Does earlier use of productivity enhancers during cell line selection lead to the identification of more productive cell lines

Background After selection of a recombinant cell line for the production of a therapeutic protein, attempts are often made to increase volumetric productivity. Various techniques have been employed during the production process when trying to increase product concentration. Some aim to increase the time integral of viable cell concentration (IVC; the number of hours viable cells are available to produce the product) by increasing the maximum viable cell concentration and maintaining high viabilities. Techniques include (i) optimization of media and feeds, (ii) optimization of feeding strategies and (iii) genetic manipulation. Others aim to increase specific production rate (QP) by the deliberate inhibition of cell growth (controlled proliferation). Three methods commonly used to control proliferation are use of (i) chemical agents, (ii) hypothermic conditions and (iii) genetic manipulation. In this study, we focused on increasing volumetric productivity by manipulating QP; in particular, by the use of chemical agents. As a cell line has typically already been selected as a manufacturing cell line prior to assessing such methods to increase QP, the likelihood of success is not predictable: resulting in the frequently heard comment that results are ‘cell line specific’. But what if we were to look at these methods with many cell lines, at a much earlier stage of development (before the final cell line has been selected)? It could be that the cell line with the highest product concentration is typically a non-responder. The work described looks to answer the questions: (1) To what extent does the response to such methods vary in a large panel of cell lines producing the same antibody? and (2) Would their use in an earlier stage of cell line development enable the selection of a ‘better’ manufacturing cell line?