The threat of “superbugs” and the frustrating prevalence of hospital-acquired (nosocomial) infections are spurring stepped-up vigilance for microbial contamination in health-care settings. In addition, pharmaceutical and biopharmaceutical manufacturing companies are being tasked not only to develop therapies for these infections, but also to re-evaluate and strengthen their efforts at preventing them, and are finding success in applying risk-based approaches to contamination control in their processes and equipment.
By Bruce Flickinger
Now living in San Diego, Louisa Johnson is a transplant from the UK, where the public health-care system might be oft-maligned in terms of service, but also has a reputation of being more aggressive than its counterpart in the US in adopting new infection-control strategies and technologies. “I was back in the UK two years ago and was astonished at all the news of the MRSA bug,” says Johnson, who is the marketing manager with ITW Texwipe, based in Mahwah, New Jersey. “It seemed that every television news segment was running scare stories on the mysterious flesh-eating bug. Newspapers carried graphic reports on how patients were entering NHS [National Health System] hospitals for routine treatment and coming home with hideous infections. I decided this would be an interesting area to research.”
What Johnson found is that MRSA, or methicillin-resistant Staphylococcus aureus, infection rates increased 19-fold between 1990 and 2001 in the UK. Similar numbers are corroborated by numerous reports from studies around the world.
A recent example is a report released in early March by the Infectious Disease Society of America (IDSA; Bethesda, MD), which says that nearly four of every 1000 patients discharged from US hospitals between 2001 and 2004 were infected with MRSA, the most well-publicized superbug among the current crop of pernicious pathogens. Most alarming, the report also identifies a newer threat in community-associated MRSA infections, which are increasingly reported in prisons, military and athletic facilities, and other situations where people are in close proximity.
Drug-resistant superbugs have entered the public consciousness in recent years and have renewed the call from such groups as the IDSA for federal legislation to galvanize the pharmaceutical and biotechnology industries into fighting the growing epidemic of antimicrobial resistance. The IDSA’s most wanted list includes MRSA, Escherichia coli (E. coli) and Klebsiella species, Acinetobacter baumannii, Aspergillus fungi, vancomycin-resistant Enterococcus faecium (VRE), and Pseudomonas aeruginosa. These offending organisms also have helped spawn a renewed interest in cleaning and sterilization practices and standards across the health-care continuum.
“The reason for these huge increases is poor cleanliness in the hospitals,” Johnson says. “Just speak to any ER or OR nurse and they will tell you how they dread the thought of an MRSA outbreak, and how they are instructed to return to basics, such as washing their hands regularly.”
Obviously, in the health-care environment, better hand hygiene can significantly reduce infection rates, as can good practices for sterile processing of instruments. The application of new devices, new cleaning protocols, and new technologies has also been mandated by several groups. While many of these areas are being addressed, efforts must be heightened.
That is because, by most counts, current practices for protecting both patients and practitioners are marginally effective. For example, research announced at last year’s AMBEX, the UK’s Ambulance Services Association’s annual conference, shows that traditional cleaning and disinfection practices have little effect in removing bacterial contamination in ambulances, leaving crews and patients potentially at risk from microbial infection, which can then be transported into hospitals. The same report found a dry vaporized hydrogen peroxide (VHP) disinfection procedure to be more effective in ambulances, and recommended its use.
Findings such as these have health-care facility administrators broadening their thinking beyond hospital doors to consider the pathogens that might be brought either via patients or products. The latter concern speaks directly to the pharmaceutical and medical device industries, which have long had their cleaning and sterilizing practices subject to regulatory liability, but are now finding themselves challenged to re-examine these processes.
Lessons and lapses
The health-care sector would do well to look to their brethren in pharmaceutical and biopharmaceutical manufacturing for cues about running effective, efficient cleanrooms. There is a significant parallel between pharmacy compounding practices and the aseptic compounding and contamination-control practices of pharma/biopharma. By extension, suppliers of cleanroom equipment and consumables to these companies are looking to health-care as an expanding market, particularly in the US.
