Subscribe to Newsletter
Manufacture Bioprocessing - Upstream & Downstream, Bioprocessing - Upstream & Downstream

mAbs: Hybrid Style

The community of monoclonal antibody (mAb) producers and researchers continues to work hard to realize fully continuous production of mAbs. The main focus is on implementing continuous production using disposable equipment. Nearly all the necessary unit operations are available in continuous process mode today and, although there are still obstacles, such as the validated viral clearance step, major progress has been made, with successes at the miniplant scale (1).

Most publications focus on fully continuous or semi-continuous processing using continuously operated equipment for the upstream part of the process, with the remaining processes being operated in batch mode. Economical comparisons of fed-batch and continuous processing have been published for the upstream part of the process only (2), (3). Hammerschmidt and colleagues focused on the comparison of a complete fed-batch process with a continuous process based on precipitation (4). But what about the cost of goods (CoG) between a typical fed-batch platform process and a fully continuous platform process for mAb production? Information in this important area is lacking, which is why we decided to perform a study to address the question: does the fully continuous production of mAb offer CoG benefits?

Our CoG analysis (5) considered the main process related costs, such as labor, capital, consumable, medium, waste treatment, maintenance, and buffer and media preparation costs (but not building costs). The initial base case scenario was set to an annual production of 200 kgAPI. The results? A fed-batch upstream process (USP) is more favorable than a continuous USP, but the continuous downstream process (DSP) is more favorable than a batch DSP.

Specifically, within the upstream part of the fed-batch, as well as the continuous process, the fermentation medium costs dominate the CoG. Although the cell-specific perfusion rate was set to the lowest level published so far – 0.05 nL cell-1 d-1 (6) – the perfusion medium costs of the continuous process were much higher than the fed-batch fermentation medium costs. Overall, the analysis showed a CoG difference between continuous and fed-batch USP of 33 €/gmAb. Further analysis revealed that the continuous USP CoG stayed higher than the fed-batch USP CoG over a large range of cell specific productivities (20-90 pg cell-1 d-1) and perfusion medium prices (10–30 €/L). The picture only changed in the unlikely event of perfusion medium prices as low as 5 €/L. Therefore, fed-batch mode is more cost-effective for the upstream part of the process.

Regarding the DSP, the continuous process mode was more cost effective than the batch mode by 8 €/gmAb. Within the continuous DSP, resins and filters were used much more effectively than batch DSP, leading to lower consumable costs and lower overall costs.

To conclude, the fed-batch USP and the continuous DSP were the preferred variants, which led us to investigate a hybrid process. The hybrid process consists of a fed-batch USP and a continuous DSP, which were connected through a harvest vessel. The hybrid process combined the advantages of both process modes; the hybrid process led to total CoG of 50 €/gmAb, whereas the fed-batch process CoG was 59 €/gmAb and continuous process CoG was 84 €/gmAb.

The hybrid process stayed the preferred process mode within a wide range of capacities between 100 and 1000 kg/a. The fully continuous process could only be more cost effective if the cell-specific perfusion rate of the culture could be decreased below 0.017 nL cell-1 d-1 – a goal that can only be reached through the development of new types of media.

In the future, fully continuous processes may provide a good alternative regarding CoG. For now, we believe the hybrid process shows great potential, and should be considered as a process mode for mAb production based on disposables. Our current research focuses on the successful demonstration of the hybrid process at miniplant scale.

Receive content, products, events as well as relevant industry updates from The Medicine Maker and its sponsors.
Stay up to date with our other newsletters and sponsors information, tailored specifically to the fields you are interested in

When you click “Subscribe” we will email you a link, which you must click to verify the email address above and activate your subscription. If you do not receive this email, please contact us at [email protected].
If you wish to unsubscribe, you can update your preferences at any point.

  1. S Klutz et al, J. Biotechnol., 213, 120–130 (2015). PMID: 26091773
  2. AC Lim et al, Biotechnol. Bioeng., 93, 687–697 (2006).
  3. J Pollock et al, Biotechnol. Bioeng., 110, 206–219 (2013).
  4. N Hammerschmidt et al, Biotechnol. J., 9, 766–775 (2014). PMID: 24706569
  5. S Klutz et al, Chem. Eng. Sci., 141, 63–74 (2016).
  6. KB Konstantinov et al, Adv. biochem. Eng., 101, 75–98 (2006).
About the Author
Laura Holtmann, Stephen Klutz, Martin Lobedann and Dr. Schembecker

Laura Holtmann started studying biochemical engineering at the TU Dortmund University in 2009 and completed her bachelor’s degree in 2013 and her master’s degree in 2014. She wrote her master thesis at INVITE GmbH in Leverkusen under the topic “Cost evaluation of monoclonal antibody production processes in different operation modes”. Since 2015, she works as a research associate at INVITE GmbH where she focuses on viral clearance for continuous, biopharmaceutical processes.


Stephan Klutz completed his diploma degree in mechanical engineering at RWTH Aachen University in 2011. From 2011 to 2015 he worked as a research associate at INVITE GmbH where he focused on continuous processing of monoclonal antibodies. In parallel he completed his master´s degree in economics at RWTH Aachen University in 2015. Since 2016, he works in the field of project management at Bayer.


Martin Lobedann is a biochemical engineer and a PhD in Biotech-Engineering. He joint Bayer in 2010 before having an assignment at the Bayer daughter company Invite GmbH in 2011, heading the group Biotechnology. He is working in the field of biopharma covering conceptual design, engineering, process control and process analytical technology.


Dr. Schembecker received his diploma as well as his Ph.D. in Chemical Engineering from TU Dortmund University in Germany. He is co-founder of the consultancy firms Process Design Center, inosim Consulting and b-value. In September 2005 he was appointed Professor for Plant and Process Design at the Department of Biochemical and Chemical Engineering of TU Dortmund University. His research interests focus on the conceptual design and simulation of (bio)chemical processes with special interest in innovative downstream processes and on module based plant design.

Register to The Medicine Maker

Register to access our FREE online portfolio, request the magazine in print and manage your preferences.

You will benefit from:
  • Unlimited access to ALL articles
  • News, interviews & opinions from leading industry experts
  • Receive print (and PDF) copies of The Medicine Maker magazine