Little in life can be as arduous as wading through a chapter from the USP. The minimum practice and quality standards laid out in USP <797> may never be a New York Times bestselling book, but many do look for a better way to understand the cumbersome language of regulatory texts.
Maintenance of any controlled environment starts with personnel and aseptic manipulation skills. The chapter specifically recommends audio-visual instructional sources and professional publications as training in theoretical principles. Furthermore, there is the initial requirement of a passing written and media-fill testing.
Continued testing varies according to the risk level of the CSP compounded: low- and medium-risk compounding must retest personnel, at minimum, annually; high-risk compounding must retest, at minimum, semiannually. The failure of written tests or media-fill test vials resulting in gross microbial contamination must be immediately re-trained and re-tested by expert personnel.
Sterile fluid culture media is commercially available for this testing. USP <797> uses Soybean-Casein Digest Medium as an example of such media, but also refers the reader to Sterility Tests <71> for appropriate media. Generally, after personnel have performed their media-fill test, the vials are incubated at 20- 25ºC or at 30-35ºC for a minimum of 14 days. If a site opts to incubate media-fill vials at both temperatures, the vials are to be incubated at each temperature range for a minimum of seven days. Visible turbidity in the medium on or before the fourteenth day is indicative of failure.
Environmental quality and control
The quality of the environmental air should increase as one moves from an external boundary to the direct compounding area (see Fig. 1). The effect of items on the designated environmental air and surface quality will dictate the position of those items within the ante and buffer areas. This quality must be verified by monitoring. Environmental sampling provides information to personnel and leadership, demonstrating a primary engineering control (PEC) is maintaining an environment consistently ensuring low viable and nonviable particle levels. A comprehensive quality management system includes environmental sampling, at minimum, at initial commissioning and certification of new facilities and equipment; after servicing of facilities and equipment; every six months as part of re-qualification of facilities and equipment; in response to identified problems with end products or staff technique; and in response to issues with CSPs, observed compounding personnel work practices, or patient-related infections.
Nonviable particle testing
This program is meant to directly measure the performance of engineering controls creating the various levels of air cleanliness. Certification procedures, like those detailed in Certification Guide for Sterile Compounding Facilities (CAG-003-2006), must be performed, at minimum, every six months, and whenever there is a major service performed or when the device or room is moved or altered. Total particle counts are taken to certify that each ISO classified area is controlled to the established guidelines (see Table 1). It is important to note the requirement for testing to be performed by qualified operators, using the current, state-of-the-art electronic equipment and all records maintained and reviewed by supervising personnel, or designate, to ensure compliance.
Pressure differential monitoring
Pressure gauges or velocity meters must be installed between the buffer area and ante area and between the ante area and the general environment. If this is not monitored by a continuous monitoring system, the results must be reviewed and documented at least every work shift, no less than once per day. The pressure differential between the ISO Class 7 area and the general environment must not be less than 5 Pa or 0.02 inch water column. Remember that the pressures are additive — a gauge reading from an ISO Class 7 area to an ISO Class 8 area and a second gauge reading from an ISO 8 area to the general environment is sufficient to know the pressure differential between the ISO Class 7 area and the general environment as required by the standard.
Viable particle testing
A successful viable airborne particle testing program has many components. First, a sampling plan must be created based on risk assessments of the compounding activities performed within each area. Sample plans contain many components and must specifically define sample location, method of collection, frequency of sampling, volume of air sampled, time of day as related to activity levels, and action levels.
Impaction is the preferred method for volumetric air sampling, as the use of settle plates may not adequately determine the quality of air in the controlled environment. The manufacturer’s recommended procedures must be followed for the operation, calibration, and service of an electronic air sampling device. Furthermore, only a properly trained individual shall perform the collection of sufficient volume—between 400L and 1000L—at minimum semiannually. It is important to note that any facility construction or equipment servicing may require air sampling during these events in addition to the semiannual minimum requirement.
Surface sampling is useful in evaluation of facility and surface cleaning and disinfecting procedures and employee competency in work practices. Surface sampling should be performed at the end of compounding to ensure contamination is found if it had occurred during compounding. Immediately after sampling a surface with a contact plate, be sure to thoroughly wipe the sampled area with a non-shedding wipe soaked in sterile 70% IPA to remove any growth media residue left behind. If using a swab for sample collection, be sure to follow procedures that will sample an area approximately equal to that of a surface sample plate—24 to 30 cm2.
Direct touch contamination is the most likely source of microorganism introduction to CSPs prepared by humans. After being observed performing proper hand hygiene and garbing procedures, all compounding personnel must successfully pass an initial competency evaluation and gloved fingertip and thumb sampling with zero cfu after incubation no less than three times prior to compounding CSPs for human use. Re-evaluation for all personnel must occur at minimum annually for low- and medium-risk level CSPs and at minimum semi-annually for high-risk level CSPs. Immediately prior to sampling, the personnel’s gloves are not to be disinfected with sterile 70% IPA to avoid false negative results. The evaluator is to perform the sampling of the personnel’s fingertips by gently pressing each fingertip and thumb into separate agar plates for each hand. The sampled gloves are to be immediately discarded after sampling and proper hand hygiene procedures performed. Despite action levels for fingertip samples are based on the total number of cfu on both gloves, results must be reported for each hand separately.
Incubation parameters require, the air sample plates to be inverted with secured lids. TSA should be incubated at 30º to 35ºC for 48 to 72 hours. Suitable fungal media should be incubated at 26º to 30ºC for 5 to 7 days. Incubation parameters for surface and fingertip samples require incubation at 30º to 35ºC for 48 to 72 hours. After incubation the number of discrete colonies are to be counted and reported as cfu. Air sample counts should be converted to cfu per cubic meter (1000L) of air.
Counts should be evaluated for adverse trends. Should any cfu count exceed recommended action levels (see Table 2), an investigation into the source of contamination should be started. Be sure to re-evaluate personal work practices, cleaning procedures, operational procedures and air filtration. These numbers are to be used a guideline only.
Action levels are to be determined by the cfu data gathered at each sampling location and trended over time. Once identified the source of the contamination must be eliminated, the affected area cleaned and the area resampled. All recovered organisms must be identified—at least to the genus level—by an appropriate credentialed laboratory, regardless of cfu count, to help dictated further corrective actions as necessary. The presence of Gram negative rods, coagulase positive staphylococcus, molds and yeast must be immediately corrected, regardless of cfu count, with the help of a competent microbiologist, infection control professional, or industrial hygienist, due to these organisms’ highly pathogenic natures.
Jillian Berkowitz, a certified Quality Process Analyst, works as the Quality Specialist at Azzur Labs, which provides analytical GXP compliant testing services for the pharmaceutical, medical
device, food, and cosmetic industries. Her expertise includes environmental monitoring, cGMP testing, Lean projects, and validation. www.azzur.com/labs
This article appeared in the April 2015 issue of Controlled Environments.