Controlling Contamination in Parenteral Packaging
Technological advances in filling methods lessen the risk of contamination in parenterals.
Erik Swain, Senior Editor
|West Pharmaceutical Services employs two Huber washers to process Westar ready-to-sterilize components.|
Contamination control is a task that affects practically every area of parenteral packaging. Parenterals often entail volatile drugs and high-risk routes of administration, so regardless of what filling method is used—from aseptic processing to barrier isolation to blow-fill-seal—pharmaceutical companies must be extremely alert for potential contamination.
In recent years, there have been all kinds of technological advances to prevent contamination of parenteral drugs during filling and packaging—from the overall systems down to the smallest components used in them. Whether these are a result of regulatory pressure or marketplace competition is open to debate. But whatever the cause may be, people in the industry believe there are more developments to come that will make parenteral drugs even safer.
The most prominent development has been the increasing adoption of barrier isolation systems for use with aseptic filling lines. These systems provide a theoretically airtight environment, and thus do not need to be placed in areas subject to cleanroom requirements as stringent as those housing conventional aseptic processing lines.
"There is continued growth in isolators and RABS (restricted access barrier systems, which are essentially isolators without bottoms) because of the removal of people from the process," says Jack Lysfjord, vice president of technology at Bosch Packaging Technology (Minneapolis). "Filling is filling, but those devices make for greatly improved cleanliness. Also, the use of isolators for containment purposes and for protecting the operator from the product is rapidly increasing and becoming a reality in production."
In fact, says James P. Agalloco, president of Agalloco & Associates (Belle Mead, NJ), a consulting firm, "I believe the entire industry is moving toward isolation technology. I don't know how long it will take, but they will get there."
One reason for the anticipated industrywide adoption is that newer drugs tend to need a higher level of contamination control, Lysfjord says.
"If you go back 20 years, achieving a sterility assurance level of 10–3 was difficult to do. Today, we can easily achieve that with conventional cleanroom equipment," he says. "But back then, a lot of drugs were chemicals in a solution. They were not typically protein-based or sugar-based. Newer drugs that are, though, can be contaminated with a bioburden. If a biotech product picks up a contaminant, the contaminant will grow and destroy the drug. Also, modern drugs can't be terminally sterilized because they are often damaged by heat. And products before had pesticides, which are now being removed.
"We are seeing more and more lines where containment is required all the way through, not just being enclosed in mixing, but all the way to even cartoning and labeling." Agalloco continues. "There is more need to have a design that works as a whole system—filling, stoppering, and isolation together with an HVAC package, with everything controlled from one controller. That reduces validation time and time to market."
Other drivers, Agalloco notes, include return on investment, operator costs, and the ability to do longer runs.
Some firms still see impediments to adoption. "Invested costs in existing facilities and the belief that isolators take a long time to validate" get in the way, Agalloco says, but he notes that there are usually valid arguments to trump them. For example, he says, "rumors circulate about companies having been at it five or six years. That's the worst case. But the best case is under a year for validation. There is also uncertainty about what FDA is going to do, but that is being clarified." The agency is planning to update its aseptic processing guidance to include a section on barrier isolators, though the timetable is as yet unknown.
Dimitri Wirchansky, pharmaceutical technology specialist with Jacobs Engineering Group (Conshohocken, PA), says that the case for isolators was hurt at first by unrealistic expectations, but once firms learn that isolators can be extremely effective in the right environment, they might be willing to adopt them.
"Initially, isolators were not looked upon too favorably," he says. "Some people were saying that you could put your operations in a garage as long as you had an isolator and took an aggressive stand as to the requirements for barrier environment. That hurt the case a bit. But folks in Europe have been using isolators more than in the United States, and more broadly. So that has helped. The lesson is that any system is a combination of all of its environment as well as its own elements. There are some risks in placing an isolator in a lower-classified environment. Every system has to be evaluated for its level of security and ability to provide safety through aseptic processing. Isolators are now understood better by the agency and by people trying to use them."
