Not-So-Trivial Cleanroom Pursuits

Cleanroom gowning, to the layman, would seem one of those simple, rote tasks of daily existence—like brushing your teeth or walking the dog. How tough could it be?

Professionals who work in sterile environments, however, know gowning to be a science, or even an art. It’s something to take seriously and do by exact protocol, lest you be the one that introduces contaminants into what is supposed to be a sterile environment.

Kimberly-Clark A5 coveralls

“The dirtiest thing to enter the cleanroom is the person,” says Damon Larkin, scientific apparel and mask category manager at Kimberly-Clark Professional. “You want to do absolutely everything possible to protect the process from the person.”

Kimberly-Clark, known for its cleanroom apparel, has made an effort to gather more data on what it is that cleanroom professionals really want. In a nutshell, says Larkin, they want more comfort, more protection, and better performance.

The company has spent the past two years visiting cleanroom operators at their workplaces and interviewing them regarding features and functions of traditional sterile cleanroom gowns (from various manufacturers). Some of the most intriguing findings include:

• The sterile cleanroom gowning process takes between 5 and 10 minutes for the vast majority of cleanroom operators.
• Donning coveralls takes an average of 30 percent of the entire gowning process time.
• Operators dispose of an average of 10 percent of their sterile garments due to exterior contamination during the gowning process.
• Most new cleanroom operators need 30 hours of initial training on cGMP donning procedures before they are allowed in the cleanroom itself, and an average of 6 hours of ongoing training each week.
• More than 50 percent of cleanroom operators reported garments ripping out or billowing due to poor fit.
• More than 40 percent of cleanroom operators report the need to exit the cleanroom due to overheating on a regular basis.

Not surprisingly, Kimberly-Clark is trying to meet these demands in its Kimtech Pure line of disposable garments. Regarding comfort, it has introduced more breathable materials, such as the SMS (Spunbond Meltblown Spunbond) fabric in its A5 coveralls (photo), that contrast with suits designed to create a moisture barrier between operator and outside. “It’s a bit like walking around in a HEPA filter,” says Aaron Smith, research scientist for the company’s Product & Technology Development group. Indeed, in research, 100 percent of operators preferred this material to other “hot, sweaty and plastic-feeling” gowns.

The data also showed that professionals have trouble making sure that they touch only the inside of the garment when they open up a sealed package. In response, gowns are now folded and packaged with the outsides in, and open up so that cleanroom professionals can step into them easier, Larkin says.

In terms of performance, Larkin notes that clients are looking more to disposables, choosing to forego any risk that product or bacteria may remain in laundered materials. This may especially be true in the contract manufacturing sector. “If you’re going to be manufacturing a variety of drugs in your facility, you’re going to do everything you can to make sure there’s no cross-contamination,” he says.

Protective Clothing: The Swine Flu Factor
It’s been widely reported that there has been a spike in sales, and thus production, of hand sanitizers and face masks since the inception of the H1N1 flu pandemic. Kimberly-Clark Professional has seen a “significant uptick” in demand for its masks, gloves, and other protective garments, says Larkin. In North America, demand peaked near the end of April, the time when the flu season is usually ending, he says.

Larkin and colleagues are now closely monitoring what’s happening in the southern Hemisphere as winter and the flu season set in there, and will be watching North America again closely this fall. Larkin recommends that manufacturers be prepared: Encourage good health and hygiene practices amongst employees in advance of the flu season, and stockpile a fair amount of supplies that might be needed should the pandemic flare up again.

Many manufacturers, with and without scruples, are seeking to profit from the flu scare. Added Value Pharmaceutical Services, for instance, has just launched two new masks which were developed for pharma purposes, but have been cleared by FDA for use by the general public and are thus being marketed for pandemic preparedness—you can find them at the fear-mongering www.truthaboutflu.com.

