Isolator technology is emerging, albeit slowly, as an alternative to classified space in the manufacture of pharmaceutical and biological products. Isolators’ principal value is a reduction in the need for classified space, which is expensive to build and manage.
Baxter’s (www.baxter.com) Halle, Germany, facility manufactures highly potent, sterile anticancer drugs as liquids, crystallates, dry powders, and as lyophilized products. The plant has been in operation since 1978, but a new facility, built in 2002, was designed for isolator technology. At Halle, all mixing, formulation, and compounding operations are performed inside negative-pressure isolators. Lyophilization equipment serves as its own isolator, but its products may be transferred to either a negative- or positive-pressure isolator for further processing.
Baxter relies on automatic transfer systems from several German vendors and a manual transfer system from LaCalhene (www.lacalhene.com) to move product from one isolator to the next. The LaCalhene transfer systems provide processes with a high degree of flexibility, says Baxter’s Frank Generotzky, manager of manufacturing for cytotoxics, and permit sterile processes even in nonsterile Class D environments.
Sterile filtration and filling are performed under positive-pressure isolation to keep out contaminants. Filling isolators employ controllers for temperature, differential pressure, and humidity as well. “Because physical volumes are smaller with isolators than with cleanrooms, personnel do not enter the classified space, so processing is more economical,” Generotzky notes.
Baxter’s isolator, transfer, and filling systems were custom-built for individual processes and machinery by vendors, among them Bausch & Strobel and Metal + Plastic, both German firms. Non-custom isolators lack flexibility, according to Generotzky. “The result is a huge improvement in microbiologic and particle contamination, and hence product quality. We have not found microbiologic or particulate contamination inside isolators since the plant opened. Before that, these were common issues.” These days, isolators are sterilized using vaporized hydrogen peroxide.
The only drawback to isolators is their relative lack of flexibility in processes that entail many manual operations or that are adjusted on the fly. Non-custom isolators are even less adaptable, says Generotzky.
From his perspective as vp, liquid pharma packaging, at Bosch Packaging Technology (www.boschpackaging.com), John Kirk sees a trend toward greater utilization of isolator technology for aseptic processing, for example in syringe filling. “In the past, this would have been done in a cleanroom. Today, the entire process is put inside an isolator.”
Another welcome advance is vendors’ interest in the science behind isolators. Bosch, for example, recently formed a process technology group to investigate how its products can improve productivity at customer sites. “It’s not good enough anymore just to build the machine, you have to understand the process.”
Like other top vendors, Bosch integrates its isolator systems directly into process machinery, so customers can acquire everything they need from a single source. “Customers can, of course, purchase equipment without the isolator,” Kirk notes.
Bosch’s integrated isolator-vial fillers come in a range of capacities. Bosch also offers its GLoveFIT glove-testing product for determining the integrity of isolator inlet gloves, and a decontamination system, SafeVAP, that uses industry-standard vaporized hydrogen peroxide.
Isolator technology is better established in Europe than in the United States and has been adopted primarily by small-molecule drug manufacturers. According to Sterling Kline, director of project development at IPS (www.ipsdb.com), larger biotech companies use isolators extensively in fill/finish areas. Early on, biotech companies were reluctant to adopt isolators due to regulatory uncertainties, primarily because cleaning cycles lasted as long as 18 hours. With the introduction of improved vaporized hydrogen peroxide sterilization by Skan (www.skan.ch), and more recently by Bosch, cycles have been reduced to three hours or less. Skan has performed extensive testing on various isolator materials for stability to peroxide sterilization.
Then there is the matter of priorities. “With the exception of the largest firms, biotech prefers to invest in manufacturing processes, not in isolators,” notes Jim Agalloco, president of Agalloco Associates (www.agalloco.com). “Smaller firms, especially, are not going to play around with exotic fill/finish technologies.”
Isolators increasingly make sense in biotech filling and finishing suites because the value of biologics per unit weight or volume is so high. Before blockbuster biologicals became commonplace, it was simply easier to process these products in classified rooms rather than invest in dedicated isolator technology. “Today, you just can’t afford to lose a batch,” Kline adds. Bristol-Myers Squibb (www.bms.com), for example, has introduced isolators to its fill/finish operations to reduce the potential for human error contaminating a batch.
