Scaling-out — a game-changing manufacturing shift, seen to transform clinical manufacturing in the 21st century

The influx of scientific discoveries and the positioning of personalized therapies as viable clinical interventions are progressively challenging the linear scale-up logic that defined pharmaceutical manufacturing for decades. The capacity advantages and automation solutions associated with scaling-out extend beyond operational efficiency, ultimately shaping treatment accessibility in ways that are not immediately visible at the facility level.

Autologous CGTs, derived from the patient, are currently commoner in clinical practice due to lower risks associated with immune rejection, further incentivizing the implementation of scaling-out in manufacturing. © Green Elephant Biotech.

Having previously defined scale-out as increasing the number of operating units in parallel — and distinguished this form of scalability from vertical scale-up — we now turn to the strategy that continues to reshape biomanufacturing. Scaling considerations must be embedded early in workflow design, as indicated by an industry perspective: “No scaling, no impact” (1).

Within biomanufacturing, scaling-out has gained traction largely due to the rise of personalized medicine, particularly cell and gene therapies (CGTs). Production intensification through parallelized systems has enabled manufacturers such as Lonza to achieve commercial milestones with therapies like Zynteglo® and Skysona®, demonstrating that CGTs can reach meaningful clinical scale without relying solely on massive vessel expansion (2).

The advantages of horizontal scaling include modular validation, improved cost control, and reduced operational risk. However, the choice between scale-up and scale-out remains product-specific. Allogeneic therapies, which rely on donor-derived cells and standardized batches, may still benefit from conventional scale-up approaches. Personalized autologous therapies, by contrast, inherently favor modular scaling-out architectures due to their individualized manufacturing profiles (3).

This article explores the drivers behind the shift from scale-up to scale-out, outlines best practices for implementing horizontal scaling, and examines the real-world implications extending beyond manufacturing facilities. As legacy systems built around equipment limitations give way to biology-driven design, the pace of transformation in biomanufacturing continues to accelerate.

Scaling-out is about process consistency, modifiable capacity, and cost-efficiency

Although commercial strategy ultimately dictates scaling decisions, the technical advantages of scaling-out are consistent. Consider a CGT that reaches commercialization at 200 L scale. To meet rising demand, manufacturers may either invest in a 5,000 L bioreactor or operate multiple 2,000 L units in parallel (4).

The latter scenario illustrates the core strengths of horizontal scaling: flexibility, distributed risk, and capital efficiency. Capacity adjustments can be achieved by adding or removing units without full process revalidation (5). Large-scale equipment typically requires substantial capital expenditure and ongoing costs associated with cleaning and sterilization, which become significantly reduced through single-use technologies (SUTs) in scale-out environments (2).

Smaller modular units also facilitate automation and reduce manual intervention during inoculation, feeding, and harvesting steps. Reduced open processing correlates with lower contamination risk. Supporting data indicate that facilities operating above 1,000 L reported batch rejection rates due to contamination of 2.3%, compared to 0.8% in facilities operating below 1,000 L volumes (6).

Space utilization further improves with SUT adoption, eliminating the need for clean-in-place (CIP) and steam-in-place (SIP) infrastructure. While environmental concerns regarding plastic waste have been raised, lifecycle analyses demonstrate that reductions in water, energy, and overall utility use frequently offset disposal impacts (7).

There is a guide for everything, including how to make the most out of your scaling-out advantages

Unfortunately, technical benefits alone do not guarantee successful implementation and an effective scale-out requires deliberate planning. Transitioning from stainless steel infrastructure to SUT platforms — across both upstream and downstream processes — establishes a foundation for parallelization.

Standardization and automation must follow, with workflows designed for simultaneous, identical operations to minimize revalidation during capacity expansion. Downstream purification processes must be dimensioned accordingly to handle increased parallel output without compromising quality (5).

Cost avoidance strategies are equally critical. As failed batches can potentially reach costs of up to USD 2 million, reliance on trial-and-error approaches becomes unsustainable. Simulation modeling offers a resource-efficient alternative for process optimization (6). Furthermore, SUT adoption must not replace robust contamination control strategies. Reduced manual handling lowers risk, but does not eliminate the necessity for aseptic discipline.

Logistics planning is the final component that is frequently left underestimated. Operating multiple parallel units increases demands on raw material supply chains and waste management systems, making the early-stage integration of these considerations vital to prevent downstream bottlenecks.

In personalized medicine, patient outcomes are the primary measures of success

To appreciate the clinical relevance of scaling-out, consider therapies such as Zynteglo®. By 2025, approximately 115 patients had completed treatment for β-thalassemia, gaining independence from regular transfusions (8, 9). Although high in cost, single-dose autologous therapies can dramatically improve quality of life (e.g., sparing patients from up to 8 blood transfusions a year in the case of β-thalassemia).

