Maintaining a clean, controlled pharmacy work environment is a challenging and perpetual task. Thus, creating and controlling a defined, sterile environment for pharmaceutical compounding is typically performed through the use of primary engineering controls (PECs)—usually cleanrooms, biological safety cabinets (BSCs), and compounding aseptic isolators (CAIs or CACIs). Areas where sensitive and hazardous medications are mixed and compounded must be environmentally controlled to minimize the risk of contamination of critical sites and materials; PECs enable this by minimizing the levels of viable microorganisms and non-viable particulates within these areas.
Every PEC is designed to maintain a certain level of cleanliness as defined by the United States Pharmacopeia (USP) and ISO 14644-1. By USP <797> definition, a PEC is a device or room that will maintain an ISO 5 environment. Typically there are cleanrooms in use within a facility in addition to the ISO 5 PEC. There are three major classifications utilized within the industry listed from cleanest to dirtiest; ISO 5, 7, and 8, or class 100, 10,000, and 100,000. Each classification has a specific set of acceptance criteria for viable bacteria as well as non-viable particulates. The engineering features that PECs and cleanrooms use to achieve and maintain a clean environment include HEPA filters, unidirectional air flow, air velocity, positive pressure, temperature, humidity, and numerous air changes per hour. Operational criteria for some of these controls, such as air velocity and the number of air changes per hour are specified within industry guidance documents. Despite these advantages, engineering controls alone cannot be relied upon to maintain a controlled environment.
Proper PEC Operation
Once a PEC is installed and qualified, detailed policies and procedures (P&Ps) must be adopted or written and implemented in order to properly maintain and utilize the device moving forward. Among the first elements of the P&Ps should be information on proper personal protective equipment (PPE), disinfection, and monitoring for each classified room and/or PEC. The details of these activities typically will depend on the scope and risk level of the compounding being performed, as well as the classification of the PEC intended for use. Proper use of PPE plays a large role in maintaining a clean environment, as it serves to protect both the user from any hazardous materials, as well as the environment from any contamination that personnel could potentially introduce to the area. Bacteria are constantly being shed from clothing, shoes, and skin, so it is imperative that adequate gowning is donned prior to entering and working in classified areas.
A common controlled environment setup of classified areas in the pharmacy will begin with an ISO 8 anteroom, which will lead into an ISO 7 cleanroom that contains one or more ISO 5 BSCs, CAIs, and/or laminar air flow workbenches (LAFWs). PPE requirements should become more stringent as the classified areas decrease in number:
In addition to PPE, frequent spraying of gloved hands with 70% IPA will help prevent any contamination from spreading via hand contact. Although gloves are sterile when donned, they do not remain so once in use; therefore, spraying with 70% IPA is an effective way to minimize bacterial buildup on glove surfaces while working in the cleanroom. Regardless of the amount of 70% IPA being used, it is vital to don new sterile gloves in between different compounding activities.
Cleaning and disinfecting cleanrooms and PECs is another key to maintaining a clean environment and should be performed by specifically trained individuals. Many robust cleaning programs utilize both in-house employees and outsourced cleaning vendors that specialize in cleanroom cleaning and maintenance of engineering controls. In such a dual operation, written P&Ps should be generated that describe in detail the roles and responsibilities of each group—hospital personnel and any contracted cleaning personnel. The proper procedure for cleaning and disinfecting equipment (ie, back to front, top to bottom) and the appropriate products and materials to be used also should be defined within these P&Ps.
When any type of cleaning and disinfecting activities are being performed, be sure the HEPA filter remains operational at all times to maintain a supply of clean air within the cleanroom or PEC. According to USP <797>, ISO 5 PECs should be wiped down with 70% IPA before and after each use, and at least every 30 minutes when ongoing compounding activities are being performed. Because of their specific use, trained compounding technicians experienced with ISO 5 PECs should perform disinfection activities. Furthermore, a more significant cleaning using a sporicide or bleach solution in addition to the 70% IPA should be performed at least once a month. This activity, as well as other routine cleanings, should be documented.
While performing the more in depth disinfection on a BSC, always use dedicated, non-shedding wipes to clean surfaces. Remember to remove the work tray and grate in order to clean the area underneath with disinfecting agents. These agents can be sprayed directly onto the walls and work tray of the BSC and LAFW, but avoid spraying any liquids directly at the HEPA filter grate, as this may compromise the functionality of the filter. The HEPA filter is typically located in the top of a BSC and in the back of a LAFW. In order to clean these surfaces, the disinfecting agent should be applied directly to a lint free wipe, which then can be used to delicately wipe the surface of the HEPA grate.
