Environmental monitoring and sampling are key components of any sterile compounding quality management program. While USP Chapter provides guidance for developing both facility- and personnel-related environmental performance metrics, all data routinely obtained about the sterile compounding environment—not just sampling data—should be considered in measuring performance. Environmental data may be the result of actual sampling (referred to in USP as environmental sampling), however, monitoring data and viable surface sampling data also provide important information about the suitability of the compounding environment (Figure 1).
Environmental sampling and daily monitoring data can be categorized as measuring either facility- or personnel-related metrics (Figure 2). Once work practices, such as contracting with a properly licensed vendor to regularly service and maintain the HVAC system, are built and tested according to design requirements, the physical plant generally functions without much deviation. Employee work practices are the most significant source of inconsistency in any organizational system and therefore must be consistently supported and continuously monitored.
While the requirements for environmental air sampling and monitoring (see the Environmental Air Sampling Requirements sidebar on page 16) as well as the requirements for at least daily monitoring of temperature and air pressure/velocity are clear, those for surface sampling are less specific. Keep in mind that USP specifies minimum requirements only, and in some circumstances, more frequent monitoring and sampling may make sense. For example, if the pharmacy manager sees that the CFU data is trending in an undesirable direction or if cleaning is being performed by a large number of new employees, it probably makes sense to engage in more frequent monitoring and sampling. Because personnel metrics, such as viable surface sampling, are influenced by more variables than facility metrics, pharmacy leadership must determine the frequency and type of additional monitoring that will provide the most useful information based on risk levels, staff tenure, and other variables that can affect the compounding environment.
Non-Viable Particle Count Sampling
Because non-viable particles essentially act as transport vehicles for microorganisms (bacteria and other living organisms can attach themselves to non-viable particles and be carried by available air currents), reducing the number of non-viable particles is critical to reducing
the bioburden in ISO classified compounding areas. Non-viable
particle testing is an important facility-related metric, and must be performed at least twice annually during routine room and equipment
Non-viable particle testing occurs inside:
•Primary engineering controls (i.e., LAFWs, BSCs, CAIs, and CACIs)
•ISO Class 7 buffer area/cleanrooms
•ISO Class 7/8 ante-area/rooms
•Segregated compounding areas
Since improper work practices can adversely impact non-viable particle testing, personnel conducting particle counts, whether pharmacy staff or an outside vendor, must comply with the pharmacy’s hand hygiene and garbing procedures. Particle testing should be performed according to CETA guidelines2 and the manufacturer’s recommendations for the specific equipment being used to perform the testing. Non-viable particle testing is required each time a primary or secondary engineering control certification/recertification is completed and pharmacy leadership must review the findings of non-viable particle counts. If non-viable particle counts in a particular location trend in an undesirable direction, consideration must be given to additional follow up activities such as:
•Further investigation, maintenance, or repair of the primary or secondary engineering control (e.g., a damaged HEPA filter)
•Evaluation of cleaning and disinfection practices
•Evaluation of staff work practices
When possible, it is best to avoid situations in which vendors bring their own cart into controlled areas. Offer the vendor the use of a cart already in the cleanroom for their use and limit their equipment to only that which is needed for testing—in this case, a particle counter. Vendor equipment must be treated like any other inventory brought inside the compounding environment and wiped down with the designated agent before entering the buffer area. Additionally, any equipment that will be placed inside an ISO Class 5 compounding area must be cleaned with sterile 70% isopropyl alcohol (IPA) and allowed to dry before it is placed inside a hood or isolator. Consider performing a monthly cleaning program after the certification of controlled environments or whenever maintenance is performed.
Viable Air Sampling
Viable air sampling must be performed at least semi-annually in conjunction with the recertification of primary and secondary engineering controls and occur under dynamic operating conditions, that is, while compounding or compounding-related activity is occurring. The personnel conducting air sampling must have received training and be knowledgeable about the use of the specific air sampling device being used, regardless of whether they are pharmacy staff or personnel from the contracted cleanroom certification vendor. Sampling must be conducted according to the pharmacy’s environmental sampling plan. Personnel, including vendors, must perform hand hygiene and garbing according to policy.
Volumetric air sampling is required rather than gravimetric sampling (open plates laid on the compounding deck for a specific period of time) as this process does not consistently and accurately reflect the amount of microbial contamination in the environment. Volumetric air sampling is performed using a device that draws a predetermined volume of air onto an agar plate; it is preferred that the volumetric air sampling device use impaction methodology.