“The vendor companies have significant expertise to offer to the pharmacy profession, but it is important for these companies to really understand what pharmacists and technicians need to do to comply with new regulations,” says Eric Kastango, president and CEO of Clinical IQ, a health-care and pharmacy consultancy in Florham Park, New Jersey. “The requirements are not the same as GMP [good manufacturing practice], and the level of rigor, validation, and documentation required by the FDA is not necessary for pharmacies. If these companies fail to accurately communicate what pharmacists and technicians need to know and do, it can result in increasing confusion and misinformation.”
Always a concern in sterile processing environments, microbial contamination is receiving greater attention of late by drug makers, a trend precipitated largely by the same concerns about infectious disease that are mobilizing the health-care sector. Drug and device manufacturers also are feeling pressure to energize their pipelines to combat these threats, as well as the threat of bioterrorism. These efforts require working with pathogens and other nasty microbial agents with which companies might not have long experience.
“Pharmaceutical and biotechnology companies are demanding higher microbiological performance while minimizing the personnel and environmental impacts of their contamination-control programs,” says Jon McCabe, product manager for critical environments with STERIS Corp. in St. Louis. “Although cost is always a consideration, most customers evaluate the total cost of ownership, which includes other factors such as long-term material compatibility.” As an example, many non-formulated cleaning chemistries can be corrosive to common pharmaceutical manufacturing materials, such as stainless steel.
Equipment degradation, both naturally over the course of time and due to cleaning and sanitizing chemistries, is an important, often-overlooked component of cleaning validation. This is particularly the case in light of the risk-based approaches being sought by the FDA. “The risk-based approach says, I know my process line, and should be able to determine the critical areas where the possibility of contamination-such as particulates, residues, and equipment deterioration-may be at high risk levels. So then we create a maintenance schedule that allows me to get out in front of this developing scenario,” says Art Vellutato Jr., vice president of Technical Support Operations with Veltek Associates, Inc. (VAI) in Malvern, Pennsylvania. “People who know their processes should know that cleaning is an integral part of disinfection. Without first instituting a rigorous cleaning program, disinfection of surfaces will surely fall prey to possible problematic contamination situations. It’s about better understanding and controlling your environment.”
Vellutato says the FDA’s focus on identifying risk and directing priorities accordingly is having a noticeable effect in environmental monitoring, but not on actual cleaning and disinfection practices. Here, he says, “people don’t know how to clean scientifically,” and, as such, preventative issues in disinfection and cleaning are not being fully addressed. “Ninety percent of our industry thinks that you just spray disinfectant on the surface or paint the walls with a disinfectant, and you’re okay,” he says. “They forget you need a mechanical action of cleaning first, followed by effective disinfection. People lose sight of this.”
While a closer assessment of cleaning and disinfecting practices might be warranted, “with the advent of the risk-based approach, industry is spending more time on critical items,” says Keith Kazmer, marketing manager with STERIS Life Sciences Service. “So while less emphasis is put on items further removed from the process chain, things like sterilization are seeing an increase in scrutiny. For example, autoclaves are often used in the sterilization of equipment directly in the manufacturing chain. As a result, the autoclaves are high risk and require robust validation.”
Customization and turnkey packages
The FDA’s interest in risk-based contamination control clearly has emphasized the need for a more focused effort on validation planning and impact assessment. “When problems arise, they are often due to a lack of validation planning and coordination with the equipment vendor,” Kazmer says. “Having higher quality documentation in the early stages of validation reduces, and sometimes eliminates, potential problems later in the validation program.”
The planning and assessments also help with another significant source of problems: communication of scope. “For a company’s quality department to appropriately review documentation, it must understand where the system starts and stops, and what it includes,” Kazmer says.
