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


This year at the International Society for Pharmaceutical Engineering's Barrier Isolation Technology Forum, Rick Friedman, director of the division of manufacturing and product quality in FDA's Center for Drug Evaluation and Research, commented that nearly all submissions for new facilities at the agency are isolators or restricted access barrier systems (4).

So, the revolution that started in 1984 is now in the end game. Although the end of the manned-cleanroom era in aseptic processing has not come, the industry can certainly see it from here. Look for machine automation and robotic applications to provide the next phase of this contamination-control revolution as the industry moves from the isolator era to the gloveless-isolator era.

If I am still around to write an essay on the occasion of Pharmaceutical Technology's 50th anniversary, I predict the human cleanroom will be gone forever, and it will be possible to run plants with the lights turned off, which will be very good for the carbon footprint and for contamination control.

Areas for improvement

The improvements in aseptic processing equipment and facilities during the last three decades have resulted in a circumstance that is still not widely recognized. Although microbiological assays remain the way to best analyze moist-heat sterilization processes, the industry has reached a point in the evolution of aseptic processing where the utility of microbiological assays is now questionable in many ways. Two or three decades ago, the pharmaceutical industry did a lot less environmental monitoring in support of aseptic processing than is the current norm. Back then, the industry actually recovered organisms with some frequency, and media fills were still something of a cross-your-fingers adventure. Today, in ISO 5 environments, microbial recoveries are rare, and in isolators they are so rare that some operations have reported having nothing but zero recovery rates for years. I believe what this should mean to any pragmatic microbiologist is that we may have reached the limits of growth and recovery microbiology as a means of evaluating process control. Really, this has been an issue in the cleanest environments longer than the industry might imagine.

Now the reader might quite reasonably ask why it is that I can endorse the value of microbiological analysis in the validation of moist heat while at the same time asserting that microbiological analysis may no longer be particularly useful when applied to contamination assessment of the cleanest environments. The answer is simple. Sterilization processes begin with a very large population of microorganisms and use the well-known thermal-death kinetics of spores to determine the effectiveness of the sterilization cycle. The statistics of starting with large populations of biological indicators with known resistance properties allows operators to work in a quantitative range that is suitable for growth and recovery assays. This is to say that the biological variation that might be as much as 0.5 log in the worst case is actually of only limited significance when we have a starting spore population of >105 . The biological effectiveness of the sterilization process can be estimated well enough to establish correlations with what would be expected from thermometric data.

Contrast this with attempting to evaluate sterility in more or less the opposite manner by recovering the miniscule residual bioburden within a very clean environment. This is a task made all the more daunting by the fact that this miniscule bioburden is not homogeneously distributed. Making the situation more difficult still is that those organisms that may be present can be or are likely to be under significant nutritional and environmental stress. It is not without reason that the compendial growth promotion tests suggest a challenge population of 10–100 colony-forming units to support the fertility of microbiological media. This process is done because it is very difficult to achieve growth at low inoculum levels, even when working with healthy stock cultures. Of course, the same logic applies to the media-fill test for precisely the same reasons.

I have heard some regulators suggest that if the environmental-monitoring test results are all zeros, then there is not enough testing. The problem, however, is if the results are below the limit of detection of the assay testing, more testing will not help. Even if the possible problem was simply that there were microbes in the environment that could not be found at current sampling intensities at modern air flow rates, it is very hard to imagine how large the sample size would have to be. The answer may well be that there just is not a practical way to sample enough.


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