White Paper

Critical Considerations About The Future Of Global Cell Culture Bioprocessing

By Günter Jagschies, Senior Director, Strategic Customer Relations, GE Healthcare’s Life Sciences

global market growth

The future role of biopharmaceuticals in developing global economies is evolving rapidly. The rising number of patients and the growing presence of noncommunicable diseases is creating an increased need for both existing treatment options, such as monoclonal antibodies (mAbs) as well as advanced strategies using cell and gene therapies and/or antibody-like drugs with enhanced potency. As the biopharma industry explores strategies to tackle this growing issue, it is critical we consider several factors about cell culture bioprocessing today and the impact they will have on the future of patient treatment.

The Health Transition Challenge

When looking across the landscape of the world’s health challenges and comparing the age of a country’s population with its disease portfolio, some clear trends begin to take shape. For example, the graphs below (Figures 1-3) show the demographic and disease burden transition occurring around the globe with snapshots of Nigeria, India, China and Japan. In most sub-Saharan African countries, the majority of the population is under the age of 30 (Figure 1, left). Infectious, or communicable, diseases dominate the disease profile of these young countries, as exhibited in Figure 1 on the right. Mortality from communicable diseases is high and affects the population at a (very) young age.

Figure 1: Demographic and mortality profile for a typical Sub-Saharan African country (Nigeria); orange represents communicable diseases, blue shows noncommunicable diseases (NCDs), and green denotes mortality related to injuries.

The graph for India displays a remaining burden of communicable diseases while mortality from noncommunicable diseases (NCDs), such as cancer, diabetes, and chronic respiratory disease, grow in importance for the overall disease burden (Figure 2, right). India has a slightly older population than sub-Saharan Africa, although the majority is still relatively young.

Figure 2: Demographic and mortality profile for India

As the age of a population rises, so does the relevance of NCDs in the country’s disease and mortality profile. China and Japan (Figure 3) show the demographic profile of an aged (China) or “super-aged” (Japan, more than 20 percent of the population is older than 65) country. Middle- and high-income countries have had considerable success with fighting infectious disease with, for example, improved hygiene standards and the implementation of vaccination programs for essentially the entire population. The victory over communicable diseases is evident in the mortality profiles. The domination by NCDs continues to change the burden on healthcare systems. In Japan, the proportion of cancers and neurological disease related mortality is higher than in China, for example. The main driver for this development is the fact that people are more likely to develop an NCD and die from it the older they become.

Figure 3: Aged populations in China and Japan. Cancers (neoplasms) and neurological disease as well as diabetes increasingly dominate the mortality profile as the aging of populations progresses (compare China and Japan).

Beyond mortality, the overall disease burden, also known as disability-adjusted life years (DALYs)1, for a country is a time-based measure that adds the years of life lost due to premature mortality and the years lived in states of less than full health. Figure 4 shows the mortality rate compared to DALYs for the whole world and reveals the hot spots for cancer, diabetes, and Alzheimer’s-related challenges.

Figure 4: A comparison of the mortality rate and DALY for cancer, diabetes, and Alzheimer's in the world's largest regions; hot spots shown in yellow, orange, and red.

Not only is mortality from these diseases highest in the world’s largest populations of China and India (or similar to the U.S.’s for Alzheimer’s), but these countries also carry the burden of providing medical treatment to patients with those diseases as well as prioritizing the money to prepare their still-developing healthcare systems to care for the elderly patients at large scale. As a result, they experience losses in economic productivity and other aspects critical to societies, such as the impact of long-term, out-of-pocket healthcare costs. The number of patients for these three disease categories currently double every 17-20 years.

A Closer Look At Today’s Bioprocessing Numbers

The demographic and disease transition described in the previous paragraphs also places significant urgency on pharmaceutical and biopharmaceutical R&D developing novel preventive and therapeutic approaches. Affordability of advanced medicines for a rapidly increasing number of patients in all parts of the world, including populations with low or middle levels of income, puts pressure on financially efficient development and manufacturing as well as on rapid, systematic harmonization of regulatory efforts. As we continue to advance drug manufacturing to address these needs, there are several factors that will have a strong economic impact on the future of the industry.

The Rise Of Titers

There have been fantastic productivity improvements in mammalian cell culture of monoclonal antibodies (mAbs). What began with achievements of 0.1 grams per liter (g/L) has grown to 10 g/L. Genentech presented mAb titers between 9 and 14 g/L for nine different antibodies in its study presented at the 2018 ECI Cell Culture Engineering XVI conference2. As exciting as this is, this progress is essential for future processes to be financially viable; these milestones of achievement should be viewed not as getting ahead but as catching up. To keep pace with our challenges, we must ensure we pursue continued improvements of overall process productivity from facilities, i.e., not just product titer. Upstream costs are often described as the driver for overall cost reduction. Yet, the direct costs of upstream processing tools and methods have hardly gone down over time as more sophisticated approaches are developed, such as advanced fed batch regimes requiring more complex and expensive culture media. Upstream tools and technology are frequently protected with intellectual property or with very significant licensing or royalty costs for others, as a consequence. There are also expenses associated with developing workaround approaches to overcoming IP or with accepting lower productivity from less efficient technologies.

