Patient safety is the primary consideration when compounding sterile preparations and human interaction poses the greatest risk to the process. This risk is derived not only from any lack of knowledge or disregard of institutional policies and procedures, but by our design; humans harbor an incredible amount of corporeal microorganisms and are constantly shedding skin particles containing these microorganisms into the air. Compounded sterile preparations (CSPs) can easily become contaminated when these skin particles or other particles present in the environment inadvertently end up in the preparation being compounded, either from settling out of the ambient air onto critical sites or from critical sites coming into contact with contaminated hands, objects, or surfaces (see CASE EXAMPLE 1).
A well-designed cleanroom is the first step toward minimizing the risk of contamination to CSPs. A typical cleanroom consists of an ante-area and a buffer area; a negative pressure buffer area also may be included for compounding hazardous sterile preparations. Under the current USP standard, other configurations are permitted, but these may require a particular type of primary engineering control (PEC) or restricting of the beyond-use date (BUD) assigned to the CSP.
CASE EXAMPLE 1
A CSP showed positive bacterial growth at day five of sterility testing. Solution had been filtered with a repeater pump and packaged into one hundred 10 mL vials. Investigation revealed that multiple rows of vials were positioned in front of the HEPA filter in the LAFW, blocking first air. In addition, it is suspected that the compounder contaminated the sterile rubber stoppers when applying them to the vials with gloved hands rather than using sterile forceps.
Basic Cleanroom Requirements
USP <797> Pharmaceutical Compounding—Sterile Preparations dictates basic cleanroom design requirements that, in summary, include:
Furthermore, USP <797> recommends:
CASE EXAMPLE 2
Eliminating Failure Points
A negative pressure buffer room repeatedly demonstrated excessive airborne particle counts. Investigation revealed the ceiling tiles were not caulked. Because the ceiling tiles did not seal tightly, negative pressure pulled particles from the area above the ceiling into the buffer room.
Cleanroom Design Considerations
Serious consideration must be given to the physical location of the cleanroom within the facility as objects and activities outside the cleanroom may negatively affect the integrity of the ISO-classified environment, and ultimately introduce contamination to the CSPs. Furthermore, air currents from non-ISO classified areas may carry unwanted particles into the cleanroom when the door to the ante-area is opened or through exhaust vents located low in the cleanroom walls. This is especially worrisome for cleanroom designs that exhaust air from each ISO-classified area directly into non-ISO classified areas allowing direct access from non-ISO classified areas into the buffer area. These vents should be fitted with filters whenever possible to prevent local fauna (eg, insects), dust from brooms, dirty water from mops, and particles riding on air currents from entering the ISO-classified area.
The entrance into the ante-area and the location of exhaust vents is extremely important when designing a cleanroom and when investigating potential sources of contamination (see FIGURE 1). The entrance into the classified ante-area and any classified area vents exhausting into non-classified areas should be located in low traffic areas that are kept meticulously clean to minimize the impact of unexpected air currents (see CASE EXAMPLE 3). The location of vents that return air from non-ISO classified areas to HEPA filters also should be carefully planned to reduce the bioburden introduced into ISO-classified areas if the HEPA filter develops a leak.
CASE EXAMPLE 3
Unexpected Contamination Sources
A CSP showed contamination with a bacteria found in urine. Investigation revealed a vent that supplemented air to the HEPA filter located immediately outside the rest room. The HEPA filter had not been checked for leaks.
Inside ISO Classified Areas
Within the cleanroom, the location of HEPA filters and air exhaust (or return) vents is critical. Particles may be removed from surfaces with cleaning, but particles in the air can only be removed by exhausting air from the room. Thus, air should exhaust in a manner that pulls particles away from preparation areas or compounding areas to reduce the potential for those particles to settle on critical sites.
Because weighing and mixing activities for compounding with nonsterile components must occur in an ISO Class 8 (or better) environment, these activities typically occur in the ante-area. Given this, placement of doors from the ante-area into buffer areas needs to be evaluated so that any particles that shed from the body before garbing is complete will directly exit the ante-area without crossing preparation areas (for weighing and mixing of APIs), compounding areas, or entrances into buffer areas, especially negative pressure buffer areas (see CASE EXAMPLE 4). Potential problems arise when these particles are drawn into negative pressure areas and the only source of negative pressure is a biological safety cabinet (BSC). The only exit for airborne particles in this case is the BSC, so airborne particles leave the negative pressure area in very close proximity to the direct compounding area we are trying to protect.
PECs and work surfaces within the buffer area should be located such that airborne particles are swept away without interrupting the PEC’s airflow. Human particle shedding is inevitable and a well-designed cleanroom will minimize the bioburden created simply from our presence. Careful examination of the location and layout of the cleanroom, as well as walking through each process to identify areas of concern and possible failure points can significantly reduce the potential for problems downstream.
