Closed systems in bioprocessing: A proven story behind a 47% reduction in contamination risk through aseptic connectors

A defining feature that enables closed systems to function as controlled manufacturing environments is the aseptic connector — specialized hardware designed to securely join fluid pathways in a sterile manner. The performance of aseptic connectors, and their contrast to earlier industrial alternatives, provides a clear illustration of why closed bioprocessing has become a frequently-mentioned enabler of modern biomanufacturing.

Though features ensuring asepsis in closed bioprocessing extend beyond aseptic, luer-lock, and membrane based connectors, these parts of equipment can appear unjustifiably overlooked . © Green Elephant Biotech.

In biopharmaceutical manufacturing, asepsis or the absence of pathogenic microorganisms and cross-contamination is a fundamental requirement. Contamination remains among the top 3 causes of batch loss in commercial manufacturing, alongside operator error and equipment failure. Notably, contamination patterns have shifted since the mid-2000s, when pathogen identification was reported more frequently, prompting closer scrutiny of manufacturing practices (1, 2). What has changed since then?

Closed bioprocessing, driven largely by the widespread adoption of single-use technologies (SUT), has become mainstream over the past decade and has significantly altered the risk profile of biomanufacturing. In contrast to open systems, which are inherently exposed to the environment, closed workflows reduce opportunities for contamination, resource waste, and regulatory non-compliance (3).

Fully closed systems ensure that each stage of the workflow — from media exchange and cell harvesting to downstream processing — occurs within a controlled environment. While sterility is a defining feature, this factor is not the sole advantage of closed bioprocessing. This article compares the use of closed systems equipped with aseptic connectors to earlier approaches, highlighting the operational changes introduced by SUT and the consequences a single contaminated culture vessel can have on manufacturing outcomes.

Single-use systems were made to simplify but stay flexible

Unlike open or semi-closed workflows, fully closed systems largely eliminate direct human contact and environmental exposure. This design distinction underpins their suitability for GMP-compliant manufacturing by directly addressing critical industry requirements, such as reduced contamination risk, minimized cross-contamination, and preserved process integrity (4).

Historically, bioprocessing relied heavily on stainless steel systems (e.g., tubing assemblies, sensors, and bottle configurations), which required extensive steam sterilization prior to use. While effective, these systems imposed sensible workflow complexity. The adoption of SUT offered a practical alternative, removing the need for sterilization between batches and improving operational flexibility (5).

The advantages of SUT, particularly in clinical and vaccine manufacturing, include 50-60% lower capital expenditure and faster turnaround times driven by a 20-50% reduction in workload compared to stainless steel infrastructure. Central to these benefits is the use of sealed tubing and pre-sterilized fittings, which actively prevent contaminant ingress and maintain process security (6).

At the same time, the absence of pre-use sterilization steps has raised concerns regarding particulate contamination. Consequently, careful supplier selection, validation of aseptic processing, and quality controls remain essential considerations in high-risk manufacturing environments, such as advanced therapy production (7).

A contaminated cell culture flask is the result of frequent “open” handling steps

A contaminated cell culture flask presents significant risks across both research and manufacturing settings, ranging from batch failure to compromised experimental outcomes. Evidence suggests that contamination risk can be reduced by approximately 47% when transitioning from open processing to fully closed systems (4).

Similar to procedures performed in biosafety cabinets, open bioprocessing involves multiple manual handling steps that are vulnerable to bacterial, fungal, and viral contamination. In the absence of closed systems, Mycoplasma infections can be introduced unknowingly, often escaping routine detection and, sometimes, demonstrating resistance to antibiotic treatment. FDA studies previously reported 35% of all cell cultures worldwide to be infected with Mycoplasma alone, identifying the pathogen as one of the most common contaminants (8).

The cost of Mycoplasma contamination is substantial, manifesting as inconsistent data in research environments or, in manufacturing, as lost resources and extended patient waiting times due to failed batches. Cross-contamination poses an additional, often silent threat in open systems, where overgrowth and phenotypic drift are the common consequences (9).

By reducing contamination risk, closed bioprocessing enables more intensive and longer-duration continuous processes. The impact of this capability extends beyond product safety, influencing energy consumption, labor efficiency, and overall compliance within highly regulated manufacturing environments.

