In the manufacture of biotherapeutic drugs, the goal is to maximize production while minimizing costs, even though achieving this goal may involve a difficult transition—specifically, a transition from batch bioprocessing to continuous bioprocessing. The transition is especially challenging if it encompasses downstream operations. Nonetheless, continuous bioprocessing is being implemented more widely. The global continuous bioprocessing market, reports Research and Markets, is expected to grow from $6,695.49 million in 2019 to $12,106.36 million by the end of 2025 at a compound annual growth rate of 10.37%.
These figures suggest that for many biomanufacturers, the transition to continuous bioprocessing is becoming less forbidding. Still, making this transition requires a commitment to problem solving. Continuous processing presents a wide range of problems and solutions. Also, not all problems have easy, immediate solutions.
According to a report issued last March by Watson-Marlow, industry practitioners estimate that it will take 5–10 years before fully integrated continuous biomanufacturing is in routine use at commercial scale. However, the same report emphasizes that in the past five years, continuous processing has made dramatic progress. And continuous processing is still making progress. To substantiate the point, this article presents the observations of experts who represent biomanufacturers that have experience “going continuous.”
Addressing the options
From BiosanaPharma in the Netherlands, chief technology officer Maarten Pennings says, “[We are] developing an end-to-end continuous manufacturing process for biosimilar monoclonal antibodies, from perfusion to a final UFDF—ultrafiltration and diafiltration—step.”
He asserts that the company keeps moving ahead with continuous bioprocessing improvements. “The latest advance was the successful completion of a Phase I trial of a biosimilar—Omalizumab—that was made with a continuous process,” Pennings notes. Still, getting to those successes takes some fortitude. “At present, the biggest challenge is in developing equipment suitable for operation under GMP, as off-the-shelf equipment is not readily available,” he explains.
Progress is also evident at FUJIFILM Diosynth Biotechnologies in College Station, TX. Steven Pincus, PhD, notes, “We use continuous bioprocessing when a cell line secretes the manufactured product and the cells remain viable,” states Steven Pincus, PhD, the company’s head of science and innovation. “This allows us to obtain maximal product from a single cell train, which reduces cost.”
This benefit, though, comes with challenges. “One problem with this approach is maintaining sterility of the cells during this extended culture period,” Pincus explains. “Another consideration is how to determine the acceptability of the different media harvests before pooling for downstream processing. We want consistency in the upstream material to ensure the success in production of the bulk drug substance and final drug product.”
Engineering for exosomes
Another area in which continuous bioprocessing is being used to make innovative biotherapeutics is engineered exosome
therapeutics. For example, exosomes (or extracellular vesicles) are a specialty of Codiak BioSciences (Cambridge, MA), which has become familiar with the challenges and rewards of continuous processing.
“Early on at Codiak BioSciences, we identified the need to develop a scalable manufacturing process to produce high-purity exosomes in the quantities needed to meet clinical demands,” says principle research associate Andrew Grube. “Our approach was to adopt technologies that have been developed over the past several decades for biologics production and modify them for exosome production.”
To produce exosomes, Codiak uses engineered, suspension cells grown in chemically defined media in single-use bioreactors. “The exosome harvest from the reactor is then processed via a series of filtration, chromatography, and concentration unit operations downstream to select for pure, potent exosomes,” Grube explains. The company analyzes the qualities of the resulting exosome with various methods, including size-exclusion chromatography, ELISAs, and particle quantification methods, such as nanoparticle tracking analysis.
“Proteomics and liquid chromatography–mass spectrometry are also applied to characterize the expression of typical exosome protein biomarkers in our final product,” Grube continues. “Depending on their clinical application, the exosomes may also be loaded with drug moieties consisting either of small peptides, proteins, or chemical molecules to enhance their biological efficacy in targeted cell types.” To accelerate the development process, Codiak also uses high-throughput screening technology, such as robotics and liquid handling systems.
The production of exosomes with continuous manufacturing creates some unique challenges. “Compared to biologics, like antibodies or proteins, exosomes are very large, approximately 100–200 nm in diameter, so they can be challenging to separate without sacrificing yield,” Grube points out. “Codiak has developed a novel continuous upstream manufacturing process that allows exosomes to pass through a separation device, enabling continuous harvest of exosome product.” Grube adds that Codiak’s process increases a bioreactor’s volumetric productivity and reduces impurities in the harvest.
