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BioPharm International:Moving Closer to End-to-End Continuous Bioprocessing

2021 - 05 - 02

The past few years have brought significant cost and competitive pressures to biopharmaceutical manufacturers. Process intensification and integration have allowed manufacturers to address these challenges, improving yields and reducing timelines.

Conditions are now set for change. “For monoclonal antibodies, outputs continue to increase, kilograms per batch are getting lower, and we’re getting higher titers out of cell cultures. In addition, there is a need for more flexible, adaptable manufacturing plants, particularly multiproduct plants, that can be run more flexibly,” says Darren Verlenden, head of bioprocessing at MilliporeSigma.

More companies are moving beyond intensification and evaluating continuous processing, which would usher in a future of lower manufacturing costs, real-time product release, and predictive control. “Continuous bioprocessing promises to transform biomanufacturing by reducing inter-campaign downtime, removing time- and labor-consuming steps, and reducing risk by chaining or combining serial steps in current processes,” says Phil Vanek, chief technology officer at Gamma Biosciences, which specializes in tools and technologies for advanced biotherapeutics development and manufacturing.

However, Vanek says, “in order for continuous biomanufacturing to work, we need to think about each manufacturing process in its entirety and seek areas where product can be harvested in real time without disrupting the ongoing process.” He visualizes highly productive expression systems under tight process control, chained to efficient cell harvesting and subsequent downstream technologies, which can be developed into modular continuous biomanufacturing platforms, all within a highly efficient and compact footprint. An example of this, he says, is Univercells Technologies’ NevoLine biomanufacturing platform for intensified and automated viral production.

Focus on perfusion

Currently, most companies are applying continuous processes upstream, particularly to perfusion. Within 10 years, such efforts are expected to drive reactor productivities from 0.05–1 g/L per day to 0.5–10 g/L per day (1). Technology providers, including Cytiva, Sartorius, and MilliporeSigma have all released new automated perfusion systems and bioreactors. However, the continuous concept is also being developed downstream, enabled by new and improved alternatives to traditional chromatography. WuXi Biologics is using continuous perfusion and downstream processing in its WuxiUp platform.

Eliminating clarification and product hold time

Transcenta Holdings is working to improving continuous processing both upstream and downstream functions. Based in China and United States, the company was formed in early 2019 when two drug development companies merged. MabSpace brought a focus on novel technology in discovery and research, while Hangzhou Just Biotherapeutics contributed strengths in chemistry, manufacturing, and controls development and bioprocessing platform. “The idea was to combine two companies with complementary cutting-edge technologies in R&D and biomanufacturing. The goal is to use innovative approaches to develop and deliver affordable innovative drugs to patients with unmet medical needs across the globe,” says Chris Hwang, chief technology officer of Transcenta, and a 25-year veteran of Genzyme and Sanofi. Although there is still much work ahead, continuous bioprocessing offers a number of advantages, he says.

Transcenta’s manufacturing platform, Integrated Continuous Bioprocessing (ICB), uses continuous perfusion that can achieve very high productivities by maintaining cells at high densities in a productive state for the duration of each run to reduce downtime, he says. The company plans to rely on process integration with intensified and connected/continuous downstream to remove process bottlenecks where production takes place.

By implementing ICB, Transcenta will also be able to eliminate harvest clarification and product hold steps, says Hwang. Those changes, combined with robust process control and automation, promise to result in significant reductions in footprint, labor, materials, consumables, and operator errors and overall cycle time.

Transcenta envisions a future based on small, closed, and highly automated single-use flexible facilities that use continuous processes and can be set up quickly and inexpensively, much like its facility T-BLOC in Hangzhou China. T-BLOC was built in January 2018, using G-CON’s prefabricated modular clean room technology, the first of its kind for protein production. Also, the facility will fully leverage single-use technologies, allowing it to support multi-product and scale-out as necessary to support clinical and commercial production needs.

“Since we opened our T-BLOC facility, we have invested significant efforts in developing our own cell lines, chemically defined and low-cost cell culture media (< 1/10 of commercial media), and as well as our own continuous perfusion platform. Since then, we have demonstrated a more than 10-fold increase in process output when compared to conventional fed-batch processes for multiple cell lines and molecules,” says Hwang. He estimates that it would take 22 2000-L single-use or four 12,500-L stainless-steel bioreactors in fed-batch mode to match the output of four 1000-L single-use bioreactors using the same cell line in their plug-and-play perfusion platform.

To handle such a high cell-culture output efficiently without large-scale equipment, Transcenta is also developing continuous downstream bioprocesses in parallel. To accelerate implementation of ICB for good manufacturing practice production in its T-BLOC facility, Transcenta established a strategic technology collaboration with MilliporeSigma in mid-2020, leveraging its BioContinuum platform, as well as its expertise in continuous processing (2). However, rather than go all in to end-to end continuous, the team decided to implement in a stepwise manner, to minimize any risk to manufacturing operations.

Flow-through polishing

The first phase of this multi-year partnership, the team will co-develop a first-of-its-kind single-use flow-through polishing system, says Hwang, and the second phase will focus on expanding the boundary of continuous to the rest of the process, as well as digital technologies to optimize ICB. “To further minimize manufacturing risks, the technologies we are developing and implementing need to strike a right balance of risks and benefits with strong preference for simplicity as oppose to complex systems,” he added., “Significant progress has already been made and I expect our end-to-end continuous and automated ICB technology will be ready for operation in two years in our T-BLOC facility and ready to support clinical and commercial production,” Hwang says.