Another key component of any cleaning validation protocol is microbial testing-which is conducted in the sterile pharmaceutical industry in support of product development-for in-process monitoring during aseptic processing and filling operations, and for testing finished products. Testing typically includes environmental monitoring of air, surfaces, and personnel; microbial limits and bioburden; bacterial endotoxin; antimicrobial effectiveness; container-closure integrity; bacterial challenge testing for sterilizing filters; and aseptic processing validation using media fills.
The FDA wants to see specific environmental isolates from a particular process tested in a validation process. The validation work is to prove that the chemicals used are effective in destroying known contamination in a facility. The American Type Culture Collection (ATCC) cultures don’t always depict the actual cells seen in an operation and are just cellular representations of the actual isolate found in facilities. “People tend to become confused as to what organisms, surfaces, and contact times should be included in testing,” Vellutato says. “As a result, they end up with weak and sometimes meaningless validation reports that try to appease regulatory agencies, instead of being a valuable tool that is utilized to improve operations.” Effective laboratory services can be instrumental in helping clients develop customized contamination-control programs for their environments and processes.
Another example is STERIS’s Process and Cleaner Evaluation (PACE) program, a laboratory-based service that simulates a company’s cleaning process in order to recommend a cleaning agent and concentration, and cleaning process conditions. The PACE program helps companies select the appropriate cleaning agents and application conditions for meeting their specific soil challenges and cleaning needs. Other project objectives can include reducing cleaning time and increasing productivity, grouping studies for cleaning validation, and reducing water usage.
George Verghese, STERIS’s manager of technical services, emphasizes that, “developing a robust cleaning program is a critical prerequisite to cleaning validation. Appropriate selection of cleaning chemistries and parameters can simplify cleaning validation efforts and can have a significant impact on the overall cost of manufacturing. Not all companies pay close attention to developing their cleaning processes, and there is a tendency to prematurely embark on doing cleaning validation.”
Kazmer adds that while some customers still prefer to keep validation in-house, “we’ve witnessed a significant number of customers taking advantage of their ability to outsource non-core activities in an effort to reduce costs, better manage resources and allow industry experts to provide a more optimal solution.”
One indication of this is a trend toward more companies utilizing installation qualification/operation qualification (IQ/OQ) documentation and services packages provided by contamination-control suppliers. “Recently, customers have also been performing more intensive factory acceptance testing at the manufacturer’s facility in an effort to reduce the time required for IQ/OQ testing at their site once the equipment is installed,” Kazmer says.
Cleaning with gas
Some companies seeking time and cost efficiencies in their contamination-control programs are enhancing their processes by moving from the more basic wipe-down cleaning protocols and chemistries to the increased use of fumigation processes such as Vaporized Hydrogen Peroxide (VHP®) technology. VHP systems work by generating a dry fumigant that is pumped into an enclosed space. Decontamination is accomplished by holding the fumigant at a determined concentration for a period of time. The technique has been shown to work against a number of critical pathogens, and also is safe to use on a wide range of materials and sensitive electronic equipment.
The first widely accepted application for the pharmaceutical industry was the use of isolators and VHP decontamination systems for sterility testing in quality-control departments, according to Don Eddington, director of VHP Process Engineering with STERIS. This approach also is popular for aseptic manufacturing, where applications range from large high-speed filling lines to small compounding isolators.
Large-scale VHP is becoming a viable option, as well, Eddington says. “VHP technology is being used for pass-through rooms in conventional cleanroom environments. The customers decontaminate supplies and parts entering the cleanroom to reduce the amount of incoming bioburden,” he says. The technology also is being used increasingly to fumigate conventional cleanrooms, especially in Europe. This is done periodically as a preventative maintenance treatment to augment routine manual cleaning and disinfection with liquid chemistries.
Here, VHP treatment usually is used during shutdown periods in the cleanrooms to reduce or eliminate hard-to-kill spore-forming organisms. “Many biotech customers now have concerns about cross-contamination in fermentation suites,” Eddington says. “Contract manufacturing facilities have special concerns because their suites may not be dedicated to one product. Our dry gaseous VHP® Vaporized Hydrogen Peroxide decontamination systems are highly effective but also gentle on the materials and electrical equipment in suites.”
