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The Myth Called "Sterility"
There's been a steady stream of compliance documents from global regulatory authorities concerning aseptic processing. These regulations require the healthcare and pharmaceutical industries to do the impossible—unequivocally establish the sterility of the materials we produce. Although this goal seems logical and laudable to the ill-informed, it defies available, real-scientific capabilities. The expectation seems to be based either on personal opinion or untested hypothesis, discounting the realities that such proof might entail.
A common perspective underlying regulatory documents that call for a "proof" of sterility is the belief that industry can somehow use microbiological analysis and other select and, often-subjective, tests to prove that sterility has been attained. Such proof does not technically exist and is not scientifically possible. There are dangers implicit in regulatory authorities requiring industry to attempt to prove the unprovable. These misguided efforts create circumstances in which industry can never truly accomplish the intended objective and, as such, can always be found to have made insufficient efforts to support sterility-assurance programs.
Users of isolation technology, for example, have been asked to increase environmental monitoring (EM) to extreme levels because existing monitoring programs established for manned cleanrooms cannot detect contamination. Scientifically and legally, these standards have left industry with both feet firmly planted in mid-air. The result, as evidenced from recent inspections, is that if an inspector wishes to use these documents to insist that a firm lacks "sterility assurance," then there is virtually no way the manufacturing firm can defend itself.
It is always possible to start an inspection report with the following statement, "The firm failed to demonstrate sterility assurance in that...." It's impossible to objectively prove or disprove this allegation. Sterility is an absolute concept, and its presence cannot be proven, regardless of the effort to do so.
Examples of unprovable regulatory citations include claims of inadequate air visualization (smoke studies), claims regarding the conduct of media fills, the acceptability (or not) of a specific aseptic intervention, and charges regarding the adequacy of environmental monitoring. Metrics for smoke-test success are absent. This test is strictly an eye-ball exercise in which one party may see one thing and another sees something quite different. Although smoke tests are valuable for fine-tuning certain elements of critical-zone performance, they rarely lead to real performance improvements.
Airflow is another example. Airflow in cleanrooms is some-times incorrectly called "laminar," but in practice, laminarity cannot be achieved. No matter how well-designed or qualified an isolator or cleanroom is, there always will be turbulence and eddy currents. There is no objective standard for the point at which adequacy no longer exists or at which turbulence might affect sterility assurance, if it ever does.
Media-fill conduct is yet another issue without an endpoint. In recent years, regulators have required larger and longer media fills and placed an increased emphasis on using media fills as long as the longest production run. However, change does not enable proof of sterility. No media fill, no matter how large or intensive, can ever prove sterility. New conditions can always be added to a media-fill program, even if those conditions are atypical. Recently, FDA has expected that the production and filter sterilization of media parallel the compounding and filtration of product. Yet, media and product are two very different materials with different attributes. The most obvious of these differences is that media will amplify the presence of contamination, which the majority of products will not do. Also, media may contain insoluble particu-late in quantities not seen with most aqueous formulations which means prefiltration is a must. There is nothing to be gained from ever larger media fill tests with activities that really don't relate to process simulation being required
Another prevailing notion is that some aseptic processing interventions are inherently bad. There's no question that heroic efforts during aseptic processing should be avoided. But what makes a particular intervention good or bad? We have no useful metrics, to assess the difference, yet such categorization is all too swift and final. Furthermore, media-fill tests, no matter how intensive, cannot reliably demonstrate (or validate) that an intervention is low-risk, nor can they unequivocally prove that an intervention is bad. Neither media-fill or eyeball tests are inherently sound arbiters of sterility assurance. In absolute terms, they are both inadequate for such a task. Destroying a batch because an intervention is arbitrarily assumed to be "bad" is not much different than accepting a different batch made with a series of "good" interventions.
EM has been increasing as a consequence of regulatory pressure for at least 20 years, but there is never any consideration of diminishing return or even patient risk arising from EM-related interventions. Quite simply, it is not possible to monitor quality into product (something we've known since the very origins of validation in the 1970s) and it will never be possible to use EM to prove sterility. EM is neither sensitive nor accurate enough to pinpoint when intervention might put a patient at risk. EM has significant and inherent, technical limitations and we have likely passed the point of diminishing return on it within even manned cleanrooms. This is an acknowledged fact that's never contemplated in current regulation.
The need foranewdirection. The absolutist thinking regarding sterility assurance plays a significant role in standards development. Both industry and regulatory authorities would benefit from a serious dialogue about the nature of aseptic processing regulation. Intensity and length of effort cannot alone ensure sterility. Monitoring, even if continuous, and smoke tests, even if comprehensive, cannot ensure sterility. Unfortunately, subjective evaluation of such data can result in regulatory observations that are not pertinent and may be irrelevant.
The authors are raising this issue now because we believe that evolving aseptic-processing technology has rendered the traditional evaluative methods less useful. These more advanced processes consistently operate below the limits of detection for the presently available microbiological assays.
As processes have improved and "zero" results have become the norm, the regulatory reaction has been to multiply the test and in-process workload which, while intuitively logical, is scientifically inappropriate and, unfortunately, valueless. We suggest that rapid microbiology, drawing increasing attention by industry, only provides the same imprecise information about the aseptic process we already have, albeit somewhat sooner. The use of that "information" is what the authors are concerned about, not the time it takes to obtain it. Rapid microbiology is very useful technology, but it cannot overcome the sampling limitations that exist. No analytical method (microbiological, chemical, or physical), regardless of how advanced and sensitive, can measure the complete absence of something. Sterility is, by definition, the complete absence of viable contamination.
