Part 1 of this article, Best Practices for Environmental Monitoring: Air and Surface Sampling is available at www.pppmag.com/article/2524
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. Documentation of environmental monitoring serves to substantiate the facility’s efforts and most importantly to identify any developing contamination trends that require an immediate response.
Environmental monitoring scrutinizes the environment surrounding the compounding area to assure that it does not contribute to a breach in product sterility; 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.
There is a saying in regulatory parlance that “If it isn’t written down, it didn’t happen.” In the current heightened regulatory atmosphere, not only is it imperative to record what happened, it is equally important to accurately and precisely record what was done in response. Many times, activities that are performed are not documented properly and the FDA does not hesitate to cite this type of finding in a 483 observation. To maintain compliance, and to ensure a robust quality program, it is incumbent upon pharmacy to establish sound documentation practices.
USP <797> is direct regarding documentation and states that facilities must have and maintain written or electronic documentation to demonstrate compliance with the chapter requirements; the documentation must include environmental air and surface monitoring procedures as well as the results of investigations and corrective actions. Additionally, the documentation must comply with all laws and regulations of the applicable jurisdiction. Records must be legible and stored in a manner that prevents their deterioration and/or loss and must be readily retrievable for at least 3 years after preparation or as required by laws and regulations of the applicable regulatory jurisdiction, whichever is longer.1
Documenting environmental monitoring is most readily accomplished by generating tables (data sheets in logbooks) that denote the date, time, and person conducting the monitoring, as well as the results that are obtained. The data must be reviewed by a second person and verified by the head of quality, who may also act as the reviewer. An example data sheet is presented in TABLE 1 as a guide for recording environmental results.
While it may seem controversial, the following concept must be acknowledged: Trending of data over time is more important than finding a single point that exceeds the established limit. This is because microorganisms and non-viable air particles are unevenly distributed in air, surfaces, and even in products. Not only are they tiny, but they are also subject to dissemination in the air, soil, and on surfaces. Because they are microscopic in size, one surface sample may have completely different results than a subsequent surface sample that is separated by only 1/64th of an inch or less. The first site may be pristine, while the second, adjacent site may harbor microorganisms. Similar conditions exist with air sampling: there may be differences between the air sampled from one time to another. These differences are part of the normal distribution of microbial and non-viable air particles and account for why particles are defined by limits rather than specifications. Normal fluctuations are expected, and variations from time to time are quite likely to occur. Hence, it is the patterns, or trends of particle counts, that create a true picture of the operating environment.
At the same time, there is a challenge in establishing trends: many data points are required to ensure accuracy. This review is not intended to be a treatise in statistics because it would take too much time to develop and the reader would soon tire of it. Thus, in simple terms, a trend is a pattern that is observed over time; the more data points that are collected, the easier it is to spot a trend. Since pharmacies are only required to obtain air samples every 6 months, this means that over the course of a year there will be only two air samples; it is very difficult to declare that a trend exists with only two data points. Surface samples are required to be taken every month, resulting in 12 samples every year; trends can be more readily observed, yet with only 12 data points spread out over a year, trends are still difficult to ascertain. To overcome this dearth of data, increased sampling frequency, such as weekly, would provide additional data points to more easily identify developing trends.
Despite increasing demands from the FDA to use GMP standards, some pharmacies may be unwilling to increase the sampling frequency, as it is not required and therefore they must attempt to determine if trends exist with a paucity of data points. This can be accomplished by using existing data that have been collected. The hypothetical data in TABLE 1 provides a template for this approach. In the table, note the air sample results for BSC 1 were <1 CFU/m3 on January 2 and 2 CFU/m3 for BSC 2 on January 2. It is not possible to determine if a trend exists for either BSC until 6 months later when the BSCs are next sampled. At that time, another excursion in BSC 2 could be considered a trend even though there are only two data points. The analysis is simpler for the LAFW surface samples: both LAFWs exhibited an excursion 2 months in a row (3 CFU/plate), indicating a distinct pattern, or trend. When trends are found, the microorganisms should be identified. Microorganisms should also be identified whenever a limit is exceeded, even if a trend is not observed. As shown in TABLE 1, the 2 CFU/m3 found in BSC 2 (January) exceeded the limit of <1 CFU/m3 and required identification. The 3 CFU/plate that was found from surface sampling on both LAFWs in January were at the limit of 3 CFU/plate, and also required identification. Of course, when a trend was spotted in February, identifications were required, based upon both the trend and on meeting or exceeding the limit of 3 CFU/plate.
The key to an effective environmental monitoring plan is to establish the next steps in the event that a limit is exceeded, or if a trend is suspected. The current best practice is to conduct repeated sampling for 5 consecutive days to determine if a trend exists. If this additional sampling is negative, then normal sampling frequency can be resumed. If the sampling confirms the trend, then remedial actions must be implemented, such as enhanced cleaning, utilizing different disinfecting agents, retraining personnel in aseptic practices, or applying more stringent control during material transfer. Once the corrective actions are applied, repeat sampling should be conducted for an additional 5 days to ensure the corrections were effective. If the changes do not prove effective, more drastic measures need to be taken, including cessation of operations, equipment maintenance, and potentially equipment replacement. Trending of data is a gauge that monitors the microbiological health of the operation; it is a powerful tool that serves to improve aseptic conditions in the pharmacy.
USP <797> is clear regarding record keeping: all facilities where CSPs are prepared must have and maintain written or electronic documentation, which must include environmental air and surface monitoring procedures and results. The documents must be retained for at least 3 years or longer after preparation, depending on the laws and regulations of the applicable regulatory jurisdiction.
Regulatory agencies prefer electronic records because they are readily available, provide audit trails, and are not easily falsified. Many pharmacies agree and purchase software to maintain their records. Nevertheless, numerous pharmacies continue to utilize paper records, which is acceptable as long as they are properly maintained and stored. To ensure appropriate maintenance of a paper-based system:
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. A 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 fits their needs based on 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.
Frank Settineri, BS, MS, president of Veracorp LLC, has over 40 years’ experience working with entities from compounding pharmacies to pharmaceutical companies. He focuses 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.
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