No Man’s Land

Mobile vapor-phase hydrogen peroxide biodecontamination systems like this one from Steris offer the flexibility users need to support this critical task within aseptic processing environments. (photo courtesy of Steris)

It’s pretty hard to understate the multiple layers of risk that need to be managed to successfully and compliantly accomplish aseptic drug processing. Drug safety and regulatory imperatives dictate drug makers create intensive, pervasive and verifiable systems to assure sterility in aseptic processing environments.

According to the Food and Drug Administration’s (FDA) 2004 “Guidance for Industry Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice,” in aseptic process: “the drug product, container and closure are first subjected to sterilization methods separately, as appropriate, and then brought together.”

Because there is no process to sterilize the product in its final container, says the FDA, it is critical that containers be filled and sealed in an extremely “high-quality” environment. The FDA guidance generally recommends that before final assembly the individual parts of the final product should be subjected to various sterilization processes. For example, says the FDA guidance, glass containers might be subjected to dry heat; rubber closures subjected to moist heat and liquid dosage forms subjected to filtration. As most are aware, each of these processes requires validation and control. To think that legitimate sterile drug manufacturers would ignore the risks to public health and its bottom line and willfully manufacture nonsterile product is a stretch, but the path to perdition is often paved with good intentions. Poorly instituted cGMP conditions can, says the FDA, “ultimately pose a life-threatening health risk to a patient.” 

Isolators and highly integrated process technologies within, including advanced robotics and automation, are dramatically reducing the risk of contamination in aseptic processing operations.

U.S. regulators note for each process there is the potential to introduce errors that ultimately lead to product contamination. “Any manual or mechanical manipulation of the sterilized drug, components, containers or closures prior to or during aseptic assembly poses the risk of contamination and thus necessitates careful control.”

Aseptic processes should be designed to intrinsically minimize exposure to potential contamination hazards that come from (relatively) routine manufacturing operations. To achieve a high assurance of sterility, regulators recommend drug makers take some pretty logical steps like optimize process flow, limit the duration of exposure of sterile product elements, provide the highest possible environmental control, and configuring equipment to prevent the entrainment of low-quality air into the Class 100 (ISO 5) area.

Further, to prevent unnecessary activities that increase the potential for introducing contaminants, FDA guidance notes personnel and material flow, the layout of equipment and incumbent operator ergonomics should all be optimized to limit the number and duration of personnel present in an aseptic processing environment. Essentially, best practice calls for limiting the frequency of entries and exits made into and out of aseptic processing rooms and their critical areas, including isolators.

To be clear, drug manufacturers now understand that any intervention, delay or stoppage during aseptic processing greatly increases contamination risk. The design of equipment used in aseptic processing, says FDA, should limit the number and complexity of aseptic interventions by operators. “For example, personnel intervention can be reduced by integrating an on-line weight check device, thus eliminating a repeated manual activity within the critical area. Rather than performing an aseptic connection, sterilizing the preassembled connection using sterilize-in-place (SIP) technology also can eliminate a significant aseptic manipulation. Automation of other process steps, including the use of technologies such as robotics, can further reduce risk to the product.”

Preceding the section outlining the above in its guidance, the FDA offered a caveat noting that the design concepts discussed were not intended to be exhaustive (read prescriptive). They did, however, declare “appropriate technologies that achieve increased sterility assurance are also encouraged.” Encouragement is one thing, but at the time, their vision of GMP-refined aseptic manufacturing — where human interventions become the exception rather than the rule — was a reality challenged by many factors, driven by both internal and external forces buffeting the industry.

Few have observed more closely the trends driving the uptake of advanced aseptic processing technologies than Sterling Kline, vice president of design at IPS, a processing systems integrator that’s been at the forefront of aseptic process design for decades. “The trend over the past 10 years has been very dramatic,” says Kline, “and it has been driven by the regulatory agencies.” He explains that historically the technology was not quite ready commercially to enforce regulation standards: “In the past decade, the technologies have finally caught up with where regulators want to be in the industry.” 

From a regulatory standpoint, says Kline, there are two prime factors driving the industry currently. “One is separation. As in separating the operators who are the prime source of contamination from the product and separating potent compounds from the operators.” Kline notes that this separation is much more accessible nowadays because of continuing development of barrier systems that have proven, he says, to work very well. The most prominent being restricted access barrier systems (RABs) and isolators, the more formidable (to contaminants) and favored by regulators.  

