By James Akers, James Agalloco, and Russell Madsen
For the past 12 to 18 months, I have been part of a PDA committee constructing responses to two versions of the proposed revision to Annex 1 for Manufacture of Sterile Medicinal Products. Throughout that effort I faced a personal struggle with having to deal with requirements based upon manufacturing technologies dating back over 40 years. My frustration reached a venting point with an article titled The State of Aseptic Processing: Let’s Get Serious.
Lest the reader presume that I am alone in my thinking or that I am an emerging pioneer in the application of advancing the state of aseptic processing, I offer the following paper. It is written by three friends who also happen to be among the world’s most respected authorities on the subject. They provide more detail than I have and make an even more compelling argument. It is really beyond the time when we should be paying attention to these guys. – Phil DeSantis
Slow-walking is a contemporary term that describes the purposeful delay of the approval of political appointees. It is also an apt description of the three-decade history of isolator technology in the pharmaceutical industry. Our industry has, with not insignificant regulatory assistance, obstructed the implementation of a technology that has proven safe and effective and was an enormous improvement over the conventional cleanrooms universally in place in the mid-1980s.1
Isolators are not the only technology that has had a long gestation period in our industry. Others that have been slow-walked include data management, automation, robotics, closed systems, speech recognition, and electronic record keeping/signature. The highly regulated pharmaceutical industry is understandably conservative, owing to a keen compliance focus. However, it can be argued that it is too slow to implement new technology. Industry fixates on what it has always done and ignores the considerable cost saving and process improvement opportunities created by the implementation of more modern technologies. In our experience, though, the isolator is the saddest case because it stood to help the medical product consumer, the manufacturer, and by extension, the regulatory agency(s) through improved product safety. The lessons from this experience must be well learned lest, as George Santayana warned, we repeat history because we ignore what it can teach us.
“Absolute Barriers” Eliminate Direct Human Intervention
We recall when the La Calhene company brought a table-top flexible wall “absolute barrier” to a PDA meeting in the mid-1980s. The title “absolute barrier” inadvertently triggered the first of several semantic arguments that infected the discussions about what to do with isolators from the regulatory, standard-setting, and validation perspectives in the years after their introduction. The La Calhene device, because it was “absolute,” could be seen as blurring the distinction between aseptic processing and terminal sterilization.2 The timing couldn't have been worse because underway at the time was a charged discussion about whether the use of aseptic processing for all products was (or should be) the producer’s choice. The suggestion that aseptic processing could attain a level of performance that made the distinction between it and terminal sterilization irrelevant was outlandish in the minds of many.
In retrospect, this was perhaps not as eccentric an idea as it seemed then, but it was too large a technological gap to be covered in a single stride. Coming as it did at a time when industry and regulators were embroiled in a controversy over aseptic and terminal processes, and with many finding it hard to consider parametric release even for products autoclaved in a well-validated process, the suggestion that any aseptic process might be equivalent to terminal sterilization was a non-starter. It took the isolator discussions on an unproductive tangent that resulted in futile efforts to prove the unprovable. The La Calhene system included an extremely clever rapid transfer port, or DPTE, which that company invented. The flexible barrier and the rapid transfer port had been successfully used for containment since the 1960s in France’s nuclear power industry. La Calhene coupled it with a HEPA-filtered air supply, allowing the enclosure to be operated at a positive internal air pressure relative to the room in which it was located. From this simple modification to a containment device, the pharmaceutical isolator was born. La Calhene initially focused on the sterility-test application, and by 1985 a report on the validation of isolators for that role was published by a French subsidiary of the Bristol-Myers Co. Experimental data on its contamination control capability was outstanding. By 1988 Sandoz Laboratories had installed flexible isolator enclosures over an ampoule filling line and also reported successful validation and exceptional contamination control.3 The La Calhene isolator eliminated personnel from the critical area entirely, and in that sense, it was an "absolute barrier" to the contribution of microbial and nonviable contamination by human operators. Although isolators, which rely on half-suits or glove/sleeve assemblies, had some ergonomic compromises in process interventions, it was apparent that automated equipment design could entirely eliminate direct human intervention. The isolator was potentially a near-perfect solution, coupling as it did separative enclosures with advanced technologies. The resulting environment was one where the differences between terminal sterilization and aseptic processing would become pragmatically irrelevant.
