Scaling adherent cells, highly prevalent in advanced therapeutic approaches, remains one of the largest unresolved problems in bioprocessing. Space constraints, labor intensity, and the need for even nutrient distribution routinely push developers toward high surface-area-to-volume ratio formats, away from the two-dimensional environments these cells were accustomed to inhabit. That transition carries well-documented biological consequences. So what would one sacrifice to get to scale, and should a sacrifice be required at all?
With CellScrew® at its heart, Archimedes® One bioreactor prioritizes your cells’ biology whilst offering an easy set-up and pre-assembled technology. © Green Elephant Biotech.
“What will I have to sacrifice to get to scale?” While this question may not surface in every development conversation, it is a defining reality for advanced therapy developers. In particular, those working with cell and gene therapies (CGTs) based on anchorage-dependent cells, a major and clinically significant category of cell types found throughout the human body (1). A few well-known examples illustrate the breadth of this challenge: human embryonic kidney (HEK)-293 cells, mesenchymal stromal cells (MSCs), induced pluripotent stem cells (iPSCs), and macrophages.
Conventionally, increasing production volumes from small-scale laboratory formats to industrial liter-scale bioreactors requires adherent cells to be adapted to environments other than flat surfaces. In stirred bioreactors, fluid mechanics continuously expose these cells to shear stress, meanwhile systems utilizing microcarriers carry the risk of aggregation, with downstream consequences for cell phenotype and product quality. Retention of cell function is a foundational requirement in CGT manufacturing — one that should not be traded against process uncertainty (2).
Establishing a reproducible and effective workflow at the microplate and T-flask levels already demands significant effort. Introducing the additional uncertainty of adapting that process to a functionally closed and sterile environment compounds the challenge, and actively discourages developers from pursuing therapeutic potential until a more favorable time. Yet, the criteria of time- and cost-effectiveness, ease of harvest, and operational simplicity do not disappear, becoming increasingly stringent under GMP compliance instead (2).
So how do you scale adherent cells without altering their biology or introducing process uncertainty? This overview covers the phenotypic costs of process format changes, what a consistent scale-up surface could look like in practice, alongside the automation prospects available for therapy production. For the first time, the technological landscape is able to offer solutions that maintain a constant adherent culture environment across scales, preserving biological characteristics from early-stage development through to GMP-compliant manufacturing.
Switching from 2 dimensions to 3 is a biological decision as much as a logistical one
Among the most widely studied adherent cell lines, iPSCs exemplify the scalability challenges facing advanced therapy developers. Their ability to differentiate into the three germ layers positions them as therapeutically versatile across tissue repair, targeted therapies, and disease modeling with the added advantage of reduced ethical considerations. Efforts have been made to cultivate this cell type in 3-dimensional substrates with high surface-area-to-volume ratios, including microcarrier-based systems. However, uncontrolled cell clumping is one of the most frequently encountered phenomena in microcarrier cultures when working with highly adherent cell types. Events of that nature point directly to process-related limitations rather than inherent cell behavior (3, 4).
Managing fluid dynamics in suspension culture is further complicated by the need to balance sufficient agitation to minimize aggregation while avoiding physical damage to iPSCs. A study examining the effects of shear stress on iPSCs cultivated on microcarriers reported a meaningful change in cell viability and yield across a range of just 3 rpm.
Specifically, the highest cell count with preserved pluripotency was obtained at 25 rpm, corresponding to a maximum shear stress of 0.0984 Pa. A modest increase to 28 rpm, equivalent to a shear stress of 0.108 Pa, was sufficient to reverse net proliferation, attributed to cells losing secure attachment to their 3D substrates. Although this analysis was conducted in a murine iPSC line, the findings are indicative of the persistent peripheral risks associated with iPSC cultivation in suspension, known to escalate in complexity alongside scale (5).
In the absence of established alternatives for adherent cell lines, format change is often treated as unavoidable, but its impact on critical quality attributes, such as cell purity, identity, and potency, is felt throughout the entire manufacturing workflow. Under GMP requirements, every modification introduced during scale-up must be revalidated and refiled with the relevant regulatory authority, a process that can consume months. Direct costs associated with raw material repurchase and single-use system replacement can compound with batch failures, while a 500 L perfusion bioreactor alone can consume up to $600,000 of culture medium per run (6, 7).
Together, these factors make it clear that compromising cell biology does not enable seamless scale-up. Preserving the adherent phenotype without resorting to greater numbers of T-flasks or multi-layer stacks requires a different approach: maximizing available growth surface within the same vessel format, outside of conventional culture systems. CellScrew®, a flagship product of Green Elephant Biotech, consolidates up to 10,000 cm² of growth surface into a single compact vessel. This approach expands the available monolayer space instead of fundamentally transforming the culture environment.