Josh Russell, product manager for the Life Sciences business segment of AST, another of the industry’s most trusted and experienced aseptic systems integrators, echoes Kline’s assessment. “To a certain extent, there has been somewhat of a longstanding understanding that the agency has extended regulatory relief to the industry in regards to integrating isolators with their aseptic processes,” notes Russell, citing that specifically, this relief is characterized by the amount of media fills that drug makers can do on an annual basis.

Regardless, both Kline and Russell agree that both RABs and isolators have become very prominent over the past decade. “Historically,” says Kline, “there were about 2,000 aseptic facilities of traditional design that did not have the barriers. Over the past decade, it’s gotten to the point where it’s down to about a thousand of the old, traditional facilities, with isolators and RABS making up the remainder.” The acceptance of these straightforward technologies is now pretty much a foregone conclusion. According to Kline it’s becoming more and more prominent with, most if not all, new facilities implementing isolators or RABS. “The older technologies are not being produced even in third-world countries at this point and developing nations,” observes Kline. “India has lagged and is a bit behind, but has now picked up on the technology dramatically.” The majority of the facilities are isolator and RABS controlled space, he says, noting that there are more RABS in India, but in the U.S. isolators are now beginning to really take off.

Russell and Kline agree that developed, proven technologies are finally available and now more economically accessible by the world’s drug processors. “It’s similar to computers or cell phones,” says Kline. “As the volume goes up, the price becomes more affordable and the technology has become dramatically better.” Noting that cycle times for vapor-phase hydrogen peroxide (VHP) systems have dropped off, typically down below two hours and that, Kline explains, puts the turnaround time for an isolator at par with RAB systems.

From an economic standpoint, says Kline, in most of the Western nations the capital cost for isolators is absolutely cheaper than RABS. The difference is slight, he notes, because head to head, isolators cost more than RAB containment. “But the RABS facility costs substantially more than an isolator facility,” he says, “even where you have very inexpensive construction, such as India.”

In particular, Russell says, offering his take on isolator economies, “isolators can be integrated into a grade D or class 100,000 cleanrooms. That’s substantial savings that a pharma manufacturer that uses isolator-based technology can really employ.” There have been several great studies done, notes Russell, “where it’s actually shown that end-users can save upwards of a million dollars per year between the cleanroom cost, turnaround costs, personnel utilization and equipment downtime; the list goes on and on.” From an operating cost standpoint, both Kline and Russell assert isolators are absolutely less expensive to operate and have lower lifecycle costs, no matter where you are in the world.

Isolator Advancements

Russell characterizes isolators as the “Cadillac” when it comes to protecting the product from contamination. The game changer, he says, is the isolator’s ability to be bio-decontaminated using VHP. “That repeatability, being able to decontaminate the line quickly and consistently, offers end-users a great advantage over traditional aseptic process lines with RABS integrated onto them.”

Both Kline and Russell say they rely on isolator solution builder SKAN, to create the VHP-enabled isolator systems they need to satisfy their customers’ decontamination requirements. “SKAN,” says Russell, “has really developed the technology and its practical implementation. For example, SKAN is able to guarantee a six log bio-burden reduction within two to three hours. That is a huge improvement (in terms of isolator decontamination technologies) from even five years ago, where oftentimes it took anywhere between eight to sixteen hours for isolators of similar size and shape.” [sidebar id=4] 

Vapor-phase hydrogen peroxide decontamination has become extremely popular because it’s been recognized for its efficacy, compatibility and flexibility, as well as its utility. Arthur B. Papineau, VHP solutions manager for STERIS Corp., finds that regulatory trends, as well as global health crises are responsible as well. “I think that there is a lot more focus right now on infection prevention in general given the FDA’s current investigations into the Pharmaceutical Compounding market and USP 797 as well as with the heightened awareness caused by the Ebola outbreak with the potential of other outbreaks,” explains Papineau.

