A different kind of clean
Pharmaceutical/biotech air filtration closes in on viable contaminants.
By John Haystead
Compared to the “seven-9” efficiencies (0.1 micron particles) specified for air filters by some semiconductor makers, the 99.99 percent (0.3 micron) requirements commonly used in the pharmaceutical and biotech industries may seem fairly low-tech. But, particle size and filtration efficiency is not the whole story. Although their particulate-control requirements are not as rigid as those found in the microelectronics industry, air filtration remains a priority for both aseptic pharmaceutical and biotech manufacturing operations. The primary distinction is, of course, that pharmaceutical and biotech manufacturers are overwhelmingly concerned with “viable contaminants,” or living microorganisms. Tightly regulated and monitored by the FDA`s current Good Manufacturing Practices (cGMP) requirements, the control of microbial contamination, as well as the ability to fully document this control, is of paramount importance.
The focus on control of microbial contaminants has resulted in many different and specific expectations for air filtration systems aimed at the biotech and pharmaceutical industries. For example, the use of a single HEPA filter barrier will not ensure absolute sterility, but rather that only three out of every 10,000 particles will pass through, points out Richard Friedman, compliance officer in the FDA`s Center For Drug Evaluation and Research (Rockville, MD). So, while unlikely, it`s still possible that one of those three particles could be a live microorganism. As a result, pharmaceutical and biotech concerns are strongly encouraged to implement multiple HEPA or ULPA filters in sequence to bring the probability of a microbe passing into the controlled environment to effectively impossible levels. Alternatively, any gases that are purged into the manufacturing environment should use a microbially retentive (0.2 micron or better) membrane filter.
Friedman adds that the use of two HEPAs in series addresses both economic and contamination-control issues. “Some companies use a prefilter or two and then go straight to a HEPA, but this ultimately lessens the life of the HEPA and does not provide as much assurance of high quality air.”
The prevention of cross-contamination and therefore cleanability is a mandatory requirement for pharmaceutical and biotech operations. “This usually means that filters and filter housings be constructed with impermeable materials such as stainless steel and have no surfaces or seams where bacteria can grow,” observes Richard Matthews, president, Filtration Technology Inc. (Greensboro, NC) and chairman of Technical Committee 209 of the International Organization for Standardization (ISO/TC209).
The materials must also be tolerant to the cleaning agents or cleaning systems used. Some sealants used in filter-module gasketing may be easily degraded by certain chemicals, and some sanitizing agents contain chlorinated compounds, which over time can cause corrosion and particulate shedding. Some media may also not be suitable for pharmaceutical/biotech operations because of wetability issues. The same washdown requirements usually prohibit the use of dropped ceilings in pharmaceutical/biotech applications, which must instead be outfitted with hard ceilings and precise cutouts for lights and HEPA filters.
Although ultrafine particles are not usually a concern in pharmaceutical and biotech facilities, Matthews notes that outgassing of molecular contamination is now beginning to also receive attention, particularly in operations involving organic molecules such as DNA. According to Matthews, the ISO`s working group on molecular contamination has noted the growing commonality of this concern and is making it a part of its standards work.
Certification and validation is perhaps the most important concern in the biotech and pharmaceutical industries, demanding that the effectiveness of air filtration systems be thoroughly and continually tested and documented to cGMP standards. Thorough documentation and verification is essential, explains Peter Grassam, manufacturing vice president and general manager at Protein Design Labs (Plymouth, MN). “The need to maintain the specified conditions under operational conditions requires detailed and regular testing from installation forward.” Protein Design Labs produces humanized monoclonal antibodies. The company`s Plymouth facility includes roughly 25,000 square feet of controlled space ranging from Class 100,000 to Class 10,000 with small areas of Class 100 space.
Grassam`s point is a reality that Bob Mello, vice president of quality and regulatory affairs at Chesapeake Biological Laboratories (Baltimore), shares. Chesapeake is a contract manufacturer specializing in aseptic processing and sterile liquid fills of biopharmaceuticals, monoclonal antibodies, vaccine development products, and cardiac drugs. “If I even suspect a leak in a new filter, I want it replaced immediately,” Mello says.
In fact, FDA certification and documentation requirements are a burden shared by both the end user and the cleanroom and filter suppliers. “Documentation is the life-blood of what we do here, and I expect to see our filter manufacturers` specifications to ensure they comply with our needs,” Mello says. “I want to know that the filter and gasket materials used are suitable and that the filters are compatible with the supporting system and demonstrated to be tight.”
