A Unique Blend of Art and Science
Jim Akers of Akers Associates looks at the science of aseptic processing
A commonly held belief in the pharmaceutical industry is that aseptic processing is the most difficult manufacturing challenge confronting healthcare product suppliers. Today, when at least some aseptic processing is done in isolators rather than human scale cleanrooms, we should probably modify this belief slightly. It is probably appropriate to say that aseptic manufacturing in cleanrooms is still the most difficult process control challenge in pharmaceutical manufacturing. This is not to say that aseptic processing in isolators is easy, certainly it isn't, but isolators and other forms of aseptic processing to provide means to assert a more profound level of control over the primary source of contamination- the human operator.
IS IT DIFFICULT AND IF SO WHY?
Yes, aseptic processing is difficult and the reasons for the difficulty are easy to comprehend. Aseptic processing is heavily dependent upon human performance. The equipment we have today in human scale cleanroom aseptic processing has never been better. Modern filling and packaging equipment operates at high speed and with levels of labour reducing automation that would have been impossible only a decade ago. Clothing is generally better, and cleanroom design, as befits a mature technology, is better than ever.
However, we know from numerous studies that our employees still shed particulate matter as they work and that some of that particulate matter is viable microbial contamination. We know that gowning is something of a gymnastic exercise and that even today's superior cleanroom clothing isn't perfect. Gloves develop leaks and tears, sleeves and gloves separate, small swatches of skin around the face are still exposed, and putting all this protective clothing on without contaminating it in some way is asking a great deal.
Having once put on this clothing and transitioned into the more critical zones of the aseptic processing area our operators must work carefully to keep their clothing clean and to reduce emission of contaminants. The closer our employees come to the open product, containers and closures that higher the probability that any contamination released could affect the product. Hence the art of aseptic processing- like athletes or performance artists our aseptic processing operators must do their job at a consistently high level. Concentration and in some cases coordination are required in abundance. A common mistake we make in considering aseptic processing is that we assume that once we have an employee fully gowned, nothing much can go wrong.
LEGACY OF EVOLVING MISUNDERSTANDING
If aseptic processing weren't difficult enough from the performance perspective, our industry has tended to make it more difficult still. Fifteen to twenty years ago, when many of us in the middle of our careers began working in this field, there was a tacit understanding among most thoughtful practitioners that it would be stretching the truth to call aseptically manufactured products sterile. The scientific meaning of the word is aseptic is vastly different from the meaning of the word sterile. Sterile is the complete absence of living organisms capable of reproduction, whereas aseptic is simply the absence of organisms known to cause disease.
I believe we can trace the beginning of the evolving misunderstanding of aseptic processing to the publication of the United States Food and Drug Administration's Draft Guideline on Sterile Drug Products Produced by Aseptic Processing as a draft version in 1985. As can be seen from the title, this guideline blurred the distinction between aseptic and sterile and the repercussions of that blurring echo even today. This FDA guideline was and is in many ways a superb document. Carefully crafted, concise and in many ways reasonable, this document has had an exceptionally long useful lifetime. The authors of this guideline probably did not intend readers to conclude that the goal in aseptic processing was to proof without equivocation that each unit in each lot produced is provably sterile. However, I believe that is just what happened.
MONITORING OF THE ENVIRONMENT
In the wake of this FDA guideline, the industry witnessed an increased emphasis on numerical assessment of viable contamination in cleanrooms. In parallel with this emphasis we have seen an increased tendency to assume that environmental monitoring data could be used as absolute product release criteria. We have heard some inspectors assert that any contamination found in the more critical zones of an aseptic processing area may mean that the product is "non-sterile". Reality suggests that the indirect proof of sterility in aseptic processing does not exist. If our operators release organisms into the environment, as logically they must, how can we consider products made in that environment truly sterile? More to the point, how can we say that a recovered microorganism, even in a critical area is indicative of a process control failure that can or should mandate action be taken against product?
PROCESS SIMULATION TESTING
Another parallel line of thinking that evolved in the late 1980s was that statistical criteria for "sterility assurance levels" should be established for aseptic manufacturing. The resulting debate over the use of statistics in aseptic processing media fill validation is a topic far too broad in scope to treat in this brief communication. However, the reader is urged to investigate the history and current status of these standards. There is general agreement that the target contamination rate for the process simulation testing used in the industry, as a means of aseptic process performance. should be zero. There is also a tacit understanding that contamination should be rather rare. Unfortunately, we appear no closer to harmonised standards and validation methods than we were a decade ago.
One obvious trend is that media fill tests are becoming larger in terms of units filled, more demanding in terms of activities that must be covered. Some people believe that the number of samples in a media fill test should equal an actual production lot. Such a test is obviously a time consuming and costly exercise if one considers the higher throughput systems common today. The salient point is whether or not we learn anything of value from these large population media fill tests and that is debatable. There are many things that could potentially effect the detection of contamination and the number of units filled is but one.
EMERGING TECHNOLOGIES-INCREASING CONFUSION
The introduction of new technologies that better control human-sourced contamination should make the lives of our aseptic processing manufacturing, firms and their employees easier. Many firms have invested heavily in this technology and by and large the performance achieved has been sensational. However, it hasn't been perfect and sadly that is the expectation that many people initially had particularly isolators. Unfortunately some industry scientists and engineers failed to consider how difficult it really is to prove that aseptic technology based upon the exclusion and retention of contamination could achieve "sterility" assurance levels comparable to those attained in physical sterilisation. This confusion seems largely limited to the United States, but there are other ramifications of new technology know no geographical boundaries.
The suggestion that isolators should closely approach perfection and the resulting bi-level standards for cleanrooms compared to advanced technologies causes difficulty. If a firm must achieve near perfection in isolators why use them when the standards for cleanrooms while murky at present are perceived to be less onerous? It does not seem reasonable to have confusing requirements and unreasonable performance expectations so early in the implementation cycle for new technologies, but unfortunately to one degree or another that is precisely what has happened. Of course choosing to build a new aseptic processing cleanroom suite does not appear to be a completely safe course either because the new tendency to require near perfection and the improved performance available by other means (isolators, blow, fill, seal) may mean that some years hence even the best cleanroom might not be good enough.
WHERE DO WE GO FROM HERE?
The following bulleted list contains suggestions for industry scientists, standard setters and the regulatory community as we move deeper into the first decade of the new millennium:
We must make sure that our standards and requirements are supported by engineering facts and scientific realities. Pet theories, however intuitively valid, have no place unless supported by fact. We must redouble our efforts at harmonisation. Firms deserve to be able to design and operate facilities that meet all international requirements without making specific jurisdictional adjustments. We must accept the realistic limitations of the mechanical and human systems we use in aseptic processing and we must not asked them to perform outside of their performance envelope. We must restore the linkage between aseptic processing performance and end user safety. There must be data concerning how well aseptic operations of various types perform in terms of safety when validated and operated per current good manufacturing practices. Horror stories built around operations that are clearly outside good industry practice have no value in this process, because current guidelines should already preclude their continued use. We must realise that is it impossible to prove "sterility" in aseptic processing given current analytical capabilities. In fact, a strong argument can be made that it may be technically impossible to achieve true "sterility" for at least the next decade or more. It is possible with proper risk analysis to define a proper condition of asepsis and with proper management and control reach that standard consistently. Clearly the time has come to rely more heavily on hazard analysis and control in aseptic processing. We must not "raise the bar" so high with emerging technologies that we erect barriers against their implementation. I believe that these suggestions will enable us to break free of the confusing situation we presently live with and enable us to move forward based upon good science and solid engineering principles.