Keep It Clean
In June, biotech giant Genzyme was forced to temporarily shut down its plant in Allston, Mass., when a virus was discovered in one of the plant’s six bioreactors. Genzyme said that although the virus could not infect humans, it could impede cell growth and slow production of the drugs manufactured there—Fabrazyme (agalsidase beta), which treats Fabry disease, and Cerezyme (imiglucerase), a therapy for Gaucher disease. The production suspension meant temporary rationing of the drugs, with patients asked to skip doses.
The suspension was projected to last until the end of July, and the rationing left patients taking the drugs—about 8,000 worldwide—worried about how they would get treatment. Other companies hurried to fill the gap; Shire PLC filed a new drug application with the Food and Drug Administration (FDA) for its Gaucher drug, velaglucerase alfa, under a treatment protocol that would allow the company to market the drug before approval, requiring that it be initially provided free of charge.
Meanwhile, Genzyme was expected to lose between $100 and $300 million in manufacturing revenues as a result of the shutdown. This was actually the second time the virus—called Vesivirus 2117—had hit Genzyme’s production facility; the first incident occurred in 2008 and caused declines in cell productivity. The 2009 contamination was detected by Genzyme’s own monitoring system; the company had recently developed a highly specific assay for Vesivirus.
The Genzyme incident underscores the importance of contamination control and monitoring in the biopharmaceutical industry, said Ken Christie, senior director of consulting services for VTS Consultants Inc. “Biopharmaceuticals are primarily sterile products by nature, and anything labeled a sterile drug is something that the FDA, or any European regulatory agency, is going to see as possessing the highest level of risk to the public. As a result, the control of potential sources of contamination becomes of primary importance. Because biopharmaceutical companies are growing cells and working with reactor processes, the challenges are even greater.”
Multiple elements must work effectively together to ensure good contamination control, said Christie. They include:
- facility and equipment design;
- environmental systems;
- monitoring; and
Of these areas, the facility and equipment design element remains one of the most significant challenges for biopharmaceutical companies today, according to Rebecca Brewer, director, consultancy services, validation and GMP compliance with Dober Group. “The reactor design is significantly more complex than in traditional pharma, and the bioreactors, in particular, become challenging if the cleaning-in-place (CIP) and sterilization-in-place (SIP) systems have not been designed to properly access and provide cleaning to all surfaces.”
That happens fairly often, Brewer said, because of the complexity of the equipment. People who design bioreactors are not experts in CIP, and people who design CIP are not experts in bioreactors. And they talk to each other, she said, “less often than you would hope.”
There’s no such thing as a perfectly cleanable system unless it’s “an empty tank with no features in it,” Brewer said. “Baffles, dip tubes, bottom-mount agitators—reactors have all sorts of things that make them difficult to clean,” she explained. “Because of the conditions that the product sees during processing, including heat or foam generation, there are difficult-to-remove soils in challenging locations.”
Biotech facilities today are seeking to augment CIP design by modifying factors such as spray ball type or spray ball position, or by changing them entirely. “In cases where more simple engineering fixes can’t be accomplished, you end up having to augment CIP with additional manual cleaning, which is never anybody’s favorite,” said Brewer. “If you can’t overcome a shadowed area or a blind spot, you’re left with very few choices in terms of how to manage it. But if you don’t look after those issues, you will develop buildup in [the] system, with contamination potentially spoiling batch after batch of product.”
Brewer suggested that the best approach to CIP design involves due diligence during engineering of the system, testing for coverage as it’s designed and built. “Typical coverage testing tests one spray device or one flow circuit at a time. And in the real world, to optimize the cleaning cycle, people want two or three fluid paths on at the same time. If you’re going to do that, you need to be sure that’s how they did the original testing, in order to get coverage without interference of one flow with another or cancellation of spray from having them strike each other in the middle of the vessel and miss their target.”
Cleaning, Sterilization Interface
The interface between cleaning and sterilization is also important. “If you have a microbiological contaminant in the system, biotech firms find it very difficult to eradicate it once it’s taken hold and perhaps formed a biofilm,” Brewer said. “Some of this may be due to construction and CIP issues and some due to inadequate SIP to conquer the problem after a CIP process has left residue behind. You have to look at CIP and SIP as partners in the same goal—microbiological cleanliness.”
Another key challenge to maintaining a sterile environment in a biotech facility is the very people who run it. “You can build a facility and put in systems that would give you a ‘cleanroom’ environment, but once you bring operators into that picture, the potential for contamination doubles. People are the biggest source of contamination,” said Christie. That’s where design of the facility itself comes in—systems literally have to be protected from their operators.
The FDA prefers isolator technologies when possible and, when not, restricted access barrier systems (RABS). Barrier isolators enclose the system and do not require a separate cleanroom, while RABS systems must be placed in a cleanroom. They cost less than isolators and appear to achieve the same results, but the agency does indicate a general preference for isolators.