STERIS first introduced VHP to the market in 1991 and since then, the technology’s effectiveness, Papineau explains, has helped it expand into other markets: “We actually see a push for the technology into aseptic-type food and beverage packaging, particularly for dairy products and especially most things in foil or pouches not requiring refrigeration.” To Pharma, it seems, the technology has been heaven-sent. According to Papineau, “VHP has been embraced by the aseptic processing community due largely in part to its ease/robustness in validation and re-validation; high level of effectiveness against organisms; wide range of material compatibility; ambient condition process; and a process that is safe for both the environment and user.

The other area of great interest, he says, is in the application of VHP for the terminal sterilization of prepackaged medical devices, especially pre-filled syringes. Terminal sterilization has never been practical for most pharmaceuticals for obvious reasons. “This solution,” says Papineau, “offers users a tremendous amount of design flexibility for their facility, manufacturing processes and validation protocol. It is only achievable because of the low temperature and material compatibility of the VHP process.”

AST’s Russell offers this bit of color commenting on how biotechnology products are really starting to flourish and fill today’s drug pipeline — and that is fueling demand for advanced VHP capabilities. “Biotechnology drugs really have a lot of unique properties that have to be safeguarded against as you manufacture them. Most of these biologics are proteins and monoclonal antibodies, which are sensitive to vapor phase hydrogen peroxide.” Russell explains some manufacturers need to safeguard the products against the oxidizing aftereffects of VHP. He says isolator vendors are now coming up with rapid VHP technologies using catalytic converters and other methodologies that introduce VHP into the chamber to quickly decontaminate the chamber, but also as quickly aerate and diminish residual VHP levels down to 30 parts per billion or less.

“In the past three to four years,” Kline says, “the greatest advance in isolator technology [has been] the introduction of catalytic converters,” a technology initiated by SKAN he says. “Now all of the companies are using it,” says Kline. The issue with the vapor hydrogen peroxide sanitization comes with the aeration cycle, which can take a long period of time to cycle the exhaust operation completely. Kline explains that during the exhaust cycle operators are trying to get the VHP out of the machine and exhaust it out, but that can cause the pressure differential in the room to go negative, which, like the longer cycle time is not desirable. Catalytic converters speed up cycle time.” For biologic products, the catalytic converter is a tremendous improvement to aseptic operations, says Kline.

Are there any other isolator technologies worth mentioning? Kline points to isolators now being engineered for clinical scale operations: “There now is a modular isolator, SKAN has one and other companies are now introducing them as well. That drops the price, so if you can reproduce a module, it drives the cost down and makes it much more affordable.”

Processing Flexibility

Faster decontamination cycles from advanced VHP offer drug makers a number of operational economies, but Russell maintains just as important is the flexibility companies need from their aseptic processing lines to address a variety of high-value, low-volume drugs — as Russell put it, “personalized in nature.” However, that is not to say that drug companies processing parenterals and other common compounds in commercial volumes aren’t clamoring for the flexibility advanced aseptic processing technologies can deliver. “These lines need to be highly flexible, able to adapt to both current manufacturing needs and regulatory demands, as well as be able to forecast and address future manufacturing and new regulatory challenges that they may be faced with. Especially with fill line purchases — often multi-million-dollar system integrations — it’s key that these systems are able to address the long-term needs of the organization.”

Kline mentions isolator modularity as a path to aseptic process line flexibility and cost efficiency — a well-understood technical response to the often “bespoke” and expensive nature of filling and other systems custom-engineered to create a site-specific solution. The availability of effective, mass-produced off-the-shelf technologies are making an affordable difference and manufacturers are also following suit, designing fill-finish and similar systems to fit into relatively standardized isolator real estate. “We’ve actually put a freeze dryer in one of the modules,” says Kline, extrapolating that aseptic drug processors could use one for staging, for example. “A number of companies have done that … so if somebody buys a single module for one application, there is nothing to prevent someone from buying three or four modules and put them together for a specific process; regardless, it’s still cheaper than building custom filling lines.”