Volumetric sampling must occur at the following locations:
•ISO Class 5 air: One sample at each primary engineering control (PEC) or at each workspace (if using a contiguous compounding bench) in zones of air backwash turbulence within the PEC. If the PEC is eight linear feet or longer (e.g., an eight-foot LAFW or 16-foot continuous compounding bench), it is suggested that one sample be taken every four feet of ISO class 5 linear compounding surface.
•ISO Class 7 buffer room air: Samples are taken where air turbulence might be expected such as the area near doors, pass throughs, or in corners.
•ISO Class 7/8 anteroom air: Samples might be taken near doorways and in areas where staging, gowning, and cart exchange take place.
•Segregated compounding area: Samples taken on counters next to and/or around the PEC.
Each sample must be equal to at least 400-1000 liters of air (0.4-1 cubic meter). Note that because sampling occurs during compounding, it may have a disruptive effect on unidirectional airflow, especially in the critical ISO Class 5 compounding. While pharmacy leadership must determine the optimum sample size for their circumstances, it may be preferable to limit sample sizes taken within the ISO Class 5 areas to 400 liters, with 1000-liter samples in buffer and ante area air.
There are several types of control plates to consider when taking air samples:
•Negative Control: A plate from the same manufacturer lot number is labeled as “negative control,” and dated and incubated along with samples to verify that the plates used were free from contamination upon receipt from the vendor.
•Positive Control: A plate from the same manufacturer lot number is purposely contaminated, labeled as “positive control,” then dated and incubated to verify that the media used was capable of supporting growth. Though manufacturers provide a growth certification for each lot, it is highly recommended that each pharmacy conduct its own positive control. It is important that this type of testing be well controlled to avoid inadvertently contaminating the other plates and or introducing known contamination to CSP production areas. Consult a certified microbiological lab for more information.
•Competency Control Plate: A plate from the same manufacturer lot number is labeled as “competency control,” dated and incubated along with the other plates. This plate is used to verify the technique of the person taking the samples. To prepare a competency plate, the user performs all the manipulations necessary to obtain the volumetric air sample with the exception of turning on the air-sampling machine. The competency sample is best obtained right before the first sample is obtained and the manipulations are performed within the ISO Class 5 compounding area.
Based on recommendations viable air sample action levels may be set as follows:3
•ISO Class 5 air: > 1 CFUs/1000 liter sample
•ISO Class 7 air: > 10 CFUs/1000 liter sample
•ISO Class 8 air: > 100 CFUs/1000 liter sample
Action levels may be re-evaluated after sufficient microbial data has established a baseline for each ISO class area; however, limits may not exceed those stated above.
Monitoring Air Pressure and Velocity
Compounding environments that are constructed with physical walls between the buffer and ante area must maintain a minimum differential positive pressure of 0.02 inches (range 0.02 to 0.05) water column between the buffer area and the unclassified general pharmacy area. Pressure gauges must be installed to measure the pressure differential between the buffer area and the ante area and also between the anteroom and the unclassified general pharmacy area.
For compounding environments using displacement airflow (i.e., constructed without actual wall separations between the buffer and ante-area), air velocities of 40 feet per minute must be maintained across the entire line of demarcation from the buffer area into the ante area. A velocity meter must be used to measure the airflow velocity at this point. Keep in mind that these types of designs cannot be used in compounding operations that perform high-risk compounding.
For hazardous drug compounding, buffer areas must be physically separated from an ISO Class 7 ante area and maintain a negative pressure differential of not less than 0.01 inches water column to the adjacent positive pressure ante area space.
Regardless of the type of engineering, pressure differentials or air velocities must be verified and documented at least daily. Pharmacy leadership must provide some means (i.e., paper log or electronic documentation system such as Simplifi 797) for staff to use that reflects the actual function and physical plant at their location. Discrepancies in operating pressures or velocities must be reported to the manager immediately since changes in this facility metric can severely compromise the quality of the sterile compounding environment.
Temperature and Humidity Monitoring
Ideally, buffer areas should be maintained at defined temperature and humidity levels that facilitate comfortable conditions for heavily garbed and gloved compounders. Facilitating operator comfort increases the likelihood that staff will perform flawlessly. Furthermore, these conditions reduce particle shed and thus the likelihood of CSP contamination. Ideally temperatures of 20°C (68°F) should be achieved and maintained during dynamic operating conditions, though a range of 18 to 21°C (64 to 70°F) is acceptable. In my experience, anything above 68°F creates unfavorable conditions, resulting in staff discomfort, difficulty concentrating, and fatigue.