CASE EXAMPLE 4
Unintended Effects of Negative Pressure
A negative pressure buffer room repeatedly experienced excessive airborne particle counts. Investigation revealed the checking pharmacist would often stand ungarbed on the ‘dirty’ side of the line of demarcation in direct line with the negative pressure buffer-room door. The door did not seal tightly and negative pressure pulled particles past the door seals into the buffer room.
Proper PEC Functionality
Ensuring the cleanroom and other PECs are functioning properly is the next step to minimizing the risk of contamination to CSPs. Integral to this, cleanroom certification reports must be carefully evaluated for accuracy and completeness. It is not uncommon for certification reports to be missing required testing or to falsely state compliance with USP <797>. With this in mind, it is the pharmacist-in-charge or designated person’s responsibility to understand certification requirements.
A recurrent problem is that airborne particle testing is not performed under dynamic conditions (see CASE EXAMPLE 5). Compounders must mimic compounding processes during nonviable and viable airborne particle testing in order to understand the impact of their processes and to ensure the ISO-classification of the area is maintained. Viable airborne particle testing often is omitted or incompletely performed. Viable airborne particle testing and the identification of any bacteria growth is an essential component of a sterile compounding practice and is often how problems are first discovered. Thus, cleanrooms and PECs must be certified before first use, every six months, after maintenance, and when adding, moving, or removing PECs or other fixtures from the cleanroom.
Furthermore, PEC certification must occur under dynamic conditions by qualified individuals using calibrated equipment. Certification of the cleanroom should include airborne particle testing, measuring pressure differentials, determining air changes per hour, and monitoring the integrity of HEPA filters. Certification of individual PECs should include airborne particle testing, measuring air velocity, monitoring the integrity of HEPA filters, and showing unilateral air flow during dynamic conditions with smoke visualization studies. Keep in mind, there may be additional requirements depending on the type of PEC in use.
CASE EXAMPLE 5
Need for Dynamic Environment Testing
After a pharmacist stated, ”I’ve never had any problems with my cleanroom certification,” An investigation revealed the cleanroom was certified ‘at rest’ for particle count only. Retesting revealed multiple problems including insufficient air changes and excessive viable airborne particle count.
Environmental monitoring can help detect problems with cleanroom function, effectiveness of cleaning and disinfection procedures, personnel competency, and institutional procedures related to sterile compounding. According to current USP <797>, viable airborne particle testing (often performed as part of cleanroom certification) shall occur at least every six months and viable surface testing shall occur periodically. For both viable airborne particle testing and surface testing, sample locations in each ISO area should be chosen based on risk for contamination.
Media used in surface testing must include additives to neutralize the effects of disinfecting agents. Media that supports the growth of bacteria also must be used for both viable airborne particle testing and surface testing. In addition, pharmacies that compound sterile preparations using nonsterile chemicals or devices (high-risk level) need to use malt extract media or another medium that supports the growth of fungi for viable airborne particle testing. Viable testing results should be charted and tracked for adverse trends and all viable air growth must be identified to at least the genus level to help identify the cause of the growth, as well as the appropriate remediation.
Per USP <797>, highly pathogenic microorganisms (eg, Gram-negative rods, coagulase positive staphylococcus, molds and yeasts) can be potentially fatal to patients receiving CSPs and must be immediately remedied, regardless of cfu count, with the assistance of a competent microbiologist, infection control professional, or industrial hygienist. In addition, any cfu count that exceeds the determined action level needs to be investigated, the source of the problem eliminated, and resampling performed. Common sources of problems include:
Cleanroom and ISO-Classified Area Issues Related To:
Personnel and Process Issues Related To:
CASE EXAMPLE 6
Viable airborne particle testing, which had previously demonstated consistently acceptable results, suddenly resulted in numerous fungal counts. Investigation revealed that sterile compounding technicians had begun eating lunch outside in the grass wearing their scrubs.
CASE EXAMPLE 7
Unsealing Ceiling Tiles
Previously consistent viable airborne particle testing resulted in counts exceeding actionable limits ten-fold. Investigation revealed that HEPA filters were leak-tested for the first time. Testing was performed by breaking the integrity of the ceiling to access HEPA filters. Airborne particles from above the ceiling fell into the ISO-classified areas.
Patient safety cannot be ensured without understanding and complying with the requirements for sterile compounding. Thus, it is imperative that physical and environmental standards be in place. Furthermore, standard operating procedures form the foundation for training programs and good work practices, which in turn ensure safe, high-quality compounded medications. Pharmacy management needs to continuously monitor their operations, environment, and personnel for compliance, risks, and potential patient safety concerns.
Brenda S. Jensen, CPhT, CNMT, MBA, is the owner of Compounding Consultants, LLC. She helps compounding pharmacies achieve USP compliance and PCAB accreditation. Although Brenda is a member of the USP Compounding Expert Committee, the information presented in this article is her opinion alone and should not be construed as official USP standard. She can be reached via email at: email@example.com.
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