The 70-90-day manufacturing cycle involves cell collection, transport, genetic modification, quality testing, and storage (8). In such time-sensitive workflows, reliance on large single units introduces operational risk and rigidity. Parallelized scale-out architectures are better aligned with the individualized and on-demand nature of personalized therapies.

Delays or batch failures do not only represent financial setbacks, but carry psychological and clinical consequences for patients awaiting treatment. In the cases of aggressive diseases, such as malignant neoplasms, timing may be directly linked to survival. Scaling-out therefore transcends capacity expansion and becomes a patient-centered manufacturing philosophy.

While commercial success cannot be guaranteed, scale-out strategies offer improved flexibility, faster deployment, and distributed risk mitigation. This infrastructure also supports the integration of automation technologies that are shaping the next milestone in clinical manufacturing (10).

Scaling-out is not solely a technical adjustment to legacy manufacturing, this scaling strategy represents a structural response to the biological and logistical realities of personalized therapies. Evidence presented in this article supports the promises of scaling-out in reducing contamination risks, distributing operational exposure, and enabling on-demand flexibility, favored in CGT manufacturing.

More importantly, scale-out aligns manufacturing capacity with patient-specific timelines, mitigating delays that can have clinical consequences. Both industrial performance and commercial CGT case studies demonstrate that sheer volume is no longer the ultimate criteria of success.

Green Elephant Biotech’s recent whitepaper on clinical manufacturing reinforces this perspective, emphasizing that scalable infrastructure must combine closed-system processing with biological compatibility. Designed around biology, CellScrew® and its Configurable Closed Transfer (CCT) extension stand out among today’s cultivation systems and seamlessly integrate into horizontal scaling of adherent cell culture processes.

References:

1. No scaling, no impact. (2023). Sole Bugge Møller, DTU. Available https://www.dtu.dk/english/newsarchive/2023/03/opskalering-er-impact (Accessed 26 February 2026).
2. Scale-Out Plus Single Use Can Multiply Yields. (2019). Genetic Engineering & Biotechnology News. Available http://genengnews.com/topics/bioprocessing/scale-out-plus-single-use-can-multiply-yields/#:~:text=“Deciding on scaling-out versus scaling-up is not,associate director of commercial development at Lonza (Accessed 25 February 2026).
3. Scale-Out Biomanufacturing — A Paradigm Change to Scale-Up. (2018). WuXi Biologics. Available https://eu-assets.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/blt890498c23044d8f1/658d765be003a70408a21c2e/WUXI_Whitepaper-Scale-Out.pdf (Accessed 26 February 2026).
4. Scaling Cell and Gene Therapy Processes from R&D to Production. (2025). That’s Nice, LLC. Available https://www.thatsnice.com/thought-leadership/scaling-cell-and-gene-therapy-processes-from-rd-to-production/#:~:text=Indeed%2C many pharmaceutical manufacturers strategically,shortages and risks to patients (Accessed 27 February 2026).
5. 7 Key Questions for Understanding the Benefits of Scale-out Biomanufacturing. (2022). BioProcess International. Available https://www.bioprocessintl.com/sponsored-content/7-key-questions-for-understanding-the-benefits-of-scale-out-biomanufacturing (Accessed 26 February 2026).
6. Biotech Facilities Average a Batch Failure Every 40.6 Weeks. (2008). Eric S. Langer, BioProcess International. Available https://www.bioprocessintl.com/bioanalytical-methods/biotech-facilities-average-a-batch-failure-every-40-6-weeks (Accessed 12 January 2026).
7. Single-Use Technologies in Biomanufacturing: Scaling with Sustainability. (2025). V Square Technologies Private Limited. Available https://vpharmahorizon.com/single-use-technologies-in-biomanufacturing-scaling-with-sustainability/#:~:text=Environmental Concerns and the Sustainability,energy recovery or recycling initiatives (Accessed 27 February 2026).
8. Genetix Presents Recent Patient Experience Data from U.S. Commercial Gene Therapy Implementation at the 67th American Society of Hematology (ASH) Annual Meeting. (2025). Businesswire. Available https://www.businesswire.com/news/home/20251208576201/en/Genetix-Presents-Recent-Patient-Experience-Data-from-U.S.-Commercial-Gene-Therapy-Implementation-at-the-67th-American-Society-of-Hematology-ASH-Annual-Meeting (Accessed 27 February 2026).
9. Schuessler-Lenz, M, Enzmann, H, Vamvakas, S, Regulators’ Advice Can Make a Difference: European Medicines Agency Approval of Zynteglo for Beta Thalassemia (2019), Clin Pharmacol Ther 8, pp. 492-94. doi: 10.1002/cpt.1639.
10. Scale-Up vs. Scale-Out Strategies for Continuous Pharma Manufacturing. (2026). Dirk Leister, ThermoFisher Scientific. Available https://www.thermofisher.com/blog/behindthebench/manufacturing-strategy-in-pharma-scale-up-vs-scale-out-for-continuous-processes/ (Accessed 02 March 2026).