What's smaller than a clean room, cooler than a glovebox, and able to leap any aseptic standard in a single bound? It's Super-Barrier, better known as the isolator system.
In its Technical Report 34, Design And Validation Of Isolator Systems For The Manufacturing And Testing Of Health Care Products, the Parenteral Drug Association (PDA) defines an "isolator" as a structure that:
,is sealed or supplied with air through a microbially retentive filtration system (HEPA minimum) and may be reproducibly decontaminated. When closed it uses only decontaminated (where necessary) interfaces or Rapid Transfer Ports (RTPs) for materials transfer. When open it allows for the ingress and/or egress of materials through defined openings that have been designed and validated to preclude the transfer of contamination. It can be used for aseptic processing activities, or containment of potent compounds or simultaneously for both asepsis and containment.
Quality of rooms surrounding isolators is of "very minor consideration," notes the PDA guidance, since "properly designed isolators do not allow the exchange of contaminants with the surrounding environment." Nevertheless, isolator systems are generally installed in classified environments.
Because of occasional confusion on terminology, it makes sense to spend a little time defining differences between "barriers" and "isolators." PDA defines "barrier system" as "an open system that can exchange contaminants with the surrounding area, and cannot be decontaminated to the extent possible in an isolator." Any mechanical or physical separator, including gloves and gowns, are considered barriers, although in this article "barrier" usually refers to structures or "boxes" enclosing work areas, processes or equipment.
Isolators come in two varieties: open and closed. Open isolators used in aseptic pharmaceutical filling "allow for the continuous or semi-continuous ingress and/or egress of materials,while maintaining a level of protection over the internal environment." Open isolators are becoming popular in fill areas because they protect products while allowing vials to enter and exit the work space.
Closed isolators, according to PDA, are "capable of levels of separation between the internal and external environment unattainable with other technologies." Nothing goes into or out of closed isolators during their operation except for air, whose direction distinguishes aseptic closed isolators from containment closed isolators: The former use positive pressure to keep germs and particles out, while the latter operates under negative pressure to keep toxic or potent materials away from workers and out of the work space.
Confusion sometimes arises when the terms "barrier" and "isolator" are mixed. James Agalloco, president of Agalocco Associates, Belle Mead, N.J., believes these terms are poorly understood, as exemplified by the proliferation of such hybrids as "barrier isolators," "locally controlled environments" and "minienvironments." Misuse of terminology, says Agalloco, is delaying the "revolution" in sterile products manufacture. Agalloco compares barrier systems to the curtains separating first class from coach on an airliner, and isolator systems to the fuselage, which maintains a life-supporting environment at 40,000 feet.
Despite the need for consistent nomenclature, purists can do little to prevent the evolution of technical terms, especially with clean work areas used by so many diverse industries. Drug makers refer to structures that keep contaminants away from products as "isolators," and use "containment" to describe strategies or systems that keep toxic or potent products from workers. PDA uses "aseptic isolator" and "containment isolator," respectively, to describe the same things.
In practice "barrier isolator" is often used synonymously with isolator, and occasionally "minienvironment" is used, especially with regard to semiconductor fabrication. Sematech's Integrated Minienvironment Design Best Practices defines a "minienvironment" as "an integrated and controlled environment in the production equipment where exposed wafers reside that separates the wafers from personnel and the general, ambient fab environment."
Many processes require both isolation and containment, either during the same operation or in different steps. For example, containment systems protect workers from heart or cancer drugs (containment) which subsequently need extra protection from the environment during fill (isolation). Cytotoxic drugs, potent hormones and radiopharmaceuticals are examples of products that often require containment and isolation during the same step.
Since operators must limit their exposure to these materials, processing must take place inside the isolator , which prohibits the straightforward use of positive pressure to keep contaminants out. In these situations, facility designers use both containment and isolation, with an airlock in between. "Protecting product and worker simultaneously is a challenge," says John Kirk, vice president for sales and marketing at Bosch Packaging Technology, Minneapolis, "and for large-scale production, it's still relatively new technology."
When specifying isolator or containment systems, smaller is better. Pilot or bench-scale equipment may be enclosed completely, while for large manufacturing processes, isolators surround only critical operating areas or interfaces. "The size of the isolator is not as much an issue as how much of a process needs to be outside, and how much needs to be inside," notes Jim Agalloco.