Benefits Of Isolators Get Lost In Industry Disagreements
The so-called “absolute barrier” arrived at a time when some in the industry had begun to focus on the sources of contamination in aseptic processing. This was potentially a massive step in risk reduction based on accurate risk assessment, and also a highly practical one adaptable to many applications. The fundamental risk assessment stressing the criticality of human contamination in safe, effective aseptic processing was facilitated by the existence of a validation discussion group comprised of about 10 aseptic manufacturing companies located along the East Coast of the United States (the authors of this article participated in these group discussions). It was obvious in reviewing process simulation results that the only important source of microbial contamination in aseptic processing was personnel. Quite simply, some combination of machine automation, fewer operators, and higher throughput speeds always resulted in lower media fill contamination rates. As should be expected, it also dramatically reduced the frequency of environmental monitoring recoveries.
Although some regulators maintained that humans were only one source, as opposed to the major source of contamination, those involved in validation of aseptic processing observed that new processing lines that operated with fewer personnel had far fewer media fill positives. In the late 1980s, in our validation discussion group, we were able to see in operation what was perhaps the most advanced conventional aseptic processing system installed at that time in the United States. This system provided automated product weight adjustment and could automatically load and unload lyophilizers without human intervention. It could fill at speeds up to 300 containers per minute. This system and others with similar attributes would operate with only one or two people in the cleanroom and could produce spectacularly low media fill contamination rates. Combining an isolator with highly automated aseptic processing lines had the potential to allow us to operate in what is effectively a microbe-free environment. In fact, by the mid-1990s, the aseptic beverage industry had effectively already reached that objective.4
What happened next saddens us to this day. By 1990, books on how to use isolators appeared, technical publications proliferated, competing suppliers emerged, and associations hosted symposia on isolator, or barrier, technology. The fundamental purpose of isolators, which was to largely eliminate contamination risk in aseptic processing, got lost in the warring factions either supporting or denigrating the technology. Fights over whether "laminar" airflow was required led to arguments about whether it was actually necessary in an isolator and, for that matter, if laminar flow even existed.5
Regulators’ Skepticism Further Discourages Adoption
For every person who suggested that because isolators had lower rates of contamination in media fill testing and environmental monitoring there should be less testing, others believed that the data meant just the opposite. Some regulators counterintuitively argued that it was necessary to look harder for “residual levels” of contamination they presumed to be present. There were questions about whether open isolators were isolators at all and whether a discharge “mouse hole” could be protected by air overspill. One well-known regulator even made the unsubstantiated claim that flying insects could enter the mouse hole, ignoring the fact that insects could and sometimes did walk into manned cleanrooms. Loud and occasionally angry debates took place on “sterilization” of the isolator or barrier system. (Yes, we argued about what to call these devices as well, with candidates including barrier, barrier isolator, isolator, locally controlled environment, and other names since forgotten.) There were long and fruitless arguments over whether an isolator could be used in lieu of terminal sterilization. This brought further disputes about system integrity and glove leaks and whether every bolt, nut, or clamp should be sterilized even if it was a meter or more distant from the nearest open product container.
Regulators, with the exception of those in continental Europe and Japan, took extremely conservative views on everything. Some complained that, unlike the robust 300 series stainless-steel equipment commonly used in pharmaceutical factories, isolators looked like “inflatable beach toys,” while others termed them “erector sets." Regulators wanted manned cleanroom design criteria applied, they wanted equivalent or even more monitoring and they wanted more significant, longer media fill tests. They wanted validation using 106 spore populations as used in autoclaves for sterilization, which created problems that are still with us today. These requirements lengthened validation timelines and discouraged potential users from moving to these new systems. Regulations are fixated on products and are only imposed on manufacturers. A model like that of the Federal Aviation Administration (FAA) might be more appropriate for the biopharmaceutical industry, where approval of new technology involves all affected parties: equipment designer, equipment owner, and, most importantly, the overseeing regulator.
Pharmaceutical manufacturers are complicit in much of this. Many firms avoid novelty as a matter of principle, strategically waiting until a practice or technology has attained "regulatory approval." Some organizations also have specific and, at times, outdated engineering or manufacturing principles to which they are devoted. Still others view manufacturing as an unfortunate necessity but one unworthy of investment and improvement. Older processes are kept in operation, because the approval process for technology and innovation is so incredibly slow. Innovation is actively avoided until regulatory approval; however, approval of technology is so tied to product approval that technical advancement is viewed with considerable suspicion.
