Supplement: Moving toward Continuous Bioprocessing

Industry Fast Forwards with Hopes of Boosting Productivity and Lowering Costs

The manufacture of biopharmaceuticals using fully continuous processes has the potential to improve product quality and increase the productivity of biomanufacturing facilities. During batch processes, conditions are always changing as cells grow. Cells reach peak concentration and then decline in viability.

These changing conditions can affect the product quality of labile products and even stable biologics such as monoclonal antibodies (mAbs). Conditions within a continuous process tend toward a steady state, so product quality is much more consistent.

Increasing productivity can lead to lower cost of goods and the potential to make biologics more affordable, which could improve access to biologic treatments for a greater number of patients around the world.

The Integrated Solutions team at Sartorius Stedim Biotech (SSB) recently worked on a continuous bioprocessing project with a small biosimilar company. The process modeling of different scenarios provided powerful insights into the relative drug production costs using batch and continuous approaches.

We identified that the biosimilar company could improve productivity by running higher cell density cell cultures that allow a 10-fold increase in titer. We determined that the volumetric productivity that can be achieved from a 5K-L bioreactor in a month could be obtained from a 100-L bioreactor operated in continuous mode—10 kg/month of product could be produced, and this could be achieved with smaller equipment and a lower footprint leading to lower costs.

Eliminating Hold Steps

The concept developed was to have a small suite with fully connected unit operations, thereby eliminating hold steps. Producing multiple products in a single facility using continuous processing can be a challenge. Products must be segregated from one another, but unlike during batch processing, this cannot be on a temporal basis, when they are undergoing continuous production. To overcome this challenge, a multiproduct facility can be operated using the ballroom concept with different suites dedicated to different drugs (Figure 1).

Figure 1. Ballroom concept with smaller suites doing connected processes from upstream to downstream (where DS is drug substance and DP is drug product).

For a small biosimilar company, operating a continuous manufacturing process with a smaller footprint is a very desirable option. It allows the companies to compete effectively by allowing them to reach the market quickly with low production costs. It avoids the need to build large stainless-steel facilities or outsource their production capability to a third party.

Exploring Process Intensification

The advent of single-use technology has allowed firms to build new production plants much more quickly than was possible than former set-ups, which featured stainless-steel plants and were associated with a lower upfront cost. The technology is reaching a level of maturity such that engineers are increasingly considering it for commercial manufacturing facilities.

However, an analysis performed by the industry investigating the costs associated with running single-use facilities (in which fed-batch processes are operated and generate titers of 3 g/L from six 2,000-L bioreactors), has shown that the output of these facilities is limited to around 500 kg/y.

If market demand exceeds this figure, more investment is required to build additional production lines. When operated to produce over 500 kg of product per year, this can lead to much higher net present cost. Fully continuous processes are likely to provide the most consistent product quality and the lowest footprint overall.

However, several challenges related to implementing these technologies remain. These include assuring robust process-control strategies across the entire production chain and defining appropriate regulatory pathways for product approval. While fully continuous bioprocesses show great promise, the benefits will most likely be realized in the medium- to long-term.

This is why we at Sartorius Stedim Biotech (SSB) believe that, particularly in the short-term, process-intensification projects can add immediate value to our customers’ operations while still providing lower cost of goods and great flexibility. Scalable technologies for process intensification are available now. The industry analysis shows that companies can reach productivities of 1,500 kg of product per year simply by intensifying steps in the production process and without needing significant additional investments over a single-use fed-batch facility.

Single-use process intensification serves as a compromise to end-to-end solutions; it allows manufacturing agility, keeps cost of goods low, and improves product quality. The approach is particularly useful in multi-product facilities, when rapid changeovers between products are required.

Upstream Processes

Upstream processes can be intensified by using N-1 perfusion steps that allow production bioreactors to be seeded at a higher viable cell density. Doing so increases culture productivity, especially during what would normally be the growth phase of a standard fed-batch process. The integral of viable cells, a proxy measurement for product titer, can be increased still further by implementing concentrated fed-batch processing using a continuous culture feeding strategy coupled with a cell-retention device. Extremely high cell densities can be achieved because depleted nutrients are replaced and spent media removed.

The optimized scheduling of concentrated fed-batch cultures can allow production managers to gain productivity improvements so significant that they need not invest in a fully continuous production scenario.

Downstream process scientists can intensify the purification of harvests from such cell cultures using multicolumn chromatography techniques. Companies can drive this still higher by replacing conventional chromatography resins with single-use membrane-adsorber technology. Product binding to membrane adsorbers is not diffusion-rate-limited because mass transfer of the product to the membrane is dominated by convective flows (Figure 2).

Figure 2. SSB’s newly developed Sartobind cassette system is a unique single-use solution enabling large-scale bind-and-elute membrane chromatography that has the potential to replace conventional chromatography resins.

Sanofi has showed that biomanufacturers can achieve specific purification productivities of 125 g of mAbs/liter/hour using SSB’s Sartobind® membrane adsorbers and the Sanofi ASAP process. This represents twice the productivity of multicolumn resin chromatography approaches reported in the literature thus far.

Already in the Continuous Processing Space

SSB has a platform of technologies that will enable customers to develop and implement process-intensification projects and continuous bioprocessing within their facilities with the support of our Integrated Solutions team.

Glycotope has reported, for example, that process-development scientists can use the ambr® 15 automated microbioreactor system to mimic the performance of perfusion bioreactors. Also at the development scale, BiosanaPharma and Mycenax has used the Sartorius Biostat® B-DCU benchtop bioreactor for experiments to determine the optimum retention filter for extreme cell density cultures.

We can provide our clients with single-use N-2 and N-1 perfusion bioreactors solutions and we have successfully demonstrated that our large-scale single-use Biostat STR 2000 bioreactor has the mass-transfer capabilities to run concentrated fed-batch processes at very high cell densities using an appropriate cell-retention mechanism. The trials showed that the Biostat STR 2000 could generate results equivalent to those from the existing process performed in a stainless-steel bioreactor. These data are in line with those from Patheon, which has shown that its XD® processes deliver over 200 million cells/mL in a Biostat STR 500 (Figure 3).

Figure 3. The single-use bioreactor Biostat STR’s direct linear scalability is crucial for ensuring the efficiency and cost-effectiveness of bioprocess development campaigns.

Clarifying high cell densities of more than 50 million cells/mL from intensified upstream processes can be performed with SSB’s Sartoclear Dynamics® filters with body feed technology. These filters provide consistent clarification irrespective of the cell viability and the point of harvest.


Gerben Zijlstra is platform marketing manager, continuous biomanufacturing, integrated solutions marketing, and Priyanka Gupta is global senior bioprocess modeling consultant, integrated solutions marketing, at Sartorius Stedim Biotech.

Read the rest of GEN’s supplement on Continuous Bioprocessing.
Continuous Bioprocessing Is Coming
Integrated Continuous Manufacturing of Biologics
Continuous Bioprocessing: Is It for Everyone?
Bioburden Control in Continuous Capture of Monoclonal Antibodies
Single-Use Sensors in Continuous Bioprocessing
MilliporeSigma Sees Opportunity in Continuous Processing
Case Study: Insulin Increases Influenza Virus Yield