Good manufacturing practices (GMP) for therapeutic cell production have been based on using cleanrooms and isolators. However, the industry is moving toward novel alternatives that accomplish what an air environment cannot: better protection of cells from both microbial contamination and chemical toxicity, and better control of cell–temperature and carbon dioxide (CO2), and oxygen (O2) levels.
Recent industry news points to the popularity of presterilized, single-use systems (SUSs), inside of which it’s easy to ensure cells remain aseptic. These systems require less cleaning and virtually no biocide, which explains why closed SUS devices are a dominant trend in modernization.
However, SUSs don’t necessarily produce the best or most cells. Recent comparability studies from the NIH show surprising results. Although the exposure to air in SUSs is assumed to be minimal, what is not clear is how well these systems can avoid exposing cells to suboptimal temperatures and levels of CO2 and O2, which can significantly influence the final cell product.
New category of SUS devices challenges dogma and terminology
Alternatives in SUS devices are starting to appear that achieve all objectives: complete closure, complete avoidance of air, and virtually no limitations. Some SUS devices are difficult to describe because they do it in a different way. One example is a modular closed system.
Unlike closed SUS devices, the modular closed system is not constrained to any particular process but can accommodate entire cell production processes—large or small, simple or complex, centralized or distributed, manual or automated.
With interconnected glove chambers, the closed system looks like an isolator from the outside. However, isolator dogma brings preconceived notions with it: HVAC connections, filtered air blowing through, thick heavy gloves, etc.
Unlike any other isolator, a modular closed system is very configurable with plug-and-play modularity. It assembles from a comprehensive library of modular chambers, co-chambers, and sub-chambers, interconnecting in all different ways to efficiently close by form and fit around the workflow of any production process, including all analytic, processing, and automation equipment.
Cell production often consists of many diverse steps. Technicians or industrial robotic arms use the gloves from the outside for manual or man-mimetic robotic steps, or for tending to the equipment or automation inside. However, in the context of producing high-quality cells and avoiding contamination and toxic chemicals, it is more comparable to SUSs.
Instead of ease with presterilized disposables, a modular closed system self-sanitizes the entire internal production environment automatically without risky biocides. No biocides may sound like heresy according to GMP dogma, but the data trumps the dogma. In this regard, a modular closed system could be called a next-generation isolator, or a cytocentric isolator.
How does a modular closed system impact cell production?
Instead of air inside, the modular closed system is filled with a mix of pure nitrogen (N2), O2, and CO2 gases from tanks. CO2 and O2 can be controlled at optimal levels for cells throughout the system, just like an incubator or bioreactor. Temperature can also be controlled, just like an incubator or bioreactor. Consistent and better-quality cells can be produced by eliminating the fluctuations and transient exposures to suboptimal temperature, CO2, and O2 usually caused by all the typical exposures to air in cleanrooms or traditional isolators.
Notably, most stem cells and primary cultures fresh from the patient do best at low O2 levels, which simulate normal physiologic levels. In fact, it is the only cell manufacturing platform that can optimize this critical parameter at every step of production, simultaneously with physiologic CO2 and temperature. However, where necessary, you can simulate air without air, inert with 100 percent nitrogen, or chill down to refrigerator temperatures.
Compared to cleanrooms, a modular closed system reduces facility costs by 90 percent when you look at the total cost at equivalent production capacity over the facility lifecycle.
Extremely low operating cost is the game changer, although many forget to factor that into future facility cost estimates. When you do, it brings cGMP cell production within reach of the smallest companies. Combine that with fast flexible deployment, multimodal capability due to closure, easy path to regulatory approval due to closure, reduced risks, and high quality of the live cell products, the modular closed system is, indeed, next-generation.