AST says it clearly sees the trend towards clinical scale isolators as well as the implantation of interchangeable filling machines. “We’re definitely seeing that there are a lot of advantages to having a standard isolator platform like the SKAN PSI, which stands for pharmaceutical safety isolator.” Russell says SKAN has cut out the backside of the isolator to allow for docking different trolleys with traditional filling equipment into the isolator. “What that’s done, according to Russell, “is it’s really driven down the cost of technologically advanced isolators. But systems integrators may not be getting all the flexibility they can affordably purchase,” Russell explains. “What you’re buying is a flexible isolator, but a not-so-flexible filler. What AST is doing is putting together the best of both worlds by combining a flexible filler with a flexible isolator.” Russell explains that such a scheme allows the end-user to have a single trolley that performs all the fill-finish operations for vials, syringes and cartridges, and then it can be removed with another trolley for other activities placed within the isolator and used. One simple advantage of this is that the operators can remove the filling system trolley from the isolator for maintenance. “That way,” says Russell, “you don’t have to do it within the clean space of the isolator.”

Isolators work phenomenally well with the traditional filling lines, says Kline, in terms of keeping operators away. He explains that it’s not just putting an isolator on an old filling line: “The technology of all the filling [systems] companies have gone up dramatically in the last few years. The filling lines are much narrower — a design feature so that people can reach with the gloves to all the appropriate locations inside the filler.”

Kline also points out that the electromechanical, automated aspects of filling, capping — essentially technologies that manipulate and convey products to and through process operations — have improved as well. “From that standpoint, there’s not the glass breakage or the tippage that we had years ago,” says Kline, so [there’s been] incredible improvement, which reduces the interventions that folks have to do.”

Regardless, even if manual interventions are required, the increasing implementation of isolators means operators are doing it through gloves and not by opening doors. “Another great advancement in isolators that help in terms of the turnaround and also for cleaning from one product to another,” says Kline, “is single-use product contact parts.” Kline explains that by installing pre-sterilized contact parts, the cost savings can be significant. According to Kline “probably 90 percent of our customers that we design facilities for use this technology, so it’s driven the cost of the single-use disposable contact parts down dramatically and reduces the cleaning time.” Kline says that for potent products, it’s really the only way to go. “You don’t risk contaminating one product with the next product — the technology has worked out incredibly well.” Talking about potent products, Kline notes isolators have now transitioned into formulation operations. “When you’re formulating potent products, all the additions into the tanks, etc., are done through isolators at this point and provide a much safer environment for operators.” According to Russell, process flexibility sprouts from the fertile soil of contemporary technological advances in automation, control and robotics. “We’re seeing a couple different approaches. The approach that AST has adopted is leveraging robotics — to create a truly flexible aseptic platform. We use a robot to be able to fill and finish, pre-sterilize vials, syringes and cartridges. It’s ideally suited for companies that are looking for the ability to fill multiple formats in a low- to mid-volume production setting.”

Lower Risk, Higher Reward

When it comes to advances in aseptic processing technologies, the cost curve is being driven down and along with that, a lot of risk. Drug makers need to a have very high degree of confidence in the sterility of their processes, and technology is making that happen. “Yes, absolutely,” agrees Kline, “and risk is the key driving word here. Everything in terms of designing aseptic facilities is based on risk management. One could drive to zero risk, but your costs go up exponentially, thus it’s not a viable project. The economics don’t work out; there is a delicate balance to be maintained,” says Kline.

Kline explains that beyond segregation (FDA’s term) regulators are seeking high levels of isolator contained process line integration. “It’s not just the filler. It’s isolating transport to capping machines, or the conveying into and out of loading and unloading of freeze dryers. They’re looking for fully isolated manufacturing in a continuous process via tunnels.” He explains that traditional back-end process systems and operations like vial washing, then manually transferring vials to drying and transport to the filler is becoming a thing of the past. “So the risk has dropped off dramatically through separation and integration, and the cost of the technology has now dropped dramatically. It’s also reduced the number of operators. So there are significantly fewer operators on an isolator filling line or a RABS traditional line.

The conversation with Kline and Russell continued, ranging from the upside and downside of blow-fill-seal technology and the numerous benefits of creating highly collaborative relationships with both the users and the aseptic processing technology builders. Risk is also being driven out by advances in production-related control and automation, as well as information systems and remote monitoring and service via the cloud. Aseptic manufacturing environments are also being well managed by similar applications of advanced control technologies across building automation and HVAC elements of controlled space. Ultimately, it is the systems integrators’ task to deliver on regulators’ vision for efficient, cost-effective and safe aseptic drug processing, and drug maker’s equal need to achieve the same to stay in business. For sure, AST and IPS are creating a no man’s land in controlled Pharma space, and that’s how it should be.