GloveLock sealing tabs

Off the Cuff: Another cleanroom apparel problem: the dreaded glove cuff rolldown. In response, GloveLock brand is marketing glove sealing tabs (photo) with no adhesive-to-garment contact. The tabs, for use with thin latex, vinyl, or nitrile gloves, have a peel-away liner that, after a bit of pressing and maneuvering on the part of the gowned operator, keep gloves and garment sealed together and, the company says, is less bulky and more effective than double-cuff garments.

For those looking to match safety gloves with a particular chemical, Cole Parmer has just made available its safety glove chemical compatibility database, at: www.coleparmer.com\safetychemguide. The interactive database contains permeation and degradation ratings of glove materials for up to 160 chemicals.

4x4 safety goggles

Style Meets Safety: They may not be for highly sterile environments, but for those who like style with their safety, Gateway Safety has introduced the 4X4 Sport safety goggles (photo), which it says provide “high-end sunglass styling” and “rough-and-tough impact protection and 99.9% protection from eye-damaging ultraviolet (UV) radiation that comes from the sun.” Think of them as the Oakleys for the lab and plant crowd.

Bug Spray: Another means that manufacturers are applying to keep cleanrooms and other work areas even cleaner is antimicrobial coatings, in particular silver ion coatings. Terra Universal, a provider of cleanroom and laboratory equipment, began offering AgIon coatings to benches, glove boxes, work stations, cleanroom pass-throughs and other stainless steel products after seeing the technology catch on in hospitals, says Terra’s Mike Buckwalter. Many customers prefer the coatings for small-scale stainless products, and some are asking for entire stainless steel rooms to have it as well. Some clients prefer it for aesthetic reasons as well, he says, since silver ion provides a non-smudge, matte-like finish.

The silver ion chemical substance is sprayed on the surface of equipment and baked, notes Buckwalter. Thus, mixed-material objects (such as those that contain plastic) cannot be treated.

Clean Air Trakker

Does it work? Buckwalter supports the notion that the coatings inhibit the spread of infectious bacteria among workers and generally promote an aseptic environment, but says there is inconclusive data as to whether they eliminate all bacterial, viral and fungal agents equally well. (Author’s note: Consultant and microbiologist Michael Miller, PhD, informs us that most manufacturers will shy away from using the coating for production equipment, since current aseptic processing environments provide ample sterility, and some may fear that the silver might leach into the process environment.)

Just Add Water: The Clean Air Trakker from Clean Air Solutions is a portable, stainless steel fogger that helps you see airflow patterns in a cleanroom environment. The fog completely dissipates afterwards, leaving no residue.

Safety Storage

Gimme Shelter: Safety Storage specializes in the design and construction of buildings for materials management and cleanroom purposes, both free-standing structures and those adapted to an existing facility.

Explosion-proof and temperature-controlled, the systems can serve as labs, production facilities, storage areas, and air-lock suit-up chambers.

Integrated Validation and Commissioning Promise Savings

Most pharmaceutical companies today handle facility commissioning and validation separately. A new approach to engineering projects, Outcome CV, developed by the engineering firm Syska Hennessy Group (New York) and BioMetics, Inc. (Waltham, Mass.) integrates the two processes in an approach that, Outcome CV's developers say, can eliminates costly delays. The problem with the conventional model, they say, is that commissioning typically occurs after construction and before validation. Since the commissioning process starts before validation, it doesn't support it.

Developers began to work on the Outcome CV methodology, which was formally launched at the Interphex conference in New York in March, after noticing recurring patterns in commissioning and validation problems. At one East Coast pharmaceutical manufacturing facility, for example, validation costs budgeted at $800,000 actually reached $2.4 million, and requiring an extension of 20 months. For the manufacturer, these translated into $16 million in lost drug revenues and nearly two years lost on the patent expiration clock. Outcome CV dictates that validation be considered as early as possible in the planning stage, and involve members from different functional silos, Syska Hennessy principal Paul Liesman says. The integrated commissioning and validation process then continues during the design phase, when commissioning/validation plan and protocols are developed along with drawings and specifications. The integrated process then continues during construction, Liesman says, ensuring a link between design operation and utilities and process to production, and during operation and maintenance turnover, when final documents are turned over to the owner and standard operating procedures and training programs are developed. Liesman says the new integrated process is expected to speed validation and eliminate the 20-25% error rate found in facility systems.