Grube asserts that Codiak has improved scalable continuous manufacturing of exosomes for biopharma: “Through implementation of a novel continuous manufacturing platform, we can produce large quantities of high-purity exosomes in a small footprint.” In addition, this approach produced the maximum productivity without relying on technology that is specifically for exosomes. As Grube explains, “Continuous manufacturing can also be used to produce a variety of engineered exosomes, as our research team identifies new and novel targets.”
Overall, the work at Codiak allows the company to, as Grube describes it, “supply ample exosomes for clinical development for indications both known and to be discovered.” He adds, “We hope that by reducing manufacturing bottlenecks and footprint through continuous processing, Codiak can help unlock the potential of exosome therapeutics for the industry.”
A factory-level facility
On October 15, 2019, Paris-based Sanofi opened a facility for continuous biologics production in Framingham, MA. “The new facility leverages many new technologies to achieve improved process performance and increase the pace of technology transfer and commercialization of new product modalities, which was necessary for the candidates in our pipeline,” says Dean Morris, the facility’s director of process engineering and development. “These new manufacturing technologies are enabled by significant breakthroughs in process intensification, continuous-processing technology, and digital integration across the product lifecycle from development to commercialization.”
The facility, which won the 2020 Facility of the Year Award in the Facility of the Future category, benefits from its continuous capabilities in various ways. “Continuous manufacturing enables significant reductions in process scale and improved process consistency over traditional batch technologies,” Morris notes. “This reduction in process scale and footprint allows for significant reductions in raw material usage and energy consumption, improving our environmental footprint and sustainability.”
The facility’s the most interesting advance in continuous bioprocessing used in that facility, Morris declares, is the integration of a continuous perfusion bioreactor with continuous chromatography systems. “[This integration] results in a manufacturing process that can produce a purified and concentrated therapeutic protein from a continuous raw material feed stream,” he explains. “Sanofi’s implementation of this integrated continuous biomanufacturing approach, combined with adoption of Factory 4.0 concepts, has significant immediate and long-term benefits.”
For example, steady-state cell culture conditions improve product quality and consistency, and process robustness is increased. According to Morris, “Process automation and online analytics enable automated control and maintenance of steady-state conditions, and the generation of massive process datasets enables advanced process control strategies with over 770 million data points sampled per day across the process and facility.”
The Sanofi facility’s benefits, though, don’t come easily. Like Pennings at BiosanaPharma, Morris mentions the lack of off-the-shelf equipment, a problem that can be attributed to continuous manufacturing being relatively new to biologics. (On a positive note, this problem is being addressed by several companies—see “Democratizing Continuous Bioprocessing”). Morris notes that Sanofi faced other difficulties. Nonetheless, he continues, “Sanofi made the decision to develop a continuous manufacturing platform technology requiring significant investment in development, pilot facilities, and at-scale production systems.”
Developing the technology meant incorporating customized equipment and systems, all developed to deliver a fully operational and flexible commercial facility. “The Sanofi team collaborated closely with our industrial suppliers and our internal process expertise to solve technical challenges,” Morris emphasized. “[And we] worked to develop and qualify novel commercial solutions to meet our unique process needs.”
For now, in Framingham or any other implementation of continuous bioprocessing, a company must shoulder much of the load. Without a range of commercial platforms to pick from and a lack of manufacturing experience to rely on, companies must jump in and do what is needed along the way, including developing custom devices. Eventually, more tools and platforms will be available, as more biomanufacturers turn to continuous processing. Until then, only fairly adventurous companies will try to adopt continuous methods.
Democratizing Continuous Bioprocessing
Although many bioprocessing facilities must develop their own continuous systems, Belgium-based Univercells hopes to change that. This company’s approach, says product manager Lola Yomi-Baker, is “designed to overcome industry challenges and make bioprocessing accessible and affordable.”
Bioprocessors can use Univercells’ NevoLine platform when manufacturing viral vaccines and viral vectors for gene therapies. “The NevoLine platform consists of a series of modules which combine to form a solution for bulk-product manufacturing,” Yomi-Baker explains. “Different modules offer different functionalities—for example, upstream, downstream, formulation, and inactivation. The modules also create microenvironments that are consistent with the product’s biosafety level and with a grade C cleanroom classification.”
In exploring the market needs in continuous bioprocessing, scientists and engineers at Univercells realized that several areas needed improvement. “We found that for the gene therapy market, much of the process equipment available was largely oversized for purpose, and many users were relying on manual processes,” Yomi-Baker points out. “This has a limiting effect on the batch-to-batch consistency of the final product.” That’s why this company kept the footprint of the NevoLine platform as small as possible while keeping it fully automated. Yomi-Baker adds, “The platform also minimizes human intervention, protecting the product and operator.”