Transitioning to closed systems in cell culture represents a milestone in the manufacturing of advanced therapies. These technologies balance reduced contamination risk and minimized handling while aligning with GMP requirements. Solutions like CellScrew® illustrate how scalable closed cultivation systems can enable scale-out, supporting the “living drug” manufacturing for thousands of individuals.
While both open and closed systems have evolved in physical design over time, closed processing typically relies on more sophisticated culture vessels than open multi-well plates and cell culture flasks. © Green Elephant Biotech.
Representing a fundamentally different therapeutic class than small-molecule drugs, Cell and Gene Therapies (CGTs) are subject to some of the most stringent manufacturing standards in modern medicine. Despite this, many processes underlying advanced therapy manufacturing continue to resemble academic research workflows, relying on multiple “open” or exposure-prone handling steps.
Current strategies to ensure product quality — including purity, identity, sterility, and viability — alongside patient safety requirements remain key contributors to persistently high manufacturing costs, which can reach USD 100,000 per treatment and above.
Even after extensive investments by biopharmaceutical companies to renovate and standardize manufacturing facilities, risks related to contamination and batch-to-batch variability persist (1). These challenges not only deter the initiation of advanced therapy development programs, but also directly limit patient access to highly effective treatments.
Traditionally, cell culture is performed in open systems, commonly using polystyrene-based vessels. A distinction is made between fully closed systems (i.e., never exposed to the external environment) and functionally closed systems, which are periodically re-opened during processing (2).
While the transition toward closed cell culture systems is increasingly evident, changes in manufacturing practices can substantially affect product quality. This entry therefore outlines the major considerations to mitigate risks when implementing closed systems.
The difference between open and closed systems in a nutshell – is the extent of risk
The choice between open and closed systems in cell culture has a direct impact on manufacturing reliability and cost structure. Open systems, such as T-flasks, microtiter plates, and roller bottles, require manual handling and environmental exposure during critical operations, including media exchange and sampling for quality assessment.
These interventions significantly increase the likelihood of microbial infiltration (e.g., Bacillus, Staphylococcus, Pseudomonas, Enterococcus) and cross-contamination. The consequences range from batch rejection and resource loss to inability of administering time-sensitive treatment to the patients.
In contrast, closed systems, such as bags or bioreactors, utilize sterile connectors and tubing ports to maintain a controlled, aseptic environment throughout processing. This design minimizes external interference during fluid exchange, sampling, and harvesting steps (2).
By sealing cultures from the external environment, closed systems have been shown to enhance reproducibility and enable process automation. The latter represents a critical driver of modern bioprocessing and is estimated to reduce manufacturing costs by up to 30% (1). The industry-wide shift toward closed systems is therefore largely driven by two interrelated factors: reduced risk of contamination and operational footprint.
Sealed environment and aseptic connectors prevent batch failure due to contamination
Contamination remains one of the most significant challenges in cell culture, as sterilization methods such as filtration, heat, radiation, or chemical treatment cannot be applied to CGTs. As a result, manufacturing relies heavily on highly controlled aseptic environments. Despite this, contamination rates remain substantial, as illustrated by reports of microbial contamination affecting up to 40% of adipose-derived stem cell batches intended for therapeutic use (3).
Open systems are particularly vulnerable due to the number of potential contamination sources involved. These include fluid transfer, sampling, manual assembly and disconnection, and failure of barrier mechanisms under pressure. Given that many contamination agents originate from human skin flora, increased handling frequency correlates directly with higher failure rates, batch loss, and constrained manufacturing capacity (3, 4).
Closed systems mitigate these risks through design. For example, rather than openly preparing and adding culture media, closed configurations employ aseptic connectors linked to media vessels, enabling primarily sterile transfer without environmental exposure.
Although these systems offer clear benefits for CGT manufacturing, trade-offs remain — particularly, in relation to integration into existing workflows and the rigidity of certain configurations. Nevertheless, when contamination represents a primary cause of batch failure, the long-term benefits of employee training and system integration often outweigh the initial implementation burden (5).
