New medicines bring new concerns for product and personnel protection, and the cleanroom industry is evolving to cope with these challenges in two key areas: pharmaceutical manufacturing and the compounding of sterile preparations (CSP) within hospitals and pharmacies.
By John Williamson
The life sciences industry, from manufacturers to compounders to the various regulatory and standards agencies involved, is in the midst of extraordinary changes, the end of which may never be in sight. Underlying this is the fact that drugs are becoming more complex.
“New treatments call for more aseptic potent or aseptic cytotoxic drugs, which can have an extremely adverse affect on personnel should they become exposed,” says Bill Friedheim, technical sales representative for Skan US, Inc. (Broomfield, CO). “At the same time, these drugs must be protected from contamination, the largest source of which is people.”
It is an environment where laminar flow air benches and cabinets are becoming less relevant and where constructing traditional ISO Class 100 cleanrooms also often proves financially impractical.
“Cleanrooms can be expensive places, ranging from $200 to $2,500 per square foot in the life sciences industry,” says Richard Matthews, chairman of Filtration Technology, Inc. (Greensboro, NC). “Such expense is driving industry to look for better ways to enclose critical process areas into smaller spaces. Instead of classifying an entire room as a cleanroom, concentrate on those spaces where a controlled environment is critical. Self-contained, controlled clean environment enclosures around a critical core process are an economical alternative.”
The changing paradigm is causing new thinking in containment technology and how cleanrooms and cleanroom processes are incorporated into manufacturing and compounding sterile preparations.
“While all agree that protection is paramount, there is disagreement on terminology used to describe equipment involved,” says James Agalloco, president of Agalloco & Associates (Belle Mead, NJ). “For example, definitions of an isolator or a barrier can differ within the life sciences industry, across national borders, within applications such as hospitals and labs and even within a single organization.”
Among the life sciences terms used for containment devices are enhanced clean devices, barriers, isolation systems and restrictive access barrier systems (RABS) as distinguished from “cleanrooms” as covered under ISO 14644 standards.
The IEST, which serves as the secretariat to ISO Technical Committee 209, Cleanrooms and associated controlled environments, went through several iterations in developing ISO 14644-7, Cleanrooms and associate controlled environments-Part 7, which is the standard relating to these devices. The working group wrestled with a number of terms to describe what the standard covers and how the products differ from conventional cleanrooms. It settled upon the term separative devices, defined in the standard title as clean air hoods, gloveboxes, isolators and minienvironments.
“The standard purposely stayed away from being industry-specific,” Agalloco explains. “It was left to the users and equipment providers to iron out the details of just what is needed-while hoping they speak the same language.
“For example,” he says, “there is a difference between a barrier and an isolation system, although the isolation system can have a barrier. Barriers can be breached, like jumping the line for playoff tickets. But isolation systems are like Fort Knox, which can, but should not be, breached without very strict procedures. The weakness of a true isolation system is generally the use of gloves, also known as access devices. Thus, we compare the use of RABS to the ‘perfect’ isolator that, via total automation, functions independently of human intervention.”
RABS and isolators: An ISPE definition
In August 2006, the International Society for Pharmaceutical Engineering (ISPE) issued a definition describing RABS. Jack Lysfjord, vice president of consulting for the Valicare Division of Bosch Packaging Technology (Brooklyn Park, MN), chaired the ISPE definition committee and provides commentary on the differences between RABS and isolators.
“Both RABS and isolators serve as barriers between operators and the ISO Class 5 critical zones where fill-finish operations take place,” he says. “Both use rigid walls, glove ports and transfer ports for components. RABS are typically open on the bottom and provide product protection by airflow. In contrast, isolators provide product protection by overpressure or perhaps negative pressure for containment applications. RABS operate in an ISO Class 7 surrounding room and isolators in an ISO Class 8 surrounding room.”
Lysfjord notes that before beginning batch manufacture in a RABS there must be thorough high-level manual disinfection procedures for all non-product contact surfaces using an appropriate sporicidal agent. Isolators typically use an automated vapor high-level disinfection.
