Charting Process Improvement in Sterile Product Manufacturing - Pharmaceutical Technology

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Charting Process Improvement in Sterile Product Manufacturing
Sterile product manufacturing and related testing have evolved significantly during the last 30 years. From requirements for acceptance criteria for media-fill tests, to developing validated approaches for moist-heat sterilization, to the introduction of formalized sterility-testing practices, the pharmaceutical industry has made significant advances in testing and in key technology such as isolators, prefilled syringes, automation, and robotics. The author outlines the key regulatory and technical..

Pharmaceutical Technology

Milestone. 30 years of Pharmaceutical Technology
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.

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.


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