Introduction Of RABS Leads To Further Confusion
The design and validation of isolators had the potential to be straightforward, and some regulators touted an expectation of some form of isolator or barrier in new facilities. These regulators appeared to tacitly agree that the isolator’s risk reduction advantages could reduce some validation requirements. However, the reality was that isolator validation, particularly of the decontamination processes, proved tedious and subject to lengthy delays. This led to equipment suppliers and drug and biological manufacturers trying to find what they hoped were alternatives that were easier to implement than isolators. These designs, which were said to require "high level disinfection" rather than decontamination, came to be known as restricted access barrier systems (RABS). The emergence of RABS led to additional arguments and even more confusion. We soon had “open” RABS, which one prominent regulator labeled “bad RABS,” and “closed” RABS, which was characterized by one firm as "an isolator with no pants.” RABS came with new jargon such as "passive" and "active" designs and real confusion over what "restricted access" meant when opening the enclosure during the aseptic process was allowed.
What the industry was trying to accomplish with RABS variations was the avoidance of vapor phase hydrogen peroxide (VPHP) "decontamination" technology. The desire to avoid VPHP arose not because it was ineffective but rather because of the standardized 1-million spore biological indicator challenges imported from autoclave validation. The validation issue associated with VPHP was unrelated to the lethality of hydrogen peroxide as a sporicide. This stubborn adherence to misunderstood and misapplied sterilization dogma could have been easily avoided. However, narrow-mindedness in this important activity remains to this day. It may seem incredible that there exists in our industry a poor understanding of what sterilization is and what sterile means. This leads to fruitless discussions and unintended consequences and, at their worst, the inability to supply the safest possible treatments to patients.
It is difficult for anyone outside the pharma/biopharma world to look at these responses to the introduction of new aseptic technology as a good thing. Consider another breakthrough technology introduced at roughly the same time as the isolator, the mobile or “cell” telephone. In 1983, Motorola Introduced the hand-held DynaTec, commonly used as a "bag phone" and requiring a car-mounted antenna. By 1989 the MicroTec was introduced and we had a handheld but not pocketable telephone. In 1993, the "flip" phone hit the market, and almost every city larger than 100,000 in population soon had a cell phone network. In 2007, Apple introduced the smartphone, and landlines have since become virtually obsolete. The payphone has been almost extinct for more than a decade and today, no one can live without a mobile phone. In about 20 years, mobile communication technology went from an expensive novelty to an indispensable part of our lives. And as the capabilities of the mobile phone have increased, serviceable smartphones can be had at prices, after correcting for inflation, of less than 1/10th of those of the original bag phones.
The isolator has been around nearly twice as long and is a technology that has as many technical advantages in its domain as the mobile phone has in its realm. However, in 2020, we are still arguing about the path forward for aseptic processing operations and continuing to operate systems that have advanced very little since the 1980s and, in some cases, even earlier.
The hoped for and very nececessary aseptic processing revolution still hasn’t occurred in our industry. Interestingly, though, it did occur in another aseptic industry and its takeover was as complete as the mobile phone’s domination of personal communication. While the pharma/biopharma industry was busy fighting over a near-endless number of sidebar issues, the aseptic food and beverage industry rapidly embraced the isolator or, as they term it, the “aseptic chamber." Since the early 2000s, human-scale cleanroom aseptic processing in those industries has been obsolete. The aseptic food industry has no RABS, open or closed, and gloves, while present, aren't used much because of the degree of automation they have implemented. Throughputs as high as 1,000 units per minute are not uncommon and, yes, they use hydrogen peroxide as a sterilant. So, while we were arguing about it, they, to borrow a marketing phrase, just did it.6
An Urgent Need To Reassess Our Relationship With Technological Progress
Since our industry has fallen behind, we need to make up lost ground to the current technological leaders in aseptic processing. While catching up, we need to figure out how we can efficiently move other evolving or revolutionary new technologies to regulatory approval. There is plenty of opportunity for new concepts to move forward, more smoothly benefitting from greater standard-setting and regulatory transparency. We need to put our customers, who are primarily patients, first and worry less about our parochial self-interest. We need less concentration on maintaining the regulatory status quo and defending our turf. Even more importantly, we need to align our regulatory and compliance requirements with science and periodically review our guidance and industrial standards documents to ensure they reflect the best understanding of advancing technology.