There are no specific requirements in USP relative to humidity. Optimally, relative humidity should be maintained within a range of 25% to 60%. This range ensures employee comfort, minimizes static electricity, and reduces safety and infection control issues, which can occur when floors and other surfaces become slick with moisture.
To ensure product potency is retained through the manufacturer’s labeled expiration date, drug storage areas must be monitored at least daily for conformity to these storage conditions:
•Controlled cold temperature: 2 to 8°C (36 to 46°F)
•Controlled frozen temperature: -30 to -10°C (-13 to 14°F)
•Controlled room temperature: 20 to 25°C (68 to 77°F), allowing excursions from 15 to 30°C (59 to 86°F)
To ensure accurate results of incubation from personnel or process media-fill testing, gloved fingertip samples, surface sampling, and volumetric air sampling, incubators must be maintained at 30 to 35°C (85 to 95°F) for tryptic soy broth/agar samples, which are incubated for 48 to 72 hours. Malt extract agar, or other suitable fungal media used in high-risk level compounding operations, is incubated at a slightly lower temperature of 26 to 30°C, but for five to seven days. In the future, requirements to use two different media types (such as TSA and a media supporting fungal growth such as MEA) may be extended to low- and medium-risk level operations as well.
Appropriate temperature and humidity recording devices must be placed in all environments where temperature and/or humidity is monitored. Temperature-sensing mechanisms in the storage space, incubator, or buffer area must be placed to ensure a sampling of the environment’s accurate temperature, thus not immediately adjacent to a door or directly beneath a cooling duct. Staff must be aware of the potential negative influence they can have on controlled storage spaces, including refrigerators, freezers, and incubators as well as buffer and ante areas. Significantly prolonged temperature fluctuations can occur when doors are left open too long or manual adjustments are made to temperature settings.
Personnel-Related Metrics Gloved Fingertip Sampling
All compounding personnel must be trained on hand hygiene and garbing as well as successfully complete that competency prior to initiating the gloved fingertip sampling. These personnel should include compounding technicians as well as all pharmacists, whether they perform or supervise compounding. All new compounding staff must successfully complete three gloved fingertip sampling occurrences prior to compounding CSPs for human use. It is suggested that this testing might occur daily for three days in a row just prior to the new employee performing their initial media fill testing. Subsequent gloved fingertip sampling for tenured compounding personnel can occur during yearly (for low- and medium-risk compounding) or semi-annual (for high-risk compounding) employee media-fill testing.
The designated action level for gloved fingertip samples is dependent upon the location of the employee when the sample is taken. For instance, if the gloved fingertip sampling is taken immediately after performing hand hygiene, garbing, and donning sterile gloves, but before disinfecting gloved hands with sterile 70% IPA, then the Action Level is 0 CFUs (total for both hands). If, however, the gloved fingertip sampling is taken upon completion of media fill testing or even randomly when employees are working within the ISO Class 5 PEC (but not immediately after hand disinfection with 70% IPA), then the Action Level is > 3 CFUs (total for both hands).
Pharmacy leadership may consider performing additional gloved fingertip sampling since touch contamination is the most common way to introduce contamination in CSPs. Frequent hand disinfection is extremely important and routine and random gloved fingertip sampling events and their results may help leadership drive that point home. This relatively inexpensive personnel metric is easy to perform and can be highly effective in raising staff awareness and vigilance.
Surface sampling is an integral part of the maintenance, proper cleaning, and disinfection of controlled environments. Furthermore, data from surface sampling is used along with other environmental sampling results to detect inadequate disinfection procedures and adverse shifts in microbiological conditions in a timely manner, allowing for effective corrective action. Surface sampling data assists in the evaluation of personnel work practices related to surface cleaning and disinfecting as well as disinfection of components; material handling; vial surface cleaning and glove disinfection. Surface sampling must be performed in all ISO classified areas on a “regular” basis. The frequency of surface sampling is not specified in USP since that decision is dependent upon several factors that differ among pharmacies compounding sterile preparations.
These factors include:
•Compounding risk level: Perform surface sampling more frequently as the complexity of manipulations, and therefore the risk level, increases especially because transfer of microbial contamination from inadequately cleaned work surfaces is a likely cause of CSP contamination.
•Environmental sampling results history: Consider performing surface sampling more frequently if the facility is newly constructed and does not have any environmental sampling history.