Vellutato concurs that the technique works well in operations where multiple vaccine strains are being produced, but he strikes a cautionary note regarding large-scale fumigation processes. “You’re going to have particulation everywhere, even in a large-scale aseptic area: garments shedding fiber, incoming packages being opened, trash,” he says. “So cleaning first is essential. Then you can consider something like large-scale VHP fumigation.”
Even then, “People think they can just push a button, fumigate, and be ready to go. But while large-scale VHP achieves good kills, tests have shown you’ve got to gas for an extended time period that may reach six to seven hours or so before it’s safe for people to enter again,” Vellutato says. “And you’ve got to clean before that. So you’re looking at a shift and a half or two shifts before operations can begin again. Many firms will find this to be an unworkable situation for daily operations, which may limit its usefulness to a come back from a shutdown period.”
Material degradation and lost processing time also are concerns when operating clean-in-place (CIP) and sterilize-in-place (SIP) systems. Lost process time can be addressed in current-generation systems, however. Tim Hoover, business development manager with GEA Liquid Processing, part of Niro, Inc. (Columbia, MD), for example, says that well-designed CIP systems employing matrix piping technology with mix-proof valves will enable one part of a plant to be safely cleaned while other areas continue to produce product. “You don’t want to tie up your entire manufacturing chain during CIP. Matrix piping technology enables part of the plant to automatically clean while other parts are in production,” he says. “The business challenge is to identify how best to segment the plant for cleaning so as to maximize asset utilization for production.”
The main purpose of a CIP system is to remove solids and bacteria from tanks, vessels, and pipe work, which, if not done correctly, could lead to cross-contamination and resulting material degradation. By most accounts, available systems and chemistries are effective at meeting demands of biopharmaceutical processing, which largely use closed filling processes. “Available chemicals are handling these applications well,” Vellutato says. “Most biotech processes are still relatively small, and they don’t create major residue problems. Some processes have protein and sucrose issues that require longer cleaning times, but, again, these issues are largely being addressed with available chemistries.”
“The CIP skid has become a commodity. It is the interface of the CIP skid to the process that is critical,” says Hoover. “There are really two aspects to CIP, and one is the skid, which is pretty straightforward. The skid is responsible for maintaining the controllable parameters of temperature, chemical concentration, cleaning action [velocity and pressure], and duration time. The difficult part is integrating this into the process design, with fixed equipment geometries, variable soil conditions, etc. From our standpoint, this is when things get interesting.”
“For many biotechs and biopharmaceutical companies, the cleaning process is an afterthought-where it should be built in from the beginning,” Hoover says. One point of interest: Supply and return can be problematic, because if it’s not done right, the plant can be reinfected, “so drainability and proper evacuation of the CIP supply and return lines need to be considered as though they were process lines.”
Hoover says to address these issues, Niro takes an audit of the plant’s process equipment, and challenges them in terms of their capacity to clean, using industry standards such as the ASME-BPE and 3A as guidelines. However, he notes that following these standards is not a panacea to compliance, as it takes knowledge and experience to realize a successful implementation. He says in some cases, aspects of the plant may need to be dismantled and cleaned manually per a rigid SOP to ensure targeted results.
Regarding dry fumigation, Hoover says it’s a good option for “some smaller manual producers that don’t have the required utilities-such as a boiler for clean steam-to SIP. ”
Clearly, whether the site in question is an aseptic processing line, a medical device manufacturing facility, an ambulance, or a hospital pharmacy, organizations responsible for the delivery of health-care to the public are being sorely tested by drug-resistant infectious diseases, and are being challenged to implement appropriate measures to combat them. In the process, these stakeholders are looking to one another for best practices and knowledge gained in their respective efforts to control microbial contamination.
“In my opinion, it is just a matter of time until we see cleanroom mats and cleanroom-inspired cleaning protocols applied to hospital environments,” says Louisa Johnson. “We are already seeing this with the compounding drug markets and USP 797.”