Unclear regulatory expectations hinder the use of barrier isolation technology, despite its potential. But FDA and industry are working to address issues.
by Erik Swain, Senior Editor
Aseptic processing of liquid pharmaceuticals is perhaps the most complicated task in healthcare packaging. A mastery of chemistry, biology, engineering, sterilization techniques, and personnel procedures is essential for the product to be packaged without contamination.
Executing barrier isolation—taking an aseptic filling line and enclosing it in an isolator that separates it from the external environment—is even more complicated. There are few isolators in operation to serve as models for new lines, and there are no official standards on how to implement the technology properly. Without a set of standards, pharmaceutical companies carry out barrier isolation as they see fit. Therefore, one company's method will differ from that of another.
"When one pharmaceutical company does barrier isolation one way, and another does it another way, that makes it very hard for a vendor," says Mark Zarembo, manager, barrier isolator division, The Baker Co. (Sanford, ME). "There is still a lot of custom stuff being made. My goal is to build the exact same unit twice."
There may be guidance for industry soon. The International Society of Pharmaceutical Engineers (ISPE; Tampa, FL) just published a guide on sterile manufacturing facilities, which contains a chapter on barrier isolation. While it is not an official regulation, standard, or guideline, FDA has provided comments on it.
Perhaps as early as this year, FDA plans to revise its 1987 aseptic guideline and add a section on barrier isolators, according to Richard Friedman, compliance officer with FDA's Center for Drug Evaluation and Research. "FDA for the first time will publish barrier isolation guidance," he says.
This will be a very positive development, as industry has been abuzz for years about what FDA will expect from this technology, especially in terms of validation. FDA, in turn, has eagerly sought input from industry about which barrier isolation methods and procedures have worked and which ones have not. With the publication of barrier isolation guides, pharmaceutical companies will have a resource to direct them as they add this technology to their capabilities.
POPULARITY UP
If designed and maintained correctly, a barrier isolation line can provide a lesscontaminated environment, lower long-term facility and staffing costs, and better operator protection than conventional filling lines. Despite the current difficulty in setting up such a line, the technology is becoming more widely used.
Jack P. Lysfjord of TL Systems Corp. (Minneapolis) and Michael E. Porter of Merck & Company, Inc. (Whitehouse Station, NJ, and West Point, PA) released a study last year showing that there were 84 barrier isolator lines delivered, more than anyone had expected. The lines were used more widely in Europe, but were catching on in the United States. Last year, six systems had FDA approval, and there have been a few more since.
"The more biotech drugs there are, the more important [barrier isolators] will be," says William Arden, marketing manager for TL Systems, part of the Bosch Group. "The original reason for them was to keep humans outside the filling process. Now, with drugs that are potentially dangerous to operators, the question is how to keep the drug inside the isolator." This may explain the increasing need for barrier isolation systems.
DEFINITIONS
Although becoming more widely used, barrier isolation still brings up questions and concerns. Friedman says one of the foremost is coming up with an accurate definition of barrier isolation.
"If it is not a sterilized unit, supplied with HEPA, ULPA, or sterile filtered air and providing uncompromised continuous isolation of its interior, then it isn't an isolator," Friedman says. "You must isolate the two environments so that they are exclusive of one another. If a firm does something less and stretches the definition, it will in fact undermine the exceptional efforts of its industry counterparts who do barrier isolation the right way. If one company tries to bring down the standard, that will be problematic for the rest of the industry."
The key attributes of a true isolator, he says, are that it is sterilized, it is uncompromised, and it provides continuous isolation. All of these are at the core of the debate over what exactly barrier isolation can be expected to do.
"It's not coming up with an isolator with no discernible leak rate that's important," Friedman says. "It's important only that there is an adequate design and overpressure that is continuously maintained and that precludes the ingress of any particulates from the environment surrounding the isolator."
But, he says, claiming that isolators can achieve sterility assurance is a mistake, because aseptic processing does not involve a terminal sterilization process of known lethality. Rather, media fills are performed to determine a contamination rate, which is the more accurate phrase. "Aseptic processing, no matter how it is done, is not the equivalent of terminal sterilization," he says. "A barrier isolator is still housing an aseptic filling line."
BREACHES
If the definition of an isolator is something that completely separates the inside from the outside, then the methods of getting the product in, such as mouseholes and transfer ports, will continue to be considered one of the technology's problem areas. This is where breaches of isolation often occur. To combat such breaches, IMA North America (Fairfield, CT) recently patented a method of using vaporous hydrogen peroxide in the cold zone of the sterilizing tunnel, says Warren Roman, vice president.