“While the design intent for RABS is to operate as closed at all times, operator intervention is permitted with product protection provided through the use of HEPA or other filters, a controlled unidirectional airflow and an upgraded local surrounding classification to ISO 5,” he says. “The intent is to always maintain ISO 5 in the critical zone.
“Some firms are using RABS that are never opened during operations and are achieving very good results,” Lysfjord says. “Others have RABS that, while operating closed, may have rare exceptional events that require opening of the enclosure. Such interventions create product risk and are considered deviations that must be documented so that any risk to the exposed sterile product can be assessed.”
Operators must be properly attired. System design and process control are as much a matter of how you do it as how you defend your position to the FDA during an inspection.
“It is important to view RABS as a concept for enhancing conventional equipment and tightening up procedures instead of making excessive equipment investments,” Lysfjord explains. “Although they are not as robust as isolators, they can provide initial capital cost savings and are certainly more advanced than traditional conventional cleanroom operations.”
Isolator process equipment systems are experiencing a paradigm shift in cost perception, Lysfjord says. “The system does much more to protect the product while saving other capital and operational costs. With isolators, the facility footprint is smaller, and multiple-line operation results in reduced personnel, reduced HVAC and utility costs and reduced gowning and environmental monitoring costs.”
Smart pharma design
Julian Wilkins, vice president and senior consultant for PharmaConsultUS, Inc. (Bridgewater, NJ), says factors reshaping the life sciences industry include trends toward live vaccines, small molecules, larger molecule combination and small-volume, high-value, highly targeted drugs.
“This means high-throughput manufacturing churning out millions and millions of dosages is becoming impractical,” Wilkins believes. “Constructing cleanrooms under the old operating standard to meet new market realities would cost and waste billions. Instead, we’re moving to highly flexible facilities that meet stringent standards while being tailored to small product runs.”
Put another way, the trend in pharmaceutical manufacturing is toward continuous small-scale production in facilities that will minimize the need for conventional cleanrooms.
The mini-cleanroom is geared to produce small-volume, high-value drugs as opposed to mass-produced products. “This is lean manufacturing,” Wilkins says. “It uses continuously running, closed-production equipment that is easy to monitor from the outside.” Major added benefits are substantial cuts in labor, gowning and other costs.
According to Wilkins, smart pharma design includes several continuous-output, isolator-based production lines that allow a stepwise increase to suit demand and a stepwise decrease as demand falls. “Such a scenario allows downtime without significant impact on throughput,” he says. “The lines are adaptable, so that they can be reconfigured for other products. Product-contact parts can be used for other compounds where science-based risk assessment is made, or can be product dedicated. With multiple mini-lines available, maintenance can be scheduled. The plant gains production flexibility because it does not rely on a single process system.
“Pharmaceutical production equipment must go through a design revolution,” Wilkins says. “For instance, little has been done in the oral solid dosage (OSD) area. OSD design would move away from the unit operations that our grandfathers would recognize. Closed systems would be used to provide a product environment, while the operator would be in a separate environment tailored to meet human comfort. The result would be a cleanroom-in-a-box using a fraction of the energy currently used in conventional cleanrooms.”
Wilkins says that the biotech industry-the architects, engineers, safety, compliance, R&D, QC, production, packaging and other personnel-must get on board with this thinking.
What’s the holdup?
Despite the apparent benefits of new aseptic processing systems, the industry has been slow to respond, especially in the United States. Sterling Kline, R.A., senior director of project development for Integrated Project Systems (Lafayette Hill, PA), says one of the reasons is that pharma failed to take ownership of the challenge.
“There’s an obligation in the pharma industry to achieve aseptic processing, and the reason is patient protection,” he says. “That is the position of the Food and Drug Administration (FDA), and it’s up to the manufacturers and compounders to prove that their processes achieve that end. It’s not up to the FDA to tell them how to make it happen.
