The Origins of Continuous Bioprocessing

May 23, 2019

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Virtually all mature manufacturing industries have adopted elements of continuous manufacturing. This is the case for the automotive industry, food and beverage, oil refining, pulp and paper, chemicals, steel industries, etc. So, what is continuous bioprocessing? Let’s take a look at the history and origin. 


A manufacturing unit operation is considered continuous if it is capable of processing a continuous flow input for a prolonged period of time. The output can be continuous or discretized in small packets produced in a cyclic manner1.



Why Adopt Continuous Bioprocessing?


The most important driver for these industries to adopt continuous manufacturing was process intensification. This resulted in a reduction of the capital investments that are needed to establish manufacturing capacity. In addition, they also realized significant savings in cycle times, consumption of auxiliary materials (chemicals and water), energy consumption and waste production. In fact, continuous manufacturing has been one of the key enablers to make certain technologies available to a wide audience. A good example of this is automobiles, which only became affordable to the majority of the population after Ford Automobile introduced the conveyor belt manufacturing platform for its Model T.



What Does It Offer to The Pharma Sector?


The biopharmaceutical industry has always been known as a research based industry. Manufacturing costs are not the main driving force during process development and process innovation. Yet, with the rise of biosimilars and the availability of multiple therapies targeting the indication, the biopharmaceutical landscape is becoming more competitive and hence manufacturing costs start to become a more relevant business factor.


The history of penicillin shows how a combination of technical advancements, improved analytical methods and business drivers can affect prices of medicines. Over the course of approximately 60 years, the price of penicillin dropped by four orders of magnitude from around $200,000 per billion units in 1939 to around $20 per billion units in 19952. It is highly unlikely that we will witness similar dramatic changes in monoclonal antibody manufacturing, but it should serve as an inspiration for all scientist that are working towards improving biomanufacturing efficiencies.


In biopharmaceutical industries, continuous cell culture processes or perfusion cell culture processes have been used for monoclonal antibody production (among others), since its early days. Continuous downstream processing, however, didn’t receive any attention until about a decade ago. To a certain extent, one could argue that this is strange since downstream doesn’t have to deal with the genetic stability of the cell line. Instead, the conversion of batch to continuous downstream processing is more of an engineering challenge than anything else.


The reason for this phenomenon lies in the fact that in the early days of biopharmaceutical manufacturing, the upstream processing was the limiting factor. With titers still being below or around 1 mg/mL, the driver to consider continuous downstream processing technologies is very low. During the first two decades of the 21st century, the expression levels of monoclonal antibodies in suspension cell culture reached levels where commercial amounts could be produced in much smaller (single-use) bioreactors. This initiated the era of process intensification in biopharmaceutical manufacturing.


In downstream processing, however, there was limited room for further improvement of the specific productivity in batch processing. As a consequence, continuous downstream processing technologies became an intriguing direction for further process intensification.


In 2003, Jörg Thommes presented the first ever case study on the potential impact of multicolumn chromatography for the Protein A capture step3. It would still take quite some years before the first technical solution that would be suitable for implementation in a biopharmaceutical manufacturing platform would become available. Since 2009, various promising solutions for multicolumn chromatography processes have been introduced, all relying on similar concepts. Over the course of the subsequent years, the most promising solutions were translated into process scale systems that eventually found application in cGMP manufacturing.


As a solution for continuous chromatography became available, solutions for other steps also gained more traction. This includes single-pass tangential flow filtration and continuous virus inactivation. This allowed end-users to assemble end-to-end continuous processing platforms for monoclonal antibody production. In 2019, the first monoclonal antibody that was produced in an integrated end-to-end production platform received approval to start Phase 1 clinical trials5.


Learn more about continuous bioprocessing in the next blog: Market Trends Driving the Need for Continuous Processing.


To learn more about continuous bioprocessing solutions that have been commercialized, please visit our web page where you can download white papers, watch videos, and view other information on continuous bioprocessing solutions.





K.B. Konstantinov and C.L. Cooney. White Paper on Continuous Bioprocessing. J.Pharm.Sci., 104 (3) pp 813-820 (2015)

2 S.R. Adamson. Role of Technology and Science in Manufacturing Economics. Presented at Antibody Development and Production Conference, Carlsbad CA (March, 2007)

3 J. Thommes. Protein A Affinity Simulated Moving Bed Chromatography. Presented at Recovery of Biological Products XI, Banff, Alberta, Canada, (September, 2003)

4 M. Bisschops, L. Frick, S. Fulton and T. Ransohoff. Single-Use, Continuous-Countercurrent, Multicolumn Chromatography, Bioprocess International Magazine (June, 2009) p18 – 23

5 BiosanaPharma. BiosanaPharma gets approval to start phase I clinical trial for a biosimilar version of omalizumab, the first monoclonal antibody produced with a fully continuous biomanufacturing process, Press Release (February, 2019)


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Marc Bisschops – Director, Integrated Process Solutions

Dr Marc Bisschops is the Director of Integrated Process Solutions at Pall. Marc has completed over 250 continuous chromatography and continuous downstream processing projects, authored over 15 continuous publications, and invented 8 continuous bioprocessing patents. Marc holds a PhD in Biochemical Engineering.
Dr Marc Bisschops is the Director of Integrated Process Solutions at Pall. Marc has completed over 250 continuous chromatography and continuous downstream processing projects, authored over 15 continuous publications, and invented 8 continuous bioprocessing patents. Marc holds a PhD in Biochemical Engineering.
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