The truth about cleanrooms and isolators

07/01/2001

Barrier Isolation Forum

Mark A. DeSorbo

ARLINGTON, VA—Are contamination control end users demanding too much from barrier isolation technology?

The answer is "yes," according to Gordon Farquharson, a consultant for Bovis Lend Lease Pharmaceutical Limited (Surrey, England), who addressed industry professionals at the International Society of Pharmaceutical Engineering's (ISPE) 10th Annual Barrier Isolation Technology Forum, held here last month.

Here's why: Farquharson says isolation technology allows higher manufacturing volumes, so drug makers and suppliers often push the equipment. Because it is a sensitive device, the more it is used, the more maintenance required. Lastly, isolation technology has sparked great interest in the pharmaceutical industry and that curiosity has generated a thirst for what other capabilities exist.

"We demand more because we are learning all the time," he says. "The technology is young and problems and issues are being discovered all the time. We demand more because the systems are inherently more sensitive to variation and fluctuation than the cleanroom equivalent."

A technology coming of age
Amid ratification of a worldwide cleanroom and controlled environment standards, ISO 14644, the ISPE reports that there is a movement driven by drug makers, suppliers and associated societies to continually improve upon industry specific recommendations for isolators, namely the proposed good automation manufacturing practices (GAMPs) for barrier isolation filling systems, a published set of guidelines that first appeared in 1995.

Isolation technology clearly seems to improve on "classical processes," says Richard Friedman, a compliance officer for he U.S. Food and Drug Administration's (FDA) Center for Drug Evaluation and Research (CDER).

"Most processes out there do not use barrier isolation technology, and it offers better protection to the product," he says.

Friedman's session, "Aseptic Processing Isolators," indicated that GMP deviation, lack of sterility assurances, validation and microbial contamination were some of the main reasons for drug recalls from 1997 to 2000. His presentation illustrates the need for improved aseptic processing technologies, including, and most prominently, isolation technology.

In fact, Friedman says the number of drug recalls has increased significantly in the last four years, and many of the problems that were once caught by the manufacturers are now being discovered by the FDA.

From 1995 to 1998, approximately 65 percent of the recalls were discovered in-house, Friedman says, but that number of manufacturer discoveries declined to fewer than 40 percent in subsequent years. Lack of sterility assurance cases, he adds, more than tripled in that same time frame.

"This is a remarkable turnaround in problem detection and may reveal an emerging problem with effectiveness of QC Unit oversight in the industry," Friedman says. "These failures underscore the need for attention to improving the control of variables that impact product sterility through automation and more advanced barrier technologies."

Positive pressure isolators, however, do allow product protection advantages and can offer better defense, while taking up less space than cleanrooms and eliminating costs and procedural steps incurred with gowning, he added.

The consensus at the ISPE forum was that communicating the trials, tribulations as well as the differences between isolation and cleanroom technology will completely advance contamination control, especially once the pros and cons of each are fully understood.

Differences and similarities
Many attendees, like Narendra Prasad, general manager of projects for Pharma Plan, a design and consulting firm based in New Delhi, India, believe isolators along with cleanrooms complete the ultimate contamination control mission.

"If it's glucose or IV saline, you do not need an isolator. It should be done in a cleanroom," he says. "Isolators are needed, too, especially for products that are highly sensitive to microorganisms, or if the product is toxic and poses a threat to personnel. There is a need for both."

There is a difference, Bovis' Farquharson says, in integrity between the surrounding environment in an aseptic processing cleanroom and within the isolator, which is no less than an ISO Class 5 (Class 100) equivalent.

Cleanroom technology works, he explains, because of an "imperfect science" of a "shell-like protection" layering between the critical process core and the surrounding environment.

"If we move to the aseptic processing isolator scenario, we see that generally there is an expectation that the aseptic core and the immediate surrounding environment loses a step of environmental cleanliness control separating them," Farquharson adds. "This means that the boundary between the surrounding environment and the aseptic processing isolator becomes a lot more critical."

The consensus of ISPE forum attendees was that background-environments surrounding isolators should be at least an ISO Class 8. "Unclassified rooms should not be used to house isolators," Friedman says.

There are also differences in leakage, pressurization and disinfection methods, Farquharson says.

For a cleanroom, additional air can be provided to make up for leakage, but for an isolator, small changes in airflow will have greater affect on the pressurization, which alters the cleanliness, especially for a small isolator.

With sterilization, there are as many similarities as there are differences between cleanrooms and isolators.

"With isolators, it is clear that there is no regulatory requirement for sterilizing internal surfaces in aseptic processing. If we compare the cleanroom expectation, we also see that there is also no regulatory requirement, and no specific bio-decontaminating cleanrooms unless they are associated with biological hazards," Farquharson says.

However, within the GMPs, Friedman points out that there are specific design guidelines and regulations that pertain to cleaning and sanitization. Construction materials, he says, should be durable, non-reactive and be able to withstand pressure and frequent decontamination.

Code of Federal Regulations (CFRs) also indicate that ventilation, air filtration, air heating and cooling equipment must have adequate and appropriate control over air pressure, microorganisms, dust, humidity and temperatures, Friedman says. Cleaning and maintenance, according to CFRs, also dictates equipment design, construction and overall location.

When it comes to cleaning isolators, Farquharson explains, the industry uses vaporized hydrogen peroxide (VHP) to kill the growth of the bacillus steathermophilus bacteria indicator.

Sterilization of contact parts, however, is a different matter, Farquharson says.

"Within the aseptic processing cleanroom, we would expect to see all direct contact parts sterilized either by sterilization-in-place systems or by autoclaved sterilization of suitable equipment components," he adds.

With isolators, Farquharson says, cleanroom methods, such as surface cleaning, are extremely difficult. "We therefore see the drive is towards sterilization of product pathways and surface sterilization of other direct parts, such as bowl feeders, delivery chutes, and pick and place devices," he says. "In the case of the isolator, this would most commonly be undertaken using hydrogen peroxide."

In cleanrooms, disposable gloves are used and additional steps at preventing contamination are taken by using a topical disinfectant to gloved hands.

That is not the case with isolators, which use the glove box concept. Within the isolator, gloves provide a much more fundamental barrier between the highly controlled and background environments.

"If you are operating an isolator with torn gloves, you are not running an isolator," Friedman says.

Farquharson adds that the glove is an "integral part of the isolator barrier and we need to prove its integrity more definitively."

"Glove change would occur on a shift or batch basis or in the event of damage occurring. Frequent change of gloves, following the cleanroom approach, would tend to be very disruptive to the isolator environment and may create a greater opportunity for contamination," he adds

The number and location of HEPA filters within the air handling systems of isolators in cleanrooms are similar, all protecting the aseptic core. But filters in isolators are more vulnerable in isolators than cleanrooms because the units are so much closer the actual process, making them susceptible to vibration and, ultimately, damage.

"Leak testing methods and frequency need additional considerations, as filters may be subjected to higher stress than in cleanroom applications," Farquharson says.

The integrity of filters, gloves, halfsuits, seams, gaskets, seals and piping within an isolator, Friedman says, must be kept up within standard operating procedures (SOPs). In his inspections, Friedman found that some facilities did not have SOPs that defined replacement frequencies for gloves, gaskets and seals.

As far as what the future holds, Friedman told ISPE members that he does not want to speculate or cause alarm with FDA inspection findings.

"I don't think that everyone will need to go out and buy an isolator," he says. "But our findings for conventional lines indicate a general need to add more measures for product protection and automation to processes. Similarly, it is very important to conceive a solid design for an isolator because problems with validation and maintenance are generally intertwined with the design."