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Tackling process development early on can better optimize manufacturing processes for emerging therapies.
An early start on process development helps optimize biomanufacturing processes, shorten time to market, potentially cut costs, and keep product in line with current good manufacturing practices. While the approach to process development for emerging therapies (e.g., gene therapies and cell therapies) is similar to the approach used for more traditional biologic medicines (e.g., monoclonal antibodies [mAbs]), the nature of emerging therapies means there are further nuances to consider in optimizing their manufacturing processes.
“Many of the general bioproduction concepts for gene therapies are similar to the more mature protein therapeutic market; however, there are many nuances in raw material costs, supply chain, technologies, regulatory standards, and overall scale that make gene therapy production a more dynamic process,” says George Buchman, vice-president of Pre-Clinical and Process Development at Catalent’s Paragon Gene Therapy.
Viral vector manufacturing, for example, is a complex process, Buchman notes. Add to that the influx of various and ever-evolving enabling technologies and growth platforms, and viral vector manufacturing becomes even more dynamic. “For example, the supply chain process for standard biologics is more mature and optimized, offering a relatively clear path for manufacturers to follow. However, due to the exponential growth being experienced with increasing numbers of gene therapy molecules with regulatory agency fast-track status, and a large influx of gene therapy assets in the clinical pipeline, raw material supply can be outpaced,” Buchman says. “Additionally, the cost of gene therapy raw materials is generally higher and more varied than what is seen in traditional biologics. Therefore, it is critical to plan ahead and have a risk mitigation strategy for secure supply and cost management.”
Process modeling is also critical to any good development and scale-up process, Buchman points out. Various scale-down approaches can replicate large-scale conditions at small scale, and this is a relatively inexpensive modeling method. It is often highly predictable at large scale for both upstream and downstream processes.
However, there are cases in which process modeling is not very predictive, Buchman notes. “A good example is when a given platform may not scale linearly. However, if you focus on the relative data rather than the absolute data, side-by-side comparison rather than the actual numbers, it is still somewhat effective. All of these modeling approaches take time and deep gene therapy production expertise to develop a trustworthy and predictive model,” he says.
For viral vector manufacturing, yield and recovery are key factors considered when optimizing processes. A good deal of focus is on developing a process that creates more full capsids versus empty ones and optimizes the percentage of material that can be recovered from the total production, Buchman explains. Optimization can also occur in the downstream development process by removing the empty capsids while decreasing the full ones that are removed at the same time, he continues.
“Additionally, we are always focused on vector safety (making sure non-vector components are removed) and vector function (making sure the vector not only is properly isolated but also transduces correctly). For lentivirus production, a key factor is reducing stability issues during viral recovery,” Buchman says.
“For gene therapy manufacturing, material costs (virus and plasmids) are actually higher than the cost to manufacture the product, so reducing material costs is essential for economical production. Of course, creating an optimized manufacturing process to achieve an economy of scale is the goal for the industry, but with so many changes and new technologies and platforms, this will need to evolve over time. We are in a great position as a focused development and manufacturer because we have experience and exposure to a variety of biologic entities, platforms, and processes,” Buchman adds.
Cell therapies have their own set of process development challenges. Cell therapies can be either autologous (one individual is both the source and the recipient of the therapy) or allogeneic (a donor is the source of cells used for the therapy, which can be administered to a number of recipients). In both approaches, it is critical that the therapeutic cell be characterized to define which properties of the cell determine that is has been produced to acceptable standards and quality. This characterization is necessary to ensure that the risk of incorporating anomalies or shifts in cell function have been minimized, because such discrepancies may compromise the safety or efficacy of the therapeutic cell (1).
To be successful from a clinical or commercial standpoint, cell therapy manufacturing processes must create a consistent, safe, and effective cell therapy product, regardless of the cell type or the application for which it is used. Process development for a cell therapy must therefore apply to all elements of the manufacturing cycle-cell isolation, cell characterization, cell culture media, scale-up, and removal of impurities.
Process development for a cell therapy, whether autologous or allogeneic, must address at least the basic questions about how the therapeutic cells will be expanded and manufactured in ways that will retain their potency. Process development should additionally consider what characteristics must be monitored that define the particular cell product of interest. Further, what assays should be used to measure these desirable cell characteristics? The process development approach (1) must also consider how the cell therapy product will be stored and administered as well as take into account the lot size dictated by the market for that specific product.
Monoclonal antibodies have had decades to establish robust and economical commercial biomanufacturing processes and are today considered the leading modality for biotherapeutics (2). Blockbuster success with some mAb therapeutics has also encouraged refinement and innovation in bioprocessing steps, making the manufacture of mAbs further efficient and more productive while retaining safety and efficacy.
Lessons learned during the growing pains of mAb process development may also benefit cell and gene therapies. The introduction of single-use bioreactors, for instance, offers more flexibility in the cell culture approaches that can be taken for a cell therapy or vector manufacturing for gene therapy. While the traditional cell-culture methods for cells used in cell therapy or for vectors used in gene therapy have primarily relied on adherent-based cell culture (i.e., a surface must be provided to which the cells/vector can adhere to and be grown out), there is more movement toward suspension-based cell culture (i.e., cells/vectors are grown in a vessel without the need to attach to a surface). Single-use bioreactors offer that flexibility and are offered in sizes more appropriate to the smaller lot sizes (compared to mAbs) at which a cell therapy or a gene therapy are produced.
“Dynamic changes in platform processes and scale are prevalent in gene therapy bioproduction,” says Buchman. “Many companies have moved-or will move-from cell factory-based growth platforms to suspension bioreactors. Additionally, there have been changes with the implementation of nanofiltration to make processes more robust. It is this type of constant process evolution that requires developers to be open to all emerging ways to increase efficiency and scale.”
Buchman also emphasizes that any actions taken to maximize efficiency, generate more patient material, and improve vector yields safely and effectively and at a better cost are shaping the gene therapy industry today. “Early in our gene therapy experience, we were using centrifugation, which ultimately wasn’t scalable, so we moved to chromatography, and now, most recently, to affinity resins,” he says.
Another example of constant industry growth and change lies in the versatility and use of multiple viral serotypes with the various technologies available for gene therapy manufacture. “It used to be limited to a few serotypes, but now there are resins that will work with all adeno-associated virus serotypes,” Buchman notes.
Overall, the gene therapy industry can take some lessons from the mAb world, Buchman concludes. Moving toward the use of stable cell lines and improving critical and inefficient steps, such as plasmid transfection, are more examples of how gene therapy can learn from mAbs. “However, innovators should not dismiss various incremental improvements, such as the use of more efficient resins or the optimization of reactor feeds. These types of efficiencies might not be game changers, but every incremental improvement will help reduce costs and time,” Buchman adds.
1. A. Campbell, et al., Stem Cells Transl Med. 4 (10) 1155–1163 (2015).
2. A. Abhinav, et al., Bioengineering & Translational Medicine 2, 58–69 (2017).
Vol. 44, No. 3
When referring to this article, please cite it as F. Mirasol, “Optimizing Process Development for Emerging Therapies,” Pharmaceutical Technology 44 (3) 2020.