with Alice S. Weissfeld, PhD
and Paula H. Vance
Pharmacy Purchasing & Products: How serious is the risk of contamination to products compounded in the cleanroom?
Alice S. Weissfeld and Paula H. Vance: The possibility for contamination to compounded sterile preparations (CSPs) is very serious. In the lab tests we have conducted over the past five years, contamination rates for CSPs have been between 0.5% and 3%, and there have been several published reports over the years of patient harm and death due to contaminated CSPs. One case from 2002 involving the mold Exophiala dermatitidis resulted in serious patient harm.1 This microorganism was introduced into compounded solutions of steroids that were to be infused intrathecally. Because this mold, which usually does not cause infections in humans, was infused directly into the spinal column of patients, it caused meningitis in three patients, sacroiliitis in another, and death from meningitis in one additional patient. One reason this outbreak was quickly traced to the compounded steroid is because Exophiala is not a typical cause for infection, so a common link was sought among the cluster of cases.
Through environmental monitoring we have conducted, we have linked microorganisms present in the air in the cleanroom to a contaminated sterile preparation that was compounded in that cleanroom. It just happened that the randomly selected CSP we were given to test was contaminated with the same microorganism found in the cleanroom air. Using a microbiological typing technique, we were able to show that the two microorganisms were identical, meaning the contamination was most likely the result of a break in aseptic technique on the part of the person compounding.
Keep in mind that improper technique is not always the cause of contaminated CSPs; in some cases it is a result of malfunctioning equipment, such as a faulty autoclave, that was not monitored carefully. While contamination is a serious problem, <797> offers standards to help avoid this; it is key that pharmacy diligently follow these standards.
PP&P: What microorganisms should hospital pharmacy be most concerned about being introduced to CSPs?
Weissfeld and Vance: The most common microorganisms in contaminated cleanrooms or CSPs are Bacillus species. This is frequently seen in hospital pharmacies that do a lot of their cleaning with 70% sterile alcohol; pharmacy staff often do not realize that Bacillus species can survive in 70% alcohol. So when that is the primary agent used for cleaning the cleanroom, that pharmacy is, in effect, selecting for Bacillus spores. Using bleach or other sporicidal agents can help avoid this. Skin organisms, such as corynebacteria, alpha-hemolytic streptococci, and coagulase-negative Staphylococcus, also are common, and some of these microorganisms can cause serious problems in patients.
There are some molds that are commonly seen as well. The risk for introducing Aspergillus, Cladosporium, Penicillium, and Alternaria into the cleanroom increases when construction occurs adjacent to the pharmacy, and precautions should be taken in the pharmacy if construction is going on nearby in the hospital. Keep in mind that whenever construction is going on in a hospital where sterile compounding is performed, the two most important environmental controls are containment of the area under construction and the use of appropriate engineering controls.
During environmental monitoring, make sure to look for gram-negative microorganisms, many of which are found in water. Depending on where a hospital is located, municipal water—which is clean enough to drink and bathe with—can have anywhere between 500 and 1000 colony-forming units of microorganisms per mL—and that is a substantial amount. These microorganisms are considered harmless under normal circumstances. However, it is important to remember that once the cell wall of gram-negative bacteria break down and the bacteria start to die, endotoxins are released, and these endotoxins can cause shock in patients. We also monitor carefully for certain pathogens that are known to cause hospital-acquired infections, also called nosocomial infections, such as Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus.
Depending on a hospital’s patient population, certain microorganisms are more of a threat than others. For example, if you are in a hospital with a large population of cystic fibrosis patients, Burkholderia cepacia, which is commonly present in soil and water, is a serious concern. Burkholderia cepacia can cause a respiratory infection, and this can ultimately result in a cystic fibrosis patient being denied for a lung transplant.
PP&P: If a hospital pharmacy chooses to use an outside lab for environmental monitoring, what criteria should be used to evaluate providers?
