Modular vs. End-to-End Automation in Cell and Gene Therapy Manufacturing: Finding the Right Fit
The field of cell and gene therapy manufacturing is revolutionising medicine, offering the potential to treat and even cure diseases once considered intractable. As these therapies move from research to commercialisation, the need for robust, scalable, and cost-effective manufacturing processes becomes paramount. Automation plays a critical role in achieving these goals, and two primary approaches have emerged: modular and end-to-end automation.
This blog is the first in a series exploring the nuances of automation in the cell therapy manufacturing process. Here, we compare modular and end-to-end systems, examining their respective strengths and weaknesses across key aspects of the manufacturing workflow. Our goal is to provide an unbiased perspective, helping stakeholders navigate the trade-offs involved in selecting the right automation strategy for their specific needs.
Connections and Disconnections: Labour and Sterility
One of the most touted benefits of end-to-end automation is its promise of a largely closed system, minimising manual interventions and the associated risks. The concept of a single-use consumable encompassing the entire manufacturing process (from starting material to final product) is certainly appealing. It reduces the number of in-process connections and disconnections, enabling a more “walk-away” approach for manufacturing personnel.
However, even the most integrated end-to-end systems aren’t entirely connection-free. Sampling for quality control and the introduction of or temperature or time-sensitive reagents, like lentivirus, often necessitate operator involvement. While an end-to-end system might boast around 15 connections throughout the process, a modular approach can require 30+, as material moves between different unit operations.
This increased number of connections in modular systems raises concerns about sterility. Each connection point represents a potential breach in the closed system and a risk of contamination. Furthermore, the manual execution of these connections adds to the overall labour burden.
Conversely, while end-to-end automation aims to minimize connections, the complexity of the single-use consumable often necessitates sterile connections during its initial setup. The key difference lies in the frequency and timing of these connections throughout the manufacturing process.
Ultimately, while end-to-end systems can reduce the number of in-process connections, this benefit comes with trade-offs in other areas, as we will explore further.
Suggested Graphic: Infographic comparing the number of manual interventions and connection points in modular vs. end-to-end systems.
Consumable Complexity: Cost and Reliability
The drive for fewer connections in end-to-end systems often leads to significantly more complex single-use consumables. These aren’t just a sum of individual components but involve intricate networks of tubing, chambers, and integrated sensors. Manufacturing these with high reliability and cost-efficiency presents significant challenges.
Innovations such as diffusion-bonded manifold blocks offer potential solutions, however many end-to-end systems still rely on complex branching tubing networks. While these may be packaged in user-friendly casings, the complexity is merely transferred from the GMP facility to the consumable supplier. Any reliability issues or difficulties in consumable loading can cause production delays and increased costs.
In contrast, modular automation typically employs simpler, more standardised consumables for each individual unit operation. Although this means a greater number of individual consumables, their simplicity can enhance reliability and reduce costs due to established manufacturing processes.
Suggested Graphic: Side-by-side comparison of a modular consumable vs. an end-to-end consumable, highlighting complexity differences.
Load Balancing and Efficiency: Capital and Space
Cell therapy manufacturing processes vary significantly in duration. Some steps, (fluidic transfers, mixing, cell counting), take minutes, while others, e.g. centrifugation, magnetic selection, and filtration, require an hour. Crucially, incubation steps (activation, transduction, expansion) can span hours to days.
Traditional manufacturing lines are designed to balance machine capacity with process bottlenecks. In cell therapy, this would mean ensuring sufficient incubation capacity relative to thawing, for example. End-to-end systems, however, present a challenge: all components—including centrifuges and magnetic separators—remain occupied throughout the entire process, even when idle during long incubation steps. This results in capital inefficiency and larger facility footprints, as each batch requires a dedicated “mini-factory” regardless of the actual utilisation of individual components. E.g. an end-to-end system might occupy 1m³, a bioreactor within a standard incubator requires only 0.03m³, despite incubation making up 80% of a 7-day process.
Modular systems enable flexible scaling of unit operations, adding incubators without requiring more centrifuges or cell selection devices, improving capital and space efficiency. They also enhance fault tolerance, allowing replacement or bypass of failed units, unlike end-to-end systems where a single failure can halt the entire batch.
For small-scale production, an end-to-end system may initially appear space-efficient. However, as production volumes increase, the inefficiencies of tying up expensive equipment for extended periods become more apparent. A useful analogy can be found in the diagnostics industry: modular production lines dominate when turnaround time isn’t critical, whereas end-to-end systems are common in point-of-care settings.
Suggested Graphic: Diagram illustrating the footprint of an end-to-end system vs. modular components, emphasising space utilisation and efficiency.
Flexibility and Process Optimisation
The inherent integration of end-to-end systems can limit flexibility in process development and optimization. To simplify consumable and capital complexity, manufacturers often standardise core technologies across multiple process steps, even if more optimal tools exist.
Modular automation however empowers developers to choose the most appropriate technology for each step of the cell therapy manufacturing process. This enables greater customisation and optimisation, leading to potential improvements in product quality, yield, and process efficiency. Additionally, modular systems allow for gradual process evolution – swapping/upgrading individual unit operations without requiring a complete platform overhaul.
Suggested Graphic: Flowchart showcasing different technology choices enabled by modular automation vs. a fixed end-to-end system.
Choosing the Right Automation Strategy
Both modular and end-to-end automation offer distinct advantages and challenges in cell and gene therapy manufacturing. End-to-end systems aim to streamline workflows and reduce contamination risks by minimising manual connections but comes with increased consumable complexity, reduced capital and space efficiency, and limited flexibility for process optimisation.
Conversely, modular automation (while requiring more in-process connections and labour) provides greater flexibility, cost and space efficiency, and the ability to integrate best-in-class technologies for each process step.
The increased number of manual connections/disconnections in modular systems leads us to our next blog topic: Automated Sterile Connections. We will explore the various methods and technologies available for automating these critical steps, examining their impact on sterility assurance, labour reduction, and overall process efficiency in modular cell therapy manufacturing.
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