Fill in splendid isolation
Pharmaceutical manufacturers have recently begun to evaluate how they could incorporate isolators into their filling operations.
Isolators incorporate sealed environments that are supplied with filtered air, and are decontaminated through reproducible
means. The industry took particular notice when Richard Friedman, director of the Division of Manufacturing and Product Quality
at the Center for Drug Evaluation and Research, and Robert Sausville, supervisory consumer-safety officer at the Center for
Biologics Evaluation and Research, both of the US Food and Drug Administration, stated at the International Society for Pharmaceutical
Engineering's 2009 Washington Barrier Isolator conference that isolator technology is the new standard in aseptic processing.
Isolators constitute one of the largest leaps in aseptic technology, according to Jack Lysfjord, principal consultant for
Lysfjord Consulting. This technology improves sterility assurance by at least 1000, if not 10,000 times, says Lysfjord, who
has more than 29 years of experience in aseptic fill–finish equipment design and application.
The trend towards isolation is influencing equipment vendors, who increasingly are designing processing equipment to run more
reliably with fewer interventions so that it is suitable for installation inside an isolator. Some new aseptic fill–finish
equipment can operate for as long as 28 days without interventions, says Lysfjord. These machines include automation with
sensors that detect faults (e.g., missing stoppers) and eject unsuitable containers.
Vendors such as VanRX are developing integrated robotic isolator systems for sterile-manufacturing applications. The company's
Raptor Aseptic Workcell uses a multiarm robotic architecture that performs clinical-scale aseptic filling of potent and nonpotent
products. With its digital vision-guided system, the Raptor targets containers inside the isolator, according to Chris Procyshyn,
the company's chief executive officer. After containers are transferred into the system on a tray, sensors scan them to identify
their type (e.g., vials or syringes), verify that they are the correct containers, determine their locations, and complete
the fill–finish process.
Vials or syringes are transferred from a sterilizer to an interface isolator, and then directly into the system. This transfer
removes the largest source of product contamination, human intervention. For example, one of the system's advantages is that
it does not require any part changes other than simple fill-tubing sets. Operators can fill a batch of 5-mL vials in the morning
and, after changing the peristaltic tubing and decontaminating the system, can fill 50-mL vials in the afternoon with no other
adjustments. "The average company might spend $25,000–50,000 on change parts for a new vial set on an automated filler, and
it can take as long as 20 weeks to get it ordered, installed, and ready. In this case, for a manufacturer, it's as simple
as installing a new set of tubing and going," says Procyshyn.
Robotics traditionally have not been used in isolator systems because of concerns about hermetic sealing, particle generation,
and vapor-phase decontamination systems. The Raptor system incorporates hermetically sealed, peroxide-compatible, stainless
steel robotics to enable the first gloveless isolated filling system, according to Procyshyn.
VanRx had to select the robots for its system carefully. Other systems have used six-axis robots, which are highly configurable
and move much like human arms. These robots, however, require large and complex sealing to be enclosed in an isolator. "If
you add more robots and keep your motion planar, that allows you to use a simpler, more reliable seal design," Procyshyn explains.
The Raptor system's design is similar to that of robots long used in the semiconductor industry.
While the robotics and vision system are unique to the Raptor system, VanRx chose not to develop new filling technology for
the system, relying instead on conventional peristaltic filing. "This means that the product is only seeing something with
a good history of reliability in terms of product-contact materials and processes." Although other isolated systems are compatible
with specific products and dosage containers, the Raptor system was designed to work with any product and any dosage container.
"We know that, by the time it hits manufacturing, a dosage has been picked, stability has been done, and nobody really wants
to change the product at that point, even for a manufacturing efficiency. So you really have to make your system work with
what the formulators have worked out if you want your system to have readiness and acceptability," says Procyshyn.