPAT SIMCA® from Sartorius and Unscrambler Process Pulse II® from Camo are some of the common platforms (Wasalathanthri et al, 2020). In this technology, we employed CMET®, a built‐in results visualization functionality of the Bruker Mid‐IR software infrastructure.…”

“…Real‐time monitoring of bioprocess has evolved significantly in recent years with the advancement of analytical technologies, and cyber‐physical systems (Ündey, Ertun, Mistretta, & Looze, 2010; Wasalathanthri et al, 2020). Reliable PAT tools are the cornerstone of any real‐time monitoring platform, which could feature chromatographic, spectroscopic, mass spectrometric or other type of sensors (Wasalathanthri et al, 2020).…”

“…Vibrational spectroscopy and multivariate data analysis (MVDA) technologies are attractive tools for real‐time monitoring of product quality attributes as they are non‐destructive, fast, and do not require any sample preparation (Rathore et al, 2010; Wasalathanthri et al, 2020; Wasalathanthri, Tewari, Kang, Hincapie, & Barrett, 2019). Techniques such as Raman and Fourier Mid Transform Infrared (Mid‐IR) spectroscopy allow in‐line integration of data acquisition probe into the process stream for real‐time monitoring lasting 10–20 s per measurement (Wasalathanthri et al, 2019, 2020). Mid‐IR spectroscopy, corresponds to about 800–4,000 cm −1 wavenumber region in electromagnetic radiation, for real‐time monitoring of product quality attributes and impurities in bioprocess has been previously reported at various unit operations.…”

“…Even though this technology suffers from redundancies associated with probe calibrations, it offers several benefits including the minimal use of DF buffers due to product stability concerns (Sharma et al, 2006). Vibrational spectroscopy and multivariate data analysis (MVDA) technologies are attractive tools for real‐time monitoring of product quality attributes as they are non‐destructive, fast, and do not require any sample preparation (Rathore et al, 2010; Wasalathanthri et al, 2020; Wasalathanthri, Tewari, Kang, Hincapie, & Barrett, 2019). Techniques such as Raman and Fourier Mid Transform Infrared (Mid‐IR) spectroscopy allow in‐line integration of data acquisition probe into the process stream for real‐time monitoring lasting 10–20 s per measurement (Wasalathanthri et al, 2019, 2020).…”