In a classic batch process, 10 g/L translates to about 0.7 g/L per day, assuming there are two weeks of cell culture time. It is possible to achieve significantly higher productivity (up to 3 to 5 g/L per day) with continuous perfusion culture, but there is also considerable skepticism from management about its risk profile. Managers may prefer batch processes over perfusion culture, due to business continuity reasons and a perceived risk of batch failure with subsequent drug shortages.

The Productivity of Chromatography

Chromatography resins are also demonstrating significant productivity improvements, but concern about a mismatch in productivity in upstream versus downstream process steps is still regularly expressed. Next-generation Protein A materials typically have 10- to 15-fold higher productivity than legacy resins and up to 30 grams per liter per hour (g/L/hour) of productivity. However, when the full volume from a bioreactor where antibody has accumulated during two weeks of processing time is harvested and captured in the first purification step (Protein A) within a day, a design glitch becomes obvious. : Assuming a 2,000 L reactor, 9,000 grams per hour need to be processed on a Protein A capture column requiring a large resin volume and, possibly leading to a productivity mismatch and financial challenge. In reality, though, the problem is not in the productivity itself but in how we arrange the process when we assume that one part must handle within hours or a day what has produced over two weeks. The issue can be mitigated by cycling the large batch in smaller portions. When manufacturing for clinical trials or low-market demand drugs, there may be financial concern when it is not clear whether the capture resin will be used to its full lifetime and acquired value.

The Financial Promise Of Mammalian Cell Culture

From a business perspective, mammalian cell culture offers considerable promise, as it is used in many processes with much success. While nearly 50 percent of all approved protein therapeutics are manufactured using cell culture processes and the remaining 50 percent with E.coli and yeast-based processes, mammalian cell culture actually generates 70 percent of the revenue of this industry.

As long as drug prices are at current western market levels (multiples of $1,000 per gram of antibody), manufacturing costs are low in proportion, mAb production may indeed be considered a low-cost operation. Still, the impact of manufacturing on the overall financial performance is likely to increase, and companies may feel the pressure to prepare for that scenario, assuming that increased competition will drive down drug prices (see market fragmentation section below).

The Impact Of Market Fragmentation

The fragmentation of today’s biopharmaceutical market not only has implications for the supply chain and for facility requirements but also on the scale of operation. Of the approximately 180 recombinant therapeutic proteins publicly reported to generate $190 billion in revenue in 2017, 95 percent require less than 500 kilograms (kgs) of annual production; 75 percent require less than 100 kgs. Most biosimilars currently require even less (10 to 50 kg).3 For the three legacy drugs Humira, Remicade, and Enbrel, there are eight originator biologics and soon 10 additional biosimilars entering the competition. These molecules compete for a limited number of patients. Even if patient access increases, competition will still be destructive for most players involved, as any increase in size of the patient population likely requires/dictates lower prices for better affordability and the corresponding deterioration of the intended business cases. To prevail in a competitive environment like this, the industry needs to continuously develop the next level of drug safety and potency with novel originator drugs for key medical indications. It should also explore additional benefits for any commodity drug that could make it more competitive, rather than just developing yet another copy of the same molecule or a different mechanism of action without significant enough clinical benefits over the first generation. Examples could be devices for convenient delivery, advanced diagnostics for better targeting of responsive patients, and disease management programs supporting patients beyond medication. Many branded biotherapeutics, and certainly most biosimilars, will see reduced demands on manufacturing scale as a result of market fragmentation. Over time though, some biosimilar products may become the most used alternative for their medical indication, requiring higher production at more economic levels to achieve any financial benefits at the low prices.

Selected Trends In Manufacturing Technology

mAbs still dominate the later-stage development pipeline, but the industry must prepare for challenges from new types of molecules. The diversity of these novel drug modalities, and thus the fragmentation of a relatively homogeneous manufacturing technology landscape (platforms), calls for a review of our biomanufacturing toolbox and the facilities we build. Specifically, the community of bioprocessing experts must think about how to integrate different technologies and steps and modularize the design of processes, including both preparative and analytical or process control aspects. Another challenge appears with the technology and economic efficiency of production processes supplying large patient groups with small quantities of personalized medicine. This trend labeled “precision health” focuses on detailed diagnosis, patient specific treatment, and a low level of side effects as key aspects in future treatments, such as gene and cell therapies, as well as novel immunotherapeutic modalities.

