Of all the activities that constitute a bioprocessing operation, a good argument could be made that the most critical step involves optimizing cell-line development.
That was one of the main messages delivered at CHI’s “Bioprocessing Summit”, in the late summer.
Jesús Zurdo, Ph.D., head of innovation for biopharma development at Lonza Biologics, discussed the challenges and advantages of various strategies for minimizing high attrition rates related to “dwindling R&D productivity and spiraling development costs,” and the resulting cost pressures on process development for microbial fermentation and mammalian cell culture.
According to Dr. Zurdo’s model, risk may enter the picture anywhere during development, including preclinical studies, human testing, or manufacturing.
“Because we get involved early in the development process, we are often the first to notice issues in the form of low yield, aggregation, low chemical stability, immunogenicity, and immunotoxicology,” he said.
Dr. Zurdo’s approach to assessing “developability” involves in silico computational methods to predict productivity, aggregation, stability, and immunogenicity. This helps investigators select, from a collection of potential candidates, a molecule optimized with respect to these properties.
Next he examines, through in vitro and ex vivo assays on cultured human cells, immunogenicity-related events such as T- and B-cell activation and cytokine secretion. The objective of this two-pronged is not to characterize the molecule fully, but to select optimal candidates with low risk of stability and immunogenicity issues.
“Once you are comfortable with biological activity, you can select the lead molecule based on all these assays,” he added.
Most biopharmaceutical developers employ some of these activities already.
“They attempt to bring research and development teams closer together to differing degrees. But our computational approach, which reduces cost while increasing throughput, allows investigators to explore things they could not otherwise explore.”
Lonza’s other innovation consists of integrating stability and immunogenicity studies. “Only a few companies have achieved this, and it’s unheard of in the CMO space,” claimed Dr. Zurdo.
Identifying and analyzing for key quality attributes early in development, rather than trying to solve them through process tweaks, requires a higher initial commitment but its reward is lower risk and, ultimately, greater flexibility in designing the eventual manufacturing process.
Delivery and formulation are two other factors that Dr. Zurdo believes companies should be thinking about earlier rather than later. The later these critical development activities begin, the more constrained the development space will be with respect to concentration and administration route.
Biopharm is perhaps the only industry, according to Dr. Zurdo, that generates prototypes—candidate molecules—through a fully developed commercial manufacturing process. “And this affects development cost and time,” explained Dr. Zurdo.
Industry must continue to seek ways to create “prototypes” that are safe (through early developability and immunogenicity testing), but which also facilitate the rapid transitioning of candidate molecules into the clinic. Only after a molecule has shown promise in early-stage clinical phases should the all-out effort be placed on a Phase III or production-worthy process.
Parallel, Multimolecule Strategy
Through her presentation, Marguerite Campbell, a scientist in biologics research at Janssen Research & Development, unveiled a unique approach to reducing biotherapeutic attrition. According to Campbell, molecules continue to fail during preclinical development despite great strides in molecule and cell development. Her company’s technique for minimizing early-stage attrition involves front-loading early development by introducing as many as five different cell lines that express an equal number of candidate molecules.
This parallel-development approach requires analytical, purification, and formulation to become involved early in the process on multiple molecules.
“Once the preclinical enabling stage begins we continue to engage all stakeholders,” Campbell said. “Their involvement throughout development allows us to create shorter learning cycles, with go/no-go decision points as we build molecules and cell lines to fit our manufacturing platform.”
The objective is to test and learn as much as possible about multiple candidates before committing to one molecule. “It’s all about options.”
According to Campbell the parallel approach is less risky than committing to five different projects for five different therapeutic targets or indications. She presented a case study of an oncology drug. At initiation, her group had two basic molecules with differing mechanisms of action: one, thought to be the most promising, with two variants and a back-up protein with one variant.
The first group of molecules failed due to aggregation problems, which under a more traditional development paradigm might have ended the project then and there. The second variant of the backup molecule did not exhibit the aggregation problem and showed high activity and the potential for market differentiation.
So in the end, the molecule that may have been the fifth-most-promising was the one that moved forward.