Despite the best-laid containment or isolation designs, barriers inevitably leak to some degree. "Sometimes people get hung up on that," says Agalloco. "So users need to ask 'what leak rate can I tolerate?' The simple answer is, it probably doesn't matter as long as the system leaks in the direction that protects workers and product, as appropriate."
Even when everything goes right, users need to know what they're getting into before installing an isolator or containment system. Topping the list is the level of cleanliness required based on reasonable operator exposure limits. "It's very important that customers know, for example, that they can tolerate one or three micrograms per cubic meter per shift," says Erik Barman, special projects manager at Fette America, Rockaway, N.J., "and that they don't change their mind after purchasing a piece of equipment."
Fill 'er Up
Aseptic filling is traditionally carried out in Class 100 clean rooms, with the filling machine at the same classification as the surrounding area. Soft barriers are sometimes deployed at fill stations, but generally this operation occurs in the same environment as the operator.
More and more manufacturers are downgrading fill clean rooms and installing isolators that enclose filling machinery. John Kirk of Bosch describes such enclosures as "mini clean rooms within clean rooms" and refers to them as "barrier isolators." Barrier isolators represent an added cost to a filling line, since the clean room is a constant. However, Kirk claims that operating costs are lower for isolators when less wasted product, smaller workspace footprint, lower utility costs, reduced (or eliminated) gowning, and lower classification for the room are added to the equation. He estimates gowning and de-gowning time at 45 minutes per worker per shift. At a cost of $100 to $150 per hour per worker, isolators could save about $25,000 per year.
Kirk states that more than 60 pharmaceutical manufacturers are using such systems today and more than 25 have been validated in the United States and Europe.
Validation seems to take on a life of its own, especially when adopting a new technology. An isolation system can take 18 months to validate, which considering the complexity of structures, materials, air flow, etc. is not out of line with other facility installations. Once isolator structures are validated, cleaning validation for isolators is not particularly burdensome. Nevertheless, cleaning and cleaning validation raise interesting issues, since users are now cleaning an enclosure as opposed to a room. Because isolator enclosures are much smaller than rooms, some feel that isolator cleaning requires validation, the same as equipment that comes in contact with product. (Clean room sanitization need not be validated).
PDA recommends a middle ground in its Report 34, which states that the only additional cleaning validation burden imposed by isolators "relate(s) to ergonomic issues related to manual cleaning of the surfaces." PDA recommends that cleaning of non-product contact surfaces be validated, but to a somewhat lower standard than surfaces that touch product.
Cleaning and cleaning validation issues aside, to isolate or not to isolate is a decision that must be made company-by-company, facility-by-facility, based on an organization's predilection, or aversion to, new technology. "We've had some customers who want all manufacturing and filling to be done traditionally, with the smallest number of question marks," observes Kirk. "Others say they have to go with barrier isolators because it's 'the wave of the future.'"
Greater sterility assurance and cost savings are cited most often as reasons for deploying isolators, either within clean rooms or instead of them. The case for isolator systems becomes compelling as drugs of higher potency and purity become the norm. Air pressure differential, small footprint and relative ease of decontamination (compared with clean rooms) make a good case for isolators' superior sterility assurance potential when used in aseptic mode. The same could be said for isolators used for worker protection, that is, in "containment" mode.
"It's a lot more effective and ergonomic to contain either the operation or source of contamination rather than to wrap the person up," says Robert T. Hsu, Principal and Senior Director at Kling, Philadelphia. "We do both, of course, especially with very potent drugs. But even after isolating a process, we still often employ a secondary means of containment."
The argument for cost savings is a bit trickier. "It's difficult to come up with an accurate answer that weighs the value of one system or approach against another," John Kirk of Bosch told Pharmaceutical Manufacturing. "There has not been an exhaustive economic analysis that points companies in one direction or another in terms of choosing a barrier isolator or a clean room."
Manufacturers have long believed that the smaller the classified space, the less expensive the facility. However, even this maxim of facility construction misses the point with regard to potent or labile drugs. Clean rooms still represent the lowest risk from the standpoint of validation, manufacturing and operation.
