Designing a robust and cost-effective “off-the-shelf” supply chain for cell therapy
At Cell & Gene Therapy Manufacturing Digital Week, Anne- Sophie Lebrun, Head of Operations at Bone Therapeutics presented lessons learned in a successful scale up of osteoblastic cell therapy. Silvia Hnatova picks the top takeaways.
How to design a robust and cost-effective “off-the-shelf” supply chain for osteoblastic cell therapy was a question central to the presentation by Dr. Anne-Sophie Lebrun, Head of Operations at Bone Therapeutics.
In the first part of her talk, Dr. Lebrun introduced Bone Therapeutics’ unique differentiation protocol producing MSC-derived osteoblasts and its use in current clinical trials in patients with complex fractures.
Second, Dr. Lebrun used the company’s journey towards scaling up their protocol to illustrate common challenges in scaling up processes in a commercially viable fashion.
Bone Therapeutics is focused on addressing unmet medical needs in orthopedics, bone diseases, and other conditions.
For this, they developed a unique platform for differentiation of mesenchymal stem cells (MSC) into osteoblasts, through expansion, conditioning, and gene modification.
MSCs are harvested from bone marrow donations from healthy donors and are amplified and differentiated into bone-forming cells.
The MSC-derived osteoblasts are incorporated into ALLOB products, that could potentially be used as a non-invasive alternative to invasive treatments (e.g., spinal lumbar fusion), requiring injection into the patient at the site of administration.
ALLOB products are allogeneic products, meaning that a bone marrow donation from a single donor could generate 10-12 treatments for different patients, leading to a fresh product with a short shelf-life.
Currently, the differentiation protocol is used in several ALLOB products tested in clinical trials, including in knee osteoarthritis, fractures, lumbar spinal fusion, and inflammation.
Bone Therapeutics has 3 products in clinical trials, including JTA-004, next-generation viscosupplement. The differentiation protocol was tested in vitro and in vivo to demonstrate bone formation in mice.
Previous preclinical studies showed that ALLOB products were able to improve the speed of healing and bone formation in mice, who had a portion of their tibial bone removed.
ALLOB products, using either ALLOB alone or ALLOB with compatible scaffold, induced a faster recovery of complicated fractures in mice, preventing delayed union or non-union of fractured bones.
The results were replicated in Phase I/IIa clinical trials in human patients, who were given ALLOB products after demonstrating non-recovery from fractures.
Radiography showed that 73% of patients exhibited bone formation at 12 months, and 90% of patients after 24 months.
There is currently an ongoing Phase IIb placebo-controlled, randomized, double-blind, multicenter study to confirm the preliminary findings in patients with tibial difficult fractures.
Dr. Lebrun used the next part of her talk to learn lessons from Bone Therapeutics’ journey towards scalable and commercially viable solutions for their MSC-derived ALLOB products.
The requirements for developing a commercially viable solution included improved yield, the potential for scale-up, and intermediate cryopreservation so that the final product could be created on-demand, once available patients are recruited.
ALLOB products were optimized addressing large patient populations having these three requirements as targets.
To improve process yield and the manufacturing process, removing process bottlenecks was crucial.
Dr. Lebrun explained that improvements in medium composition led to a 200x yield improvement, that together with process redesign and extended culture improved the final shelf-life of the product, leading to an exponential improvement in the yield, achieved consistently from different donors.
Xeno-free culture media was used, maintaining the quality, potency, and safety of the modified protocol, which were further evaluated in Mice calvaria.
After establishing the quality of the cells generated from the modified protocol, Dr. Lebrun turned to explain the requirements for cryopreservation.
The priorities were to eliminate centrifugation steps and ideally injecting post-thaw cells without additional manipulations.
Several cryopreservants were evaluated, using cell viability as a measure to identify the best cryopreservant.
Bone Therapeutics concluded that cryopreservation of the final product had no impact on the bone formation cells capacity in mice.
Finally, to increase the scaling capacity, Dr. Lebrun highlighted the commercial needs for ALLOB products and the need for an aseptic filling to increase the overall capacity.
She explained that reduction in operator’s skills variability, agitation of cells, and introduction of air bubbles was key to consistent production. That is why Bone Therapeutics chose bioreactors to scale up the capacity.
This allowed maintaining control of the process, and limiting the passage numbers of cells whilst maintaining the same confluency, as this was known to affect the differentiation of the cells.
Multiple experiments were set up to identify the ideal culture medium and to reduce clotting in the spinner culture while preserving the yield in the bioreactor.
Dr. Lebrun concluded that cells were able to reach the same confluency while retaining ALLOB in vitro specifications when growing cells in the bioreactor – an outcome critical to successful scaling capacity.
Dr. Lebrun concluded her talk by summarizing that Bone Therapeutics optimized yield and cryopreservation in their differentiation protocol, and progressed their capacity to scale up production.
She highlighted that the lessons learned from the scaling-up exercise showed that taking into account long-term market perspectives and testing simple solutions could lead to cost savings in the future.