“This was a hurdle,” Kline continues. “Although isolator technology was proven in Europe, the attitude of the FDA was ‘show me.’” This involved companies making financial and other resource commitments to prove the process. Today, however, there has been positive progress. For example, three pharma companies, the ‘LUM’ group (Lilly, Upjohn, Merck), stepped up to the challenge and made investments to prove the process, without a guarantee that the FDA would accept the findings. Today the FDA considers isolators, specialized barriers and robotic systems as among the advances in aseptic processing technology.
Another key aseptic operating issue was resolved with the reduction of vaporized hydrogen peroxide (VHP) cleaning cycles from eighteen hours to three. This provided a positive impact on system flexibility.
Internal struggles have also often impeded progress. “Decisions on achieving advanced aseptic processing can be hampered due to conflicting objectives within a company,” Kline says. “Management looks at financial performance and sees investment in a process it might not understand as a risk to that performance. This can lead to the position, ‘If conventional cleanrooms work, why change?’ Conversely, however, with the unit cost of some of today’s formulations reaching astronomic levels, the risk of losing a batch of drugs due to contamination can likewise be extreme.
“Summing up,” says Kline, “the challenge is to get people on board. The FDA accepts isolators as a means of achieving reproducible performance. Operating issues are being addressed. It comes down to the mindset of corporations and the people within; their attitudes, prejudices, being ‘risk averse’ and other notions of changing the way things are done.”
There’s no question that companies thinking about advanced aseptic processing face important decisions. Fortunately, more data is available to help them. Valicare’s Lysfjord says, “Looking at the big picture, designing and installing an advanced aseptic processing system must be well-thought-out, with the ultimate goal being validation by FDA and/or other agencies. We believe the best approach is a design of isolators and fillers where components work together while being fully integrated into the building power, HVAC and plumbing systems (see Fig. 1). System monitoring must be continuous. Similarly, personnel training is crucial in order to raise knowledge of cGMP aseptic processing to protect the product as well as containment of potent products to protect themselves.”
Compounding sterile preparations
IEST 146447-7 addresses “separative devices” from the perspective of pharmaceutical manufacturing. Compounding sterile preparations at the corner pharmacy, in the hospital, in physicians’ practice facilities and similar locations is addressed by United States Pharmacopeia Chapter 797 (USP <797>). It covers low, medium and high risk levels.
“Pharmacy compounders work in an environment substantially different from that of pharmaceutical manufacturers,” says Henry D. (Hank) Rahe, technical advisor for Containment Technologies Group, Inc. (Indianapolis, IN). “That’s because they take components from several sources and then manually sanitize them before compounding. Although the insides of the container are considered sterile, the outside of the container is not, due to touch contamination.
“Within this segment of the industry there are also a number of terms used to identify equipment,” Rahe explains. “Examples include isolators, barrier isolators, biological safety cabinets and aseptic compounding isolators. Whatever the name used, however, the objectives are similar to those on the manufacturing side-product and personnel protection.”
One firm, The Baker Company (Sanford, ME), uses the term isolators. “These replace open-fronted laminar flow cabinets in the aseptic preparation of drugs-mostly intravenous or parenteral-which are immediately given to patients,” explains David Eagleson, vice president of business development. “Positive pressure isolators are used for sterility assurance in instances where drugs do not pose a hazard to the pharmacy worker, whereas negative pressure systems are used where such exposure is hazardous.” The most common class of the latter are drugs used in chemotherapy.
“USP <797> provides guidelines for these activities, but changes are in the making,” Rahe says. “Since 2006, more stringent proposals have been under review by the industry, attracting hundreds of comments, many of which are not favorable. For example,” he points out, “there is a high level of questioning on the validity and science of proposed revisions. But what is consistent between the original 2004 guidelines and the proposed 2006 revisions is that isolators are not required to be in a cleanroom and that they are recognized as superior tools for compounding because they provide high sterility assurance levels. In short, they are proven in practice because they eliminate touch contamination.”