Weissfeld and Vance: First, it is important to make sure that the lab has the necessary credentials. Chapter <797> states that all samples should be read by a credentialed lab, whether it is a clinical lab or an environmental lab. Clinical labs, by law, must have a CLIA (Clinical Laboratory Improvement Amendments) certificate, and the federal government is responsible for inspecting and accrediting all clinical labs. Some labs have chosen, in addition to having their CLIA certificate, to be inspected by a private accrediting agency—the two most common being the College of American Pathologists (CAP) and The Joint Commission (TJC). Any lab within a hospital will have the appropriate credentials.
For environmental labs, both the American Industrial Hygiene Association (AIHA) and the American Association for Laboratory Accreditation (A2LA) certify based on International Organization for Standardization (ISO) standards, specifically ISO/IEC 17025. Having these accreditations does not ensure an error will not occur, but it does offer some level of comfort that the lab meets certain quality standards.
One note of caution: some labs will state that they are “accredited” by the Food and Drug Administration (FDA). However, the FDA does not accredit labs, and all this means is that the labs are registered with the FDA; the FDA does not inspect a lab unless there is a specific complaint against it.
When evaluating labs it is also wise to ask to see results from their proficiency tests. Proficiency tests are unknown samples that labs receive at least two to three times a year from the agencies they are certified under. Sometimes a lab can actually fail several tests in a row before their certification is withdrawn. Also, make sure to verify the credentials of the microbiologists employed by the lab. Check to see if they have a BS or BA in microbiology, and if they do not, make sure they have taken enough microbiology classes to be qualified to read samples. Also, look at what certifications the staff have; having professional certifications does not automatically qualify someone as the best choice, but it does offer the security of knowing these individuals were concerned enough about their professional growth to study for tests and pass them.
PP&P: What steps should pharmacy take to address positive test results?
Weissfeld and Vance: If environmental sampling turns up contamination, pharmacy must investigate and uncover the reasons for the positive results. One hospital pharmacy that we have been monitoring on a monthly basis had never shown positive results in their laminar flow hoods over the three years we had been working with them, and then one month we uncovered high numbers of Staphylococcus in one of the hoods. The hood had undergone its six-month certification right after our last visit, so it seemed an especially unlikely time for the hood to be contaminated. When we called the pharmacy manager to investigate, she revealed that after the certifier had inspected the hoods, and right before we came to do our monthly sampling, they installed a magnehelic gauge on the hood. Suspecting that metal shavings resulting from the gauge installation might have something to do with the contamination, she called her certifier back to reinspect the hood, and the certifier discovered tears in the filter. Keep in mind, had they not been sampling on a monthly basis, this issue could have gone unnoticed for months and potentially have lead to patient harm.
We have encountered other situations where we have found Aspergillus in the air in a cleanroom and in the laminar flow hoods, both of which are unusual occurrences, only to later discover that there was construction going on adjacent to the pharmacy, and this was the first time the pharmacist learned that the HVAC system in the cleanroom communicates directly with another department in the hospital that has totally different environmental specifications.
In another instance, we found Streptomyces, which are present in soil, in large numbers in one cleanroom that we were monitoring. When the pharmacist inquired about what might have caused this, I told him that compounding staff were probably wearing their booties when they went outside to smoke on the grass, and tracking the microorganisms into the cleanroom when they came back inside. It turned out that he had seen his staff doing this, and did not think it was going to be a problem. Microorganisms can be very telling; and working with microbiology to uncover the root cause of the problem will help quickly eliminate the threat.
While uncovering the causes of contamination is vital to reducing patient harm, it is equally important that pharmacy understands exactly what the impact of the contamination could be. For example, if coagulase-negative Staphylococcus were found in the cleanroom, depending on the species, it may or may not be pathogenic. So the lab has to be knowledgeable enough to understand what can cause problems in patients, and pharmacy needs to ask about the potential impact on patients.
PP&P: How often should environmental monitoring be conducted?
Weissfeld and Vance: USP <797> states that monitoring should occur biannually, but it should be stressed that this is the minimum, not a best practice. Hospital pharmacies that see the greatest benefits are those where environmental monitoring is conducted monthly or quarterly. I recommend monitoring four times a year at a minimum, and ideally monthly for the first year to accurately trend the data. Performing environmental monitoring every six months makes it difficult to see any trends in the data, unless it is two or three years down the line.
