QRM Process

Handling Highly Active Ingredients

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.

Flexible film enclosures are relatively expensive, but as more vendors enter the business the price will come down. “We’re not yet at the point where we can justify disposable containment 100% of the time for every process, but we’re close,” says Heath. “It’s not for everybody, but it can certainly be justified for hazardous, highly active materials. It all comes down to the type of product handled, and the frequency with which the operation is done.”

Disposable enclosures are particularly useful for mixing or blending, the last step of which involves opening the bowl and scraping the last bit of active from the blender. “This makes a mockery of containment,” says Heath. “They’ll charge and discharge the bowl in a contained manner, then go off and get PPE [Personal Protective Equipment] and breathing apparatus, come back into the room, open the bowl and physically scrape the product out—in the process, they contaminate the entire room.” The mechanical flexibility of disposable containment allows operators to clean all the equipment within the enclosure rather than bringing it outside.

Disposable containment is a good idea, but costs for all applications can be high, says Jim Agalloco, then there are the environmental issues concerning plastics disposal and exposing product to polymers and plasticizers. He’s also skeptical about the gowning cost savings argument, especially for oral solid-dose products. “I can understand it when you’re talking isolators versus cleanrooms, where you need sterile or aseptic gowns,” he says.

Fuzzy math

For their part, disposable containment system vendors make a strong economic case for using their products, although they keep their spreadsheets to themselves. Doug Durney, director for new business development at ILC Dover (Frederica, Del.), claims the cost savings from disposable PPE alone more than offsets the price tag for disposable containment. One of ILC Dover’s customers, Durney claims, saves more than a million dollars per year by using disposable containment.

“There’s definitely a trend towards getting workers out of protective equipment,” comments Durney. “OSHA has been pushing for use of engineering controls rather than PPE. Then there’s the cost of cleaning and cleaning validation. Even if you absorb it, you’re doing that instead of working on your next product.”

ILC Dover has sold more than 60,000 of its DoverPac Flexible Containment bag systems, which the company designed in collaboration with Eli Lilly. DoverPac, made of a fabric outer restraint and a durable film liner, serves as both a storage and shipping container. ILC also sells flexible plastic gloveboxes.

Smaller is better

The logical extension of the “more potent” argument for containment systems is that, as drugs become more effective on a milligram basis, less drug is needed. As a result, says Chad Ranpuria, process manager at Powder Systems Ltd. (Liverpool, U.K.), chemical processes are shrinking and therefore more easily contained without resorting to cleanrooms or other types of classified space. “The industry is downsizing in volume terms, almost to pilot scale,” he says. “Today, processes that used to be carried out in cleanrooms can be downsized to smaller enclosures.”

OELs have been falling steadily, if not by regulation then through practice, to the point where industry standards surpass government mandates. A decade ago, new plants were routinely specified at 10 micrograms per cubic meter of air, whereas today the built-in OEL is more like one microgram. Ranpuria believes OELs will fall into the nanogram range. “OELs are moving downward so rapidly that exposure limits have become a hot topic,” he notes. “Very few available technologies can guarantee that low level of exposure.”

How far can containment go? To Ranpuria, nothing short of working in short-sleeved shirts will do. “Pharmaceutical workers will one day don protective equipment only when they’re cleaning equipment,” he predicts.

Since a good deal of operator exposure occurs during material transfer and not during the actual process, many vendors offer advanced valves that interface transfer vessels to isolators. For example, Powder Systems’ ChargePoint split butterfly containment valve, developed with a major pharmaceutical partner, employs a direct metal-to-metal seal that minimizes the gap between disks on the discharge and receiving sides. After docking, coupling and transfer the two halves are coupled, un-docked and split apart again. Used alone, ChargePoint reduces OELs below 10 micrograms per cubic meter. Adapting ChargePoint with an extraction ring that draws air away from the valve reduces OELs to below one microgram, according to Ranpuria.

In the bag

Pharmaceutical manufacturers began using bag isolators during the mid-1990s for primary components like stoppers, syringes and plungers. Before that, components arrived either in stainless steel drums fitted with a sterile port, or in non-sterile containers (requiring end user sterilization).

ATMI Packaging (Minneapolis) entered the disposable enclosure marketplace with its Cleansteam bi-laminar microbial-barrier bags made from uncoated Tyvek on one side and high-density polyethylene on the other. Cleansteam is available in standard configuration, which requires cutting to open the bag, as well as an Easy-Tear version. Products like Cleansteam may seem trivial, but the expense of purchasing a sterilization line and validating its operation is anything but trivial. Cleansteam packaging is typically specified at the OEM level, where most of the sales for the product occur.

ATMI currently only sells Cleansteam for components, but is launching a powder transfer bag at Interphex 2005 based on a similar design.

A Baffling Solution for Powder Blending

As pharmaceutical processing evolves towards completely contained processing, process analytical technology (PAT, or however we name its occupational safety counterpart) will provide real-time monitoring of airborne materials. Several companies already offer the tools for doing this, particularly for cleanrooms. How soon the industry at large will adopt these methods is anyone’s guess.

For now safety from airborne powders remains a function of containment, cleaning and validation.

Since the vast majority of containment devices are not disposable, cleaning and clean-ability are the safety-limiting qualities. It doesn’t matter how well an isolator protects workers during the process if unlatching the frame to clean it opens a Pandora’s box of contamination.

“Cleanability is not just a matter of adding spray balls to existing equipment,” notes Andre Petric, manager for material handling systems at Glatt Air Techniques (Ramsey, N.J.). “Every aspect of equipment must be designed from the start for cleanability.” For years, Glatt has specialized in fully-contained, completely cleanable process granulators, fluid bed dryers, powder handling equipment and tablet coaters.

Rather than relying on real-time monitoring, in-process workplace exposure is determined by offline analysis during a facility’s startup and commissioning phases. Validating OELs takes time, so workers wear “space suits” until someone determines that containment systems are doing their job. A first-approximation of worker exposure is also possible by testing placebo materials instead of HAPIs.

Powder blending always presents a containment issue, even with less-than-hazardous materials. The use of baffles inside equipment makes blending more efficient but results in generation of finer powders as well as post-blending cleaning issues. Glatt Air has designed a baffle-less twin-axis blender that raises the bar for mixing/blending containment. The TAM (twin-axis mixer) product will be showcased at Interphex 2005.

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