Aseptic processing is perhaps the most critical of all production activities performed within the healthcare industry (1,
2). The risks to patients are higher for aseptic processing than any other process in current use, and the technologies used
for the aseptic production of sterile products are among the most complex and costly in the industry. Regulators worldwide
recognize the importance of proper practices for aseptic processing and have established several guidance documents pertaining
to its application (1, 3).
James P. Agalloco
Firms that produce aseptic products, pharmaceuticals, or medical devices have attempted to reduce the microbial contamination
risk associated with their assembly by using individually sterilized materials and packaging in pristine environments. Beginning
in the 1950s, firms relied for years almost completely on cleanroom technology in which critical activities were performed
by gowned personnel.
As product sophistication and machine automation capabilities advanced, industry increased its use of machinery to produce
many aseptically processed sterile products. Despite these advances, human presence in aseptic areas, though substantially
reduced, has remained a constant. Although the aseptic fill rooms of the 1960s and 1970s may have used several operators per
line, that number has often been reduced to one in newer installations using the most advanced equipment. This reduction was
made with the knowledge that personnel have always been the single greatest source of microbial contamination in the aseptic
process, and reducing their influence on the aseptic process presence should be a high priority.
One must only visit facilities using automation, blow–fill–seal or form–fill–seal, robotics, remote particle sensors, and
other technologies to understand that patients who are administered aseptic products would be at greater risk had these advances
not taken place during the past 20–30 years.
This article reviews the history of isolator implementation and address why the vast majority of these obstacles are either
no longer meaningful, nonexistent, or were self imposed without good reason.
The advent of isolation technology
The current pinnacle of aseptic processing capability is isolation technology, in which personnel have been removed from the
aseptic environment almost entirely. In the most advanced isolator installations, operators perform only a limited number
of tasks, roughly equal in number to those required with an advanced filling system in a cleanroom. The isolator makes those
tasks substantially safer because the gloves are hermetically sealed to the isolator wall. This barrier provides a degree
of separation between the operator and the critical operating environment that is substantially more secure than is possible
in a manned cleanroom containing aseptically gowned personnel.
Designs are on the drawing board to take this concept substantially further, using robotics and advanced equipment designs
inside an isolator, thus eliminating the need for gloves. The introduction of these systems is some years away. In the interim,
isolators are considered the best available technology for the production of aseptic products. This rationale was acknowledged
by the US Food and Drug Administration in its 2004 aseptic processing guidance, and similar perspectives were advanced by
leaders in the European and Japanese regulatory communities (in which the introduction of isolators for aseptic processing
has progressed at a far greater rate than within the United States) (1, 3, 4).
It was first predicted nearly 15 years ago that isolators would make the conventional manned cleanroom obsolete (5, 6). At
that same time, I identified 10 obstacles to isolator implementation that had to be overcome. These obstacles included:
- attempts at replacing terminal sterilization resulted in over-specification and validation problems;
- perceived materials transfer or ergonomic problems;
- reports of excruciatingly long timelines;
- change in operating philosophy;
- chemical activity of decontaminating gasses and residuals;
- existing facilities and equipment designed for conventional operation;
- nonindustrial appearance of isolators;
- expected advocate-created confusion and FDA skepticism;
- proprietary technology;
- conflicting vendor claims.
The transition to isolation technology from manned aseptic processing was slower than anticipated. Consequently, nearly five
years after my initial prediction, I added some additional items to my list of delaying influences (7). Between 1997 and 1998
these items were added:
- over emphasis on the importance of leaks;
- management of mouse holes considered problematic;
- requiring Class 100 laminar flow internally;
- requiring Class 10,000 or better outside;
- higher initial cost of isolator installations.