Joining fluid paths without a cleanroom environment is more impressive than it seems

Aseptic connectors are a key component of SUT, designed to prevent external contaminants from entering closed workflows. Within a closed process, these connectors enable the secure integration and separation of multiple unit operations, which is particularly critical in seed trains and downstream processing where fluid paths must be modified without compromising sterility.

Bioburden control is achieved through connector designs mentioned earlier, that incorporate sterile membranes and interlocking mechanisms, exposing a sterile fluid pathway only once a secure connection is confirmed. Compared with tube welding and quick-connect fittings, aseptic connectors are widely regarded as more robust and regulatory-aligned solutions (10).

Traditional industry-scale bioprocessing often relies on continuous asepsis maintenance through steam-in-place (SIP) and clean-in-place (CIP) procedures. In contrast, aseptic disconnectors allow components to be safely removed without breaking containment, reducing the risk of accidental environmental exposure.

When combined with straightforward processes such as peristaltic aseptic filling, aseptic connectors significantly reduce reliance on SIP and CIP operations. This simplification helps maintain system integrity and is noticeably advantageous in GMP-compliant manufacturing, where minimizing operational complexity directly supports process robustness and regulatory confidence (11).

Across modern biomanufacturing, the shift toward closed bioprocessing reflects a fundamental reassessment of how sterility, operational complexity, and regulatory expectations intersect. Data suggesting an almost 0.5-fold reduction in contamination risk underscores the meaningfulness that each part of a fully closed system possesses (4).

As advanced therapies continue to progress toward broader clinical adoption, maintaining sterility while preserving flexibility will remain a defining challenge. In this context, closed systems defined by validated single-use components and aseptic connectors offer a pragmatic path forward.

Whether in laboratories or large-scale vaccine or cell and gene therapy production, this type of bioprocessing plays a critical role in maintaining the environments that deliver real-world outcomes for patients and stakeholders.

Our commitment to sustainable patient access:

CellScrew® exemplifies closed-system integrity, supporting safe, optimized, and GMP-aligned workflows. As part of the broader research-to-clinical journey, the CellScrew® CCT (Closed Configurable Transfer) with customizable aseptic connectors provides a dedicated step toward closed, clinically compatible manufacturing workflows.

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References:

1. Bioprocessing Sees Continued Improvements In Batch Failure Reduction In 2022. (2022). Joel Ranck, BioPlan Associates. Available https://www.bioprocessonline.com/doc/bioprocessing-sees-continued-improvements-in-batch-failure-reductions-in-0001#:~:text=Equipment Failure Still Looms Large,2 (Accessed 29 January 2026).
2. 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).
3. 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).
4. 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).
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6. Einweg- vs. wiederverwendbare Bioreaktoren: Kostenanalyse. (2025). David Bell, CELLBASE. Available https://cellbase.com/de/blogs/nachrichten/einweg-vs-wiederverwendbare-bioreaktoren-kostenanalyse (Accessed 28 January 2026).
7. Particulate Contamination in Single-Use Systems: Challenges of Detection, Measurement, and Continuous Improvement. (2017). James Voegel, Klaus Wormuth, BioProcess International. Available https://www.bioprocessintl.com/single-use/particulate-contamination-in-single-use-systems-challenges-of-detection-measurement-and-continuous-improvement (Accessed 28 January 2026).
8. Common forms of cell culture contamination and how to avoid them. (2023). Dr. Benjamin-Maximilian Schwarz, Carl Zeiss Microscopy GmbH. Available www.zeiss.com/cell-culture (Accessed 02 February 2026).
9. Cell Culture Contamination: 5 Common Sources and How to Prevent Them. (2025). Dr. Sabrina Friedrichs, Capricorn Scientific. Available https://www.capricorn-scientific.com/knowledge-center/cell-culture-contamination#antibiotics (Accessed 28 January 2026).
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11. What’s Peristaltic Aseptic Filling. (2026). Aurora Pro Scientific LLC. Available https://www.auroraprosci.com/whats-peristaltic-aseptic-filling?srsltid=AfmBOoqYR2ToQlH5hA-PtbL6mWItZBinTUZXDJuQx2O7YLJSQng-WMBD (Accessed 29 January 2026).