Ask the Expert: Integration of Cell Line, Process, and Analytical Technologies: Speeding Development and Clinical Supply of Emerging Therapy Products

Chinese hamster ovary (CHO) cells are being pushed to their productivity limits in drug development and biomanufacturing. Biopharmaceutical companies working on promising new therapies increasingly struggle with development challenges such as weak protein expression, low-yield purification steps, and poorly optimized analytical techniques. To address those challenges, innovators need robust cell-expression platforms and advanced process, analytical, and biomanufacturing technologies.

Since 2012, KBI Biopharma has performed development and/or manufacturing services using more than 20 different cell lines generated by Selexis SA. In 2017, the two companies joined under the same parent organization: JSR Corporation. Stewart McNaull is senior vice president of business development for KBI.

McNaull’s Presentation 
In 2016, over half of the development of manufacturing projects KBI worked on were for monoclonal antibody (MAb) products. In 2017, work expanded with other modalities such as bispecific and Fc-fusion proteins and vaccines. Non-MAb platforms are becoming more important to the industry, and KBI has developed some such platforms that can be customized for a given molecule.

McNaull polled the audience about development programs: “What are your expectations for the time it takes from transfecting a cell line to having drug substance in hand?” Most responses pointed to that taking about a year.

For that kind of speed, KBI focuses on integrating product quality testing with candidate selection and clone selection. “You want to make sure you get the right molecule attributes and clones that behave very well. Definitely, the more you can integrate the cell line with the upstream, downstream, and analytical development, the faster you can go. Process and equipment platforms certainly help in this regard.”

Integration: He highlighted the Selexis–KBI integrated “SKI” development and current good manufacturing practice (CGMP) workflows. First, Selexis performs cell-line engineering to transfect the first clones. Then KBI takes a dozen of the best clones into process development while Selexis continues the final cell-line development phases. KBI produces a supply batch for preformulation, downstream process, and analytical development. In parallel, KBI moves the best clones into bioreactors using a proven upstream platform.

They choose the top clone for a 200-L scale-up run, making product used for toxicology testing, and then scale up further for manufacturing. This leads to CGMP manufacturing of drug substance in about nine months to enable clients to prepare and file their investigational new drug (IND) applications. “We rarely do engineering runs these days. Rather, we leverage our scale-down platforms and perform a 200-L toxicology batch to culminate development before 500 L to 2,000 L production.”

KBI and Selexis have worked together on different product types: MAbs, fusion proteins, bispecifics, and vaccines. McNaull showed expression titer data, pointing out that even fusion proteins and bispecifics are made in the range of 2–3 g/L, with some as high as 5 g/L. For MAbs, that’s up to 9–10 g/L. To develop a process for manufacturing phase 1 clinical material of one product, they took “a couple of months” to get 4.5 g/L; later for the same molecule they optimized that production process to achieve 7–8 g/L.

Analytical Expertise: McNaull showed a panel of assays that clients can choose from for their molecule, process, and stage of development. “Typically, we pick a couple assays for candidate selection at Selexis and then a couple of assays for clone selection.” Further in development, a broader panel applies to reference material characterization, and product stability testing. McNaull said his company applies these technologies earlier in cell line development now than it did in the past.

Finally, he highlighted Selexis’s first-in-class cell-line development programs for 95 clinical candidates, with KBI performing development of 20 programs to date with titers of 2–10 g/L. “We are on our way to providing a first-in-human platform for CGMP manufacturing of MAbs in nine months.”

Questions and Answers 
What’s your mammalian cell culture manufacturing capacity for clinical and commercial supply? With our three 2,000-L reactor lines in North Carolina, we can supply up to 50 batches a year. Our clinical stream can produce about a third as many batches. The other stream has the two 2,000-L reactors and can do either clinical or commercial production.

Are many of your clients planning to launch commercial products with single-use bioreactors? Yes, that’s a trend we’re seeing. Our vision for expansion is to expand to a 6 × 2,000-L facility for high-titer production and high-throughput downstream processing. You can make 1,500 kg of product each year depending on the modality. We are doing process performance campaigns this year in single-use technology and clinical batches for new modalities.

More Online
Find the full presentation of this “Ask the Expert” webcast on the BioProcess International website.