CellScrew®: a scale-up platform built around cell biology, not despite it
Cultivation of high-maintenance cell types, such as iPSCs, places 2 non-negotiable demands on any biology-first scale-up system designed to preserve adherent cell phenotypes (8). First, shear rates must remain lower than those tolerated in primary cell cultures, and nutrient supply must be homogeneous – both proving as essential for maintaining pluripotency and differentiation capability. Second, the growth surface must scale continuously from bench to commercial production without requiring a mid-process system switch.
What distinguishes CellScrew® from conventional 2D culture formats is an adherent surface engineered with structures that support even distribution and gentle mixing as intrinsic design features. This is achieved through the Archimedes screw geometry, in which concentric cylinders expand the available growth surface while maintaining a uniform environment across it. This matters in practice, as in pharmaceutical manufacturing, 40-70% of process variability originates from manual handling, something a meaningfully-designed cultivation system can address directly (9).
Archimedes’ screw is an ancient tool, still supportsing innovation in sustainable biotech today. © Green Elephant Biotech.
Rather than multiplying vessel count, CellScrew®, a dynamic adherent cell culture flask, utilizes an Archimedes screw mechanism to facilitate even distribution of nutrients and gases throughout the culture environment. Available in three configurations — namely, mini (850 cm²), 6K (6,000 cm²), and 10K (10,000 cm²), the system enables one consistent growth surface and culture environment across scales without requiring a format change. Compatible with standard roller devices, CellScrew® reduces operational footprint by 92% compared to roller bottles and cuts operator’s handling time by up to 33% relative to multi-layer stacks. These process advantages are supported by empirical evidence from adherent cell expansion experiments.
A recent peer-reviewed publication characterized CellScrew® as a scalable platform for large-scale mammalian cell expansion, evaluating HEK-293, B16-F10, and CT-26 WT cell lines across metrics of viability, glucose consumption, and harvest efficiency. Following successful attachment to the CellScrew® mini surface, viability above 94% and 92% was recorded for B16-F10 and CT-26 WT cell lines, respectively. HEK-293 cells reached a maximum density of 0.77 ± 0.14 × 10⁶ cells per cm² at day 7, demonstrating that the system supports continued expansion well beyond the typical 48-72 hour harvest window. Metabolite concentrations equally remained stable and within physiologically expected ranges throughout the cultivation period (10).
Harvesting of HEK-293 cells was conducted using trypsin and replicated across both the CellScrew® mini and 6K formats. In the mini, trypsin diluted 1:3 in DPBS recovered approximately 95% of the yield achieved with undiluted enzyme. The same diluted protocol was successfully transferred to the 6K scale, achieving equivalent harvest efficiency across the harvesting window. Beyond demonstrating that a two-thirds reduction in enzyme concentration does not compromise cell detachment, these results indicated a protocol transferable to larger formats without loss of performance. As a proof-of-concept study though, its limitations of a restricted cell-line panel and the absence of long-term data should also be taken into consideration (10).
With CellScrew® providing one consistent growth surface across scales, the prospect of biology-preserving scale-up becomes even more attainable through automation. Archimedes® One, a dynamic adherent bioreactor built around the CellScrew® platform, was designed to automate and standardize the steps that conventionally demand intensive manual handling. For example, supplying cells with media and oxygen without disruptions or contamination risks typically evoked by open vessel handling. The single-use setup integrates an automated harvesting system with full process control, maintaining the large growth surface advantages that preserve cellular biology without the introduction of microcarriers or alternative three-dimensional substrates.
Higher yields, compromised potency – the precautions CGT manufacturing does not afford to ignore
Each manufacturing process carries its own context-dependent objectives, and that context demands an assessment of what planar cell culture can and cannot deliver. Generally-speaking, two-dimensional culture has a scalability ceiling, and a lower one than microcarrier-based or suspension formats. A cost analysis comparing planar and microcarrier-based cell expansion approaches found that, for outputs of approximately 500 million cells per batch, transitioning to a single 20 liter bioreactor could reduce overall costs by 40%. While this analysis does not encompass the full range of available cultivation systems, its findings are situated within the context of larger vessel counts — a well-documented manufacturing bottleneck (11).
However, just as biological integrity carries a cost when compromised, so does the pursuit of maximum expansion yield. The drive to achieve the highest possible output from a single cell bank in order to meet the demands of an adherent therapy’s demand can readily result in genetic instability, functional loss, or cellular senescence. A higher yield ceiling reached by altering the cell’s microenvironment is ultimately paid for in phenotypic drift and reduced batch comparability, fundamentally altering the output. Scalability alone does not support clinical manufacturing if the output is no longer the same CGT product (2).