Nutri Granulations: Validating the Team Concept

Every Wednesday, management and employees at Nutri Granulations get together for their weekly meeting. The meetings started a few years ago to help with ongoing drug validation efforts. These days, the gatherings tend towards brainstorming and idea sharing as often as they focus on, say, the finer points of 21 CFR 210 and 211. No matter the topic or purpose, the meetings are always informal and open; everyone participates and no one dominates.

&ldquoWe get together and give everybody something to think about,&rdquo says plant production manager Mike Garcia. &ldquoWe toss something out there and say, ‘Think about it and come back to us later with your ideas.&rsquo They go back to work and visualize solutions. Then, when we put the issue back on the table again, we have some good ideas about what we need to do.&rdquo

This is what teamwork is about at Nutri Granulations, a division of the chemical and raw materials distributor ET Horn Co. (both based in La Mirada, Calif.) Garcia and the facility&rsquos management have striven to give everyone, from line operators to warehouse personnel, a say in daily operations and project planning.

The approach has paid dividends. The company started in 1998 with just four employees, making bulk granulated calcium carbonate for the food industry. It saw more of a market in the pharmaceutical industry, for a USP-grade compound that could be used in antacids and other drug products. So in late 2003, with all 20 employees pitching in, Nutri Granulations undertook a major drug-licensing initiative. By the fall of 2004, it had completed the task, satisfying both state and FDA regulators.

Recent operating results at the facility have been impressive to boot:

• The plant boasted a 93% uptime in 2004, up from 80% in 2003.
  
  
• Production throughput increased from 10.3 to 12.4 million pounds last year, while reject/scrap rates dropped from 3.6% to 2.4%.
  
  
• Worker safety has not been compromised&mdashthe plant has a running string of nearly 700 days without a &ldquolost-time work injury.&rdquo

FROM FOOD TO PHARMA

Alan Huffington, director of regulatory affairs, and many others at Nutri Granulations had experience with food and pharma regulation, but the validation and documentation process required the efforts of the entire team.

&ldquoWe began by starting every Wednesday with what we call our weekly training sessions,&rdquo Huffington says. Their scope has gone way beyond training, with everyone from line operators, heads of quality and production, to VPs, contributing to process and product improvement. &ldquoWe jointly put together all of the validation packages and the documentation that were not required when we were operating under our old food license,&rdquo Huffington says. &ldquoAs a team we went through documenting and validating all of the utilities, equipment, processes and products, until everything that was required by the drug regulations, guidelines and other industry standards had been completed.&rdquo

Two particular events during the validation process illustrate the cohesion and commitment of the entire Nutri Granulations staff. The first was an unforeseen hitch when production at the facility had ramped up to the degree that warehouse space had become cramped. The group knew that it somehow had to reconfigure or expand its warehouse capacity without disrupting normal activities or slowing down the ongoing validation process.

During one Wednesday meeting, the entire staff went to the warehouse and sat down on the floor to brainstorm how it could be accomplished. They talked about things like material movement, and the need for separating quarantined and released materials. In time, the group agreed that they had to lease another warehouse nearby for released materials. Within six weeks, a new finished goods warehouse had been inspected and qualified, and the team had reconfigured the entire warehousing system while keeping true to the requirements of first-in, first-out design.

Another hurdle the team cleared was devising a cleaning validation process worthy of a drug-licensed facility.

CULTURE IS CRITICAL

None of these efforts would have worked without a culture of trust. The company encourages workers to &ldquobuddy up&rdquo with colleagues who have completely different functionalities. This paves the way for a production operator, for instance, to fill in for a QA specialist if needed. Even management jumps in. It&rsquos not uncommon to see Huffington, the regulatory expert, on the production line making batches, or Garcia, the production manager, helping the third shift at 2 a.m.

