Gloveless Isolators Offer Speedy Throughput

If you thought this was going to be yet another commentary on the impact of humans on contamination and the elimination of direct interventions, you are going to be surprised. Automated, gloveless aseptic technologies are a logical progression as our field moves into the 21^st century. These technologies promise to increase throughput, ultimately, expanding availability of product.

I first interacted with gloveless aseptic processing isolators over two decades ago. At that time, the reason for their “glovelessness” had more to do with operator safety than contamination management. In the installations I have seen over the years since, safety continues to play a key role. More recently, isolators that do not rely on human manipulations have been shown to have advantages in terms of process outcomes as well.

The True Meaning of “Gloveless”

In some respects, the focus on the glovelessness of isolators is misleading, though perhaps useful in terms of marketing. Consider for a moment what the term “gloveless” implies. How could one have no gloves in an isolator unless the isolator enclosed a fully automated aseptic processing or assembly system? The answer is as clear as it is obvious—the existence of an isolator, or any other processing system that does not require intervention during operation depends completely and absolutely on the ability of a process to run completely without human intervention. The “gloveless” part of the isolator is not what is important. What is important is the absence of intervention or, rather, absence of the need for intervention.

The first isolators I encountered that did not need gloves in operation were used to produce aseptically manufactured bottles at very high throughput rates. Many such systems have been available since the 1990s. When you have a system filling 200 mL to 1 L bottles at line speeds between 300 and 1000+ units per minute, it is unsafe for an operator to manually intervene. The weight and speed of the containers requires positive control at all times and precludes the use of bottomdrive conveying systems, resulting in a system with very high rotational mass and speed. Some may have gloves installed for emergency access or cleaning, but these gloves are not accessible during operation and are often physically blocked. This restriction on intervention is possible because the sterile parts and components are fed automatically, and all product contact systems are sterilized in place. This process removes the need for aseptic assembly or component replenishment.

Another word that often shows up when discussing gloveless isolators is robot. “Robot” is an interesting word that conjures up a number of images, but robotics represents only one form of automation, and, while they may be useful in some applications, they are by no means mandatory to eliminate interventions. Machine automation works equally well; many automated processes combine machine automation and robotics, but some, including the ultrahigh throughput systems (in both liquid volume and fill speed) just mentioned, do not rely on robotics at all.

So, the term gloveless is, at best, misleading and, at worst, a misnomer. Removing gloves from an isolator wall requires no significant engineering skill—it is easy. The challenge is operating an aseptic processing activity without human intervention. The more high throughput and complex a systemi is, the more challenging the engineering. If the system is to be trouble-free, automation must be executed well, or the system will require frequent shutdowns, and each of these will have a severe impact on productivity. Gloveless boxes are really not the point then.

Automation is where the rubber meets the proverbial road. Gloveless isolators are an effect of outstanding automated process engineering—not the cause. Manufacturing requirements and the existence of reliable automation have made it feasible to eliminate interventions. Taking a glove off an isolator without reliable full automation is like taking the training wheels of a child’s bicycle before the child gains the ability to ride unassisted.

Machine automation began appearing in aseptic operations in the 1980s and, as control systems and information technology evolved, the sophistication and capability of such systems increased dramatically. In 2004, the first robots that could be decontaminated in situ were installed and validated on an isolatortechnology aseptic processing line. The ability of robots or machine automation to accomplish component and material transfer of sometimes heavy objects with reliability and precision has led to fewer requirements for gloves and easier ways to avoid the ergonomic constraints imposed by using gloves.

Thus, elimination of gloves was a happy consequence of increasingly sophisticated process automation. We have since seen automation used with great success in positive emission tomography product manufacturing, cytotoxic drug manufacturing or manufacturing where exposure to biohazardous materials is a concern. These systems can operate without intervention in a conventional cleanroom, but it makes engineering and economic sense to have the smallest possible environmental footprint. This saves build and running costs, simplifies facility build out and increases flexibility of use. Therefore, if a sufficiently reliable and reproducible automated process can be engineered, built and operated, an isolator remains the most logical environment in which to place it. And this isolator should not need rely on human intervention.