Our standards and our regulations should promote applied technological advances and foster good science and engineering in validation, in-process testing, and quality assessment. Regulators’ time would be better spent advancing capabilities within industry rather than seeking new things to regulate. We shouldn't have to spend time and money toward attempts to monitor or test for things that are known to be unimportant to our principal missions of providing customer value and safety. Instead, we need to diagnose problems transparently, communicate about their actual causes, and propose reasonable scientific approaches to resolve them. We need to understand what we can reliably measure and what we cannot. And we need to understand that engineering innovation is the only path to improved sterility assurance, not unreliable microbiological assays that try to measure low-level contamination or assess sterilization in ways that lack statistical relevance and analytical reliability. We shouldn’t try to regulate attributes we can't adequately define or measure.7
It is not possible to avoid the conclusion that collectively we failed badly in moving to advanced aseptic technologies. This can’t be denied given the abundant evidence that other industries have succeeded. We failed not because we lacked the engineering or scientific skill but because we prioritized the wrong things. Maintaining a consistent regulatory arc in aseptic processing was considered more critical than advancing patient safety. Our regulatory and standard-setting bodies didn't just obstruct progress, they effectively sabotaged patient safety, which, ironically, is their mission.
Indeed, we've failed in the implementation of other advanced technologies as well, but we can and must learn from our errors. It's up to each of us to make sure that we do. So, if something you are being required to do seems scientifically unreasonable or indefensible, speak up — if you don't, it’s the patients who suffer. Implementing the wrong risk analysis tools or a fad in quality control that was avant-garde 25 years ago hasn't cut it. Stubborn, hard-headed adherence to the status quo has failed and suggesting solutions for scientific or engineering reasons that don't or can't work is a losing strategy. We can and must do better.
A colleague who worked for one of the pioneer suppliers described the isolator wars of the early ‘90s in what we might today call the "design space" like this: "We are spending our time trying to pick fly feces out of pepper, rather than making lives better." Ironically, this failure to comprehend design space happened contemporaneously with the publication of Dr. Juran’s concepts on quality by design (QbD).8
Today, many quality managers pepper their speech with the phrase "design space" in part because the ICH belatedly embraced QbD.9 We wonder if our industry and those who regulate it understand QbD, measures of process capability, or statistical process control. They don't appear to understand that most modern process control concepts were included in validation approaches this industry began implementing 40 years ago. Did they not notice the similarity between the life cycle elements of validation and the concepts of continuous quality improvement and QbD? Did they not notice that efforts to statistically evaluate process capability were valid forms of risk evaluation and mitigation? Somehow, they missed that some of the risk analysis tools used in chemical processing were not relevant to the control of biological contaminants. They even seemed to miss that sterilization validation itself is risk analysis followed by risk mitigation.10,11 Regulators embracing a concept makes the implementation of that concept “compliant,” but misapplying the concept compromises the entire activity or, even worse, renders it pointless. In our view, by following the principles of process validation outlined in the early ‘80s, we'd do a much better job of implementing modern technology than we have. We shouldn't confuse new regulation with better regulation. And even more importantly, we have to resist regulatory expectations derived only from podium presentations or trendy publications. We must remain faithful to the underlying scientific principles and not conjecture, hypothesis, or mistaken belief.
Of course, we should consider new concepts in process control, but we must compare them with what is already in place so we don’t end up with a crazy quilt of competing or parallel activities serving the same purpose. Heavily overlapping activities, which always thwart technical advancements, don’t add robustness or reliability. Slowing or obstructing technological advancement is a principal cause of stagnant quality improvement. We must do what we have always done in validation: challenge each process step and understand its relevance to actual quality outcomes, rather than merely assume that anything anyone in authority says must be mission critical. Until we learn to trust subject matter experts and the scientific method, we are doomed to the frustration of trying to be "compliant" to ideas scientifically unworthy of our attention. In an environment in which our industry lags the technology curve, regulation and standardization have failed us. That's why advanced aseptic technology has been slow-walked and why we urgently need to reassess our relationship with technological progress.