Closed systems as the driving force behind cleanliness and bioburden
The manufacturing price of CGTs, sometimes extending to USD 1,206,751 or above per treatment, is further inflated by facility footprint requirements and associated emissions. Following marketing authorization, reimbursement of these costs remains challenging due to limited competition and intellectual property complexities associated with the therapy’s patent eligibility or on the contrary, patent thicket (6).
Operational efficiency is further enhanced by physically separating operators from the process and using a different type of cleanrooms. Aseptic processing traditionally requires extensive gowning procedures, which consume significant operator time. Closed processing has been shown to reduce gowning time by up to 55%, allowing personnel to allocate resources to higher-value tasks while managing multiple batches in parallel (7).
Similarly, the reliance on the open handling zones or cleanrooms significantly increases energy and utility consumption. Adoption of closed systems has been reported to reduce energy use by up to 65%, while environmental monitoring requirements can decrease by as much as 88%, delivering both sustainability and economic advantages (7).
When compared to traditional bioprocessing, closed and functionally closed systems offer substantial improvements in contamination control and operational efficiency. However, as culture volumes increase and demand for CGTs continues to rise, scalability remains a limiting factor — even within closed processing paradigms.
To address scalability challenges in industry-scale manufacturing, such as vaccine production, cell banking, and seed train expansion — while maintaining stable conditions from bench to production — CellScrew® was developed. The system will soon be available in a Configurable Closed Transfer (CCT) version, specifically designed to simplify scalable adherent cell expansion.
With options ranging from 850 cm² to 10,000 cm² of growth area, CellScrew® provides the flexibility to scale out seamlessly without multiplying workflow complexity. Meanwhile, the aseptic connector design that is fully customizable is made to address GMP requirements, supporting the entirety of research-to-clinical journey.
Ready to switch from an open system to a closed one with CellScrew®?
Discover how the CellScrew® series can enhance your adherent cell culture process today by exploring the latest application notes published with our R&D Team.
References:
- How to overcome manufacturing challenges. (2023). PwC. Available https://www.pwc.be/en/news-publications/2023/how-to-overcome-manufacturing-challenges.html (Accessed 15 January 2026).
- Closed Systems in Biomanufacturing Offer a Variety of Benefits. (2015). The Cell Culture Dish. Available https://cellculturedish.com/closed-systems-in-biomanufacturing-offer-a-variety-of-benefits/ (Accessed 15 January 2026).
- Szabłowska-Gadomska, I, Humięcka, M, Brzezicka, J, Chróścicka, A, Płaczkowska, J, Ołdak, T, Lewandowska-Szumiel, M, Microbiological Aspects of Pharmaceutical Manufacturing of Adipose-Derived Stem Cell-Based Medicinal Products (2023), Cells 12, pp. 1-16. doi: 10.3390/cells12050680.
- How Aseptic Connectors Prevent Contamination in Single-Use Systems. (2025). Cobetter. Available https://cobetter.com/technical/how-aseptic-connectors-prevent-contamination-in-single-use-systems.html (Accessed 15 January 2026).
- 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).
- Seoane-Vazquez, E, Shukla, V, Rodriguez-Monguio, R, Innovation and competition in advanced therapy medicinal products (2019), EMMM 11, pp. e9992-7. doi: 10.15252/emmm.201809992.
- Value Drivers and Benefits of Closed Processing. (2025). Merck KGaA. Available https://www.sigmaaldrich.com/ES/es/technical-documents/technical-article/pharmaceutical-and-biopharmaceutical-manufacturing/monoclonal-antibody-manufacturing/value-drivers-benefits-closed-processing?srsltid=AfmBOop5zjNRZW0Tormvg5–K6xEgDJC0JDE_6xoScG-sBoVt4pyza_m (Accessed 16 January 2026).
