Keys to faster development pathways
Compressing the mammalian cell culture development timeline
CBI / UBM Life Sciences recently launched their new bioprocessing conference series with a two-day event in San Francisco entitled “Speed to IND for Biologics”, focusing specifically on “Integration of Novel Technologies. Strategies and Cross-Functional Approaches to Accelerate Development and Compress Timelines”. Industry experts across the spectrum of suppliers, large and small biotechnology companies, pharmaceutical companies, and consultants gathered for a very lively set of talks, panels, and interactive discussions. Two related cutting-edge themes that were mentioned several times as keys to faster development were the use of targeted integration (TI) into a transcriptional hotspot in parental CHO cells and the use of pooled clones to produce material for GLP toxicology studies. Both approaches would definitely reduce the time from lead identification to IND filing and first in human studies, but both have regulatory and/or technical challenges.
Targeted integration (TI) has been a holy grail for the industry for several decades, with many people claiming that this will reduce clonal variation and improve genetic stability, thereby allowing more rapid identification of the production CHO cell line for any given development candidate. Since cell line development is probably the single most time-consuming task in early process development, a technology that truly shortens this timeline by eliminating the need for extended genetic stability testing of candidate clonal cell lines before cell banking would clearly reduce timelines. Is this realistic given the state of targeted integration technology?
While the proponents of TI would say yes, the consensus opinion in one discussion group that I participated in was that TI is another tool in the toolbox of production cell line development, but it would not reduce requirements for testing the candidate clones for stability. Well-designed parental CHO cell lines with a single target site should enable most clones to have an insertion in the active target site. But one participant noted that nothing is preventing off-target integration as well and that there often are second copies found elsewhere in the genome. Therefore, there could be instability from other integration sites, and the population as a whole is not going to be isogenic.
The similarity of clonal cell lines that were created by TI was also discussed, and several participants agreed with my opinion that each cell line responds differently to the stressful conditions imposed on cells during single cell cloning. The epigenetic background, expression profile, and therefore the growth and productivity of cell lines from TI strategies will not necessarily be more consistent than the profiles of cells created from random integration. TI is a tool that is welcome in the industry but is not yet providing a way to shorten timelines dramatically.
Pooled clone production of GLP tox material is another story. This exciting concept was presented by a speaker from Genentech and further elucidated in a panel discussion. No-one will deny that having GLP tox material sooner would greatly accelerate overall development programs and enable “Speed to IND for Biologics”. Waiting for the final production clone following identification of a few candidate clonal cell lines adds at least nine weeks to the timeline; waiting for the MCB adds another six weeks. The strategy of pooled clones is simple: take 4 – 10 candidate clonal cell lines, combine them to make the tox material, and concurrently continue with the activities that will lead to one of these candidates being selected as the production cell line. Technically this approach is feasible, and the comparability risk is relatively low; however, from a regulatory risk perspective, this has not been widely adopted and could pose a significant regulatory issue to smaller companies without significant development and regulatory firepower. A Pre-IND meeting would not even remove the risk as the agency reply to a question about using pooled clones would most likely be “submit the comparability data in the IND.” Not exactly an endorsement and not a risk most smaller companies would be willing to take.
My conclusion from this very exciting and interactive conference is that technology continues to evolve and provide us with approaches to shorten the timeline to IND. However, for most companies with products produced in mammalian cell culture, timelines will not be less than 14 months with current technologies and regulatory expectations. Continued changes in both these areas are needed to bring much-needed medicines to patients and the market more quickly.
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Blog article by: Susan Dana Jones
See our recent BioProcessBlog and Presentations on cell line development topics.
Was CHO The Right Choice for Biotech? – https://www.bptc.com/cho-right-choice-biotech/
The Pressures in Developing Fast-Track Products – https://www.bptc.com/pressures-developing-fast-track-products/
Speed To IND: Risks To Achieving Aggressive Breakthrough/Fast-Track Product Timelines – https://www.bptc.com/speed-ind-risks-achieving-aggressive-breakthroughfast-track-product-timelines/
Multiplexing for Efficient Product Development – https://www.bptc.com/multiplexing-efficient-product-development/