Testing and documentation is one of many key discriminants between meeting pharm/bio and semiconductor filtration requirements, says Scott Mackler, general sales and marketing manager at Clestra Cleanroom Inc. (N. Syracuse, NY). “Some people say there`s little or no difference between a room built for a semiconductor operation and one for pharmaceutical/biotech, but that`s simply not true. There are specific requirements from filter specification, through design of ductwork, to specification of air handlers and architecture that are night and day different.”
According to Mackler, “It`s all about validation and how you specify and document the filters.” For example, Mackler points out that filters intended for Class 100 aseptic environments require significant additional certification testing such as in-situ cold dispersed oil particulate (DOP) integrity testing to validate that the filters are working prior to acceptance.
Still, while “it`s certainly helpful to put as much of the documentation burden as possible on suppliers,” Grassam of Protein Design Labs emphasizes that “it`s still ultimately up to the end user to know and approve the methodology and results, and the final responsibility for ensuring effectiveness and providing documentation is still always on the owner and operator of the systems.”
According to Friedman of FDA, “the FDA`s air-filtration requirements and inspection principles are largely premised on the dosage form and intended use of the final product.” Friedman reviews both domestic and international inspection reports for sterile drug products and notes that while many microorganisms are safely swallowed every day, the same organisms can pose a serious medical problem if injected into a vein or applied to an open wound. “Sterile product processing is not for the meek in terms of adherence to GMP. Manufacturers must exercise vigilant control of their processes and procedures, or face potential batch failure in the end.”
The FDA`s air-filtration requirements don`t apply to just overall room environments, but encompass any air lines servicing individual process steps and equipment as well. Autoclaves, for example, a staple of aseptic manufacturing operations, handle materials that will come in direct contact with the final, already sterilized, product. Because, at the end of each autoclave operation, a backflow of air necessarily enters the system, it is crucial that this air is sterile or the materials that were just sterilized will be contaminated. All equipment air lines are therefore fitted with 0.2-micron membrane filters to prevent the passage of any microorganisms. Similarly, water purification systems and requirements are also impacted by air filtration requirements. “Since they are intended to preclude microbial contamination from the external air, we`re extremely concerned with air filters on high-purity water system components such as the Water for Injection (WFI) storage tank,” Friedman notes.
According to Friedman, although air-line filtration systems are a standard industry requirement, problems arise because some companies don`t always recognize that integrity testing and scheduled replacement of these filters is critical, and if not performed will result in a citation. “Sometimes companies don`t set up adequate controls to deal with the fact that these filters will degrade over time, especially if subjected to repeat sterilizations,” observes Friedman.
US FDA standards are not the only air-filtration requirements that must be met, however. For example, Mackler points out that British Standard BS 5295 requires DOP integrity testing of HEPA filters for critical areas to three decimal places. “Meeting this standard changes how the filters are specified, how they are tested in the factory and the field, as well as the number of spares of each size kept on hand, and their source.”
Barrier isolation systems
Perhaps the most significant development in pharmaceutical and biotech manufacturing and its air-filtration requirements is the emergence of barrier-isolation systems. “Humans remain the overwhelmingly main source of viable contaminants in any controlled environment,” stresses Jim Agalloco, Agalloco & Associates (Belle Mead, NJ), a pharmaceutical/biotech consultancy. Although properly designed air handling systems can help sweep people-borne contaminants away from products, even the best systems can`t ensure total removal and control. “Even a Class 0 room won`t address this problem,” Agalloco says. “Contamination may be isolated to one part of the room or another, but this microbial `insult` will still be a major concern.” Agalloco believes barrier-isolation systems that separate direct human contact from the equation are the only realistic solution.
Isolation systems, however, pose their own set of challenges for air filtration systems, the most basic of which is the need for special-sized filters and modules. Sealant materials also again come into play, however, since seal integrity is directly related to the aggressiveness of the chemicals being used in the process. Within isolators, seals will often come in direct contact with aggressive chemicals such as hydrogen peroxide, chlorine dioxide, ozone and other sterilizing gases, and, “seals are probably the weakest point in an isolator, and all seals, whether vinyl, rubber or nitrile, will break down over time,” Matthews notes. In isolators, these chemicals may not just impact seals around the filter itself, but the entire air-handling system, including blowers, return ducts and gasketing materials.