Huffington, Garcia and VP and general manager Kurt Schneider keep their doors open at all times should anyone in the facility want some one-on-one time. And the openness and transparency extend to suppliers and customers, who are both free to visit and roam the plant (staying outside the yellow lines, of course), and to talk with employees.

Employees have strong motivation to perform. &ldquoThe line item in our budget that has to do with reward and recognition is one of the largest lines in our entire operating budget,&rdquo says Schneider.

Extending the Validated Workplace

Not so long ago, the utilities and environmental controls of a pharmaceutical manufacturing facility were a given--you needed to have a way to turn the lights on and off, or to adjust the temperature, but beyond that, you'd "set it and forget it." True, specialized areas such as cleanrooms needed extra attention, but the main focus was always on the process control systems to run actual production lines.

Nowadays, building automation systems (BAS) can be nearly as complex as the process control system--a network of controllers, data centers, sensors and video cameras. The reason: 21 CFR Part 11, the electronic-recordkeeping requirements that FDA has imposed on the pharmaceutical industry. On the surface, Part 11 rules simply require that pharmaceutical manufacturers ensure that their electronic production records are stored securely and signed off appropriately.

However, the need to ensure compliance has generated a near-revolution in BAS technology. BASs now feature comprehensive data centers, networking tools, levels of security and redundancy, along with a long list of specification requirements "The pharmaceutical industry, along with semiconductor manufacturing, is leading the way in [adopting] integrated systems," says David Clayton, an analyst with ARC Advisory Group, a Dedham, Mass.-based market-research company.

"We prefer to work with both pharmaceutical clients and BAS vendors at an early stage," says Nejat Babur, mechanical department manager at the engineering-construction company Lockwood-Greene, Somerset, N.J., and now part of CH2M Hill. "We like to have a specific location guide in order to implement the design, and to produce airflow designs that can be as complex as the piping & instrumentation designs used for production systems."

Validation can be inordinately time-consuming. "Speed to market has emerged as the key issue in how BASs are specified and installed," says Simon James, buildings sector manager at Honeywell Building Solutions, Minneapolis. "We have to bring solutions to the market that do not slow down the validation process." While customers remain concerned with traditional performance parameters of BASs, such as energy management and productivity enhancement, getting through the validation tangle is paramount, James adds.

Devices and Interfaces

Most of the leading BAS vendors serve the full range of commercial and industrial clients. The pharmaceutical industry is one of many specialized markets, which, ARC estimates, add up to around $12 billion globally each year. However, those vendors competing in the fast-growing pharmaceutical field offer increasingly comprehensive and tailored systems.

In determining which hardware and software actually goes into pharmaceutical plants, the first decisions are made based on what parts of the BAS can directly affect production (and therefore need full-blown validation) and which parts do not. A dependable starting point for this analysis is the "Baseline Guide on Commissioning," a document produced by ISPE, with advisement from FDA. This Guide (there are several others that have been published or are in the works for other aspects of pharmaceutical manufacturing) defines "direct impact," "indirect impact" and "non-impact" systems with regard to building environmental controls.

If a plant's environmental control system fails and product is adulterated, that is a direct impact. If the system is simply connected to a direct-impact system--say, a chiller that provides cooling to an air-handling unit, with the air-handling unit determined to be a direct-impact system, is an indirect-impact system. And if it doesn't affect product quality at all--for example, the heating and cooling to cafeterias or offices at a facility, it is a non-impact system.

Determining whether a system is direct, indirect or non-impact is "the million-dollar question" for facility designers, says Agostino Renna, director of the life sciences group at Johnson Controls, Inc., Milwaukee, Wis. "An FDA inspector will come into your plant and ask to see how your direct-impact systems are documented. Then that inspector might ask to look at the documentation of your non-impact systems, and ask you to justify that assessment."

However the impacts have been defined, at some point, a validated component will interface with a non-validated part. Here, there is considerable debate about how to handle such interfaces, on both the hardware and software requirements, ranging from using the same networking and supervisory software to installing two completely separate BASs for each "side" of the facility. "When designing a unified BAS, you have to be careful that the unregulated part doesn't affect the regulated part," says Renna. "Otherwise, it's like the sweater with one loose thread--once you start pulling on that thread, the whole sweater could come apart."