This article will appear in the forthcoming Proceedings of the Council for Pharmaceutical Excellence, Volume II. For more information on the council and to view Volume 1, visit http://www.thewilliamsburggroup.com/proceedings.html.
- Wagner, C.M. 1995. Current Challenges to Isolation Technology, in Isolator Technology- Applications in the Pharmaceutical and Biotechnology Industries, edited by Carmen M. Wagner and James E. Akers, Interpharm Press, USA.
- Meyer, D and Gonzalez J.P. 1990. Advanced aseptic processing: Barrier system technology as applied to production (aseptic) filling lines. PDA/PMA Conference on Sterilization in the 1990’s. Washington, DC.
- Isolators for Pharmaceutical Applications. 1994. edited by Gerard Lee and Brian Midcalf, HMSO.
- Hersom, A.C. 2009. Aseptic processing and packaging of food. Food Reviews International, 1:2 215-270.
- Akers, J.E. 2005. Isolator Technology: Regulatory Issues and Performance Expectations, in Isolator Technology- Applications in the Pharmaceutical and Biotechnology Industries, edited by Carmen M. Wagner and James E. Akers, Interpharm Press, USA.
- Akers, J.E and Izumi, Y. 2010. Technological advancements in aseptic processing and the elimination of contamination risk. In Advanced Aseptic Processing Technology edited by James Agalloco and James Akers, Informa Healthcare New York/London.
- J.P. Agalloco, James E. Akers, and Russell E. Madsen Jr. 2020. Aseptic Practices: Reviewing Three Decades of Change. Biopharm Intl. Vol. 33, Issue 8, pp 27-31.
- Juran, J.M. 1986. The quality trilology: a universal approach to managing for quality. Quality Progress.
- International Congress on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use. ICH Guidenline Q8. Pharmaceutical Development 2008.
- Agalloco, J. & Akers, J., “The Myth Called Sterility”, Pharmaceutical Technology, Vol. 34, No. 3, Supplement, pp. S44-45, 2010. Continued online at Pharmtech.com
- Akers, J., & Agalloco, J., “A More Rational Approach to Sterile Product Manufacturing”, Pharmaceutical Technology, Volume 36, Issue 5, pp. s48-50, 2012.
About The Authors:
Jim Akers, Ph.D., is owner and principal consultant of Akers Kennedy and Assoc. He has 39 years of experience in the pharmaceutical/biopharmaceutical industry and has held various management positions in quality, development, validation, and analytics. Akers is past president of PDA and spend 15 years on its Board of Directors. He has served the USP in several capacities since 1993, including chair of the Microbiology Expert Committee, where he continues to serve as a member. Akers has also served as a technical advisor to Shibuya Corporation since 1991. He has published 36 book chapters, edited two books on Isolator technology, published over 100 articles, and lectured widely on aseptic processing, analytical microbiology, sterilization, cell processing, and advanced aseptic processing.
James Agalloco, president of Agalloco & Associates (A&A), is a pharmaceutical manufacturing expert with more than 45 years of experience. He worked in organic synthesis, pharmaceutical formulation, pharmaceutical production, project/process engineering, and validation during his career at Merck, Pfizer, and Bristol-Myers Squibb. Since the formation of A&A in 1991, Agalloco has assisted more than 200 firms with validation, sterilization, aseptic processing, and compliance. He has edited/co-edited four texts, authored/coauthored 40+ chapters, published more than 150 papers, and lectured extensively on numerous subjects. He is a past president of PDA and a current member of USP’s Microbiology Expert Committee, and serves on the Editorial Advisory Boards of Pharmaceutical Technology and Pharmaceutical Manufacturing.
Russell E. Madsen is president of The Williamsburg Group, LLC, a consulting firm located in Gaithersburg, MD. Prior to forming The Williamsburg Group, he had served PDA as acting president and was senior VP of science and technology. Before joining PDA, he was employed by Bristol-Myers Squibb as director of technical services, providing technical and general consulting services to Bristol-Myers Squibb operations worldwide. He is vice chairman of ASTM Committee E55 on Manufacture of Pharmaceutical and Biopharmaceutical Products, a member of the USP Microbiology Expert Committee, a member of Pharmaceutical Technology’s Editorial Advisory Board, and an honorary member of PDA. He holds a BS degree from St. Lawrence University and a MS degree from Rensselaer Polytechnic Institute.