In addition to integration, the simplification of processes is critical. Just as continuous processing is an option for successful process integration, single-use technology offers an important opportunity to simplify bioprocessing. Other aspects of simplification are related to reduction of footprint and the number of operators and steps in a process. Focus on inline and online analytics rather than offline operations can reduce process times and delays in release decisions. Simplification and integration are key to the processing strategies needed to efficiently address the diverse portfolio of the future.

The development of the upstream process components, as well as the operation of the upstream process (mammalian cell culture), is clearly the longest part on a Gantt chart of the overall process development (PD) project or the end-to-end manufacturing process. Cell line, expression system and culture PD used to take close to a year or longer in less experienced organizations; running the process from cell bank to product harvest from the bioreactor could easily last up to one and a half months (cell expansion, seed train, and production culture). This typically leads to debates and new initiatives to research alternative production systems, such as bacteria or yeasts. Since these currently have limitations related to typical product quality profile requirements, e.g., glycosylation, efforts to improve performance with mammalian culture are still dominating the industry. Cell line development time has been reduced to 10 weeks in advanced PD laboratories, and the length of inoculation and seed train operations has been compressed by 50 percent using high-density (HD) perfusion culture. For example, high cell number inoculation of the production reactor with HD N-1 culture has reduced process time for the N reactor by up to 30 percent, leading to the corresponding productivity increase for the whole facility. High product titers with advanced fed-batch regimes allow a significantly lower cost burden per single-use bioreactor used in the operation.

Continuous perfusion culture has been selected in the early days of mammalian cell culture to either protect sensitive proteins, such as coagulation factor VIII, from longer exposure to the culture environment or to achieve financially viable productivities from the culture of some monoclonal antibodies.3 Today, perfusion culture has emerged again with a promise for significantly increased productivities.4 It has also been studied in combination with fed-batch operation to boost cell numbers and to attain extraordinarily high product titers (~60 g/L) within normal run times of 14 days, thus achieving best utilization of the reactor bag. This is also considered when looking to reduce overall facility footprint and the perceived risk for batch loss during long run times of classic perfusion cultures.6

The Amgen facility in Singapore is an example of a biomanufacturing plant designed for future processing with an output capacity at one ton of antibody from six 2,000 L bioreactors and columns that do not seem to exceed 80 centimeters in diameter (with no obvious scale inconvenience from extremely large equipment installations downstream in the process). A long-lasting debate about a “downstream bottleneck” seems to have found its resolution. A factor in achievements like this is the availability of Protein A capture resins with capacity up to 80 g/L and ion exchanger-like stability to sodium hydroxide at 1 molar (M) concentration (e.g., MabSelect™ PrismA, GE Healthcare). In the foreseeable future, an even more productive format will become available using derivatized fibers that will allow full “consumption” of the useful life of the device while capturing the antibody from a high titer 2,000 L bioreactor over less than a day (2.4 L device volume). Continuous operation of the capture process, currently discussed as the future way of operating Protein A steps may become obsolete with such single-batch Protein A affinity device.6 However, continuous operation of the step on a periodic counter-current chromatography/simulated moving bed (PCB/SMB) system maximizes the useful capacity of packed Protein A resins with an increase of about 30 percent over an optimized batch operation. Many teams are investigating this option and evaluating the balance between a resin cost reduction opportunity and the increased system complexity required to make this gain.

Footprint reduction has a significant impact on capital expenditure. Switching to perfusion culture can reduce the bioreactor size and the scale of subsequent processing steps three to five-fold at constant product output (Figure 5). Deletion of the centrifugation step becomes possible with perfusion in combination with a cell retention system. Downstream steps can be connected and operated with direct delivery of buffers from an inline conditioning system, which together deletes up to 90 percent of the tank volume otherwise required to support the process with intermediate product and buffer storage.

Figure 5: A simplified overview of integrated bioprocessing. Each step in the process can be operated in batch or continuous mode. Most steps can be operated in single-use or re-use equipment.

Once process technology is optimized in all economically viable ways, an area for improvement that must be prioritized is process monitoring and control with advanced sensors and analytical technology, algorithms derived from process modeling, and, consequently, the use of these approaches to address typical delays in decision making on the performance of the process and the quality outcome of the product. In the Amgen Singapore facility, these advanced analytical approaches have been introduced on the production floor to achieve the maximum benefit for efficiency and cost of the operation. These or similar concepts are spreading to other facilities too, e.g., as presented by Biogen speakers for their new facility in Solothurn, Switzerland.7

Changing The Outlook On Patient Treatment

Addressing the needs of today’s patient population remains the top priority of the bioprocessing industry. Nevertheless, it is believed that up to 60 percent of all mortality could be prevented by changes in lifestyle, avoidance of key risk factors, and better, earlier diagnosis.8 The future business field for successful biopharma companies may also be in disease prevention and creating a better overall approach to healthcare. Countries with emerging economies may be ill-advised to copy what Western countries have done in terms of developing healthcare systems, as they are characterized by large inefficiencies, high treatment costs, and a bias for very expensive infrastructure that increasingly turns out to be unaffordable even in high-income countries.

