Bioprocess Development Forum - Insights, Solutions, and Shortcuts in Bioprocessing

Kaentoh\Shutterstock.com

Innovation in bioprocessing is necessary as the capacity needs for monoclonal antibody (mAb)-based biologics increase. Disruptive technologies are typically innovative technologies (e.g., digital transformation and automation, process intensification, and cell removal technologies) that have been developed to remove bottlenecks, streamline development, and reduce costs of biopharmaceutical production.

Driving innovation

Drivers behind the development of disruptive downstream technologies include increase in demand for biologics. Demand for mAbs, for example, is expected to increase by one or two orders of magnitude, and it may not be economical to cover this demand increase using current bioprocessing technology, according to Günter Jagschies, senior director, strategic customer relations, at Cytiva.

“The use of mAbs for Alzheimer’s disease (Biogen), influenza (VIR), or as neutralizing antibodies for HIV (JustBio) are examples where such demand could come up,” Jagschies says.

Other drivers relate to gaps in process performance, for example, “the notorious weakness of harvesting technologies in the face of the ever-increasing biomass from highly productive mammalian cell culture, and even more so with yeast systems,” notes Jagschies.

The high cost, or perceived cost, of an established technology is another driver. An example of the latter may be the use of affinity chromatography in the capture step of antibody processes, Jagschies says.

“When we look at the biologics market dynamics for treatment of diseases, certainly the increasing demand for biopharmaceuticals and the growing R&D expenditure in biopharma companies are factors driving the growth of the global biomanufacturing industry, including downstream bioprocessing,” adds Orjana Terova, product manager, downstream, Thermo Fisher Scientific.

The industry pipeline is growing in complexity to include emerging molecules such as bispecific antibodies, antibodydrug conjugates (ADCs), and those viral vectors for gene and cell therapies. Some of the challenges in downstream bioprocessing are therefore driven by the pipeline growth of these novel molecules. In addition, there is increased focus to expand the role of contract manufacturing organizations (CMOs) to meet market demands for biomanufacturing, Terova explains.

“Higher productivity and higher throughput processes that integrate upstream and downstream unit operations are driving technology innovation downstream. Lastly, commercialization of gene and cell therapies requires industrialized production approaches, which also drives technology innovation downstream,” Terova says.

Further, research has shown that “[b]uffer management and handling is now the top-cited area for downstream bottleneck concerns” (1), notes Becky Moore, PhD, product manager, cell culture, Thermo Fisher Scientific. “Market trends toward efficiency, single-use bioprocessing, flexible facilities, and increased outsourcing of non-core activities are driving considerations for buffer outsourcing. Customers are demanding overall efficient, cost-effective solutions, faster, just-in-time service and delivery, supply chain logistics, full [good manufacturing practice] GMP documentation, high consistent quality, and easy customer relations,” she asserts.

Disruptive innovations

“Keeping in mind the trends mentioned, there is a focus to improve productivity and have platformable processes for these new modalities, while meeting the high quality and regulatory standards for the therapeutic,” says Terova.

The biomolecule purification scheme can be very complex, particularly in the case where affinity solutions are not available, Terova continues. Purification can typically include four to five chromatography steps, which results in a product yield that decreases with each step that is added. Because product yield drives the cost of goods (COG), not having an affinity purification solution can significantly impact the COG for biotherapeutic manufacturing, she says.

“The Thermo Scientific POROS CaptureSelect technology provides highly selective affinity resins with antibody-like specificity, which can significantly improve the biomolecule purification process, making it simpler (less chromatography steps) and more economical (reduced COGs) by increasing the final product yield,” Terova states.

Thermo Fisher Scientific has commercialized three POROS CaptureSelect AAV affinity resins to establish industrialized platforms for the purification of adeno-associated virus (AAV). The move is meant to meet market demand for gene therapies, which are progressing in the clinic toward approval and commercialization.

The increase in more challenging molecules under development and the desire to make processes more efficient have led to a significant increase in interest for custom resins on high-performing beads, another example of a disruptive technology innovation. In addition, there is a need for new resin chemistries for polishing end product because the bioprocessing of complex therapeutic molecules such as ADCs, antibody fragments, and bispecifics are resulting in higher product-specific impurities. Thermo Fisher Scientific aims to address this challenge with a series of commercialized hydrophobic interaction chromatography resins with a differentiating range of hydrophobicity, resolution, high capacity, and mass transfer characteristics for increased throughput.

To address the challenge of how to increase productivity, process intensification by handling smaller volumes of material semicontinuously or continuously is also being explored, according to Terova. “Integrated upstream and downstream unit operations are being tested and scaled up. Utilizing the resins to their fullest (i.e., rapid cycling) and decreasing the cost of raw materials becomes critical. Next-generation ion exchange chromatography resins like POROS XS (strong cation exchange) and XQ (strong anion exchange) offer high capacity, high resolution, and salt tolerance at faster flow rates for increased throughput,” she says.

“Achieving good capacity and separation under higher salt concentrations for added flexibility and process simplicity is important. A salt-tolerant resin can be beneficial to a purification process by decreasing the need for dilution or eliminating tangential flow filtration steps all together. In addition, there has been increased emphasis on the use of membrane chromatography to increase throughput,” Terova adds.