•Tenure of compounding staff: Consider performing surface sampling more frequently when many staff are new or inexperienced.
•Other factors: Consider more frequent surface sampling in periods of short staffing, high volume, or to monitor the effect of changes in policy and procedure such as the change of the designated cleaning agent. Though not required, it is strongly recommended that surface sampling be performed more frequently if outsourcing cleaning duties to an external vendor/hospital environmental services or insourcing previously outsourced cleaning duties.
Surface sampling must occur at the conclusion of the compounding day or shift to capture the worst case scenario, and it must be performed according to the locations detailed in the pharmacy’s environmental sampling plan. Since surface sampling is a personnel-related metric, consider incorporating surface sampling during employee media fill procedures so that results may be tracked back to the individual(s) who may require retraining. Consideration might also be given to performing surface sampling “randomly” (i.e., sampling occurring monthly should not take place at the same time of the month and employees should not be given any warning that a surface sample is going to be obtained at that time). By noting the name of the compounding personnel working inside of the hood or isolator at the time of the sample was taken, an opportunity for retraining that individual is captured should surface sampling exceed designated action levels.
Samples are taken in order from the cleanest to the dirtiest and in the following locations:
•ISO Class 5 PECs: 1 sample per 4 linear feet is suggested
•ISO Class 7 buffer area: locations which are representative of and at greatest risk, such as work surfaces near ISO 5 areas, counters near doors, walls, and pass through surfaces
•ISO Class 7/8 ante area and surfaces: Either the plate or swab method of collection is acceptable, however, even with the swab method, plates are still required and must be 24-30 cm2 in size. For all risk levels of compounding, tryptic soy agar medium with polysorbate and lecithin added to neutralize cleaning agents (TSApl) are used in addition to media that supports the growth of fungi such as malt extract agar.
Action levels must be established with recommendations4 as follows and should be the starting point for new compounding facilities:
•ISO Class 5 surfaces: >3 CFUs/plate
•ISO Class 7 surfaces: > 5CFUs/plate
•ISO Class 8 surfaces: >100 CFUs/plate
Action levels may be re-evaluated after a significant microbial data baseline has been established for each sample area within the pharmacy, however, new action levels may not be higher than those set above.
Additional Indirect Metrics
While personnel media fill testing, process simulation testing, and sterility testing are not classified as environmental control data, these data do indirectly test for the successful culmination of employee training and competency verification; cleaning and disinfection; physical plant function; and a host of employee work practices that can reduce the risk of contamination to CSPs. For instance, when the pharmacy acquires a new automated compounding device, such as a TPN compounder for both macro and micronutrients, leadership may choose to perform a media fill process verification to ensure that the automated compounding device is capable of producing sterile TPN. Process verification is performed by substituting sterile media for source containers. Though not required, it is strongly encouraged that pharmacy run media fill process verification at least initially on new pieces of compounding equipment. By performing the media fill process verification, the compounding staff and environment are verified (or not) as well. Sterility testing may also be negatively impacted by the environment or by the operator performing the sterility testing. Therefore, it is important to remember that multiple factors in the environment as well as personnel work practices can affect the sterility of the final CSP. Only data points derived from many areas, at different time points, and sampled continuously, can provide information that can be meaningfully trended and used to improve sterile compounding practice.
These facility and personnel performance metrics are not set in stone. As science evolves and provides additional or better ways to measure the effectiveness of compounding facilities and personnel work practices, these metrics are expected to change to reflect the new findings. Pharmacies that compound sterile preparations must review, evaluate and apply relevant new information as it becomes available. In the meantime, it is important that pharmacy leadership understands how their specific facility, equipment, and personnel work practices influence each other and the compounding environment. Routine and systematic data collection as well as thoughtful review of that data will remain the best way to truly understand and manage the many forces that exert influence over the achievement of a compounding environment that maximally reduces the risk of contamination to CSPs. Data obtained through environmental monitoring and sampling ensures objective evaluation and subsequent changes in policy and procedure that will ensure consistent performance and improve quality.
Kate Douglass, MS, RN, APNC, CRNI is the president of Performance Strategies, LLC, a consulting company assisting the pharmacy, nursing, and health care markets. Kate is a co-author of CriticalPoint’s Interactive USP Chapter Gap Analysis Tool and is a module author for CriticalPoint’s web-based training. She has written a number of articles on sterile compounding quality and training. During her tenure as COO of SoluNet LLC, Kate personally supervised the design, engineering, and build of four pharmacy compounding complexes that met or exceeded USP requirements.
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