For products that can’t be terminally sterilized, aseptic processing offers the best solution
By Sarah Fister Gale
Advanced aseptic processing strategies offer manufacturers the best solution for protecting the quality and safety of their products and for ensuring the highest contamination control standards possible for products that cannot be terminally sterilized-but it comes at a cost. Unlike terminal sterilization, aseptic processing lines don’t involve a high-heat kill step for final products, which can mute food flavors and destroy pharmaceutical potency. But because they can’t rely on that all-powerful, microbial-destroying heat treatment, manufacturers have to put in place strict controls, in-process control testing and validation steps throughout the manufacturing process to ensure that no contaminants ever find their way into materials, components and final product.
Terminal sterilization involves filling and sealing product containers under high-quality environmental conditions to minimize the microbial and particulate content of the final product, and then subjecting the final product to a sterilization step. In most cases, the product and the container closure exhibit low bioburden going into the process, but they are not sterile until the final container is subjected to the sterilization process, such as heat or irradiation.
While terminal sterilization is an ideal choice for heat-resistant products because there are fewer opportunities for error, it’s not usually a viable solution for heat-sensitive products such as vaccines and other biologic products. The high heat used in the autoclave to eliminate microorganisms can weaken or destroy heat-sensitive pharmaceutical ingredients, particularly in the case of biotech products, which feature bioactive proteins that would be denatured under the intense heat of an autoclave.
These delicate products can be affected not only by temperature but also light, pH balance, sheer, and the velocity at which the product runs through a nozzle and hits the surface of a storage container.
“The slightest damage will destroy it,” says Jack Lysfjord, vice president of consulting for the Valicare Division of Bosch Packaging Technology (Brooklyn Park, MN).
“If you have one percent degradation in a product, the rest of it will die within days. Once it starts, you can’t stop it.”
As a result, many pharmaceutical as well as food and beverage products are manufactured using advanced aseptic processing strategies, and as the biotech industry matures, the ratio of aseptically produced products to those that are terminally sterilized continues to expand.
Separating people from product
An advanced aseptic process is one in which direct intervention with open product containers or exposed product contact surfaces by operators wearing conventional cleanroom garments is not required or permitted. Because there is no opportunity to sterilize the product in its final container, it is critical that containers be filled and sealed in an extremely high-quality environment.
Through aseptic processing conditions, manufacturers of pharmaceuticals, vaccines and similar products produce sterile end products by compounding and assembling sterile bulk drugs or raw materials with sterile packaging components. The key is to maintain the sterility of all the ingredients and packaging by using containers, closures and processes that are already sterile and are kept inside a high-quality environment, typically within an ISO 5 (Class 100) cleanroom.
“Aseptic processing is not a choice; it’s product dependent,” Lysfjord points out. “Regulations state that if you have a product that can be terminally sterilized, that’s what you must use.”
Unfortunately those products are limited to simple chemicals, saline and other heat-resistant substances that won’t easily degrade when exposed to heat. The rest of the industry relies on aseptic processing strategies to keep products and workers safe in the cleanroom environment.
According to the FDA’s Guidance for Sterile Drug Products Produced through Aseptic Processing (September 2004), there are basic differences between the production of sterile drug products using aseptic processing and production using terminal sterilization.
Figure 1. Image from a real-time, interactive 3D scene in a simulated cleanroom training program. Photo courtesy of 3D Solve.
The guidance notes that because aseptic processing involves more variables than terminal sterilization, it requires more validation and controls. For example, before assembly, the individual parts of the final product must be subjected to appropriate sterilization processes, such as heat for glass containers and filtration for chemicals and liquids.
Figure 1. Image from a real-time, interactive 3D scene in a simulated cleanroom training program. Photo courtesy of 3D Solve.
If the environment, ingredients, equipment and personnel do not meet the strict guidelines that govern the aseptic processing environment, any step in the process could introduce an error that could ultimately lead to contamination in the final product.
“Human interaction with the product is one of the biggest contamination control risks. As the involvement of operators in cleanroom activities increases, so does the risk to finished product sterility. Operators must be trained to use aseptic techniques at all times,” notes Carmen Wagner, president of Strategic Compliance International, a pharmaceutical, medical device and biotech consulting firm in Cary, North Carolina. “Problems can occur because of human error, but also as a result of natural causes, such as people shedding particulate through the performance of their daily activities.” For example, operators working within a cleanroom environment can shed millions of 0.3 μm particles in the form of skin flakes and clothing fibers. In fact, a motionless person, sitting or standing, can generate approximately 100,000 particles per minute, and with motion, as much as 500,000 to 1,000,000 particles per minute-for a grand total of up to 1 billion skin flakes per day. “There are so many things people do to contribute to contamination without ever realizing it.”
In operations in which toxic and potent chemicals are used, such as the manufacture of immune-suppressing cancer drugs, the operators also need to be protected from the product, Lysfjord says.