PP&P: What is the value of having an in-house microbiology lab analyze environmental monitoring results?
Weissfeld and Vance: An in-house microbiology lab is going to have better insight into what is going on at the hospital, meaning they are going to be aware of what microorganisms are problematic as they are the ones generating the infection control data. They also will be more aware of changes or potentially problematic situations at the hospital, such as construction. For an outside lab, it takes more of an effort to understand what is happening within the hospital. In addition, using an in-house lab means working with individuals you already have an established rapport with.
One of the problems in clinical microbiology right now, as in most health care disciplines, is that clinical microbiologists’ time is being stretched to the maximum, and so it is understandable that when they are asked to do one more thing, there is often resistance. However, the American Society for Microbiology and local clinical microbiology associations are taking the time to educate clinical microbiologists on the essentials of <797> compliance.
PP&P: What should pharmacy do to help microbiology with environmental monitoring efforts?
Weissfeld and Vance: An ideal relationship is one where pharmacy, the microbiology lab, and the certifier work hand-in-hand, and this means continuous communication among these parties about what is going on in the cleanroom. Whether it is via email, texting, phone conversation, or scheduled meetings, there needs to be discussion about what the environmental monitoring results mean, and when issues are uncovered, they need to be investigated in a collaborative fashion. Many of the pharmacists we work with ask us questions pertaining to microbial growth that are not necessarily spelled out completely or even addressed in USP <797>, and in cases like this, collaboration is especially important.
In addition, pharmacy managers need to make sure that staff are fully informed about environmental monitoring efforts—why monitoring is taking place and what it will entail. This way, employees are not concerned or confused when environmental testing is being conducted while they are compounding; they understand that this is not being done to punish anyone, rather it is to improve infection control efforts and bolster patient safety. When pharmacy staff understand exactly what a microbiologist or certifier is there to do and why, it allows for a more collaborative environment and everyone can do their job better.
PP&P: Do you have any final ideas on pharmacy’s role in bolstering infection control efforts in the cleanroom?
Weissfeld and Vance: When CLIA was passed in 1988, it set new standards for clinical labs, and we had to make it an integral part of our thinking and our work practices, with the recognition that it was improving delivery of care to patients. I would say the same to hospital pharmacy staff about USP <797> standards. These standards should not be regarded as efforts that get in the way of workflow; rather, they need to be embraced as tools to improve the safety of compounded drugs. As with CLIA, I imagine that down the road, 797 will be seamlessly ingrained in pharmacy consciousness and accepted as just a regular part of compounding workflow. If pharmacy managers take the time to ensure staff understand the principles behind <797>, are adequately trained in aseptic technique, and that the primary and secondary engineering controls are working properly, environmental monitoring results will reflect these efforts.
Alice S. Weissfeld, PhD, D(ABMM), F(AAM), is the president, CEO and laboratory director of Microbiology Specialists Incorporated, a reference laboratory she co-founded in 1984. She also currently serves as an adjunct assistant professor in the department of molecular virology and microbiology at Baylor College of Medicine. Alice earned her doctoral degree in microbiology at Rutgers University and completed a postdoctoral fellowship in public health and medical laboratory microbiology at Baylor College of Medicine. Her areas of expertise include virology, pathogenic bacteriology, mycobacteriology, administration, and regulatory affairs.
Paula H. Vance, RM/SM(NRCM), SM(ASCP), CIE, is the vice president of Microbiology Specialists Incorporated. She is certified as a general supervisor in all subspecialty areas of clinical microbiology. Paula graduated from the University of Texas at Austin. She maintains certifications as a specialist microbiologist (NRCM), a specialist in microbiology (ASCP), a clinical laboratory specialist in microbiology (NCA), and a certified indoor environmentalist (IAQA). Paula’s areas of expertise include mycology, mycobacteriology, and virology. She also specializes in investigating pathogenic bacteria and mold in buildings.
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