Johnson Controls recommends that either "logical" (software) or "physical" (hardware) separation be made between the two components, Renna says. Logical separation is created by employing strict access-control to BAS setpoints and operating parameters, and by ensuring that a change in, say, the lobby airflow will not affect airflow in a temperature-controlled warehouse. Physical separation, while more expensive in terms of installed hardware, might be justified to ensure complete independence of the regulated space.

The distinction between regulated and nonregulated components can also carry over into the BAS's hardware, notes Lockwood Greene's Babur. Typically, the BAS encompasses sensors for temperature, relative humidity and other environmental factors, controllers or other field devices for executing instructions, and centralized data centers or control rooms for supervising overall operations.

"Commercial-grade devices usually don't have the same accuracy or performance as industrial-grade devices," Babur explains. "Industrial sensors might have a +/-0.5-1.0% accuracy, while commercial units might be 5%." In these cases, Lockwood Greene might produce a design that blends the two types of devices, with the industrial-grade units going into the regulated, direct-impact areas.

Because of validation concerns and differences in equipment quality, Lockwood Greene generally favors physically separated systems. "Validation is definitely a factor in the design process," says Faroukh Butt, department manager for instrumentation and automation. "If you have to validate the entire BAS, clients may benefit from having two smaller systems rather than one united BAS. We've had clients of both separated and united systems," he says.

Siemens Building Technologies, Buffalo Grove, Ill., has tried to structure its BAS offerings to the pharmaceutical industry by bundling solutions for four distinct areas: laboratories, animal-research facilities, manufacturing, and warehousing. "There's a specific problem with many facilities whose workspace is continually changing," notes Diane Welpe, marketing manager. "We've had instances where office space is converted to production, and we need to certify that area for production."

More than HVAC

Traditionally, "building controls" have mostly encompassed heating, ventilation and air conditioning (HVAC), especially in the context of commercial buildings. But the new need to secure facilities, as well as the steady growth in automation of other building functions, means that fire safety, access control and other types of systems are being incorporated into an overall BAS.

Most of the leading BAS vendors offer these systems, either themselves or through alliances with other vendors. Here, too, though, questions about whether activities are regulated or non regulated have crept in. Many validated facilities put strict controls on access to clean rooms, for example, and thus records on who entered such rooms can become a part of the documentation a manufacturer needs for an audit trail.

Most pharmaceutical companies are holding back on an overall integration of these systems, however. "I might be an old-timer, but I would be nervous about having all my automated systems on one platform," says James Agalloco, president of Agalloco & Associates, a consulting firm in Belle Mead, N.J. "You need to have some redundancy."

Siemens' Welpe, whose company offers a variety of BAS types, notes that special care must be taken when optimizing alarm system design. "Some responses might be properly handled by an operator onsite, but others might require telephone or pager response," she says.

BAS Meets Process Control

The most intriguing connections are occurring between the BAS and the process automation system. After all, if the BAS--or parts of it--have to meet the same regulatory requirements as the production line, and improved communication technology makes it possible to integrate the two, why not do it?

ARC, in an informal online survey of its pharmaceutical clients this summer, found that more than half of respondents expected some degree of integration between their BASs and their process control systems over the next five years. "In past years, this would not have been cost-justifiable, but now the hardware costs are not as significant," says ARC's Clayton. "Both process control and building automation are more IT-dependent. It might be time to break down the conception of these being two separate worlds."

Most industry experts, however, believe that such integration is still a long way off. "Today, the basic unit for much production control is the programmable logic controller [PLC]," notes Johnson Control's Renna. "That's a good platform for control, but it lacks the embedded logic that is used for environmental control." He says that installation engineers can go through simple yes/no lists in programming an environmental control unit, but a PLC's programming would be a difficult exercise in ladder logic. He concedes, however, that "industry is headed in this direction."

