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12 Pharmaceutical Technology BIOLOGICS AND STERILE DRUG MANUFACTURING 2019 P h a r mTe c h . c o m performance. At this point, the facility is turned over to the owner. The certification considers only non-viable particles and it comprises the 'classification' of the facility. The certifying classification is repeated on a periodic basis, as well as after any repairs or modifications to the facility. Owner. The owner performs initial decontamination(s) to reduce microorganisms to the desired levels and com- mences operations within the facility. The initial activi- ties are commonly training, engineering, and process simulations. Owners use this period to identify 'worst- case' locations for monitoring (viable and non-viable) in the 'operational' state. Once in regular use, the firm maintains the facility with cleaning and periodic decon- tamination and monitors it periodically. Regulator. The regulator reviews the performance of the facility against regulatory standards, with the focus on monitoring conditions during operation, when contamination of materials would occur. ISO 14644-1 explicitly excludes viable particles from its expectations, but embraces a number of other con- straints (e.g., temperature, humidity, and noise levels). The ISO 14644 series of standards provide compre- hensive treatment on cleanrooms and associated controlled environments classification and drives expectations for their design and operation. Because these standards are non-industry specific, additional expectations have been established to address par- ticular needs. FDA's guidances on aseptic processing; European Medicines Agency's Annex 1 on Sterile Me- dicinal Products, and other specific guidances have added requirements beyond those in ISO 14644 to define conditions for cleanroom operations (5,6). These should be understood as monitoring environ- ments during their use. Although the term 'classifcation' is used in these documents, extending ISO 14644 crite- ria to viable expectations, the expected values in these documents are completely arbitrary (see Table I). ISO 5 environments used in the pharmaceutical industry in- clude: • Closed isolators without personnel access • Open isolators • Restricted access barrier systems (RABS ) for high speed filling • Nominally enclosed unidirectional airflow hoods in manned filling rooms • Localized undirectional air hoods in preparations areas (e.g., located above washing, drying, and wrapping activities prior to sterilization). The effectiveness of the microbial controls employed in these different configurations varies widely and precludes singular expectations for the microbial population present. Microbial classification Ongoing efforts aim to impose a facility classifica- tion scheme under ISO 14698 (7) that would require specific microbial levels. There are difficulties associ- ated with this effort, including absence of calibration standards; absence of calibratable equipment; absence of validated sampling methods; and diversity of ap- plication. In addition, other constraints suggest that the entire effort is misguided: • Environmental monitoring samples only a tiny portion of any environment's air or surface. • Operators and other staffers are the primary source of microbial contamination and their par- ticipation in monitoring perturbs results. • Media-based sampling has a limit of detection that is substantially higher than 1 colony forming unit, severely restricting its utility as a way to provide evidence of microorganisms. • Media-based sampling recovers roughly 1% of the microorganisms present. • Rapid methods can detect viable, but non-cultur- able microorganisms, but, with no commensurate Cleanroom Monitoring