Technical approaches to minimize regulatory hurdles to fed-batch and continuous medium supplementation

摘要

Mammalian cell culture biological production applications have traditionally implemented batch production techniques to minimize real or perceived obstacles to product approval by regulatory agencies. Analysis of the bioreactor environment during the course of a batch fermentation run demonstrates significant fluctuations in levels of critically-limiting nutrients, accumulation of catabolic products and increased medium osmolality. These factors can be demonstrated to impact specific productivity and to result in product microheterogeneity. Extended bioreactor campaigns may exhibit superior productivity and longevity by controlled nutrient delivery via fed batch or continuous perfusion of concentrated supplements. Regulations defining criteria for "well-characterized products" and international efforts to harmonize standards may minimize barriers to extended production campaigns and process modifications. This paper examines the evolution of these regulatory guidelines and their application to process changes which permit productivity engancement through supplementation with salt-free nutrient concentrates.