Innovative Tech for Novel Drugs

The most exciting use of highly automated, interventionless (or gloveless, if you prefer) isolators is likely to come in the production of regenerative medicine products. In March 2019, at the Japanese Society for Regenerative Medicine Conference in Kobe, Japan, Dr. Masahiro Kinooka of Osaka University’s Department of Biotechnology in the Graduate School of Engineering described his colleague’s work on the use of automation in the production of cell sheets.

Dr. Kino-oka presented data demonstrating how automation in both materials transport and fluid delivery allowed fine-tuning of processes, which resulted in more consistent process outcomes. Using computational process design, it was possible to reduce loss, improve throughput consistency and reduce overall manufacturing costs. In other words, precision automation can produce better, safer results than relying on humans for cell processing and formation of cell sheets. Automation of routine cell passage and cell sheet formation offers real practical advantages over manual operations. As engineers and scientists work to ensure not only outstanding sterility assurance and product safety, but also reliability of product outcome in commercial scale production, automation will prove essential.

Future of EM Less Certain

But what about sterility assurance, a major topic of concern for PDA Letter readers? No discussion of automated, interventionless isolators is complete without a brief consideration of microbiological safety. Isolators, when introduced to industry, had two very specific features that improved their ability to reduce the likelihood of microbiological contamination. First, they did not allow the operator to directly enter the classified aseptic clean space. The importance of this fact cannot be overstated. Although some industry specialists and regulators hastened to assert that isolators could not be as safe as terminal sterilization of products, they failed to realize that at their best, gloved isolators were so well controlled that they dramatically reduced the gap between terminal sterilization and aseptic processing.

In fact, after nearly three decades of isolator experience, we now understand that they are so good at contamination control they operate well below the limit of detection of our analytical methods. Yes, a rare “environmental hit” may be observed, but the likelihood is so low that many times we find an error in the chain of custody or exposure of the sample led to the “hit” in question, rather than contamination in the isolator. The one remaining safety hazard in the early days of isolators was the glove, as neoprene gloves were prone to loss of integrity and often degraded by widely used vaporized hydrogen peroxide decontamination systems.

The move to chlorosulfonated polyethylene gloves, which are far more resistant to punctures, tears or chemicals, dramatically reduced the opportunity for contamination introduction through glove use as has better machine automation and improved ergonomics. Still, the complete elimination of any human intervention has effectively eliminated the last known source of contamination. For the first time in aseptic processing history, the mobile contamination generator that is the human worker has been eliminated completely as a source of contamination. One need not be much of a futurist to accept the inevitability of the elimination of personnel from aseptic processing.

Of course, eliminating the human element requires a complete rethinking of how we conduct in-process control. The much relied upon method of environmental monitoring becomes far less important as contamination sources are eliminated. Traditional methods are of value only in the interim as our compliance requirements adjust to a different reality. We need to understand that once we are below the reliable limit of detection, additional sampling accomplishes nothing. In the case of highly automated, gloveless isolators, we are already there.

In summary, we should think of the fully automated isolator as simply a logical step in the evolution of aseptic processing technology. We have been on a pathway leading to fully automated aseptic processing for decades and we have arrived at a place in history where it is not just about contamination control (important though that may be) it is about better manufacturing outcomes and improving the reliability of sensitive manufacturing processes. It is also about being able to produce lowercost product at extremely high outputs, the ability to execute the safe, ergonomically uncompromised movement of heavy, difficult-to-handle objects, and also keeping work environments safer. It is also about creating a microbiological safety level that can be analytically distinguished from terminal sterilization.

The next chapter in this exciting story will be the necessary evolution of current standards and regulatory expectations built over many decades of cleanroom operations with extensive human involvement to fit the automated, intervention-free future. The days of subjective evaluation of “aseptic technique” are drawing to a close. In the future, our environments really will be germ-free and, therefore, risk-free. In fact, some early adopters are already there.

(The author wishes to acknowledge Dr. Masahiro Kino-oka of Osaka University and Shibuya Corporation, Kanazawa, Japan, for the photograph and for information used in preparation of this article.)