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8 BioPharm International ® Manufacturing and Facilities eBook November 2024 www.biopharminternational.com Bioprocessing (6). For hu ma n vacci nes ma nu fac t u r i ng, a refer- ence from the World Health Organization in 2012 encouraged the use of closed systems for products wh ich ca n not be ster i le f i ltered a nd h igh l ighted that dif ferent room classifications can result (7). A link was created between risk assessment and the use of closed systems through ICH Q 9 (2005). Annex II, dealing with applications to facilit y and equipment design, states (8), "To determine appro- priate zones when designing bui ldings and faci l- ities, e.g., • f low of material and personnel • minimize contamination • pest control measures • prevention of mi x-ups • open versus closed equipment • clean rooms versus isolator technologies • dedicated or segregated facilities/equipment." W h i le t he above most ly descr ibes t he s ystems i n c losed s t ate (i.e., a f ter c los u re or i n u se w it h product), risk assessment, risk mitigation actions, a nd operat i ng procedures shou ld consider i nter- mediate states (open or during closure). In a 2017 publication, ISPE considered pre-use, in-use, and post-use st ages a nd t hei r speci f ic requ i rement s, because risk could be higher for one or the other, a nd ca l led for add it iona l ac t ion s to prevent r isk and ensure product or operator safet y (3). Two decades of regulatory guidelines make men- tion of closed systems, and translation into an ac- tionable approach is an endeavor that BioPhor um is currently under taking. Guidance to accelerate closure and innovation in facility design Innovation in facility design still doesn't necessarily re- flect the reduced area classification requirements and flexibility brought by closed elements. Subject matter experts and industry leaders are getting together to support practical implementation of closed systems, and BioPhorum has initiated the redaction of a Closure Playbook, where manufacturers will find guidance on implementation and operation of closed systems in non-classified zones (9). This complements BioPhorum's facility modular design vision, which was augmented in the context of multi-modal manufacturing (10). It is tied to the ability to operate closed systems, unsegregated in an open manufacturing environment. Current facility designs often include classified cleanrooms, airlocks, and environmental controls. Moving forward, facilities will adopt a "ballroom" con- cept through process closure in controlled non-classi- fied (CNC) areas. These are defined by BioPhorum as, "An unclassified manufacturing environment where user-defined critical control parameters (e.g,. tempera- ture, humidity, access, pressurization, pest control, vi- able and non-viable particulates) are controlled as per process requirements. Unclassified environments are not appropriate for open processing. Environmental monitoring is not required." Most unit operations will eventually be located in a CNC space, thereby reducing the footprint of classified clean- rooms. In the "facility of the future," the entire process operates in a closed manner within an open "ballroom." FIGURE 3. The "Facility of the Future." ALL FIGURES ARE COURTESY OF THE AUTHOR.