Siemens and Honeywell, both of which have extensive process-control operations, might be considered well positioned for such integration, but both companies say that there hasn't been much demand. "It's technically feasible, but the customer perception of the value of such a hybrid system isn' there," says Phil Chou, a manager in the pharmaceutical business unit of Honeywell. "We've been involved in linking the PLCs on our process side with our BAS," adds Siemens' Welpe, "but typically we do not provide process automation from within our division."

Indeed, current technology makes it relatively simple to communicate a desired value from a BAS over to the process control system, so that the value can become part of the permanent electronic record of a batch or production step. That's one of the capabilities touted by Wonderware, a division of Invensys PLC in Lake Forest, Calif., whose InTouch and InBatch human-machine interface (HMI) software is widely used for supervisory control. "Our software doesn't run the BAS, but it can extract a data point and include that in batch reports," says Yves DuFort, pharmaceutical industry manager. Wonderware makes use of Microsoft software standards, including its SQL database tools, and DuFort says that it's simply a matter of associating a particular sensor or instrument tag to the Wonderware database.

In some pharmaceutical installations, the BAS system can be as critical as the actual production control system. That's the case at B. Braun, an Irvine, Calif.-based producer of intravenous solutions and packaging. "Because of the sterility and cleanliness needs of our products, we have interlocks on the production line. If, say, the air-handling system to a clean room is not operating properly, production will shut down until it's fixed," says Gary Collins, manager of control engineering. The facility uses environmental controllers from Johnson Controls and a variety of process control units run by InTouch.

Production typically involves mixing active pharmaceutical ingredients into solution, while another part of the plant produces IV bags and closures, Collins says. The two come together in filling stations in clean rooms, and the finished products are then steam-sterilized. Regulatory compliance issues are handled from the perspective of the production line, recognizing that there is a need for the environmental controls to transmit data--usually using TCP/IP over Ethernet protocols--to the production line where they become part of the batch record. The company has a 21 CFR Part 11 compliance program under way, but Collins says it is not affecting operations very significantly because of the high level of regulatory compliance that is already necessary.

BACnet protocol

Whenever there are major interfacing issues, there's usually an attempt to create a standard communication protocol, and that is very much the case in BAS. In this case, the standardization effort, called BACnet, comes from ASHRAE (Am. Soc. of Heating, Refrigeration and Air-Conditioning Engineers), with the support of the U.S.'s National Institute for Standards and Technology (NIST). The group has 23 corporate members, a website of its own (bacnetassociation.org) and links to many other automation associations in the U.S. and abroad.

BACnet, technically known as ANSI/ASHRAE Standard 135-2001, has been under development since the mid-1990s, and, as befits an ASHRAE-originated effort, reflects mostly the needs of commercial building systems suppliers and users. It is not tailored to the needs of the pharmaceutical industry. Nevertheless, it is generating interest in the pharmaceutical sector as a way to provide interoperability among BAS products of different vendors.

Andover Controls (Andover, Mass.), for one, is making a big bet on BACnet, offering a range of controllers and other field devices that make use of the protocol. "BACnet is a maturing protocol, but it needs additional work to be fully capable for regulated industries," says John Williams, a product marketing manager at Andover. He says that it lacks the security requirements necessary for electronic signatures, and has limited definition for recordkeeping necessary for audit trails.

The standard became "Internet-aware," and able to handle IP addresses, in 2001, but there are still details to work out. "It's an ongoing development, and there needs to be more education in the pharmaceutical industry before it becomes an option," says Clive Smith, an industry manger at Andover.

Paradoxically, another potential industry standard, LonWorks, which reaches back to the early 1990s, has been put to use in some pharmaceutical installations, especially in Europe, but most industry observers are betting on BACnet. LonWorks, originated by Echelon Corp. (San Jose, Calif.), has over 300 members, and is strong in the electrical systems used in transportation, housing and commercial buildings. It, too, has a members'website (lonmark.org). "It's a bit of a turf battle," sums up Andover's Smith.