“All of these types of systems are designed to minimize the amount of interaction that an operator has around the critical areas of where a product is filled and stoppered,” Christie explained. “They restrict an operator’s interactions around the critical step where an open vial or syringe or plastic bottle is.”
Isolators and RABS have been around for quite some time, but recently their designs have become more efficient and better able to accommodate a variety of sizes in the filling lines they can encase. “You can have a small company down the road that may need to only fill several hundred vials for a clinical study, while larger companies will have lot sizes of hundreds of thousands of vials at a time,” said Christie. “Because of that, the overall size of the filling line gets to be rather large, and companies are coming up with much more efficient design, with access to motors and things that might break without jeopardizing the cleanroom environment in which these things are placed.”
A current RABS design, for example, allows access to the motorized components of the filling unit from the outside wall of the cleanroom. “This way, an electrician or mechanic does not have to go into the clean area and open the machine,” Christie said. “All access is from the wall on the non-controlled side of the equipment, so the environment where the filling actually occurs is not jeopardized. That’s involved in a lot of the new designs.”
—Rebecca Brewer, Dober Group
Although the bane of Genzyme’s existence these days is a virus, many biotech facilities struggle with prevention, control, and cleanup of molds, according to Jim Polarine, a technical services specialist at STERIS Corporation who focuses on microbial control in cleanrooms and other critical environments.
“I was brought into a site in California where they had such a problem with molds that it got into the stainless steel and ductwork in the cleanroom, and they had to spend about $200 million to replace the stainless steel and the flooring,” he said. “By the time I got called in, contamination was running rampant. We tried all the usual chemistries and they could control it for a while, but they had let things get out of hand and the mold was innately in the surfaces. When it gets into the flooring and up into the gaskets of the HEPA filter, then you have a big problem.”
At another facility, this one in Boston, an operator dropped a glycol tube, which broke on the floor. Growing in the tube was a spore-forming bacterium called Bacillus polymyxa. “He tracked it all through the cleanroom and the entire biotech site, and it ended up getting into the product, on the walls, and on the floor,” Polarine said. “Needless to say, it became a very long, drawn out process.”
STERIS most often uses a liquid cold disinfectant called Spor-Klenz, a stabilized blend of peracetic acid, hydrogen peroxide, and acetic acid. “We’ve also been getting some accounts where we bring in vaporized hydrogen peroxide for room decontamination, to kill really resistant or recurrent spores. For regular routine decontamination of the cleanrooms, I see a lot of end users using phenolic disinfectants. Probably 80% of the industry in the U.S. and Puerto Rico uses phenols, which can kill higher end bugs such as mycobacterium and [have] surfactant technologies to remove particles, soils, and dirt.”
Although cleaning validation methods are fairly standard, Brewer said that some in the industry still aren’t adequately justifying their decisions. “Particularly in biopharma, I still see companies relying on not more than 10 ppm [parts per million] in the next batch without adequate justification.” That’s the most common quality threshold applied to pharmaceuticals, but it’s been called a convenience value and may not have a lot of meaning.
“I also see people employ the purified water limits of 500 ppm carbon without adequate justification of what that particular limit means,” Brewer added. “Part of the reason that exists in biopharma, in particular, is that the determination of what would be a therapeutic dose-based limit or an appropriate contamination-based limit—particularly in upstream processing—is very difficult to do. As a result, they fall back to generic values. But that’s not adequate science for cleaning validation limits. They should be driven by the impact of carryover to the next drug they’re going to be producing.”
At Genzyme, Vesivirus 2117 was discovered by the company’s own monitoring, a still-evolving process. “Past practices had companies take periodic samples throughout the course of the filling process, which could last two shifts or 24 hours. The attitude was to sample at the beginning, middle, and end of a run, which might have occurred three times over a 16-hour period,” said Christie. “It varied. Now, the FDA wants to see more routine monitoring during the course of every shift, with their preference a continuous monitoring of the environment for both nonviable particulates and viable organisms.”
The technologies available to achieve that goal are becoming more user-friendly. “Technology is being developed where the counts or organisms can be downloaded to a database for trending of the results, which allows companies a better ability to detect potential sources of contamination before it adversely affects a filling process,” Christie said. “But don’t forget, the FDA wants to see you do something with that trend data. They like to see trends of environmental monitoring results—how do they vary between seasons? Is there one person who sticks out for routinely failing or having counts detected? But their next concern is what are you doing about it.”
Aspects of contamination control can’t be looked at in isolation. “Facility design, environmental systems, routine maintenance and calibration of those systems, the sensors used to monitor them, training of personnel—they all have to be controlled to give you a final ability to eliminate potential sources of contamination,” Christie said. “It’s really astonishing to somebody coming into biotech for the first time from, say, solid products or over-the-counter. The levels of regulation you’ll have to deal with are like nothing else you’ve ever encountered.”