A decision-support model for evaluating changes in biopharmaceutical manufacturing processes

Abstract

A simulation is described that evaluates the impacts of altering bio-manufacturing processes. Modifications designed to improve production levels, times and costs were assessed, including increasing feed volumes/titres, replacing initial downstream stages with packed or expanded bed affinity steps and removing ion exchange steps. Options were evaluated for manufactured product mass, COG, batch times and development costs and timescales. Metrics were combined using multi-attribute-decision-making techniques generating a single assessment metric for each option. The utility of this approach was illustrated by application to an FDA-approved process manufacturing rattlesnake anti-venom (Protherics U.K.). Currently, ovine serum containing anti-venom IgG is purified by precipitation/centrifugation, prior to antibody proteolysis by papain. An ion exchanger removes F(C), before affinity chromatography yields the final anti-venom. An expanded bed affinity column operating with an 80% higher IgG titre, 66% higher feed volume and without the ion exchanger delivered the best multi-attribute-decision-making value, potentially providing the most desirable alternative.

IMAC capture of recombinant protein from unclarified mammalian cell feed streams

“…EBA, a format with similar process advantages to large‐bead resins, has been compared with standard bioprocess techniques resulting in reduced COG/g and simplified recovery in microbial and mammalian cell downstream processing (Chhatre et al, 2006; Tolner et al, 2013; Willoughby et al, 2004). Similar efficiency gains from the removal of clarification steps could be expected with large bead diameter resins.…”

Global Sensitivity Analysis for the determination of parameter importance in bio‐manufacturing processes

“…The initial feed material is hyperimmunized ovine serum containing a mixed population of IgGs, including rattlesnake antivenom IgG and other serum proteins, including ovine albumin. The IgG is initially separated from the contaminating albumin by a synthetic affinity ligand adsorbent column step [8]. The antibody molecules are then digested enzymatically by papain into Fab and Fc fragments [28], after which the material is concentrated by ultrafiltration and desalted in preparation for an ion‐exchange step.…”

“…Regulatory, competitive and financial pressures in recent years now necessitate early‐stage optimization in order to maintain financial viability [3,4] and are driving the exploration of novel technologies that facilitate rapid evaluation of process options. These include high‐throughput analysis [5], ultra‐scale‐down techniques [6] and decision‐support simulations for rapidly assessing manufacturing strategies at facility or company level [7,8].…”

Global sensitivity analysis for the determination of parameter importance in the chromatographic purification of polyclonal antibodies

“…9 This paper models a synthetic Protein A based chromatographic capture of antibodies from sheep serum, an option that is being considered by Protherics UK Limited (Blaenwaun, Ffostrasol, Llandysul, Wales, UK) as an initial purification step for the manufacture of the FDA-approved rattlesnake anti-venom CroFab  . 10,11 The synthetic adsorbent step was simulated using the Thomas model, 12 which was then used to predict the amounts of antibody that are captured and lost upon application of the ovine serum to the column. Assumed data values used to populate the model were obtained from Protherics.…”