The two technologies most often referred to as advanced at the present time are isolators and blow–fill–seal systems. These technologies represent two different strategies for contamination control. Isolators rely on what can be termed a separation strategy in which the human operator cannot access the aseptic work environment directly. Access to the isolated aseptic zone is achieved only through features that allow separated manipulation. Glove and sleeve assemblies and, in some cases, half-suits are used to provide indirect access with a substantially reduced potential for human contamination.

In the case of blow–fill–seal systems, human-borne contamination control is achieved by not requiring human access into the critical aseptic area during production. Because blow–fill–seal systems usually fully form the container system in situ, they do not require interventions by operators to supply components for closure of an open container. Sterilization of the fully assembled product contact pathway in place obviates the need for aseptic connections. The intended result is aseptic production without intervention.

If isolators and blow–fill–seal systems represent the apogee of current aseptic processing technologies, it seems reasonable to ask where evolutionary development in aseptic processing will take industry in the future. The authors believe that equipment concepts already under development, or even in use, clearly point the direction forward. This article will discuss systems that are already in validated operation and others that are likely to follow in the foreseeable future (1, 2).

Air quality

All current aseptic processing environments, including isolators and blow–fill–seal systems, rely on filtered high-efficiency particulate air (HEPA) to provide air that is free of microorganisms to the aseptic zone. Concerns have been raised about the effectiveness of HEPA filters, but experience has shown that in well-designed and properly operated systems, the risk of contamination from HEPA filters is so low that it can be considered insignificant. A frequent criticism of HEPA filters is that they are depth filters rather than the pore–size-controlled membrane filters used for the removal of microorganisms from liquid or gas process streams that come in direct contact with aseptically produced product. HEPA filters have been particularly valuable in human-scale cleanrooms because they are efficient at submicrometer particulate removal and also present a manageable level of backpressure.

As a result, high flow rates of air that is free of detectable microbial contamination can be supplied with reasonable efficiency. In human-scale cleanrooms, high air-exchange rates of as many as several hundred clean-air changes per hour effectively dilute contaminants derived from personnel. In systems that do not allow direct human interventions (and thus exhibit lower contamination potential), lower air-exchange rates are more than adequate to protect the critical environment. This reduces air-flow requirements, hence air-conditioning and dehumidification systems can be downsized. The resulting energy savings could be significant in an era of rising energy costs.

The authors do not believe that a scientifically compelling argument can be made at this time for filtering air by means other than HEPA-grade filters. In modern air-handling systems with prefiltration of makeup air, the risk of microbial contamination entering the environment through the air-handling system is negligible. From a risk perspective, significant gains in aseptic processing contamination control can be made only by better control of human contamination. It is obvious from risk-analysis modeling that the best way to control human contamination is the elimination of human interventions of any kind (3).