Another positive trend for biotech isolators has been the migration from lyophilized products to liquid formulations, especially prefilled syringes. IPS typically specifies isolator-based vial- and syringe-filling equipment from Bosch and Inova (www.inova-ger.com), respectively. Groninger (www.groninger.de) also produces state-of-the-art filling equipment that is adaptable to isolator technology. “Most major companies are now building syringe lines within isolators,” notes Kline.
According to Andre Petric, product manager, material handling and containment, at Glatt Air Techniques (www.glattair.com), the need to contain process equipment through dedicated, integrated isolation units is growing among pharmaceutical companies. Glatt, for example, builds isolators around several equipment lines to provide a system where machine and barrier are married for the best performance. Among Glatt’s customers are manufacturers of pharmaceutical powders and oral solid-dosage forms.
Glatt’s small-scale isolator system for development work, Containment-Lab, is an array of modular isolators positioned sequentially for enclosing relevant operations: dispensing, wet granulation, fluid bed drying, sieving, tableting, and coating. Users may combine, add, or delete isolator modules as they modify processes. Each module contains a port for locking one module onto another without exposure to the ambient environment.
Never at a loss for a vivid analogy, Agalloco describes isolator-enabled unit operations in pharmaceutical manufacturing as “islands,” with processors striving to “ferry product from one island to another within the archipelago.”
For mid-sized pilot or large development-scale processes, Glatt offers its Glatt Process Coater-Granulator (GPCG2) system with a designed-in fluid bed processor. Larger processes and equipment, says Petric, serve as their own containment systems. “The machine itself is the isolator.”
RABS vs. Isolators
Pharma and biotech companies employ a myriad of barrier technologies that lack a rigorous airtight seal to provide product or operator protection. Most of these systems rely on air flow to provide protection, as do many less formal types of barrier systems found in manufacturing suites and associated laboratories.
“Within a facility, there are multiple spaces with varying needs for pressurization or air flow direction control to provide either containment or isolation,” says Steve Davis, president of Laboratory Control Systems (LCS; www.labcontrols.com). “Technologies and equipment create a space within the space and require their own level of control within the overall environment.”
LCS, which provides air flow control systems for critical environments in pharmaceutical and biotech, works with designers at the owner level to manage air- and temperature-control systems.
Restricted access barrier systems (RABSs) are another emerging, less costly, and less rigorous alternative to isolators, which work well for many processes.
ISPE defines RABSs as a barrier system with a rigid wall enclosure, unidirectional airflow providing an ISO 5 environment, glove ports with sterilizable (preferably sterilizable-in-place) surfaces, and are typically surrounded by an ISO 7 or lower environment. ISPE’s analysis of RABSs vs. isolators goes into a great deal of technical detail. The bottom line is that RABSs provide a good deal of protection for products from operators, but not quite as much as isolators do since RABSs are not airtight and are not sterilizable using vaporized hydrogen peroxide.
RABSs are particularly attractive in the food and beverage industries. Serac (www.serac.fr), which manufacturers filling and capping machines, recently launched a new RABS for aseptic packaging of milk and drinks in and around sterile areas. Like most RABSs, Serac’s is not hermetically sealed. The barrier results from positive pressure inside the enclosure.
According to Kline, manufacturers believed that they could save money by installing RABSs instead of isolators, but savings do not always accrue. While capital costs are lower for RABS, operating expenses may be higher.
Agalloco, a big booster of isolators, thinks of RABSs as a poor cousin. “An isolator has a complete seal with different pressures inside and out, and can be exhaustively decontaminated. If you eliminate the seal and keep gloveports, walls, and transfer mechanisms, you have a RABS,” he says.
Regular readers may recall Agalloco’s analogy for comparing true isolator systems from what used to be known as barrier systems or barrier-isolators, a term he loathes. He likens barrier systems to the different environments in first class and coach on an airliner; an isolator system is comparable to the skin of the plane, which shields passengers from the harsh outdoor environment.
Similarly, Agalloco compares RABSs to the Rocky Mountains, which although not an insurmountable barrier to populating the West, nevertheless caused many pioneers to settle in the plains states.
“Everyone knows that isolators are superior, but not all believe they bring in the proper return on investment.” Some processes will do fine by employing a less expensive RABSs installation, a fact that even Agalloco admits is likely to increase demand for RABSs. “I hear people say that RABSs are pretty good, and that isolators are too complex, expensive—overkill.”