Overall, Friedman of FDA notes that barrier isolator air connections must simply adhere to the same operational requirements imposed on any closed system, such as the requirement that all air supplied to the system be sterile. But, while Agalloco agrees with this, he also feels that too much pressure is being put on barrier-system designers and implementers to carry over some of the design methods and requirements developed for cleanroom operations. Agalloco observes that “some of these requirements have become almost sacred cows, and I`m not convinced that many of the factors that apply to cleanrooms also apply to isolators. Overall, the industry and the FDA haven`t yet really come to grips with these issues. A lot of work still needs to be done to evaluate the merits and drawbacks,” Agalloco says.
For example, Agalloco cites the FDA`s (requirement for) laminar flow (90 feet/min.) conditions in many barrier-isolation systems and asks why “if human`s aren`t present in the environment to reintroduce organisms, do isolators need the same high phase air velocities that we see in cleanrooms?” Similarly, he points out that while a cleanroom laminar flow room will often have a perforated floor for air return, this can create a lot of cross-contamination and liquid-handling problems in an isolation system. “In these cases, returns may be better located higher up in the barrier system with a unidirectional as opposed to con ventional laminar flow,” says Agal loco. Matthews agrees. “As long as you maintain the direction and uniformity of flow, the speed of the air is not necessarily im portant. If something interrupts the airflow, then it`s really a matter of whether the airflow is adequate for the contamination-control process.” According to Hank Rahe, director of technology at Contain-Tech (Indianapolis), “in an isolator, this is often in the neighborhood of 30 to 40 feet/min. or less.”
Friedman ac know ledges that there has indeed been confusion and misunderstanding over this question in the industry, but wants it clearly stated that the FDA does not have a doctrine requiring 90-feet/min. laminar air flow in barrier isolators. “We have said `unidirectional air and an appropriate velocity.` Although 90 feet/min. is an aseptic guideline, it is simply that — a guideline, and it is written to accommodate new technologies such as barrier isolators that we recognize represent different manufacturing conditions and philosophies. Moreover, FDA plans to provide specific guidance on barrier isolators in the upcoming revision of the 1987 guideline on sterile drug products produced by aseptic processing.”
Agalloco also sees a trend away from HEPAs and more toward membrane filters for air filtration. Although currently capable of providing far less total air-throughput than HEPAs, membrane filters have been in widespread use for years in air lines and other low-volume, air-filtration applications. One example can be seen in the use of membrane filters as vent filters on liquid storage tanks. As fluids are drawn down into the tank, the air that replaces it is passed through a membrane filter. Then, when the tank is refilled, the membrane filter allows for reverse flow of the fluid while maintaining freedom from contaminants. Membrane filters are also now being explored for a number of new uses in other closed-system, air-filter applications including barrier isolators. Still, Agalloco points out that a more widespread use of cleanroom membrane air filters “is currently more in the eyes of isolator designers than conventional air-filter-system manufacturers.”
Safety and containment issues
Because of the nature of many of the compounds and organisms used in pharmaceutical and biotech operations, air-filtration, quality-control initiatives must also be continually balanced with personnel-safety concerns. “The types of drugs and organisms being worked with today as part of production are often a lot more toxic than days past, with adequate containment or other safety precautions critical to protecting both the workers and the environment,” Agalloco points out.
However, the need for containment can also greatly complicate air filtration requirements, often involving a delicate balance of positive and negative pressure isolation environments. “It`s a double-sided problem, simultaneously dealing with a sterile environment and the need to contain a nasty active component,” says Agalloco. For example, as Mary Petit, vice president of quality, Barr Laboratories Inc. (Pomona, NY), notes, “this places greater requirements on our air filtration systems.” Barr develops and manufactures a wide range of prescription drug products including antibiotics, cardiovascular agents, and cancer treatments. “The FDA requires all multi-product facilities to implement air-handling systems that prevent any possible backflow of contaminants (such as powder) from one room into another, but those such as ours that also have a line of toxic products, must also ensure that the systems meet the safety concerns of OSHA,” Petit observes.
Agalloco believes barrier-isolation systems will ultimately be a key part of the solution. “Industry is taking the best approach to the problem by using isolators where sterility and protection of the patients (product) can be the first priority, and dealing with worker safety and containment through additional protective equipment for personnel and supplementary alarms and other safeguards.”