Although the debate on the proposed revisions is having an impact on investment decisions within organizations impacted by <797>, until such time as the 2006 revisions are adopted, the 2004 recommendations remain in effect. Rahe says, “Organizations expecting a ‘final product’ won’t see it happen. That’s because the final product is the USP process itself, which allows for annual changes.”
Biological safety cabinets
Biological safety cabinets are another member of the barrier and containment system family, sharing many attributes and similarly charged with protecting people, product and the environment from biohazards and cross contamination during routine procedures (see Fig. 2).
“This is becoming increasingly important,” says Baker’s Eagleson. “Protection is provided in Biosafety Levels (BSL) 1, 2, 3 and 4 corresponding to Class I, II and III cabinets, with the latter specified for high-risk (BSL 3 and 4) biological agents. Standards are set and periodic testing is administered by NSF International through NSF/American National Standards Institute (ANSI) Standard 49.
“The highest BSL levels of agents must be handled in a Class III cabinet operating under negative pressure and with gas-tight construction,” Eagleson says. “Supply and exhaust air must also be suitably treated to protect the environment.” Cabinets are fitted with rubber gloves to provide the highest containment reliability consistent with high-risk agents. Some Class III cabinets used in containment laboratories (BSL 3 or 4) provide aseptic conditions within the work area.
There are many sources for equipment used in advanced aseptic processing and the selection procedure can be extremely complex. Decisions, made with the help of experts, should focus on the processing to be accomplished, maximizing efficiency and flexibility, and complying with applicable standards. Several features can contribute to achieving these goals.
Equipment should be easy to clean and sanitize inside and out. Stainless steel, glass, high-performance scratch-resistant plastic and rounded corners contribute to this. Accessibility, spray guns, vacuum wands, well-placed drains and quick-drying capability are also pluses.
Choosing between conventional cleanrooms, RABS, isolators and their various configurations is not an easy task. As Kline notes, “Think of what you need to do, then design the process to make it happen.” Kline suggests setting up procedures in advance, focusing less on the building and more on the fact that you are making products. Isolator-based manufacturing can work in a variety of configurations, he says. “It works for vials and pre-filled syringes. Properly designed, it can work for mass production, and because it is easy to validate cleaning between batches, it works for generics and contract manufacturing.”
Bristol-Myers Squibb’s Manatí Sterile Expansion Project in Puerto Rico provides an example of the thinking that goes into investing in a new aseptic processing system for parenteral manufacturing.
Robert Roy, associate director of global engineering, says design considerations called for incorporating new technologies in a multi-purpose facility producing both liquid and lyophilized products.
“We wanted four production cells, each capable of independent manufacturing capacity, and each capable of being taken off- line without impacting other cells,” he says.
Cell capabilities include formulation, primary packaging and ancillary support services such as autoclaves and parts washers. Although current cells are non-potent, future cells can accommodate potent products.
ISO Class 5 biological safety cabinets in a high-risk blood labeling operation. Photo courtesy of Radiology Services of Hampton Roads.
After looking at cleanrooms vs. isolation technology, Mr. Roy said his team determined that the latter had matured to the point where it could be reliably deployed. “The next decision process was RABS vs. isolators,” he says.
There were three key considerations. “First,” Mr. Roy says, “the VHP decontamination schedule is validatable, reproducible and short-four hours in our case. In terms of facility layout, isolators eliminate the Grade A (ISO Class 5) space required around the RABS and the attendant gowning rooms. And third, in terms of operating factors, isolators eliminate manual sanitization and reduce the need for environmental monitoring.”
Ultimately, the Manatí team recommended isolators for the project. “Benefits include an improved compliance profile, product and personnel protection, expectations of reduced operating costs, and a validated VHP decontamination schedule-more effective and reproducible than manual sanitization,” explains Mr. Roy.
