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Global Sensitivity Analysis for the determination of parameter importance in bio‐manufacturing processes
Author(s) -
Chhatre Sunil,
Francis Richard,
Newcombe Anthony R.,
Zhou Yuhong,
TitchenerHooker Nigel,
King Josh,
KeshavarzMoore Eli
Publication year - 2008
Publication title -
biotechnology and applied biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 70
eISSN - 1470-8744
pISSN - 0885-4513
DOI - 10.1042/ba20070228
Subject(s) - bioprocess , biomanufacturing , ultrafiltration (renal) , chromatography , chemistry , affinity chromatography , antivenom , downstream processing , cross flow filtration , microbiology and biotechnology , biology , biochemistry , engineering , chemical engineering , membrane , venom , enzyme
The present paper describes the application of GSA (Global Sensitivity Analysis) techniques to mathematical models of bioprocesses in order to rank inputs such as feed titres, flow rates and matrix capacities for the relative influence that each exerts upon outputs such as yield or throughput. GSA enables quantification of both the impact of individual variables on process outputs, as well as their interactions. These data highlight those attributes of a bioprocess which offer the greatest potential for achieving manufacturing improvements. Whereas previous GSA studies have been limited to individual unit operations, this paper extends the treatment to an entire downstream process and illustrates its utility by application to the production of a Fab‐based rattlesnake antivenom called CroFab™ [(Crotalidae Polyvalent Immune Fab (Ovine); Protherics U.K. Limited]. Initially, hyperimmunized ovine serum containing rattlesnake antivenom IgG (product), other antibodies and albumin is applied to a synthetic affinity ligand adsorbent column to separate the antibodies from the albumin. The antibodies are papain‐digested into Fab and Fc fragments, before concentration by ultrafiltration. Fc, residual IgG and albumin are eliminated by an ion‐exchanger and then CroFab‐specific affinity chromatography is used to produce purified antivenom. Application of GSA to the model of this process showed that product yield was controlled by IgG feed concentration and the synthetic‐material affinity column's capacity and flow rate, whereas product throughput was predominantly influenced by the synthetic material's capacity, the ultrafiltration concentration factor and the CroFab affinity flow rate. Such information provides a rational basis for identifying the most promising strategies for delivering improvements to commercial‐scale biomanufacturing processes.