The latest editions of USP <797> and USP <800> provide instructions for performing proper environmental monitoring during formulation of compounded sterile preparations (CSPs).1,2 While USP <797> concentrates on preventing microorganisms from entering CSPs, USP <800> focuses on protecting the individuals who are preparing the drugs. Notably, USP <800> defers prevention of microorganisms to USP <797>. The directives in both chapters need to be followed to ensure robust and reliable environmental monitoring programs.
Simply put, environmental monitoring ensures that the heating, ventilation, and air conditioning (HVAC) systems, high efficiency particulate air (HEPA) systems, and aseptic practices of individuals who compound CSPs provide conditions to minimize the number of microorganisms in the compounding cleanrooms. Environmental monitoring sampling includes:
Environmental monitoring examines the environment surrounding the compounding area to assure that it does not contribute to a breach in product sterility; maintaining clean air and clean surfaces being the goal in the pharmacy. Nevertheless, it is important to note that simply conducting environmental monitoring does not guarantee product sterility; rather, it serves to support sterile operations, while the final onus resides with the individuals preparing the CSPs.
It is well known that people are the greatest obstacle to maintaining aseptic conditions. As the weak link in the aseptic process, staff members must be trained and scrutinized to ensure that their influence on product integrity is minimized; the environmental monitoring program should focus on monitoring both staff and their surrounding area. The primary monitoring sites should include air and surface samples close to the hands of the individual(s) who are preparing the CSPs (ie, inside the primary engineering control [PEC], which must be a Class 5 biological safety cabinet [BSC] or a Class 5 laminar airflow workbench [LAFW]). Samples should encompass the interior of the PEC and the equipment contained within, staging or work area(s) near the PEC, and frequently touched surfaces. Secondary sampling sites should include areas outside the PEC, such as the segregated compounding area (SCA).
To facilitate sampling site selection, USP <797> requires that each sampling site be mapped onto a diagram of the pharmacy. FIGURE 1 demonstrates the necessary sampling points in a hypothetical cleanroom. As shown, every BSC and LAFW is sampled for viable air particles, non-viable air particles, and surfaces, in close proximity to where the sterile compounding is conducted; each room is sampled for one viable and one surface sample. This diagram can be modified based on the exact configuration of a given compounding pharmacy.
A wide variety of equipment options are available for environmental monitoring sampling; each pharmacy should diligently consult with equipment manufacturers to determine the specific equipment that best suits their needs. Following is a review of the equipment types.
Non-viable Monitoring Equipment
Monitoring non-viable air particles is typically conducted via handheld portable air samplers in which a vacuum pump pulls air from a sampling probe through a sensor and laser beam. The sampler then converts the light into electrical pulses that are counted by the internal particle counter. Larger particles reflect more light than smaller particles and the counter differentiates between the two.3
Many compounding pharmacies use hand-held particle counters; however, it is important to note that continuous non-viable air particle monitors—the preferred option in the pharmaceutical industry—are becoming more cost efficient. Although compounding pharmacies are under the jurisdiction of USP <797> and <800>, it is not uncommon for them to also be audited by the FDA under cGMP requirements. This increasing level of regulatory oversight has many implications, from the frequency of environmental monitoring sampling to an expectation of the use of continuous non-viable air particle equipment. Forward-looking pharmacies may want to consider continuous non-viable air particle counting equipment as a useful alternative to handheld non-viable air particle monitors. The requirements for non-viable air particles are presented in TABLE 1.
Viable Monitoring Equipment
USP <797> requires that microbiological air monitoring be conducted using a viable impact volumetric airborne particulate sampling device. Handheld portable samplers are typically utilized wherein the vacuum pump pulls at least 1 cubic meter or 1000 liters of air through a perforated opening and impinges the air onto a plate of culture media. The culture media plate is then removed and incubated at 30° to 35°C for no less than 48 hours followed by 20° to 25°C for no less than 5 additional days, and the media plates are subsequently enumerated for colony forming units (CFU). The requirements for viable particle counts are presented in TABLE 2.
Surface Monitoring Equipment
Surface sampling must be performed at the end of the compounding activity or shift, but before the area has been cleaned and disinfected. Surface monitoring devices (eg, plates, paddles, or slides) containing microbial growth media must be used for sampling flat surfaces. The growth media (eg, tryptic soy agar [TSA]) should be supplemented with neutralizing additives (eg, lecithin and polysorbate 80) to offset the effects of any residual disinfecting agents. Surface sampling devices must have a raised convex surface. Sterile swabs wetted with sterile water or a sterile neutralizing buffer may be used when sampling irregular surfaces and difficult-to-reach locations, such as crevices, corners, and spaces between surfaces.
Some pharmacies collect two samples concurrently for each sample location. Both samples could be TSA or one sample could be TSA and the other a fungal media (eg, Sabouraud dextrose agar [SDA] or malt extract agar [MEA]). Each sample is incubated in a separate incubator: the TSA sample at 30°to 35°C for no less than 48 hours for bacterial enumeration, and the second (fungal) sample at 20°to 25°C for no less than 5 days. All media plates are subsequently enumerated for CFUs. The requirements for surface sampling are presented in TABLE 3.
Certification of the classified areas, including the PECs, is to be performed initially, with recertification occurring at least every 6 months. Non-viable particle testing must be performed under dynamic operating conditions using calibrated electronic equipment. Non-viable particle sampling sites must be selected in all classified areas and in each PEC location.
Viable Air and Surface Monitoring
Viable air monitoring must be conducted in all classified areas during dynamic operating conditions using an impaction device and must occur at least every 6 months. Surface sampling must be conducted monthly. Both must also be performed:
As noted, the FDA has been inspecting pharmacies using cGMP requirements. Under these regulations, sampling frequencies of 6 months for air and 1 month for surfaces are inadequate. Forward-looking pharmacies may want to consider more frequent sampling, not only to satisfy FDA inspectors, but more importantly, to ensure that the air and surfaces in the pharmacy are conducive to producing sterile products.
Environmental monitoring provides the data necessary to demonstrate that the areas supporting the sterile compounding operations are devoid of any microorganisms that can undermine the integrity of CSPs. Pharmacy’s environmental monitoring program must encompass non-viable particle counts, viable particle counts, and surface samples. The selection of sampling sites is key to an effective monitoring program; designated sites should be as close as possible to any sterile transfer points; for example, immediately adjacent to the person preparing the CSP. Numerous companies offer sampling equipment and each pharmacy should determine which types of equipment best fit their needs based upon the number and types of sites to be sampled and the cost of the equipment.
The minimum required sampling frequency is 6 months for air samples and monthly for surface samples; however, these frequencies may be insufficient to develop meaningful trends. Effective data trending will clearly show if environmental conditions are changing; as such, increased frequency of environmental monitoring is recommended in order to develop realistic trends. Once collected, monitoring data must then be documented, reviewed by QA, and saved for a minimum of 3 years to provide evidence of the conditions that surrounded the compounding of specific CSPs. In essence, environmental monitoring supports the aseptic practices used to produce CSPs.
Part 2 of this article, Best Practices for Environmental Monitoring: Documentation will be published in a future issue of PP&P.
Frank Settineri, BS, MS, has over 40 years’ experience working with a range of entities from compounding pharmacies to pharmaceutical companies, focusing on investigations, root cause analysis, microbiological data deviations, particulate matter mitigation, and cGMP compliance. He is particularly adept in writing responses to 483s and warning letters that result in both interim controls and sustained cGMP compliance. Frank is president and founder of Veracorp LLC.
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