Handling Highly Active Ingredients

PharmaManufacturing.com

The latest containment systems and disposables are reducing compliance costs.

A baffle-less twin-axis mixer
represents one approach to
tackling containment that is
now available to manufacturers.
Photo courtesy of Glatt Air.




By Angelo De Palma, Ph.D., Contributing Editor

Containment systems which protect workers from highly active or toxic ingredients have come a long way in a relatively short time. Within the past decade, pharmaceutical containment strategies and technologies have changed as radically as the industry itself, says Eliot Cook of Absolute Control Systems (Golden, Colo.).

A few short years ago, the industry seemed to be stuck on “barrier isolator” technology—over-engineered boxes that offered containment levels between those of gloveboxes and those of cleanrooms, at costs approaching those of cleanrooms. The term for the equipment was questionable at best, since barriers and isolators do such different things, says consultant Jim Agalloco, president of Agalloco Associates (Belle Meade, N.J.) “When you’re flying in an airplane there’s a barrier between coach and first class, but isolation between the cabin and the outside.”

Today’s best containment systems are light years ahead of the old “barrier isolators.” They address the performance drawbacks of fume hoods and biological safety cabinets, and the high installation and operating costs of cleanrooms. Gowning costs at sterile manufacturers can run in the hundreds of thousands of dollars per year when suits and time to frock and defrock are included.

“With containment systems, you can work in a lab coat, do everything you need to do with the process, and if you spill material you don’t contaminate the whole facility,” notes Cook.

Modern containment strategies are based on containment of unit operations. Disposables have also broken new ground in the form of bags and containers for transferring materials from one operation to the next, and, most interestingly, through flexible-film mini-enclosures that minimize cleaning and related validation.

System designs reflect increased a focus on meeting occupational exposure limits (OELs). “Ten years ago, containment system design typically called for an OEL [eight hour occupational exposure limit] of 10 micrograms,” says Patrice Cloué of La Calhène (Rush City, Minn.), which started out over forty years ago, supplying protective equipment for the nuclear industry. “Now, they’re looking at nanograms or picograms.”

Manufacturers pay greater attention to containment issues early in the development cycle, says Cloué, before the product and its myriad intermediates and side products have been  fully characterized. In bioprocessing, where products in solution rarely pose serious problems to operators, the concern is with living microorganisms.

To optimize safe material transfer, La Calhène offers its DPTE platform, designed to permit transfer between environments without compromising enclosure integrity. DPTE systems employ a fixed (alpha) assembly, mounted on the isolator wall, and a mobile (beta) assembly which is attached and sealed to the rigid or flexible container. Using its DPTE BetaBag, Cloué says, allows solids to be transferred directly from one enclosure to another without opening the bag to the work environment or having the outside of the bag enter the containment system.

Enter the disposables

As drugs become more potent and more highly micronized, manufacturers are turning to single-use equipment made of flexible, disposable plastic film. Adoption of disposable plastic equipment in solid-dose manufacturing is following a trajectory similar to that in biotechnology. After testing the waters with bulk containers, manufacturers got bolder and began integrating plastics throughout processes. Nonetheless, pharmaceutical processors will probably never adopt plastic process vessels due to the high temperatures and solvents. Where process containers are the “killer app” in bioprocessing, containment seems to be the most exciting development in plastics for chemical-pharmaceutical processing.

Drug makers have discovered disposable plastic’s potential for eliminating the need to clean and validate cleaning for process enclosures. Plastics offer many other benefits as well, among them the ability to view the entire process (unlike metal enclosures) and more rapid design of custom-made enclosures.

Utilities are generally scaled down in flexible film isolators as well. For example, clean-in-place nozzles are unnecessary since the units are discarded after several uses. In many situations, achieving acceptable OELs does not require HEPA filtration. “It’s often quite enough to connect the isolator directly to the plant’s vacuum extraction facility without any extra fans or motors,” says Gary Heath, pharmaceutical industry manager for Envair (Haslingdon, U.K.), which builds and designs process isolators for pharmaceutical, biotechnology, device, and hospital markets. Envair designs the enclosures and subcontracts out fabrication to another U.K. firm.

Disposable containment systems are flexible in design as well as in the materials they use. Heath compares fabrication of conventional enclosures to blacksmithing, and of flexible containment systems to dress-making. Material flexibility allows construction of enclosures of almost any shape or size, with numerous ports, in a relatively short time frame.