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6 BioPharm International ® Manufacturing and Facilities eBook November 2024 www.biopharminternational.com Bioprocessing • equipment integrity: system's ability to prevent physical barriers from being breached and pene- tration of microorganisms through components before and during the process. The allowed limits for each product would deter- mine the acceptable levels of residual bioburden and material cleanliness. Closure at the system level can be achieved in two ways. A system is said to be functionally closed when it can be opened punctually (e.g., to install a filter or make a connection) and brought back to a closed state through disinfection or sterilization prior to use for product pro- cessing. A system is said to be fully closed when never exposed to the environment and when all elements in- troduced undergo an additional step avoiding contact with the environment (e.g., a pre-sterilized, single-use bag with transfer lines with aseptic connectors). BioPhorum doesn't make this distinction; it fo- cuses on the closed end state, achieved by meeting the following two conditions (2): • "removal of latent contaminants in the process zone to a level commensurate with the process requirements, whether aseptic or low bioburden, prior to process contact. • prevention of ingress of environmental contam- inants during process contact." Neither of those definitions implies sterile condi- tions; they describe achieving a state that can be quali- fied as bacteriostatic. For drug product manufacturing and final formulation, filtration, and filling, the capa- bility to assure sterility must be verified, as mentioned in Annex 1 of the European Union's good manufactur- ing practice (GMP) guideline (4). This would include the use of closed systems, when implemented. Trends, benefits, and challenges Market studies were performed, confirming a pro- nounced interest for closed systems across all geo- graphic areas and professional functions surveyed (number of respondents N=42). The following is a sum- mary of the findings. The main motivations for the adoption of closed systems include: • reducing the risk of contamination • decreasing cleanroom requirements • minimizing the risk of cross-contamination of products, especially when multiple products are manufactured in the same area. It is perceived to be applicable for all types of biophar- maceutical products, and particularly beneficial for products that require a high classification cleanroom such as Grade A. The consensus is that downstream steps would bene- fit the most from a closed mode of operation. This goes hand in hand with the opinion that they would be the easiest to convert—in particular, bioburden reduction and virus removal filtrations. Nevertheless, the study highlights the challenges associated with the implementation of closed systems. The greatest obstacles are gaps in technology and facility design, such as connection solutions, to maintain clo- sure, for transfer between different equipment; process monitoring and analytical tools management in closed mode; ready-to-use consumables to eliminate prepa- FIGURE 1. Survey Question: What significant financial impact do you anticipate the adoption of a fully closed process will have on your future operations? N=41. ALL FIGURES ARE COURTESY OF THE AUTHOR.