The authors seek to highlight the increasingly arduous regulatory spiral into which we have been drawn. The most practical way forward is to carry out honest and detailed dialogue between all stakeholders. In many technical endeavors, there's a time at which paradigm shifts are required. Discipline of aseptic processing is now at such a point. Continuing to follow the same path of the past two decades will neither improve end-user safety nor the economics of manufacture.
A process-centric approach for superior performance
To successfully manufacture sterile products by aseptic means, it's necessary to redefine the process controls essential for success. Central to the authors' suggested approach is the use of the Akers-Agalloco (A-A) method for aseptic-processing risk analysis to support the evaluation and selection of the specific means for aseptic-process design and execution (1,2). Our preference for this over other methodologies is based upon the absence of inference from EM results. Katayama et al, in their review of aseptic-processing risk models, identified the A-A method as having the closest correlation to the operational performance evidenced for a variety of different installations (3).
The authors believe it's the decisions, selections, and approaches—made with respect to each of the factors depicted in Figure
1—that have the greatest effect on results. Poor choices, regardless of the monitoring outcomes associated with them, must
be acknowledged as unsound. Our approach differs from those derived from EM expectations because of our focus on personnel
and their impact on contamination levels. The rankings in the A-A method devolve from a singular focus on the operator. From
that perspective, the authors established the following basic precepts to the A-A risk method and the recommendations outlined
below (4, 5):
In turn, these steps should be followed with respect to aseptic processing: separate personnel from the aseptic environment;
limit employees' interaction with sterile materials; where possible, entirely remove personnel from the aseptic environment;
and combinations of the above. The means for accomplishing these goals are embodied in following methodologies (6):
These methods are central to our recommendations for the supportive elements of aseptic processing. In defining these elements,
the authors are adapting a quality-by-design (QbD) approach as defined in recent regulatory documents (7,8). The details for
QbD in aseptic processing are somewhat different from the applications of this concept in the typical formulation or synthesis
process. As we outlined in the first half of this paper, the establishment of direct linkage between a monitored condition
and the outcome, with respect to an aseptic process, is uncertain. The situation, with respect to the definition of physical-design
elements, is very similar. Contemporary aseptic-processing facility and process design include several seemingly rigorous
design expectations for performance, including such precepts as:
These expectations, and others like them, should be considered suggestions rather than definitive requirements because they have less correspondence to the process outcome than EM. The authors' recommendations for QbD, with respect to aseptic processing, are non-numeric because it is our strong belief that there are no ready means to demonstrate their suitability. Instead, we suggest that QbD for aseptic processing be driven toward eliminating the impact of personnel on the process. The means to accomplish this vary depending on the particular aspect of the overall process under consideration.
The following recommendations for various aspects of the aseptic processing facility adhere to our central premise of reducing the potential adverse impact of personnel on the core aseptic process. They are not intended to be inclusive—other suggestions could be added.
Equipment and utensils:
The first section of this work addresses the limitations of monitoring tools used for aseptic processing. The current methods cannot prove sterility (or its absence). It is the authors' contention that to achieve success with aseptic processing, the practitioner must properly address the relevant issues outlined in the latter half of this work. There is nothing industry can do to provide proof of sterility. The authors believe, however, that adherence to the recommendations herein will make aseptically-produced products as safe as currently possible.
The methods proposed are largely incompatible with existing aseptic processing guidance, regulatory, and pharmacopeial doctrine because the authors have, essentially, deconstructed monitoring as a means for defining or accepting aseptic-processing activities and endeavored to outline a comprehensive QbD approach for establishing it more appropriately. If industry is to continue to improve aseptic processing beyond its current capabilities and, even to proper control contemporary aseptic-processing operations, the authors believe that greater attention should be focused on the design elements. We offer this work as an opening statement in what we hope will be a continued dialogue through which sterile products can be manufactured by—and controlled—in the safest means possible.
James Agalloco* is president of Agalloco & Associates and a member of Pharmaceutical Technology's Editorial Advisory Board, 908.874.7558,
*To whom all correspondence should be addressed.
1. J. Agalloco and J. Akers, Pharm. Technol., 29 (11), 74-88 (2005).
2. J. Agalloco and J. Akers, Pharm. Technol., 30 (7), 60-76 (2006).
3. H. Katayama et al., PDA J Pharm Sci and Tech., 62 (4), 235-243 (2008).
4. J. Agalloco and J. Akers, Pharm. Technol., 30 (7) (2006) 60-76.
5. J. Agalloco and J. Akers, supplement to Pharm. Technol., Aseptic Processing, 31, s8-11 (2007).
6. J. Agalloco and J. Akers, supplement to Pharm. Technol., Aseptic Processing, 29, s16-23 (2005).
7. M. Nasr, "Quality by Design (QbD)-A Modern System Approach to Pharmaceutical Development and Manufacturing-FDA Perspective," presentation at FDA Quality Initiative Workshop at ISPE meeting (Bethesda, MD, February 2007).
8. ICH Q8(R2) Pharmaceutical Development (ICH, Geneva, 2009).
9. L. Mestrandrea, presentation at the 4th Annual PDA Global Conference on Pharmaceutical Microbiology (Bethesda, MD, Oct. 2009).