Biotherapeutics for the most complex diseases we know, such as cancer or diseases of the nervous system, are still in the earlier phases of their efficacy- and potency-related “learning curves.” Consequently, additional generations of biotherapeutics will have to be developed before one may hope for victory over those diseases or even returning these patients to a status where life with the disease is long-term manageable. For example, there are a number of promising drugs for cancer, yet Table 1 below shows how many “escape routes” a cancer cell typically has when attacked with a therapy. To be effective, we may need to apply a cocktail of drugs and other therapeutic approaches to make cancers manageable for the patient.

Doing so means we have to be prepared to reconsider how things are done today and come up with new solutions for our biggest challenges. The power of change and our ability to initiate it requires a new level of collaboration among businesses to meet the disease challenges of the future.


The burden from non-communicable diseases, such as cancer, diabetes, or neurological diseases, is growing, driven by demographic changes in rapidly aging populations around the world.  An improving economic and political environment leads to improvements in basic health conditions and increases in NCD burden. Therefore, the largest biopharmaceutical markets by patient numbers are expected in Asia and potentially Africa. This scenario puts high pressure on pharmaceutical development pipelines to deliver the diagnostic, therapeutic, and preventive means required to meet the needs at an affordable cost for healthcare systems and patients.

Currently, affordability is a significant issue even in high-income countries, and research portfolios are not aligned with global disease burden developments. The growing phenomenon of market fragmentation suggests that R&D efforts will multiply treatment options, which may not all be linked to improvements. The product demand we foresee can be met by relatively small facilities and manufacturing installations. Available technology supports most, if not all, scenarios for manufacturing needs, with gaps identified in process monitoring and control and processing solutions for certain novel therapeutics. Gene and cell therapy are rapidly emerging fields with a still immature selection of robust manufacturing technology. Economic supply of patient specific medicines remains an infrastructure and cost challenge for the industry.

  1. World Health Organization, Metrics: Disability-Adjusted Life Year (DALY)https://www.who.int/healthinfo/global_burden_disease/metrics_daly/en/
  2. Laurel Zhang et al. (2018) Development towards a high-titer fed-batch CHO platform process yielding product titers > 10 g/L, presented at Cell Culture Engineering XVI conference, A. Robinson, PhD, Tulane University R. Venkat, PhD, MedImmune E. Schaefer, ScD, J&J Janssen Eds, ECI Symposium Series, (2018). Retrieved from http://dc.engconfintl.org/ccexvi/234G.
  3. S. Barrett (May 2018). Intensification of a Multi-Product Perfusion Platform: Managing Growth Characteristics at High Cell Density for Maximized Volumetric Productivity, presented at ECI Cell Culture Engineering, Tampa, FL
  4. J. Salm (October 2018). Building the Case for Implementation of an Integrated Manufacturing Process, presented at Recovery of Biological Products XVIII, Asheville NC
  5. G. Jagschies. Appendix 3 – Marketed Biotherapeutics in G. Jagschies et al. Biopharmaceutical Processing, pp 1237-1252, Elsevier, Amsterdam 2018
  6. Roberts, Iwan (November 2018). Combining High-Productivity Fibre Adsorbent Material with the PrismA Protein A Ligand at Pilot Scale, presented at BioProcessing Asia conference in Langkawi, Malaysia
  7. C. Jiang (September 2018). Integrating Next-Generation Processes, Technologies, and Operations to Modernize Biomanufacturing, presented at BioTalk in Berlin, Germany
  8. G. Jagschies. Disease and Healthcare Priorities in G. Jagschies et al. Biopharmaceutical Processing, pp 3-32, Elsevier, Amsterdam 2018

Dr. Günter Jagschies currently holds the position of Senior Director, Strategic Customer Relations at GE Healthcare’s Life Sciences. His experience from the bioprocessing industry stretches over nearly 30 years. He has held senior management positions at GE Healthcare in Sales, Marketing, and R&D. In 2012, he received the BioProcess International Award as “Thought Leader of the Decade”, for Downstream Processing.



This article was created from the author's presentation at the 2018 Bioprocessing Asia conference, with GE Healthcare as principal sponsor. The BioProcessing Asia Conference series was created to provide a platform to advance the contribution of bioprocessing sciences towards the development and manufacture of affordable biopharmaceutical products in Asia.