Wagner is excited about companies such as 3DSolve, from Cary, North Carolina, which is working to develop Aseptic Cleanroom Simulator training programs that use computer-based simulations of real-world cleanroom facilities, equipment and processes to teach aseptic cleanroom operations to pharmaceutical industry workers (see Fig. 1). The course covers issues such as basic microbiology, hygiene, gowning, handling of equipment, and specific written procedures covering aseptic processing area operations. Wagner adds, “For companies that can’t afford a dedicated cleanroom for training, simulated learning gives trainees a safe place to learn, without taking risks with real facilities or products. Just as there has been tremendous progress-almost revolutionary in some cases-in aseptic processing technology, there are also emerging technologies that will facilitate the development of more effective training for aseptic processing, and 3DSolve is one of those.”
Wagner believes that teaching workers in a simulated environment allows them to practice and perfect their skills before they go into a real cleanroom. She adds, “This can be done without using expensive live space, real equipment or materials just for training purposes. This simulation approach has been used extensively with military training and it has been very successful. Operators can complete several hours in the simulated environment, honing and internalizing critical skills, prior to interacting with the actual processing line, which makes them more comfortable to experiment and learn, and helps eliminate the risks of human error posed by new employees. It offers a lot of promise.”
However, as Wagner points out, humans can do everything right and still contribute to contamination, which is why the industry is pushing to create systems that eliminate human contact with equipment and the product. To achieve that goal, isolators and restricted access barrier systems (RABS) continue to claim their place in aseptic processing manufacturing as companies realize the benefits of adding controlled spaces and enclosed equipment in which product can be shielded from environmental and human interaction.
“The goal of isolators and RABS is to segregate people from product,” says Lysfjord, who has conducted annual global surveys of isolator and RABS use in aseptic processing lines since the mid-1990s. His survey data shows a steady increase in the use of both technologies, with the two most recent isolator surveys showing a significant jump from 2004, in which 256 facilities claimed to have isolator systems in operation, to 2006, in which 304 facilities were operating isolators. He notes that many of the isolator projects currently being planned mention protection of operators working with potent drugs as a key factor in the decision.
“A paradigm shift is building in the industry to separate people from product,” he says. “The use of isolators and RABS supports that.”
Isolators can be used in a wide variety of applications, including both large- and small-volume parenterals, lyophilized products, powder fills, combination products, and medical devices, as well as more typical liquid fills into a single container (see Fig. 2).
There are two types of isolator systems: closed and open. In closed systems, all components are gathered in batches into portable transfer isolators and moved into the sealed isolator through double-door systems and rapid transfer ports (RTPs). Open-system isolators feature mouse holes through which vials pass. Because the mouse holes are open during operation, continuous overpressure of the barrier isolator ensures separation of the environment inside the isolator from the surrounding room air.
Some facilities use isolator technology just for critical steps, such as filling vials. Others have implemented series of isolators to produce an entire line, with filling, overcapping and washing all taking place inside the isolator environment, Lysfjord says. Conveyors or robot exchange systems are used to transfer the vials between production areas.
According to Lysfjord, there are several benefits to isolator technology in the cleanroom. The sterilization level inside an isolator can be brought to a sterility assurance level (SAL) of 10-6, or one contaminated vial in a million, which in most cases is significantly higher than the sterilization rate of a conventional cleanroom space.
It also allows for extended campaigning, in which several product lots can be filled over the course of several days and for up to four weeks without shutting down the production line. “Existing technology can maintain aseptic conditions for 28 days. As long as you can validate that you can maintain sterility during that time, you can do it,” he says.
Campaigning offers significant cost savings by eliminating extended downtime for cleaning steps. However, Lysfjord warns, it is a serious business decision. If a problem occurs during a campaign, you can conceivably lose the entire product batch, and the longer the campaign, the greater the loss. “If it’s a five-cent product, it may be worth the risk, but if it’s a $5 million lot, you may want to think hard about how long to run the line.”
Using isolator technology for aseptic processing can also save facility owners a significant amount of money in the design and construction of new and retrofit facilities. Because the isolator maintains ISO 5 conditions internally, the equipment can be placed into an ISO 8 (Class 100,000) cleanroom. “The cost per square foot is much less in that scenario,” explains Lysfjord.
The operating space can also be much smaller, further reducing facility costs. “You do have to put more money into equipment, but the reduced cost for the facility far outweighs it,” Lysfjord says.
Like isolators, RABS can be used in cleanrooms to isolate product from people, although this type of system is less secure. RABS and isolators provide similar functions, but RABS offer product protection and contamination control by providing a “physical and aerodynamic barrier” over the critical process zone. Although there are some isolators that use this combination (in the form of the isolation barrier and a sterilizing tunnel), the aerodynamic barrier is restricted to transfer entry or exit zones into and out of the critical zone. The extent of separation of process, people and environment provides a sliding scale of product protection.
RABS use a combination of a barrier and a dynamic HEPA-filtered airflow to create isolated space and prevent human interventions. Compared to isolators, RABS can allow for faster start-up time and ease of changeover. However, because it is not a closed system, steps need to be taken to ensure the sterility of the process. Using restricted access barrier equipment on its own is not enough to protect the process. It must be supported by critical, validated operating procedures to ensure quality standards are met.
