Barrier isolation technology has progressed to a point with reliability, convenience, and operational cost savings that many life science companies are now using it to replace their standard cleanroom operations. This not only includes aseptic filling but sterility testing, small-scale cell culture operations, and even some medical device assembly.
In this Q&A, Patrick Poisson, EVP of technical operations at United Therapeutics, discusses how to choose between a barrier isolator and a restricted access barrier system (RAB), whether to retrofit or install a turnkey solution, the role of occupational exposure limits (OELs) in specification/selection, the pros and cons of new gloveless robotic isolators, and more.
There continues to be a lot of debate around the use of barrier isolators versus restricted access barrier systems (RABs). What is your view?
Barrier isolation and closed RABs are both great approaches for aseptic processing, clearly offering advantages over conventional open lines and open RABs. My belief is that if you are building a greenfield facility, the best selection is barrier isolation technology. Barrier isolation is superior on the sterility risk spectrum, automates the decontamination process, offers lower operational costs, and improves operator comfort by eliminating ISO 5 gowning.
It has been countered that barrier isolation requires greater capital investment and reduces manufacturing capacity due to longer batch turnaround times. However, I think that we are seeing downward pressure on the capital costs associated with isolators due to competition and design efficiencies. Recent advances in hydrogen peroxide aeration have also improved batch turnaround times, and I believe progress in that area will continue.
Overall, the benefits of current isolator technology outweigh the issues and limitations. Renovation of an existing facility introduces additional factors, and in some cases cost and complexity will drive a firm to select a closed RAB system over barrier isolation.
Should manufacturers retrofit their existing systems or install turnkey solutions?
Retrofitting is conceptually attractive and often worth examining as part of the capital budget request process. However, the expense and complexity of retrofitting an existing line often pushes firms to a turnkey solution / complete replacement. Some critical considerations for retrofitting are rigging and installation path, software integration with other pieces of equipment, HVAC integration, operator ergonomics, impact on other operations during installation, and the long-term operational sacrifices (e.g., room size not nominal, less than ideal maintenance access, etc.). On a larger scale, with likely changes in room classifications, firms will also need to examine the operational impact on people and material flows, especially for multiline facilities. Retrofits will always be challenging, but not impossible, and in some exceptional cases are the right decision.
How do occupational exposure limits (OELs) play into the specification/selection of isolation technology?
Many of today’s new drug products are either potent compounds or cytotoxic with very low OELs, which in turn require special handling and equipment. Barrier isolators can be used to not only protect the drug product from contamination but to protect the operator from harm by unintended exposure to dangerous chemicals. Containment isolators are specifically designed for such purposes and differ from the standard aseptic processing isolator by either operating at a negative pressure with small openings for incoming/outgoing containers, or at a positive pressure but completely closed. The design choice of the containment isolator is often driven by batch size and throughput requirements, with closed isolators limited to small batches where all materials can be loaded into the interior of the isolator prior to processing and decontamination. Waste handling and post-use cleaning procedures are also considerations for the design of any containment isolator.
What are the primary considerations when choosing between hardwall and softwall isolation?
The choice between a hardwall and softwall design is primarily influenced by cost and intended use. Softwall isolators, due to their materials of construction, are much less expensive than their hardwall counterparts and usually have shorter lead times for delivery. The most common use for softwall isolators has been for sterility testing applications and benchtop and clinical-scale aseptic processing. Some of these isolators are small and light enough to be put on casters, which allow them to be easily moved around a facility. Softwalls are more susceptible to puncture; therefore pre-use leak rate testing is important to their successful operation. Softwall isolators have a lower life span than hardwall isolators, so hardwall designs are a better choice for high-use commercial-scale operations.
When and how frequently should integrity testing of gloves take place?
Both the FDA Aseptic Processing Guidance and EU Annex 1 state that gloves should be routinely / frequently tested for integrity. This gives the user some freedom to determine what is optimal for their facility. Considerations for test frequency involve factors such as frequency of use, type/robustness of glove material, sensitivity of the test method, and glove replacement intervals. The test frequency chosen, if it is not on a per-batch basis, should be supported by a documented risk analysis. Advancements in glove design and materials have greatly reduced the risk of hard-to- detect pinhole leaks. In my experience most integrity issues occur where the sleeve connects to the isolator wall, as this is the area where the gloves undergo the most stress during use.
What are the pros and cons of new gloveless robotic isolators?
The integration of robotics with barrier isolation was an inevitable advancement. Robotic arms are now capable of very precise 360° movements, are equipped with force feedback, and operate nearly particulate free. The most significant benefit of these new systems is elimination of the glove, which clearly carries the highest risk of breach and potential impact on sterility assurance on any isolator. Additional benefits include improved reliability and performance through automation, and enhanced operator safety and comfort. I would say that the biggest drawback is that you do loose some flexibility, especially with exception handling during processing. Robotics also add an additional layer of sophistication to an already complex system, so there are also aspects to consider with programming and maintenance. In summary, these types of systems have some benefits but are best suited for well-understood processes that have been fully mapped by the user.
What will the future hold for barrier isolation in the industry?
The future is fairly clear — barrier isolation is now on its way to becoming the predominant technology for aseptic processing, testing, and handling. Closed RABs will also have a future role, especially with manufacture of products that may be sensitive to hydrogen peroxide residuals. The traditional commercial cleanroom will soon be a relic of the past, as regulatory pressure has increased to a point where there are few companies still doing true open (non-RAB) processing. Industry demand will increase the number of isolator manufacturers, and competition will continue to drive improvements.
In addition to looking ahead, it’s also interesting to go back and look at some of the original articles from the early 90s discussing barrier isolation. Although many predicted a much quicker transition to the technology than actually happened, the original vision of BUGS (Barrier Users Group Symposium) and LUMS (Lilly, Upjohn and Merck) is now becoming reality some 25 years later. As with any new technology, we have to credit these innovators who years ago had the perseverance to take the risks, suffer the failures, and work with the regulators to set the stage for the future.
Are there any good resources for more information on barrier isolators?
There have been a lot of good articles published in the PDA Journal of Pharmaceutical Science and Technology and ISPE’s Pharmaceutical Engineering over the years, with topics ranging from hydrogen peroxide decontamination to the impact of pinhole leaks in gloves. These articles can be found and purchased at each of those organization’s websites. ISPE will soon be releasing a revision to their Sterile Product Manufacturing Facilities Baseline Guide, which I was fortunate to participate in as an author. This guide contains a full chapter on barrier isolation, which has a lot of great information for both current and future users of the technology.