Systematic assessment of process analytical technologies for biologics

Abstract

The application of process analytical technology (PAT) for biotherapeutic development and manufacturing has been employed owing to technological, economic, and regulatory advantages across the industry. Typically, chromatographic, spectroscopic, and/or mass spectrometric sensors are integrated into upstream and downstream unit operations in in-line, on-line, or at-line fashion to enable real-time monitoring and control of the process. Despite the widespread utility of PAT technologies at various unit operations of the bioprocess, a holistic business value assessment of PAT has not been well addressed in biologics. Thus, in this study, we evaluated PAT technologies based on predefined criteria for their technological attributes such as enablement of better process understanding, control, and highthroughput capabilities; as well as for business attributes such as simplicity of implementation, lead time, and cost reduction. The study involved an industry-wide survey, where input from subject matter industry experts on various PAT tools were collected, assessed, and ranked. The survey results demonstrated on-line liquid Chromatography (LC), in-line Raman, and gas analysis techniques are of high business value especially at the production bioreactor unit operation of upstream processing. In-line variable path-length UV/VIS measurements (VPE), on-line LC, multiangle light scattering (MALS), and automated sampling are of high business value in Protein A purification and polishing steps of the downstream process. We also provide insights, based on our experience in clinical and commercial manufacturing of biologics, into the development and implementation of some of the PAT tools. The results presented in this study are intended to be helpful for the current practitioners of PAT as well as those new to the field to gauge, prioritize and steer their projects for success.

A Novel Approach for Non-Invasive Continuous In-Line Control of Perfusion Cell Cultivations by Raman Spectroscopy

“…With the exception of physical parameters, such as pH, temperature and dissolved oxygen, that are already controlled automatically, most biological parameters like cell count, viability, nutrient, and metabolite concentrations are only measured at-line once or twice a day. This makes process control difficult and increases the risk of batch failure ( Gillespie et al, 2022 ; Reyes et al, 2022 ). Various studies have investigated how Raman spectroscopy can be used as a PAT tool for on-line measurement of glucose and how a control loop for this parameter can be established.…”

Capacitance spectroscopy enables real‐time monitoring of early cell death in mammalian cell culture

“…[ 22 ] Additionally, the authors also identified methods aimed at monitoring culture metabolic status as having a high business value in production bioreactors. [ 22 ] It aligned with our previous work, which demonstrated the capacitance spectra as a multi‐attribute analytical tool that contains important early cell death information. [ 13 ] Multiple apoptosis‐related cellular changes may result in the capacitance spectral shape change.…”

Recent Advances and Future Directions in Downstream Processing of Therapeutic Antibodies

“…Continuous DSP processing, where there is a constant fluid transfer between unit operations, would seem to benefit naturally from a PAT approach. A recent survey of the BioPhorum Development Group, “PAT monitoring and Control”, representing several biopharmaceutical manufacturers, suggests that PAT implementation has the highest business value for the Protein-A capture and subsequent polishing chromatography steps as compared to other unit operations [ 71 ]. Understandably, much emphasis has been placed on incorporating PAT into the Protein-A capture chromatography step, given its process importance and the high resin cost in the context of antibody DSP.…”