Another breach of isolation occurs with the gloves used by the operators. Because there is no way to test gloves for smaller leaks that permit the passage of microorganisms, "conservative, mandated glove replacement schedules" are essential, Friedman says.
There have been inconsistencies with how industry has dealt with breaches, from glove, valve, and power failures to out-of-specification pressures. But there is no inconsistency in Friedman's instructions. "Any breach of the isolator . . . should be investigated and the affected product rejected, and should lead to a mandatory sterilization cycle," he says.
Other areas that draw attention during an inspection of a breach are structural integrity, materials of construction, pressure differential, clean area classification, frequency of sterilization, and personnel practices, Friedman says.
STERILIZATION CHALLENGES
Besides breaches, another concern is ensuring the isolators are designed so that all portions, especially the driving machinery, can be cleaned and sterilized properly.
"A firm should minimize sterilization challenges to the greatest extent possible," Friedman says. "There have been product failures due to cluttered design concepts that prevented surfaces from being well exposed during the surface sterilization cycle."
For that reason, FDA frowns on retrofitting—taking a line that has not been designed for use in an isolator and building an isolator around it. "A more narrow, sleek type of line is used in the isolator, with most moving drive parts outside the isolator," Friedman says. "This is not necessary for conventional operations. They are different animals. I have not seen any retrofitting, for good reason."
With that in mind, some companies are designing filling lines that they say can eventually be adapted for use in isolators, especially making sure all parts can be cleaned and sterilized.
Bausch + Stroebel Machine Company, Inc. (Clinton, CT) even offers an option to install certain brackets, holes, and other parts up front to make an eventual conversion easier. "We help the customer foresee what is in the future," says Paul R. Chimino, sales engineer. "It's best to get the hardware in place ahead of time." However, he says, the company is not trying to force customers into that option, and it is most concerned with selling the customer the most appropriate machines, with or without an isolator.
Whether FDA will approve of such conversions remains to be seen.
THE CONVENTIONAL WAY
Despite the attention given to barrier isolation, the vast majority of filling lines are produced for conventional aseptic processing. There are fewer up-front costs with conventional lines, which have a history of effectiveness. In addition, conventional lines are seeing their share of advancements. Increasing automation of filling lines is perhaps the most significant trend, because less operator involvement means less opportunity for contamination.
"The automated equipment must be gentle enough not to fracture vials or cause other unforeseen stresses to the product," Friedman says. "All in all, the trend toward increased automation has been very positive. Automated weight checks are easily adapted into current lines."
Filling machinery manufacturers say that they are applying some of what they have learned in barrier isolator design to their conventional filling lines.
"Reducing the overall footprint is important, as is making the changeover items toolless," says Joel Slazyk, vice president of sales and marketing, Chase-Logeman Corp. (Greensboro, NC). "The market is still not wide open for isolator systems, so we still spend a lot of time on standard filling systems. But when the market does open up, we'll be prepared."
One of the most important issues in designing a filling line, Chimino of Bausch + Stroebel says, is to determine which filling technique is best for the product in question—rotary piston pump, time pressure, or weight density.
Stopper technology has also evolved because of barrier isolation. Last year, West Pharmaceutical Services (Lionville, PA) introduced ready-to-use stoppers, already sterilized, eliminating the need for human contact. They also offered an autoclavable package.
Automated stopper transfer systems, such as the one West makes, remove the human factor even further. "To the extent that you remove an operator, even though in this case it is an operator outside an isolator, you are improving the process as a general rule," says Friedman. "When you have stoppers in plastic bags and rip them open, you are generating particles. Also, when you manually charge them into the stopper bowl, it is not ideal."
CHALLENGES
Barrier isolator technology, though showing great promise, will probably not be fully accepted in the United States until there are formal standards, regulations, or guidelines in place, and until more data are available to prove its superiority to conventional aseptic processing.
Yet, the technology will always require sound design, control, and maintenance—challenges that can be difficult to meet.
"If this technology is able to consistently reproduce what it is apparently capable of achieving, one of the only remaining impediments for a firm would be inattention to the stringent preventive maintenance requirements," Friedman says. "An ever-vigilant eye is of the utmost importance to this technology.
"Frankly, it may not be for everyone," he continues. "For a firm whose operating philosophy is to meet only minimal GMPs and operate on the cusp of CGMP compliance at all times, this technology is not the right one. But it is if the firm has a good quality philosophy and understands the importance of designing quality into machinery, and if the firm operates and maintains the line to exceedingly high standards on a routine basis."
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