Transcenta’s work reflects greater industry interest in continuous processing across the board. Pilot-scale continuous operations are showing progress, says Verlenden. A recent report projected demand for continuous bioprocessing to increase by nearly 23% per year through 2027, reaching $198 million by 2027 (3). At this point, the only dampening factor appears to be concern about regulatory acceptance of continuous, Verlenden says, noting a recent company survey on BioPharma 4.0, in which respondents found regulatory concerns to be the largest hurdle for companies to overcome. “This may prevent some companies from moving beyond pilot level,” he says.

At this point, savings are attracting more companies to continuous manufacturing approaches. “Continuous processing has been shown to demonstrate cost-of-goods reductions for monoclonal antibody purification, especially for orphan drugs,” says Dmitrii Sorokin, drug product development engineer at Exothera, a contract development and manufacturing organization affiliated with Univercells that specializes in viral vector manufacturing. “In these cases, the cost of Protein A resins is pushing developers and manufacturers to explore alternatives to big expensive chromatography columns, and continuous multi-column chromatography (MCC) instruments offer an opportunity to decrease investment during development, clinical trial material manufacturing, and commercialization of such products,” says Sorokin.

For products that are difficult to produce using traditional technology—often due to stability issues or cytotoxic/cytostatic effects on cell culture—a combination of upstream perfusion, continuous downstream processes using MCC, and in-line conditioning and tangential flow filtration (TFF), are being used in development, says Vasily Medvedev, head of development at Exothera. “In viral processes, more efforts are using continuous purification for sensitive viruses, to allow purification to take place more quickly, since target recovery remains one of the industry’s top challenges,” he adds.

Downstream advances

At the same time, advances continue to be made in downstream bioprocessing technology itself. In January 2021, Sartorius Biotech acquired Novasep’s chromatography business, while, in April, the company opened a new center of excellence for downstream bioprocessing in the United Kingdom.

Improvements are also being seen in traditional products such as Protein A resins. “Next generation medicines are complicated systems ranging from in-vitro transcribed RNA, purified extracellular vesicles, viral-based vectors, and vaccines, to genetically modified cells,” says Vanek.

Although these therapies promise transformational health outcomes for patients underserved by conventional medicines, Vanek explains, their complexity translates into manufacturing challenges that range from inefficient production steps to difficulties in packaging and distribution, he says.

Affinity improvements

The introduction of affinity technologies, most notably Protein A in the monoclonal antibody workflow, has boosted productivity by simplifying the number of steps necessary to achieve functional purity. Affinity methods will continue to be applied to all forms of advanced therapies with the goal of improving recovery and quality of final product, as well as reducing cost through process simplification, Vanek says. In addition, he notes, identifying highly tunable ligands and conjugating them to appropriate chromatography substrates such as resins, magnetic ferrofluids, or electrospun non-woven membranes promises to open up a whole new dimension of bioseparation possibilities.

Nanopareil electrospun nanofibers, one of Gamma Biosciences’ newer bioseparation product offerings, combine extremely efficient chromatographical properties such as short residence time and high dynamic binding capacity with large pore sizes that are better suited to advanced therapy modalities such as viral vector and exosomes. “This platform is being developed with traditional chemistries as well as Astrea Bioseparation’s affinity ligands to address new applications,” Vanek says.

Polishing applications

Nanofiber chromatography technology promises to improve cell and gene therapy capture and polishing applications, offering high binding capacities, fast cycle times, and scalable formats, says Fletcher Malcom, head of product at Nanopareil. As a result, this technology can help reduce processing time, chromatography facility footprint, buffer requirements, and waste significantly, shortening time to market while cutting costs and ensuring environmental sustainability, he says.

In viral-vector manufacturing, downstream processing is adapting chromatography and TFF steps to aseptic processing for viral particles that are too small for sterilizing-grade filters, says Sorokin. Currently, more chromatography materials are available as membrane capsules and monoliths, which can be gamma-irradiated and ready to use in closed processes. In addition, presterilized TFF hollow-fiber cartridges are available with aseptic connectors, he says.

“This trend is unlocking aseptic downstream processing at a large scale, which is critical for several categories of viral vector products (e.g., oncolytic viruses),” says Medvedev. “Another trend we are following closely is the availability of new modalities for separation of viruses (e.g., steric exclusion chromatography), which offers value in cases where conventional affinity or ion exchange resins would result in low recovery,” he adds.

Membranes and capsules

“Many anion exchange diffusion-based media (e.g., resins based on Q-Sepharose) that are suitable for viral vector purification are being replaced by single-use convective media (e.g., anion exchange membranes or Q-adsorber capsules),” says Sorokin, “but a lot of polishing steps are required for monoliths to remove aggregates and residual DNA-VP complexes.”

More biopharma developers are also looking into the idea of combining unit operations, such as the midstream approach used in Univercells Technologies’ NevoLine or coming up with innovative approaches for sensitive targets such as Repligen’s tangential flow/depth filtration concept for lentivirus, says Medvedev.


1. National Academies of Sciences, Engineering, and Medicine, Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations, The National Academies Press, Washington, DC, 2021.

2. M. Higson, et. al., “Process Development for Continuous Flow Through mAb Purification,” Presentation, online (Nov. 7, 2019).

3. Meticulous Research, Continuous Bioprocessing Market by Product, Application, End User, and Geography-Forecast to 2027, Report (April 6, 2021).

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