Evaluating Ecological Impact and Sustainability in the Manufacturing of Advanced Therapies: Comparative Analysis of Greenhouse Gas Emissions in the Production of ATMPs in Open and Closed Systems.

The primary aim of this systematic analysis is to highlight opportunities to improve the environmental impact of advanced therapy medicinal products (ATMP) manufacturing. We have compared the Greenhouse Gas (GHG) emissions expressed in CO2eq of a classic clean room open system (AinB) Cell Factory versus a comparable closed system equipped with isolators (AinD). We have therefore outlined a theoretical situation to simulate the use of a closed system with an equivalent production output to that obtained in the Cell Factory (CF) of the Regina Margherita Children's Hospital. Open and closed systems for ATMPs have been compared as regards energy requirements, ecological footprints, and costs by analyzing a hypothetic cell production cycle of 21 days. The results demonstrate energy saving and a reduction of 52% in GHG emissions using closed systems per process cycle. Moreover, a reduction in production costs in an isolator setting is also evident. This study shows that the closed system solution has evident advantages compared with the open one.

Good design practices for an integrated containment and production system for advanced therapies.

Advances in molecular biology and the possibility of differentiating stem cells have opened up new scenarios in therapies that use progenitor or variously differentiated cells. Regardless of the choice of the system, designing a plant for producing advanced therapies requires a clear understanding of the final objective (the product), taking into account all the regulatory, environment, process, risk assessment, asepsis, and validation aspects involved until its implementation. Good Manufacturing Practice (GMP) compliant procedures are a prerequisite for cell production in clinical application, and clean rooms are zones for producing cell therapies. Clean rooms for clinical application require high running and maintenance costs and need trained operators and strict procedures to prepare the rooms and the people involved in the processes. While today production mainly occurs in open systems (clean rooms), there is evidence of processes in closed systems (isolators). The isolator is a Grade A aseptic closed system that requires a controlled environment and at least a Grade D environment in the case of sterile productions (A in D closed system). The use of isolators can ensure a very high level of protection against the risk of product contamination and, at the same time, provide the operators with a very safe working environment. Furthermore, working with closed systems can optimize and facilitate the production of Advanced Therapy Medical Products in GMP environments, by providing an easily reproducible working tool even for large-scale production, with generally lower costs compared to a classical clean room approach. In conclusion, the isolator workstation as a possible alternative to the classic clean room, due to its small size and the simplification of the working and maintenance operational procedures, may represent an interesting solution in the perspective of the increasingly more stringent requests for cost reductions of GMP in clinical application.