But, Wirchansky continues, "there is still a lot of interpretation on how to do things within an isolator, such as how the inside needs to be decontaminated and to what level. You have to consider what operations are taking place, and what is passing in and out of the isolator. It has to be designed for a specific application and for specific materials flowing in and out, and has to be set up in a way to make those transfers secure. Many applications are similar, but you can't assume you can cookie-cutter something that somebody else did. You have to look at how the isolator, filling machine, decontamination system, and materials work as a fully functioning system. People are finally looking at the total task and how it has to be integrated into the total system."
|Stoppers are tested to ensure that they do not contaminate parenteral packaging (photo courtesy of West Pharmaceutical Services).|
Blow-fill-seal technology has advantages over conventional aseptic processing when it comes to contamination control and can be an alternative to barrier isolation in some applications, says Mohammad Sadeghi, new products manager at Holopack International (Columbia, SC), a blow-fill-seal equipment manufacturer.
"The machine setup and operation is done from the outside processing area, which means reduced personnel intervention into the aseptic processing area," he says. "The separation of the filling side from the mechanical side reduces the particulate contribution to the cleanroom environment from mechanical parts. It also offers direct access to those mechanical parts while in operation without entering the controlled filling area."
Agalloco and Wirchansky agree that the technology does have potential to grow. "There is a possibility that blow-fill-seal could become more widespread as an alternative to conventional vial filling," Agalloco says. "If suppliers of those systems can come up with a plastic that provides better oxygen and moisture barrier, it could be used for injectables."
Wirchansky notes that blow-fill-seal has emerged as a filling option for "sterile products such as ophthalmics because the systems have been evolving to be cleaner in how they are set up and run."
Components as well as systems need to be monitored to ensure contamination-free parenteral filling and packaging. Anything that comes into the system is also a potential source of contamination and must be controlled.
One component that has been refined in recent years to reduce contamination risk is the rubber stopper.
"There have been two advances in this area," says Fran DeGrazio, vice president of global technical support and contract lab services for West Pharmaceutical Services Inc. (Lionville, PA). "One is the component itself, which has been made cleaner, with lower extractables. This has been accomplished through better closure formulations, through postprocessing, and with the addition of barrier coatings and various films. The other is in the processing of closures. How can you get washed, processed, and sanitized closures into a sterile suite on top of filled vials? One method is through ready-to-sterilize closures. We have designed a fully validated process, washing closures in pharmaceutical washers with a final WFI (water for injection) rinse, and they are packed in a Class 100 facility. We can also have the process meet specifications as far as bioburden, endotoxins, and particles, as well as silicone if the customer desires. In the end, they are put in sterilizable bags, ready to be put in the customer's autoclave for sterilization."
Another alternative is to dispense with rubber altogether and go with an all-plastic syringe, says Paul Oberdorfer, vice president–medical products for Air-Tite Products (Virginia Beach, VA).
"The company's product is polypropylene and operates like a conventional syringe, and it seals just as well," he says. "There is no silicone oil or synthetic rubber. Both can react, and silicone oil can be a contaminant. All-plastic syringes are being used extensively for in vitro fertilization and can be applied to other sensitive applications. The controversy with natural rubber is well known, but even synthetic rubber can have very reactive curing agents."
MORE CONTROL IN THE FUTURE
Thanks to innovative ideas from suppliers and heightened expectations from FDA, industry can expect to see more developments in the future that attempt to control contamination to an even greater degree.
"One key area will be ready-to-use closures, which are the next step from a processing standpoint," DeGrazio says. "The packaging of the stoppers will continue to evolve so that they can enter into a barrier isolator. There will also be an impact on stopper coatings. With barrier isolators, it is critical that the line not be shut down. But if there is sticking or twinning of stoppers, that can cause a shutdown. Coatings can improve processability, so we have extensive applied research in that area." According to Wirchansky, FDA continues to raise the bar, and its aseptic processing guidance will cause filling technology to continue developing.