This is where the practical value of CellScrew® and Archimedes® One becomes even more apparent. Many adherent and phenotype-sensitive programs like MSC-, iPSC-, and macrophage-based therapeutics currently remain within the constraints of planar culture, unable to scale conventionally without the trade-offs outlined above. Together, CellScrew® and Archimedes® One offer a path that preserves the adherent culture environment without mid-process format change, while delivering higher yields at lower costs due to reduced vessel count. Where preserving therapeutic efficacy is a program objective, the factors that historically made planar culture unattractive at scale are no longer set in stone.
In practice, what a biology first approach needs to offer is continuity. Provision of a consistent growth surface from early-stage bench work through to GMP-compliant production that retains functional characteristics and reduces comparability burden of mid-process changes. For phenotype-sensitive cell types, this continuity does not simply serve as an operational convenience, but maintains the product integrity that clinical and regulatory frameworks require.
We would also want to be direct about what our system and vessel design does not resolve: sourcing variability, the full scope of comparability requirements, and upstream process development remain the responsibility of the developer. CellScrew® and Archimedes® One are purpose-built for adherent, phenotype-centered cell lines, not having been designed for suspension-based workflows.
If you are cultivating MSC, iPSC, macrophages or similar cell lines, and want to understand how our system fits your process and application, we are open to the conversation. To explore the budget pricing for Archimedes® One, visit the product page to submit a request.
- The Pros and Cons of Adherent Versus Suspension Cell culture. (2024). Ann Rossi Bilodeau, BioPharm International. Available https://www.biopharminternational.com/view/the-pros-and-cons-of-adherent-versus-suspension-cell-culture (Accessed 25 August 2026).
- Cherian, DS, Bhuvan, T, Meagher, L, Heng, TSP, Biological Considerations in Scaling Up Therapeutic Cell Manufacturing (2020), Front Pharmacol 11: 1-25. doi: 10.3389/fphar.2020.00654.
- Borys, BS, Dang, T, So, T, Rohani, L, Revay, T, Walsh, T, Thompson, M, Argiropoulos, B, Rancourt, DE, Jung, S, Hashimura, Y, Lee, B, Kallos, MS, Overcoming bioprocess bottlenecks in the large-scale expansion of high-quality hiPSC aggregates in vertical-wheel stirred suspension bioreactors (2021), Stem Cell Res Ther 12: 1-19. doi: 10.1186/s13287-020-02109-4.
- How to Minimise Cell Clumping During Microcarrier Culture. (2026). Smart MCs PTY LTD. Available https://smartmcs.com.au/how-to-minimise-cell-clumping-during-microcarrier-culture/ (Accessed 15 September 2026).
- Ismadi, MZ, Gupta, P, Fouras, A, Verma, P, Jadhav, S, Bellare, J, Hourigan, K, Flow Characterization of a Spinner Flask for Induced Pluripotent Stem Cell Culture Application (2014), PLOSOne 9: 1-11. doi: 10.1371/journal.pone.0106493.
- Understanding Critical Quality Attribites (CQAs) in T-Cell and MSC Therapy. (2025). Atlantis Bioscience. Available https://www.atlantisbioscience.com/blog/understanding-critical-quality-attributes-cqas-in-t-cell-and-msc-therapy/ (Accessed 28 August 2026).
- Batch vs Fed-Batch vs Continuous: Cost & Productivity Comparison. (2026). BioProcess Tools Team. Available https://bioprocesstools.com/blog/batch-vs-continuous-cost/ (Accessed 28 August 2026).
- Freire-Flores, D, Kawles, N, Caviedes, P, Andrews, BA, Asenjo, JA, Scaling iPSC production in different 3D platforms in suspension culture for their use in allogeneic regenerative therapies (2025), Biochem Eng J 217: 1-9. doi: 10.1016/j.bej.2025.109672.
- What are the most frequent causes of variation in Pharmaceutical Manufacturing? (2010). Eric W. Richmond, Vibhakar Shah, PQRI. Available https://pqri.org/wp-content/uploads/2015/08/pdf/BO-2_Summary.pdf (Accessed 14 September 2026).
- Boshof, B, Hüppner, A, Eichberg, J, Reyer, H, Käßer, L, Kölsch, A, Characterization and evaluation of a novel polylactic acid-made bioreactor for large-scale adherent cell expansion (2026), Appl Microbiol Biotechnol 110: 1-16. doi: 10.1007/s00253-026-13880-4.
- Simaria, AS, Hassan, S, Varadaraju, H, Rowley, J, Warren, K, Vanek, P, Farid, SS, Allogeneic cell therapy bioprocess economics and optimization: Single-use cell expansion technologes (2013), Biotechnol Bioeng 111: 69-83. doi: 10.1002/bit.25008.