Will BAS technology gradually blend with process control, with everything--the HVAC, the access control, the process control and other systems, all talking to each other over industry-standard protocols? It might happen, but don't hold your breath. "Im thinking of the biblical injunction to 'render unto Caesar that which is Caesar's'," says James Agalloco, who figures that process control engineers need their system, and building engineers their own.

"I question whether we'll ever get the entire industry to sit down at the same table," says Johnson Controls' Renna, citing the normal competitive pressures that keep companies from being fully open technically to each other. He notes that his company has a "black box" interface called the Integrator, which can be specified to provide intercommunication between Johnson products and some 400 other vendors' protocols. "Ultimately, if the pharmaceutical industry pushes hard enough, it will get what it wants."

Minimizing Risk in Sterilization Validation

Sterility testing is an essential part of every sterilization validation, to rule out the presence of particulate, bacterial and fungal contamination. Personnel must wear isterile gowns that prevent microbial shedding. The result is a monotonous, careful process that can still be error-prone.

While contamination is the ultimate nightmare for any manufacturing facility, a lab-induced false positive is a time-wasting worst-case scenario. “It’s easy to consider a retest, but it requires a specific cause and a lot of time and effort, and it reflects on your lab,” says Alan Dake, supervisor, Microbiology Laboratory, Quality Control/Quality Assurance for Bayer HealthCare, Shawnee, Kan.

Two years ago, the Bayer lab did all its sterility testing in a sterile cleanroom with a laminar flow hood for testing. While the setup worked well, the company saw an opportunity to upgrade its technology when the facility’s manufacturing services program was expanded. The new, larger facility would increase the amount of testing work required by the lab, so the lab had to be expanded as well.

“This was a chance to take advantage of new technologies to prevent false positives in sterility testing,” says Dake. Since the goal was to make the new and improved lab less prone to errors and easier for operators to work in, isolators reduced the risk of unrelated contamination coming from the lab, offered increased levels of sterility assurance and eliminated personnel from the aseptic area.

Bayer’s isolator configuration is actually two La Calhene isolators with separate sterilization cycles. They can be docked together and were designed with maximum docking configurations for greater operator flexibility when loading/unloading from one chamber to the other. “Hatchback-style” windows on the transfer unit are a key ergonomic improvement, considering the amount of material used for a single test session. An on-site ergonomics expert helped prevent other issues with such items as new non-PVC half-suits, neoprene floor mats and gloves acceptable for all operators.

“The isolator and loading configurations have resulted in both ergonomic and throughput efficiencies that we are very pleased with,” says Dake.

The transfer isolator is used to sterilize test materials so that they can be used later in an already sterilized workstation. Again, the goal is to prevent contamination. “Generally, we pick the worst location, such as the product vial or the point where it contacts the shelving, and wipe the contact points,” says Dake.

The isolators are completely enclosed HEPA-filtered chambers. They are interfaced with vaporized hydrogen peroxide (VHP) to sterilize the inner surfaces of the isolator as well as the supplies inside. The room to the isolator also has a separate air supply.

Sterility testing is accomplished from outside the isolator in the larger unit utilizing two half-suits. Operators enter the half-suit by ducking under the base and then standing up within the positively pressurized suit. Thus, the testing process is totally isolated from laboratory personnel and the potential for introduction of contaminants is minimized.

While isolators have simplified operation, running sterility tests still requires three months of extensive operator training, in which staff master the 38 pages of standard operating procedures required. “There is a lot to consider,” says Dake. “For example, you need to know how to load correctly, hook up and execute transfers, get the gas and evacuate.”

The decontamination/disinfection process after each sterility test is extensive. Some of the processes involved include: a pressure test, dehumidifying with VHP, and a condition-and-target phase. In all, the process takes approximately three and a half hours.

The isolator and procedures must be annually requalified, and any new materials or techniques validated before their use.

Of course, false positives can still occur, even in the most diligent sterility testing operations. However, Bayer has found that isolators help increase sterility assurance levels. “Three years without a false positive — we’re pretty proud of our record so far,” says Dake.