Jagschies says that downstream steps are typically limited by their capacity expressed as product mass bound per volume of the chromatography resin, or as the product solution volume per square meter of membrane area. “One issue that could occur is the load of a high titer product stream from a large-volume bioreactor onto a column with given, limited size and thus limited capacity (similar with filters), and all of that in a short time (a few hours compared to the two weeks while product has been allowed to accumulate in same reactor). Disruptive approaches would remove this bottleneck, for example, via precipitation or extraction of the product. Both methods would remove the challenge originating from practically limited column size or filter membrane area,” he states.

In addition, membrane absorbers have been suggested as a “disruptive alternative” to column steps for polishing a product to final purity (order of magnitude higher volume throughput). Other examples of innovation include expanded bed adsorption (EBA), which was introduced to replace classic centrifugation and filtration trains with a purification step that is run on crude harvest material directly from the reactor. Also, ion exchange is being used instead of affinity chromatography in a few processes, mainly motivated by cost reasons, Jagschies says.

“We see end-users transitioning away from internal manufacturing of downstream processing buffers and focusing on core activities; they are looking to outsource these non-core activities to ease the buffer bottleneck. Development of in-line dilution and in-line conditioning solutions will further reduce bottleneck concerns,” adds Moore.

Digital and automation

Digital transformation and automation, also disruptive innovations, offer advantages to downstream processing.

“Automation has the opportunity to close the gaps of determining how to scale up a process that was created with simple lab equipment to one that is run in a sophisticated and automated manufacturing environment,” says John Greenwood, senior automation engineer, automation, Thermo Fisher Scientific.

“Through the use of automation, R&D experts can alleviate the burden of tasks, such as manual data entry and retrieval. Similarly, automating tasks and data in downstream processes also creates efficiencies, improves data collection, and has the potential to improve quality and accuracy due to the continuous feedback of data,” Greenwood elaborates.

Further, advanced automation based on advanced sensors and at-line measurements on the production floor will eliminate hold-ups and the need to wait for decisions to be made about the next steps in the processs. This will ultimately speed up the release of the product, notes Jagschies. “Advanced automation also involves the use of trend analysis and correlations between ‘simple’ measurements and ‘complex’ quality attributes,” he says.

“This all helps to lower the cost of the analytical effort to be made in a GMP environment (which may be one of the largest cost after one has optimized the process itself) and the overall cost required to produce and release the product,” Jagschies states.

The use of an advanced digital environment where the analytical data are transformed into information and informed decisions, and then into process knowledge and an ability to predict process performance, is an essential part of the development of the future of automation solutions, Jagschies adds.

Challenges to disruptive technologies

A significant challenge to the adoption of disruptive technologies is the conservative attitude of the pharmaceutical industry itself. “This is related to the significant values handled in manufacturing requiring avoidance of any risks to that value and to the supply of medicines to patients,” says Jagschies.

For existing processes, he notes, a change of technology would require regulatory action that may lead to significant consequences in the supply chain to the patient and to a cost of change that might not be considered beneficial once the medicine in question has reached a certain “age”.

“Management would require very significant advantages of a ‘disruptive’ technology, a demand that has so far not been met by most of the proposals for such technology. When a business already owns a production facility, cost reduction is usually the smallest of the candidate advantages,” Jagschies says.

Securing continued supply from that facility to all patients, however, is a challenge. “Even with the most optimistic market growth scenario, avoidance of the investment into a new facility to meet such growing demand and the possibility to add new products into the portfolio manufactured in the facility without major upgrades are all examples of potential reasons to accept a new technology onto the manufacturing floor,” Jagschies remarks.

Even with upgrades, however, any technology candidate would have to pass a risk analysis with regard to robustness and assumed failure rate, he emphasizes. Because of doubt, fundamentally new technologies are often put on the shelf “for a later opportunity”. “Also, quite many seemingly disruptive technologies are either not quite as new and different, or they do not solve a real and serious problem, but they are instead pushed based on a commercial interest, usually from a technology or service provider,” Jagschies adds.

Collaboration and partnership are key to having the most advanced bioprocessing technologies. “When considering outsourcing to a supplier, a partnership needs to be developed to ensure that all details are captured,” says Moore. “A deeper level of supplier-customer partnerships is needed to develop and commercialize the technology needed to address industry pipeline growth and complexity, as well as meeting targets for productivity,” adds Terova.

Creating a collaborative partnership to qualify, design, and supply materials for manufacturing can be an effective way to reduce non-core activities, address buffer bottleneck challenges, and focus on drug manufacturing, Moore asserts. “It is important to think about the biomanufacturing strategy early in the process to realize implications for flexibility, economics, safety, and logistics,” she says.

“Various operational challenges and process analytical technologies for inline/ at-line/on-line controls still need to be worked out to achieve success in continuous bioprocessing. This is a highly regulated environment; therefore, timelines for the development and adoption of new technologies are lengthy,” Terova states.

Reference

1. BioPlan Associates, 14th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production (BioPlan Associates, Inc., Rockville, MD, April 2017).