Scaling-up production of plant endophytes in bioreactors: concepts, challenges and perspectives.

The benefit of microorganisms to humans, animals, insects and plants is increasingly recognized, with intensified microbial endophytes research indicative of this realization. In the agriculture industry, the benefits are tremendous to move towards sustainable crop production and minimize or circumvent the use of chemical fertilizers and pesticides. The research leading to the identification of potential plant endophytes is long and arduous and for many researchers the challenge is ultimately in scale-up production. While many of the larger agriculture and food industries have their own scale-up and manufacturing facilities, for many in academia and start-up companies the next steps towards production have been a stumbling block due to lack of information and understanding of the processes involved in scale-up fermentation. This review provides an overview of the fermentation process from shake flask cultures to scale-up and the manufacturing steps involved such as process development optimization (PDO), process hazard analysis (PHA), pre-, in- and post-production (PIP) challenges and finally the preparation of a technology transfer package (TTP) to transition the PDO to manufacturing. The focus is on submerged liquid fermentation (SLF) and plant endophytes production by providing original examples of fungal and bacterial endophytes, plant growth promoting Penicillium sp. and Streptomyces sp. bioinoculants, respectively. We also discuss the concepts, challenges and future perspectives of the scale-up microbial endophyte process technology based on the industrial and biosafety research platform for advancing a massive production of next-generation biologicals in bioreactors.