ASEPTIC PROCESSING: ONE - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 223

developed expanded guidance in this area during the 1990s [13,14]. ISO's effort
relied heavily on statistical treatment for the definition of contamination rate
acceptance criteria, while PDA's approach was more holistic and recommended
a goal of zero contamination in the filled containers.
In parallel with the regulatory/organizational efforts to define ever more restric-
tive expectations, industry dramatically altered the technologies it employed for
aseptic processing. † In the 1970s, flexible and incomplete barriers were the norm
in many facilities; yet by the end of the century, the first production isolators had
already completed a decade of operation. The changes evidenced in aseptic pro-
cessing were myriad and impacted all of the supportive elements. The absence
of major recalls or compliance initiatives during the 1980s suggest that while
“sterility” may not have been definitively established, sufficient controls were in
place to assure patient safety with aseptically produced drug products. ‡
9.2 ASEPTIC PROCESS DESIGN RESPONSE
Those charged with the preparation of sterile drug products by aseptic process-
ing have long understood the risks associated with aseptic processing and the
central role that personnel play with respect to contamination potential. Acknowl-
edgement of the adverse consequences of personnel involvement resulted in a
steady progression of improvements, all of which served to reduce the impact of
personnel. The brief history of aseptic processing that follows demonstrates an
awareness of the contamination risk associated with the aseptic operator, and the
means to minimize their impact on the aseptic process evolved without formal
risk analysis.
The earliest aseptic processes utilized rather crude environments and con-
trols, and these were replaced in some instances by gloveboxes that separated
the workers from the aseptic field where the assembly of the product contain-
ers was performed. § The US government's declassification of the HEPA filter
in the early 1950s led to the development of the pharmaceutical cleanroom, in
which equipment could perform a majority of the aseptic process, eliminating the
manual steps that had been previously necessary. The period from 1960 through
1990 witnessed refinements to cleanroom practices including barriers of increas-
ing reliability, improved HVAC systems, equipment refinements, automation and
robotics, improved components, and others that brought demonstrable improve-
ments in performance [15,16]. The next big advance in aseptic processing came
in the late 1980s with isolation technology, in which the operator was no longer
present in the same environment as the sterile materials. The restricted access
† This may be, in fact, a question of which came first—the chicken or the egg: regulatory expectations
would not have been raised unless there was a realistic belief that they could be met.
‡ 'Sterility' is defined as the absence of viability; something as unprovable in 1970 as it remains
today.
§ These were true gloveboxes as they lacked the defining features of isolators (rapid transfer ports
and automated decontamination).