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The folly of “accelerating development” with unoptimized cell lines

How many times have we heard companies say that they didn’t want to risk delays in their development programs by spending time to develop robust, high expressing production cell lines? Thinking that moving rapidly into GMP manufacturing using a cell bank derived from an unoptimized initial research cell line with low productivity and limited traceability constitutes “accelerating development,” these companies march forward with sub-optimal cell lines thinking that they are saving time. But what is the real impact of such an approach on the timelines for early stage product development? Consider the case of such a cell line expressing a monoclonal antibody at 100 mg/L.

Compared to “state-of-the-art” production cell lines with expression levels of 1 g/L or greater, manufacturing based on this low producing cell line would require at least ten times the total bioreactor volume to make a given amount of protein. This increased bioreactor volume will require either time consuming process scale up to enable the use of large bioreactors for early stage manufacturing or production of a larger number of batches just to meet Phase 1 clinical trial requirements, which will again be time consuming and costly. In either case, the immediate impact will be to increase the time and cost of producing material for first-in-human clinical trials. The low producing cell line also increases the risk of unacceptable product quality as the ratio of undesirable host cell components to the desired monoclonal antibody will be higher, putting greater demands on the downstream process to produce a product of acceptable quality.

While it’s true that media and feed optimization can result in higher productivities, even from low producing cell lines, this process development is expensive and time consuming, again impacting overall development timelines and costs. Instead, we believe that companies would be better off leveraging available technology for developing high producing cell lines before rushing to start GMP manufacturing. The misperception that cell line development takes too long has caused many companies to make short-sighted decisions regarding the future of their product. There are many technologies available today that enable the development of cell lines with expression levels for monoclonal antibodies of 1 g/L in as little as 10-16 weeks. Is this time worth it? Absolutely! Especially when you compare this to the extra time required for producing multiple production batches versus one or the time required for process development and/or scale-up. While development of a suitable cell line for initial GMP manufacturing will always be on the critical path to an IND, advances in cell line development and engineering have enabled much speedier cell line development than in the past so that the overall timelines from clone to clinic® can actually be shorter than those using low producing cell lines. Remember, drug development takes time…use it wisely!

 

Blog article by: Susan Jones and Howard Levine