title: Optimization of a Saccharomyces cerevisiae fermentation process for production of a therapeutic recombinant protein using a multivariate Bayesian approach.
abstract: Various approaches have been applied to optimize biological product fermentation processes and define design space. In this article, we present a stepwise approach to optimize a Saccharomyces cerevisiae fermentation process through risk assessment analysis, statistical design of experiments (DoE), and multivariate Bayesian predictive approach. The critical process parameters (CPPs) were first identified through a risk assessment. The response surface for each attribute was modeled using the results from the DoE study with consideration given to interactions between CPPs. A multivariate Bayesian predictive approach was then used to identify the region of process operating conditions where all attributes met their specifications simultaneously. The model prediction was verified by twelve consistency runs where all batches achieved broth titer more than 1.53 g/L of broth and quality attributes within the expected ranges. The calculated probability was used to define the reliable operating region. To our knowledge, this is the first case study to implement the multivariate Bayesian predictive approach to the process optimization for the industrial application and its corresponding verification at two different production scales. This approach can be extended to other fermentation process optimizations and reliable operating region quantitation.
authors.affiliation: Microbial and Cell Culture Development (MCCD), Biopharm R&D Unit, GlaxoSmithKline, 709 Swedeland Rd, King of Prussia, PA 19406, USA.
authors.forename: Zhibiao
authors.initials: Z
authors.lastname: Fu
authors.forename: Julie
authors.initials: J
authors.lastname: Leighton
authors.forename: Aili
authors.initials: A
authors.lastname: Cheng
authors.forename: Edward
authors.initials: E
authors.lastname: Appelbaum
authors.forename: Juan C
authors.initials: JC
authors.lastname: Aon
mesh_terms: D001499:Bayes Theorem; D004358:Drug Therapy; D005285:Fermentation; D006801:Humans; D007218:Industrial Microbiology / Q000379:methods*; D008962:Models, Theoretical; D011994:Recombinant Proteins / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use; D012441:Saccharomyces cerevisiae / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D011994:Recombinant Proteins