I am sure that many readers under 40 years of age will find it astonishing that prefilled syringes were a real rarity in 1977,
and ampuls were still a widely manufactured dosage form. Today, as prefilled syringes gain market share in most of the world,
the ampul is as extinct as the Tyrannosaurus. Most significantly, though, many aseptic processing lines in those days lacked
the now-common depyrogenation tunnel. Instead, gowned operators, who typically wore nothing more than undergarments or street
clothes under their gowns and were never required to "double glove" manually scraped vials off of the trays that had been
depyrogenated in an oven that might or might not have contained a high-efficiency particulate air filter so that the oven
could be operated at a positive pressure relative to the surrounding environment. The complete elimination of manual glassware
transfer is very close to being a reality today, although I cannot honestly say how close with absolute certainty. In my opinion,
the introduction of in-line glassware washing and depyrogenation would rank very near the top of the list of developments
most responsible for increased aseptic-product safety during the last 30 years. Of course, it has proven difficult to implement
the direct sterilization in conjunction with some product types, notably plastic containers with volumes of 100–1000 mL. Cold
sterilization technology, however, has evolved tremendously during the last 30 years, and the means of achieving direct in-line
sterilization of most products appears be within our grasp.
Milestone. 30 years of Pharmaceutical Technology
A new regulatory approach
There is one year that stands out in my mind in the 30 years that Pharmaceutical Technology has been published. That year is 1984, and it is memorable to me because in that year the pharmaceutical industry was made
aware that the US Food and Drug Administration was working on a draft guideline, which was eventually published in 1987 as
the Guideline on Sterile Drug Products Produced by Aseptic Processing (3). Word began to spread that this guideline would force industry to do some things very differently. The nature of one important
change emerged when the pharmaceutical industry learned through podium presentations by key FDA personnel and inspectional
activity that the industry practice of automatic sterility test "retests" was no longer considered acceptable.
Before that time, the formal sterility-test failure investigation did not exist; rather, sterility-test positives were considered
more like a minor glitch on the road to release than as a potential processing failure. Actually, my firm did take the occurrence
of a sterility positive seriously, and we performed a limited version of the investigation required today. My firm also immediately
did a retest while conducting the investigation. Some firms, however, skipped most of the steps involved in today's investigation
and just went right to the retest and, if it passed, released the product.
Improving contamination control
Industry was forced to face rather quickly that this change really meant that the 0.25–0.5% retest rates that were common
in sterility testing operations were no longer acceptable. The industry needed a more reliable sterility test. At the same
time, the industry needed to improve the contamination control in aseptic processing. Out of this situation came word that
a new technology had been used for sterility testing in Europe and that it seemed to effectively eliminate microbial contamination.
This technology was, of course, the isolator. Later in 1984, I saw a flexible wall isolator for the first time at a trade
show, and as I walked away from that exhibit, I mentioned to a colleague that we had just seen not only the future of sterility
testing, but also the future of aseptic processing.
Having been involved in aseptic processing for three years by 1984, and having spent over a decade before that engaged in
cell culture and virology, I knew very well that microbial contamination was almost exclusively a problem associated with
humans performing interventions. Our firm had already considered using robots to reduce reliance on personnel, and we had
a robotics laboratory to evaluate concepts. In the isolator, we saw a system that could separate the human from the operation
and, that when used in concert with machine automation and robotics, would enable us to achieve levels of control over microbial
contamination that would never be attainable in conventional cleanrooms.