"Everybody knows how to fill and validate in a clean room, so in a sense clean rooms are easier," Kirk notes. "Restricted access barrier systems (RABs) and barrier isolators are more complex and provide enhanced aseptic processing, but no doubt some early cost savings projections were optimistic. However, if you consider that an isolator system only needs to be decontaminated and pressurized when in production , unlike regular clean rooms, which must be maintained all the time , plus gowning costs and floor space costs, it seems intuitive that you could save money using barrier isolators. Isolators represent a higher capital investment , they cost more to build -- but provide lower ongoing operating costs, since you save on classified floor space, gowning space, HVAC utilities and facility operations."
Despite the need for higher sterility, Lysfjord and Porter's biennial review of "barrier isolators," published in Pharmaceutical Engineering in 2001, suggests that interest in new installations has leveled or may be declining. The authors note that a combination of complexity and limited personnel are causing manufacturers to pass , at least for the time being , on the new technology.
The success of isolator technology has not gone unnoticed by traditional equipment manufacturers. For the past five years Glatt Air Techniques of Ramsey, N.J., which specializes in fluid bed processing equipment, designed containment and cleanability into its new products. "We try to take a big-picture view of containment," says Andre Petric, product manager for material handling systems, noting that his firm's strategy is "keeping things in versus keeping things out."
Clean Room Alternatives
Acquiring and maintaining a large Class 100 facility is expensive given energy consumption, equipment, air filtration, gowning and difficulty working in such environments. In pharmaceuticals, the trend has been away from larger classified space toward maintaining ultra-clean stations wherever appropriate. "It makes much more sense for pharmaceuticals to have many smaller spaces where specific tasks are done to a specified level of cleanliness or protection," says Steve Davis, president of Laboratory Control Systems, Scranton, Pa.
Air controller specialty firms like Laboratory Control Systems prefer to offer complete control systems for critical environments, as opposed to bits and pieces of systems. "Customers prefer a single source rather than having to pick out this component and that component," Davis says. "The company is often called in early in a facility project and works with facilities personnel or a design team, long before equipment is installed." As for their installations, "you typically don't see them because they're above the ceiling or in adjacent support space. All you're likely to notice is a local monitor or alarm."
As a middle ground between traditional clean rooms and barrier isolators, manufacturers are turning to RABS , restricted access barrier systems, consisting of a hard barrier between the operator and filling process, but with no pressure differential. RABS can be less expensive to build or acquire and entail less validation than isolators.
Companies interested in specialized space need not wait until they build their next plant or knock down an existing one. Isolator deployments are appropriate for renovations as well as new facilities. Kling, for example, has installed isolators for a major oncology drug-maker "from a shell building," but has also performed very large renovations within which are 10,000- to 20,000-square-foot potent compound suites, according to the company's Robert Hsu. "QA/QC laboratories use isolators for sterility testing," he adds, "and these installations are quite routine, even as retrofits."
Powder Containment Rooms: Processing Outside the Box
For some applications, powder containment rooms offer alternatives to smaller containment or isolation chambers. By including filtration systems that maintain cleanliness to Class 100 levels, these specialized rooms combine the benefits of modular clean rooms and biological safety cabinets. A powder containment room's relatively large size accommodates workers and allows easy access to packaging or analytical instrumentation , an advantage over containment chambers.
"Powder containment rooms provide a clean processing environment, ample working space, unrestricted access and cost substantially less to purchase and maintain than conventional cleanrooms," says Nick Volpone, president of Prime Technologies of West Chester, Pa.. "These systems cost about as much as typical isolator chambers."
In powder containment rooms, air is drawn away from personnel into HEPA or ULPA filters positioned behind a processing zone, with filtered air injected into the room from a roof-mounted external manifold into ceiling filters above the work area. Localized circulation of filtered air protects personnel against pathogens, chemical powders and sub-micron particles, while a continuous wash of filtered air protects product in the processing zone.
Powder containment rooms are configured for either negative or positive pressure. Monitored by a differential pressure gauge, an adjustable air handling system controls the relative pressure of the room with respect to the external lab. Whether operating under positive or negative pressure, airborne powders remain within the filtration zone even as personnel and equipment pass in and out.
Powder containment rooms incorporate other design features found in smaller processing enclosures, including stainless or powder-coated steel walls (often with antimicrobial coatings), rounded corners and smooth interior surfaces for easy cleaning, and temperature/humidity control. Their larger size and ease of access make them attractive to manufacturers wishing to break out of a confined processing chamber.