Related to this, Agalloco perceives what he believes is an undue fascination with leaks in isolators. “People seem obsessed with finding leaks at incredibly low levels, but it`s hard to conceive of a truly effective sterile containment system running under negative pressure. On the other hand, if the system is running at positive pressure, such minute leaks don`t pose a contamination threat to the product.” While Agalloco acknowledges that any such leaks must still be addressed as a safety issue, he believes this should be done through separate worker protective wear and overall room-based containment systems.
Environmental biohazard containment is another important concern for both industries, but particularly for many biotech manufacturing facilities. Environmental protection issues require effective microbial filtration at the exhaust end of the manufacturing-area air stream as well as the input side. On the exhaust side, pharmaceutical and biotech companies will usually implement a bag-in, bag-out style filter housing to capture hazardous contaminants, describes Charlie Kwiatkowski, HEPA and equipment sales coordinator at Purolator Products Air Filtration Co. (Kenly, NC), but “the use of granular-carbon filtration systems is also growing.” Other issues relate to how to handle the hazardous materials once they are collected, however. Matthews of Filtration Technology points out that “questions remain as to whether it`s best to decontaminate the collected materials in place, or periodically remove and replace the filtration media.”
At Chesapeake, biohazard containment concerns have been raised to the level of practical business decisions. Says Mello, “we simply recognize that we can`t be all things to all people and therefore don`t take any live organisms into our facility.” Mello points out that their facility design is oriented to protecting products, and that they mainly deal with finished products that are already formulated and supplied in sealed vessels for filtration and filling.
Although most of these products don`t present a biological concern, in addition to evaluating cross-contamination issues, they initially assess all materials or products presented for introduction to the facility from a safety standpoint. “This is primarily done with regard to our employee safety but also from an environmental hazard standpoint.” Where the company is forced to handle hazardous agents such as in their microbiological testing laboratory, Chesapeake restricts such work to Class 100 laminar flow hoods, which are vented through HEPAs prior to exhausting to the outside air.
In the pharmaceutical and biotech industries, the comfort level provided by tried-and-true technology and guaranteed performance often far outweighs long-term cost/performance benefits. “We put much more emphasis on obtaining high-quality, short-lead-time products from recognizable manufacturers than we do comparing different filter manufacturers from a cost, maintenance and operational standpoint,” says Dave Johnson, Chesapeake director of facilities and engineering. “In the real world, there`s usually just not enough time to sit down and figure out which filters will give us the best performance with the least pressure drop.”
On the other hand, Johnson says integrity testing prior to leaving the factory was a critical requirement for their filters. “We were willing to incur this additional cost because we`ve had experiences where it was necessary to replace new filters right after installation with no guarantee that the replacement filters wouldn`t also fail. We can`t afford those kinds of delays.”
For similar reasons, the pharmaceutical and biotech industries may not always appreciate the nuances of the cleanroom industry`s latest filtration system designs. “We don`t have the same economic drivers found in the microelectronics industry since we`ve almost already reached the point of diminishing returns with Class 100 conditions and see little merit going beyond this level,” Agalloco points out. At the same time, however, Agalloco believes that the pharm/bio industries often don`t get the same level of attention to their unique concerns as that afforded the electronics industry.
Many filter makers disagree with this observation. “As an industry, filter makers don`t generally develop specialized products for individual market segments such as the pharm/bio industry,” says Matthews of Filtration Technology. “Our business reality is that the idiosyncrasies of end-user processes, although important to us, still boil down to a lot of common denominators.”
While Agalloco recognizes the truth in this observation and agrees that “we`re a smaller part of the overall consumption,” he adds that “I`d still like to see this change because there are some things that can be done for our industry, and some opportunities.”
Footnote: Since its inception, the term laminar flow has been used universally to describe the directed movement of air in a cleanroom. However, some confusion and controversy has now arisen over the precise meaning and implications of the term. With the implementation of Federal Standard 209B (FS-209B), a specific laminar flow rate of 90 feet/min ± 20 percent was established as a requirement for cleanroom certification, and although the revised FS-209E standard no longer specifies an air flow rate, FDA GMP doctrine continues to reference the older version. As a result, the term laminar flow has come to connote for many a specific requirement for 90 feet/min. airflow. Instead they prefer to use the term “unidirectional air flow” and avoid any association with flow rates.