To clarify the use of RABS in aseptic processing, the International Society for Pharmaceutical Engineering (ISPE) worked with the FDA to produce a RABS definition paper in September 2005 with the goal of reducing confusion about the key elements of RABS and their regulatory requirements. According to the paper, in order to be classified as a RABS, a system must possess certain criteria, including: properly designed equipment; management oversight; a quality system in place; proper surrounding room design to maintain ISO 5 in the critical zone; proper gowning practice; proper training; initial high-level disinfection with a sporicidal agent; and proper SOPs for rare interventions, disinfection, appropriate line clearance, and documentation of an event.
While much of the industry is focused on improving its aseptic processes, it is also struggling with the need to adhere to differing regulations for globally marketed products. “The vast majority of sterile drug products being produced are being distributed globally, thus they are impacted by multiple regulatory requirements,” says Douglas Stockdale, president of Stockdale Associates, an aseptic fill/finish and sterile packaging consulting company (Rancho Santa Margarita, CA). “The principal aseptic regulatory issue is that global requirements are not fully harmonized.”
In the United States, the two FDA regulatory groups primarily concerned with aseptic processing are the Center for Biologics Evaluation and Research (CBER) and Center for Drug Evaluation and Research (CDER). In most of Europe, the European Agency for the Evaluation of Medicinal Products (EMEA) provides the regulatory overview for aseptic processing according to Annex 1 of the EU GMP guidelines. In Japan, the Ministry of Health and Welfare (MHW), along with the relatively new Pharmaceutical and Medical Devices Evaluation Center (PMDEC), is the principal regulatory agency. For the rest of the world, individual regulatory agencies exist, but as a general rule they recognize the regulatory requirements of ISO, FDA or EMEA.
Although the fundamentals of aseptic processing strategies are similar across regions, the EU and the U.S. have different requirements, and they use different terminology to define their terms, including how they classify active and inactive rooms. The inconsistency in language alone makes having discussions around harmonization complicated, Stockdale points out. For example, according to Annex 1, the Grade B cleanroom requirement for particulate is the same as Class 100 without activity, but the same as Class 10,000 with activity.
This translates into challenges for processing facilities that produce global products, says Glenn Jennings, director of AAIPharma’s manufacturing center in Charleston, South Carolina, which is dedicated to the manufacture of sterile drug products as well as aseptic liquid and lyophilized products. “All of the regulations are different in their approach,” he says. “One of the biggest differences between the U.S. and the EU is that the U.S. allows more procedural controls, while the EU requires engineering controls.”
That means that U.S. facilities can use systems such as airflow design and procedural steps to cascade toward stricter cleanroom conditions, moving from Class 100,000 to Class 10 at the core; while in the EU, regulations require rigid structures, such as airlocks in gowning areas, to delineate these zones as an added level of protection. The EU also establishes classification in common-use hallways between compound areas, which may not be classified in a U.S. facility.
Non-viable particle monitoring requirements also differ. U.S. facilities sample one cubic foot of air and only sample for 1- and 0.5-micron particles, while EU facilities sample one cubic meter and test for 5-micron particles in addition to 1- and 0.5-micron particles. “The rationale is that a particle that big could act as a host to a viable particle,” Jennings says of the differing regulations. Jennings does agree that testing a cubic meter of air increases the confidence level of the room.
Regardless of which standards are better, facilities such as AAIPharma’s that manufacture products for the global market deal with the differences by adhering to the highest standards among all the regulations, which adds costs and extra steps to the process but gives them, and their clients, the assurance that products are marketable worldwide.
To achieve this goal, two years ago the AAIPharma facility began capping vials in a Class 100 filling room, which adheres to the EU expectations and exceeds U.S. requirements (see Fig. 3). In its latest facility renovation, the company added airlocks between rooms to make its Charleston plant EU-compliant.
“Striving for the strictest regulations adds a lot of extra expense,” Stockdale notes. For some companies, making such decisions becomes a purely financial consideration: When it is not economically viable for certain products, they may not be marketed in particular regions of the world. Unfortunately, this reduces financial success for the company and prevents consumers from having access to important drugs. For other companies, it means decentralizing the manufacture of critical drugs, with regional facilities handling local production.
Figure 3. A capper in AAIPharma’s manufacturing facility in Charleston, SC. Photo courtesy of AAIPharma.
Ideally, all of these regions would come together and develop a single global set of regulations, but experts agree that much work still needs to be done.
“When it happens, harmonization will only be a positive thing,” Jennings says. Moving toward a single standard for aseptic processing “eliminates the need to select the strictest requirements from each set of regulations and then meld them into a single global approach for the facility. That’s a positive thing for the industry.”
Jennings admits, though, that at this juncture harmonization won’t have a significant impact on his facility. “Because we are a global company, we’ve had to make changes to our facilities to satisfy the needs of clients all over the world,” he says. “It gives them an added level of comfort to know we meet requirements in the U.S. and the EU.”