Upstream Manufacturing: Is an Open or Closed System Better? | Bioprocess Manufacturing | Corning

Bioprocess manufacturing is playing an increasingly important role in the healthcare sector and other fields, with products including proteins, monoclonal antibodies, and nucleic acids. Upstream manufacturing for these products often requires growing cells under carefully controlled conditions. Cell harvest is followed by downstream processes to test, purify, and package the products.

For a research process to earn the necessary approvals to transition from research and development (R&D) to manufacturing is a tremendous achievement that comes with new challenges. One critical decision is whether to use an open or closed system for the manufacturing process.

Open Versus Closed Systems

As explained by Tom Bongiorno, a field application scientist for Corning Life Sciences, "An open system means that you are exposing the interior surfaces — that will be in contact with your culture — to the external environment." For example, removing the cap of a cell culture flask to add media exposes the cells to the external environment. Working within a biosafety cabinet (BSC) can minimize the risk of contamination.

In contrast, a closed system is closed off from the external environment, so steps can be performed outside the biosafety cabinet. These systems might include a single-use container with preassembled tubing, such as the Corning® Ascent® Fixed Bed Reactors, which could be attached to a pre-filled bag of media with an aseptic connector.

A completely closed system is often difficult to achieve, so a "functionally closed system" or a "semi-closed system" may be used. Bongiorno provides an example: "Some Corning products come with MPC (male/female) connectors. The connection needs to be made inside a BSC, but once it's connected, you can move it outside the BSC" and use it like a closed system.

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Advantages of an Open System

An open system is familiar to most people who work in cell culture. It offers the greatest flexibility, which often makes it the easier and more cost-effective choice for an R&D environment. While an open system does have a greater risk of contamination, this is less dire in an R&D environment, where experiments often need to be repeated for a variety of reasons.

In transitioning from R&D to manufacturing, one advantage of an open system is that it can take less time to set up than a closed system. Bongiorno and his colleagues at Corning work closely with customers to develop custom solutions that meet their specific needs. In his experience, moving from an open system to a closed system "can definitely take some time — perhaps six months to a year to go through the training and get everything validated. In an academic lab, you typically need fewer approvals, so it's going to be more about training. That process can be relatively quick — maybe a month or two. For a large company in a more regulated environment that may require an extensive validation process, it's going to take more time."

Advantages of a Closed System

The most obvious advantage of converting an open system to a closed system is the reduced risk of contamination, which may be especially important for the one-of-a-kind samples used in precision medicine. A closed system offers other advantages as well. You don't need as many biosafety cabinets, which are large and expensive. All that is required is a bench to work on. In addition, many of the components for a closed system are single-use and preassembled, which reduces the time required for sterilization and experimental set up.

Recently developed aseptic connectors are helping to move closed systems out of the BSC. Standard AseptiQuik connectors can make connections while maintaining sterility, and a slightly different version can be used to make and remove a connection. Lynx connectors allow a connection to be made and removed up to six times. Both AseptiQuik and Lynx connectors are available on Corning products.

Bongiorno adds, "As a system becomes more closed, it generally becomes more scalable. One of the best examples of this would be using a manifold." Corning offers a manifold with four AseptiQuik® connectors for its CellCube® system, which is available in 10, 25, and 100 layer modules. "Manifolding decreases the amount of time needed to manipulate a large number of vessels. Rather than repeating the process for each vessel, you essentially do it once."

Moving to a closed system also provides additional opportunities for automation to reduce operator-to-operator variability. The Corning Automated Manipulator can handle up to six HYPERStack 36-layer or CellSTACK 10-layer vessels at once.

Simplifying the Transition From Open to Closed

To facilitate an anticipated move from R&D to manufacturing, a lab may consider using systems that can easily be converted to closed systems and scaled up. According to Bongiorno, "Corning CellSTACK® comes standard as an open system, but we also offer accessories to convert it to a closed system. So you would just remove the cap, replace it with a cap that has tubing preloaded on it, and essentially turn it into a closed system." If you anticipate needing more surface area, Corning High Yield PERformance (HYPER) Technology comes pre-configured as a closed system, which supports scale-up and scale-out.

As Corning scientists continue working with customers to develop systems that meet their specific needs, the process of transitioning from an open system to a closed system will continue to improve and facilitate the upstream manufacturing process. Learn more here about the benefits of a closed system for manufacturing.