John Haystead is a freelance writer in Hollis, NH. He was formerly CleanRooms` chief editor.
A Class 100 unidirectional flow aseptic fill suite at Chesapeake Biological Laboratories in Baltimore uses full-ceiling coverage of terminally ducted HEPA modules. Photo courtesy of Clestra Cleanroom.
A Class 10,000 vial accumulation and clean packaging area at Chesapeake Biological Laboratories in Baltimore provides 99.99 percent efficiency (0.3µm) using terminally ducted HEPA modules. Photo courtesy of Clestra Cleanroom.
A Class 100 lyophilization suite at Chesapeake Biological Laboratories in Baltimore uses a low-wall return air neutral plenum design to achieve unidirectional flow. Photo courtesy of Clestra Cleanroom.
A horizontal flow hood maintains a particle-free environment in the filling area at Protein Design Labs (Plymouth, MN). Photo courtesy of PDL.
State-of-the-art microbe control
Chesapeake Biological Laboratories Inc. (Baltimore, MD) is a contract manufacturer of sterile pharmaceutical and biopharmaceutical products for both established pharmaceutical firms and emerging biotechnology companies. In July, the company completed initial FDA general facility cGMP (current Good Manufacturing Practices) inspection of its 71,000-square-foot commercial production facility for large-scale formulation, filling and packaging of sterile pharmaceutical products. Housed in an existing building, the facility incorporates in excess of 11,000 square feet of cGMP aseptic manufacturing space as part of first phase build-out, and is designed for future expansion.
Constructed by Whiting-Turner Contracting Co. (Richmond, VA), engineered by Lockwood-Greene (Spartanburg, SC), and with cleanroom space provided by Clestra Cleanroom (N. Syracuse, NY), the facility has enough production capacity to fill up to 80,000 unit lot sizes and includes a 120-square-foot lyophilization chamber (freeze dryer) for new biopharmaceutical products.
Designed to European M-3.5 to M7 standards, the facility ranges from Class 100,000 to Class 100 conditions with six levels of increasingly positive pressurization from the open warehouse area to the interior aseptic core. The facility includes overpressure autoclave and depyrogenation ovens for glassware and component sterilization as well as a clean-in-place/steam-in-place freeze dryer for lyophilized product. The component/glassware prep and sterilization areas are all Class 10,000 followed by a Class 1,000 area for storing sterilized components with Class 100 cool-down areas immediately in front of the doors to the autoclave and depyrogenation ovens. Two Class 100 filling rooms and a Class 100 lyophilizer loading room are all connected via a Class 100 corridor.
As a multi-product contract manufacturer capable of handling hundreds of products per year, sometimes with multiple products in the Class 100 core simultaneously, cross-contamination is a major concern. As a result, four separate air handling units were installed to service the Class 100 core area, with each filling suite, lyophilization and formulation areas handled by its own air system.
Each primary air handler incorporates a multi-stage filtration train. After initial cooling, dehumidification and pressurization, the air first passes through 45 percent filtration, then to 95 percent and finally through a 99.99 percent (0.3 micron) HEPA phase prior to leaving the unit. Finally, it is filtered through a second bank of terminal HEPAs (also 99.99 percent) before entering one of the aseptic rooms. This means that in the worst case scenario, any contamination in one room would have to jump between primary air handling circuits, through the HEPAs in the second air handler, as well as the terminal filtration HEPAs to enter another area, describes Dave Johnson, Chesapeake director of facilities and engineering.
Within each Class 100 area, full-ceiling HEPAs with low-wall returns provide complete unidirectional airflow. Because the original facility was constructed with 28-foot ceilings, all of the air-handling equipment was able to be installed inside the building. The bulk of the equipment is installed in a specially constructed mezzanine level just above the cGMP manufacturing areas. In addition to manufacturing, the facility also supports Chesapeake`s quality control and microbiology testing activities. Chesapeake has an extensive microbiological and environmental monitoring group that continuously monitors all aspects of the facility for both viable and non-viable particulates.
Although Chesapeake doesn`t currently implement any barrier-isolation equipment, this is something company officials may consider as part of their expansion plans, “depending on the nature of our customers` business requirements,” says Bob Mello, Chesapeake vice president of quality and regulatory affairs. — JH