Isolator Systems Take On Clean Rooms

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:

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.