Managing the Cleanroom
Regarding the cleaning and sanitization of ISO 7 and ISO 8 cleanrooms, the same aspects of frequency, types of agents used, equipment, and technique must be accommodated. According to USP <797>, daily disinfection of counter tops, tables, and floors should be performed using an approved sanitizing agent such as ready-to-use bleach solution or 70% IPA. The walls of the cleanroom need to be disinfected on a monthly basis, at a minimum, but many facilities are moving to a weekly schedule, which produces a more consistently disinfected compounding environment. While many of these functions can be performed by in-house housekeeping and facilities maintenance staff, outside cleaning vendors often have specialized equipment and microbiocidal agents to further minimize contamination within the cleanroom.
Examples of widely used disinfectant agents that may be utilized include Vesphene, LpH, and Spor-Klenz. Vesphene is an alkaline phenolic disinfectant made specifically for use on hard, non-porous surfaces and LpH is an acidic phenolic disinfectant also made specifically for use on hard, non-porous surfaces. Both of these agents kill a broad spectrum of common bacteria without harming the surface when used properly. Spor-Klenz is a sporicide, meaning it is specifically designed to kill spore-forming microorganisms such as mold and Bacillus species. Spor-Klenz is a harsh agent, though, and if used in large quantities it can pose some heath risks, particularly if proper precautions are not taken. Therefore, Spor-Klenz typically should be used to clean surfaces only on a monthly or quarterly basis, or as needed for remediation purposes.
Tools for Applying Cleaning Products
The above-mentioned cleaning agents need to be applied using equipment specifically designed for maintaining cleanliness within critically controlled environments. A cleanroom mop and bucket system is generally used for the application of disinfectant agents within a cleanroom and the system should be constructed of durable materials, such as stainless steel, which can be easily wiped down and sanitized as needed. The mop also should be made of cleanroom-grade materials and the mop head should be sterile and constructed of non-shedding cleanroom-grade materials, such as polyester.
Cleaning technique also is critical and the general order should be to start disinfecting the cleanest areas and work towards the dirtiest. Floors should always be the last surface in a room to be cleaned using a mop head designated for the floor alone. Mop heads should be changed frequently and always when moving into a new area. Mop strokes should be unidirectional and overlap each other by 10 to 20 percent to ensure areas are not missed. Cleaning and disinfection activities should not be performed while compounding activities are taking place, so a predetermined cleaning schedule should be established and communicated to all applicable parties. Most cleanroom cleaning companies are able to accommodate the busy schedules of their clients by performing their cleaning and disinfection activities during off hours.
Assessing Effectiveness through Monitoring
Once PPE, cleaning, and disinfecting P&Ps are established, a process should be established to assess the effectiveness of these programs and detect any possible issues with the controlled environment within a functioning cleanroom or PEC. This is where environmental monitoring comes into play and there are a few major aspects to consider when setting up an environmental monitoring program for a PEC.
Frequency is important, as the classified area should be monitored often enough to allow for the detection of an adverse trend, such as elevated microbial or non-viable counts, in a timely manner. It is recommended that classified areas be monitored on a monthly basis at a minimum; certain PECs may need more frequent monitoring depending on the volume and/or criticality of the operations being performed in the area.
Developing a sampling location plan is another important aspect of overall monitoring. The sampling plan should cover surfaces, viable air, and non-viable air samples. The amount of samples that need to be taken will depend upon the size and classification of the cleanroom and/or PEC along with the location of critical work areas. Surface sample locations should be distributed throughout the area in a manner that will accurately represent the major affected surfaces, such as walls, floors, and critical work areas. For a vigorous sampling plan, both Trypticase soy agar (TSA) and Sabouraud dextrose agar (SDA) should be used; TSA is formulated for detection and cultivation of bacteria and SDA is specifically formulated for detection and cultivation of yeasts and mold. If an out of specification result is obtained, the monitoring program should have a corrective action policy that indicates proper remediation. If an excursion is discovered within one area, that area should be taken out of use, disinfected and re-monitored. Once the results come back within specification, the area can be released for normal use again. If excursions persist in that specific area then an investigation should take place to determine the root cause of contamination.
Primary engineering controls play a critical part in preventing critical materials from being contaminated in the pharmacy. However, these devices will only be effective if proper procedures for cleaning and maintenance are defined and followed. Running an effective cleaning program (including processes for environmental monitoring) will require the efforts of many people to remain effective. Personnel training, routine cleaning and disinfecting, and monitoring activities must be perpetual. Once such a program is realized and implemented, it will afford a level of confidence that pharmacy PECs will perform according to design.
Ryan Burke has worked as a microbiologist within the biotech industry for over ten years in multiple biopharmaceutical companies. In 2012, he joined E/M Associates, a small independent consulting firm which focuses primarily on cleanroom design, environmental monitoring, and remediation of contamination issues.
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