Continuous Bioprocessing – The Biomanufacturing Model of the Future?

While attending IBC’s Biopharmaceutical Development and Production week (BDP), I was glad to find an entire session just on continuous processing technologies and implementation. We have covered continuous processing topics in the past on The Downstream Column, but I was interested to hear the latest developments in this area and also to hear some additional first hand accounts of implementing a continuous process including the benefits and challenges of such a system. This blog will provide a high-level overview of some of the topics associated with continuous bioprocessing and share some implementation examples in biopharmaceutical manufacturing.


Continuous processing has proved a very successful model in many other industries. As such, there has been a growing interest in utilizing continuous process concepts in the manufacture of biopharmaceuticals. Furthermore, certain continuous technologies have already been incorporated into existing biopharmaceutical manufacturing with many benefits.

While implementing an end-to-end continuous process in biopharmaceutical manufacturing may still be many years away for most companies, there are some real advantages in utilizing portions of a continuous process in certain areas of manufacturing. Continuous processing technologies can provide solutions to specific challenges and can drive the implementation of a continuous or semi-continuous process.

For certain applications, continuous process technologies can:

  • Increase productivity
  • Resolve facility utilization and facility fit challenges
  • Reduce capital expenditures
  • Improve product quality
  • Ensure manufacturing consistency

Continuous Processing Implementation in Biomanufacturing – First Hand Accounts

A Bioprocessing Facility of the Future

While at BDP, I was fortunate to be able to hear the excellent talk given by Dr. Veena Warikoo, Director, Purification Development, Genzyme. The title of her talk was “Integrated and Fully Continuous Processing of Recombinant Therapeutic Proteins – From Cell Culture Media to Purified Drug Substance,” and in it she discussed Genzyme’s work to create their vision of the bioprocessing facility of the future, which includes fully continuous bioprocessing.

Genzyme has been working toward developing an integrated continuous bioprocessing manufacturing facility with a manufacturing scale of 10-4,000 kilograms per year based on single use bioreactor and column size. Their goal was to design the future facility to address current platform limitations and to borrow from other industries to “make it lean.”

Dr. Warikoo mentioned several reasons for Genzyme’s desire to move in this direction. Key Drivers discussed included:

  • Consistent high quality with robust design and control
  • Cost effectiveness by attaining high productivity and lower capital investment
  • Standardization with a manufacturing model that can be used for manufacturing both therapeutic proteins and enzymes and that can address capacity demands. In addition, the design can be applied to multiple facilities.

Dr. Warikoo went on to describe the key features of their bioprocessing facility design:

  • Ballroom CNC facility
  • Simple facility – disposables
  • Highly flexible
  • Multiproduct, multipurpose
  • Faster and cheaper to build
  • Fast ramp up or down – to add capacity add more manufacturing lines
  • End to end fully continuous
  • Perfusion with no reservoir in between

Genzyme was able to deliver a model of this system, which was used to manufacture a monoclonal antibody and a recombinant human enzyme. The system utilized the integration of a perfusion bioreactor and a four-column periodic counter-current chromatography (PCC) system to provide an integrated continuous bioprocess. Details of this work can be found in the publication, “Integrated continuous production of recombinant therapeutic proteins,” published December 2012, in the journal Biotechnology and bioengineering.

Now that they have developed the process, they are analyzing the business impact of integrated continuous bioprocessing vs. conventional biomanufacturing, including comparison of cost of goods and net present value (NPV). Dr. Warikoo said that this information would be available in an upcoming publication.

Implementing Continuous Downstream Processes to Address Specific Challenges

In a recent blog titled “Continuous Downstream Processing – A Tool to Address Key Manufacturing Challenges,” we were able to highlight a recent webinar where Sanchayita Ghose, Principal Engineer/Associate Director of Biogen Idec discussed how they addressed key challenges including facility fit issues through the use of continuous processing solutions.

Dr. Ghose began by sharing that Biogen’s Idec’s upstream group had been successful in increasing titers to keep up with product demand. She said that titers at “6-8 g/L is the current reality,” but this increase in titer created new challenges, specifically downstream bottlenecks and facility fit issues. As a result of these changes and because they didn’t want downstream to limit throughput, Biogen Idec began looking at continuous processing as a way to achieve productivity improvement goals.

Biogen Idec already had success with implementing one continuous processing tool. They had been able to decrease culture time in bioreactor by 20-30% by using an N-1 perfusion seed culture in upstream. They began to consider the use of continuous processing in downstream. Dr. Ghose stressed that they were not looking to move to complete continuous processing at the moment, but rather they were looking to implement continuous processing in key areas to address specific needs.

