INDUSTRIAL-PRODUCTION OF HETEROLOGOUS PROTEINS BY FED-BATCH CULTURES OF THE YEAST SACCHAROMYCES-CEREVISIAE

This review concerns the issues involved in the industrial development of fed-batch culture processes with Saccharomyces cerevisiae strains producing heterologous proteins. Most of process development considera tions with fed-batch recombinant cultures:are linked to the reliabilit y and reproducibility of the process for manufacturing environments wh ere quality assurance and quality control aspects are paramount. In th is respect, the quality, safety and efficacy of complex biologically a ctive molecules produced by recombinant techniques are strongly influe nced by the genetic background of the host strain, genetic stability o f the transformed strain and production process factors. An overview o f the recent literature of these culture-related factors is coupled wi th our experience in yeast fed-batch process development for producing various therapeutic grade proteins. The discussion is based around th ree principal topics: genetics, microbial physiology and fed-batch pro cess design. It includes the fundamental aspects of yeast strain physi ology, the nature of the recombinant product, quality control aspects of the biological product, features of yeast expression vectors, expre ssion and localization of recombinant products in transformed cells an d fed-batch process considerations for the industrial production of Sa ccharomyces cerevisiae recombinant proteins. It is our purpose that th is review will provide a comprehensive understanding of the fed-batch recombinant production processes and challenges commonly encountered d uring process development.