For at least 20 years, the global parenteral industry has recognized that personnel are the dominant risk relative to microbial
contamination in aseptically produced sterile products (1). The contamination source strength of the gowned aseptic processing
operator has been estimated in several research studies. Concomitant with this awareness, we have witnessed a series of technological
advances that have endeavored to mitigate this contamination risk. These advances can be roughly categorized as follows:
- separate personnel from the aseptic environment;
- limit personnel interaction with sterile materials;
- remove personnel from the aseptic environment;
- some combination of the above.
Each of these approaches provides some added measure of security to the process by increasing the degree of separation provided
between personnel and the sterilized materials, components, and product contact surfaces required for the aseptic assembly
of the sterile product from its individual elements.
Advanced versus conventional aseptic processing
To the extent that these approaches are effective, they can reduce contamination risk in aseptic processing. Designs that
most effectively eliminate human-borne contamination have been identified as providing "advanced aseptic processing." The
term advanced aseptic processing was perhaps first used at the USP Open Conference on Microbiology in May 2002 (2). During that conference, only two aseptic
technologies were discussed under the heading of "advanced": isolators and blow–fill–seal. Over the intervening years, we
have witnessed the term advanced aseptic processing come into ever wider use. Considering the goals of aseptic processing, that other technologies intended to meet the high
expectations for sterile product manufacturing aseptically should emerge is unremarkable.
Several technical features distinguish advanced from conventional aseptic processing. We believe the following condition should
be met for an aseptic processing technology to be considered advanced: no interventions should be conducted during aseptic
operations by gowned employees. In other words, all interventions must be conducted using separative features such as isolator
gloves or half-suits. Obviously, this condition also could be met if manned interventions of any type were not required—as
can be the case in blow–fill–seal or gloveless isolators. The contamination potential from the human operator, even under
the most ideal conditions, is such that the aseptic process may be compromised by even a single manipulation by gowned personnel
in proximity to the sterile materials. At a minimum, the allowance of limited human interventions creates risk uncertainty
that we believe is incompatible with the concept of advanced aseptic processing.
A historical perspective
A brief historical review of the environmental systems used for aseptic processing is useful to understand the genesis of
today's processing technologies (see Figure 1).
Figure 1: Aseptic processing family tree.
Perhaps little known to many current practitioners is the previous use of gloveboxes for aseptic processing before the introduction
of cleanroom technology. Clearly, the early practitioners of aseptic processing understood the risk from human-borne contamination
and used physical separation between the operator and the so-called sterile field to provide greater control over microorganisms.
The emergence of the HEPA filter in the mid 1950s changed facility designs and operating practices dramatically. It was now
possible to position equipment inside a room and, using gowned personnel, produce larger numbers of units with less human
manipulation. This design has continued to evolve to the more advanced barrier designs we see today. Gloveboxes never became
obsolete, but labor requirements, throughput limitations, decontamination constraints, and other factors limited their application
in aseptic processing.
The cleanroom dominated the industry as the preferred choice for aseptic processing because it was amenable to high-speed
filling, inclusion of processing equipment, and easy adaptation for various applications. Later designs included partial barriers
to provide greater separation between operators and sterile materials.