Their first step, she said, was to consider what was causing the downstream bottlenecks. First, there was a significant problem with facility fit as these legacy facilities were built for lower titers, 5 g/L or less. Increasing titer caused challenges with lower throughput of the Protein A capture step and rising intermediate pool volumes. The process intermediates volumes started to exceed their tank capacity of 6,000-8,000 liters. To solve this problem using a traditional approach would mean tank replacement and with that would come cost, validation and facility shutdown.

They knew that it was possible to address these challenges by eliminating the intermediate product hold tanks, but they needed an engineering partner to implement the strategy and were interested in GE Healthcare’s Straight Through Processing (STP) system.

Once they had a plan, they set out to conduct proof of concept studies, but they quickly ran into their first issue – these tools were available in large scale, but no off the shelf scale down system existed, so proof of concept studies at small scale were going to be impossible. They worked with GE Healthcare to reconfigure an AKTA pure system to achieve most of the functionality of an STP system at small scale. The lab scale results showed very comparable product quality and productivity with batch process and they were able to eliminate the need for product hold tanks thus providing a solution to their facility fit issues.

Roger Nordberg, Senior Product Manager, GE Healthcare Life Sciences also discusses some of the innovative continuous downstream tools designed to solve these types of problems and Annika Forss, Senior Research Engineer, GE Healthcare Life Sciences walks through a case study to evaluate continuous processes versus batch processes in downstream. For a more detailed description, please see “Continuous Downstream Processing – A Tool to Address Key Manufacturing Challenges.”

Increasing Flexibility with Continuous Upstream Bioprocessing Tools

Also at BDP, I was able to hear another example of implementation of continuous process technologies in biomanufacturing. Shaun Eckerle, Principal Scientist, Cell Culture Development at Patheon, gave an interesting talk titled “Upstream Disposable Technology Supports the Implementation of Continuous Processing.” In the talk Mr. Eckerle, discussed how at Patheon, a Contract Development and Manufacturing Organization (CDMO), they utilize a variety of manufacturing models including batch, fed batch, perfusion and their proprietary XD Technology.

While they still have stainless steel tanks as Mr. Eckerle pointed out that larger tanks have a niche, they have largely moved to flexible facilities with disposable systems including tanks and bioreactors at the 10-2,000 liter range. This move to disposables has reduced capital expenditures and a flexible facility that includes continuous upstream solutions provides a range of scales to meet customer needs. This kind of flexibility is obviously very important to a CDMO where producing a variety of products at varying scales requires the use of different manufacturing platforms.

Mr. Eckerle went on in the talk to present two case studies where Patheon had implemented upstream continuous processes. In the first example, Patheon utilized a CHO disposable perfusion culture with ATF to produce a highly unstable recombinant protein. They operated at two volumes per day at a demonstration scale of 50 liters. The final scale was expected to be 200 or 500 liters, however the 50-liter scale was so productive that 200-500 liter scale was not needed. The process scale was reduced to 50 liters and the process duration was reduced from 60 hours to 45 hours. In examining product attributes, the continuous process was comparable to the traditional process. In this example, Patheon was able to implement disposable medium hydration, media storage, bioreactor and harvest hold vessels. This resulted in reduced capital expenditure and process cost through reduced validation and turnaround time.

In the second case study, Patheon utilized its proprietary XD Technology. The XD technology is a very high cell density mammalian continuous upstream process that increases bioreactor output 5-25 times compared to fed-batch process. Cell densities reach in excess of 200 million cells and remain high throughout the run, typically above 95%. This allows for high and consistent product quality with reduced capital expenditure. The process is ideal if ample product is needed quickly.


Several speakers have discussed a coming paradigm shift in biomanufacturing, which would make a fully end-to-end continuous process the norm. While that shift, if it comes, is still several years away, there are good reasons to consider implementing either a fully continuous process or continuous technologies to solve key manufacturing challenges. One area where continuous processes are particularly useful is in manufacturing unstable or difficult to manufacture products, as the elimination of product hold steps reduces the risk of product degradation.

Continuous bioprocessing is also beneficial in addressing facility fit challenges and it is possible to adapt a fed-batch process to incorporate aspects of continuous processing to address these challenges. Perfusion culture in upstream and periodic counter-current chromatography in downstream are good examples of technologies that can be integrated into existing processes to meet specific manufacturing demands.

Continuous process technologies are also beneficial to facilities that are multi-product/multi-purpose in that they utilize a smaller footprint and can be operated as closed or functionally closed systems. These attributes greatly increase the flexibility and scalability of a facility.

Lastly continuous processes can be used to create a fully closed or functionally closed system. A closed system can offer many potential benefits, which we discussed in a recent blog, “Closed Systems in Biomanufacturing Offer A Variety of Benefits.”

Do you think integrated continuous bioprocessing is the biomanufacturing model of the future? Please share your thoughts in our comments section.

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