Application of process analytical technology for downstream purification of biotherapeutics

Abstract

The concept of Process Analytical Technology (PAT) introduced by the US FDA has received a lot of attention lately. The use of such a scheme ensures robust process performance over the entire life cycle of the product and consistent product quality at the end of the manufacturing process. Successful implementation of PAT requires use of high resolution, orthogonal analytical tools that are able to measure the critical quality attributes (CQA) of the raw materials and in‐process materials with the aim of ensuring final product quality. This article presents a review of PAT applications for monitoring commonly used downstream biotech unit operations. Focus of the review will be on recent advancements (last 5 years). Analytical tools that have been used in these approaches have also been discussed with reference to their speed of analysis, robustness and sensitivity. Also discussed is their potential to replace the traditional high performance liquid chromatography (HPLC) which continues to be the gold standard for analysis of biotech therapeutics. © 2014 Society of Chemical Industry

Biopharmaceuticals from microorganisms: from production to purification

“…and product related impurities (e.g., aggregates, fragments, clipped species, etc.). Each purification step is capable of removing one or more classes of impurities 53, 54. Downstream processing usually encompasses three main stages, namely (i) initial recovery (extraction or isolation), (ii) purification (removal of most contaminants), and (iii) polishing (removal of specified contaminants and unwanted forms of the target biomolecule that may have formed during isolation and purification) 53, 55, 56…”

A new flow cell and chemometric protocol for implementing in‐line Raman spectroscopy in chromatography

“…Several examples of successful implementation of advanced process analytical technologies (PATs) in upstream processing (USP) of biopharmaceuticals have been reported in the literature . However, the application of on‐line or at‐line monitoring tools for downstream processing (DSP), and in particular for chromatography, is less common and only few examples have been reported . Challenging requirements like a high sensitivity, fast response time, high accuracy, robustness, wide dynamic range, and low limit of detection (LOD) with minor recalibration needs make the implementation of on‐line monitoring techniques in DSP difficult .…”

“…Challenging requirements like a high sensitivity, fast response time, high accuracy, robustness, wide dynamic range, and low limit of detection (LOD) with minor recalibration needs make the implementation of on‐line monitoring techniques in DSP difficult . Extensive reviews showcase available monitoring techniques and applications in DSP . Sensors for pH, conductivity, pressure, mass flow, optical density, and single wavelength UV spectroscopy are widely implemented in chromatography.…”

Implementation of a fluorescence based PAT control for fouling of protein A chromatography resin

“…The use of such a scheme ensures robust process performance over the entire lifecycle of the product and consistent product quality at the end of the manufacturing process. There have been various case studies reported where PAT has been successfully implemented for various downstream unit operations like protein refolding, filtration, inline mixing, protein pegylation, viral inactivation, and process chromatography . Currently, various techniques such as UV spectroscopy, HPLC, and mass spectroscopy are available to monitor column effluent and provide useful information about product purity and impurity clearance .…”