Another example can be seen in Amgen’s selection of fill/finish equipment at its facilities in Puerto Rico and Ireland. Stanley Cooper, executive director of corporate quality, describes the assignment as involving several aspects. “We wanted to conform to anticipated preferred technologies-including regulatory requirements-in effect in 2010 for aseptic filling of parenteral products,” he says. “We wanted a cost-effective solution leveraging the capabilities of modern technologies, and we needed to mitigate or eliminate the risks inherent in our current capability at least for three years post-startup.”
Cooper collected information needed to educate the company on several new aseptic fill/finish technologies. “These included isolators, RABS, cleanrooms, cleaning and sanitizing processes, operational requirements and startup/validation requirements. We found we had to overcome preconceived notions concerning these technologies,” he explains.
The Amgen team met with the FDA, manufacturers, industry experts, and pharmaceutical firms in the U.S. and Europe, created white papers, attended industry conferences, held group discussions and prepared a cost analysis of candidate technologies. Conventional cleanrooms, RABS and isolators were the areas of focus.
“Our team achieved consensus on a recommendation for isolator technology over RABS,” Cooper says. “The margin was small, and the fact that the industry is divided on the same issue was consistent with this finding. We also recommended an E-beam sterilization interface for decontaminating syringe tub overwrapping.”
Radiology Services of Hampton Roads in Chesapeake, VA, is a large, central nuclear pharmacy serving southeast Virginia and northeastern North Carolina. It supplies time-critical, sterile radiopharmaceuticals to healthcare facilities for use in disease diagnosis and treatment.
“Our intent, more than a year ago, was to evaluate our operation and make any engineering upgrades necessary to be in full compliance with USP <797>,” says manager and radiation safety officer John M. Tabb, Jr., RPh, BCNP.
Most of the firm’s radiopharmaceuticals are compounded with Tc-99m as the radioactive portion of the molecule. Tabb says, “These products are considered low-risk using USP <797> criteria: They are compounded from sterile components, prepared using closed system transfer and must be used within several hours.
At the other end of the risk spectrum, one of the specialty products they provide is radiolabeling of white blood cells (leukocytes). “This is a labor-intensive operation in which a patient’s blood is transported from the hospital to the pharmacy,” Tabb explains. “The leukocytes are separated from the platelets and plasma and radiolabeled with either Tc-99 HMPAO or In-111 Oxine, then returned to the patient’s hospital and injected back into the patient.” Radiolabeled leukocytes allow clinicians to identify an infective process. Says Tabb, “We perform a large number of these procedures and consider this to be among the highest risk operations that one could perform within the scope of our practice. We wanted to provide the best possible environment.”
Renovations called for enclosing the low-risk operations by using ceiling-to-floor vinyl flap curtains. As Tabb explains, this is because a requirement specific to nuclear pharmacy is the need for operators to move frequently in and out of the work area to elute medical generators supplying fresh Tc-99m sodium pertechnetate used in compounding. “Four banks of HEPA filters provide laminar flow to this ISO Class 7 work area,” he says. “Actual product preparation takes place within one of three ISO Class 5 biological safety cabinets.”
There were two design requirements for the high-risk blood-labeling operations. One was the ability to disinfect incoming blood shipping containers prior to their being introduced into the blood-labeling lab. This is performed before the container is introduced into the airlock, where the blood-containing syringe and documentation are removed from the outer packaging. The second requirement was to accommodate operator mobility within the blood lab, as blood components and radiopharmaceuticals must be transferred many times during the labeling process.
As Tabb reports, the new ISO Class 5 blood-labeling facility comprises eight banks of HEPA filters, an airlock, an anteroom, a new ceiling, new walls and floor covering, and stainless-steel cabinetry. The four existing ISO Class 5 biological safety cabinets were reinstalled and recertified.
Commenting on the design decision, Tabb explains, “One of the major considerations in safely handling radioactive materials is the detection of radioactive contamination and its containment, shielding, and clean-up. I believe that the unrestricted access to work space provided by a BSC makes it better suited to this function than a barrier isolator.”