Understanding USP 797
Unraveling the requirements for compounding sterile preparations
By Fran McAteer, vice president at Microbiology Research Associates, Inc.
The purpose of USP 797 is to prevent harm and fatality to patients that could result from microbial contamination and excessive bacterial endotoxins. The regulations apply to health-care institutions, pharmacies, physician offices, and other facilities where compounded sterile preparations (CSPs) are prepared.
CSPs include the following types of preparations:
- Those prepared according to the manufacturer’s label instructions that expose original contents to potential contamination.
- Those that must be sterilized before administration.
- Biologics, diagnostics, drugs, nutrients, and radiopharmaceuticals that include baths and soaks for live organs, implants, inhalations, injections, and powders for injection, metered sprays, and ophthalmic and optic preparations.
However, the hospital pharmacies are struggling with compliance to USP 797. The ranges of issues encompass everything from cleanroom infrastructure design to demanding quality requirements. The United States Pharmacopeia (USP) states, “It is the ultimate responsibility of all personnel who prepare CSPs to understand these fundamental practices and precautions, to develop and implement appropriate procedures, and to continually evaluate these procedures and the quality of final CSPs in order to prevent harm and fatality to patients who are treated with CSPs.” Sterile compounding practices are now enforceable by both the Food and Drug Administration (FDA) and the Joint Commission on Accreditation of Healthcare Organizations (JCAHO). The FDA will not directly inspect the pharmacies, but JCAHO compliance with 797 is required by all pharmacies.
Procedure development, implementation
Sterile compounding personnel have a myriad of responsibilities. These include:
- Accurate identification
- Measurement, dilution, and mixture
- Purifying, sterilizing, packaging, sealing, labeling, and storing
- Dispensing and distributing
- Maintaining appropriate cleanliness conditions
- Preparing in a manner that maintains sterility
- Minimizing the introduction of particles
Figure 1: Here, a central pharmacy technician at a major Boston hospital undergoing 797 compliance works with sterile products in a cleanroom environment. All photos courtesy of Fran McAteer.
Personnel also must be proficient in the principles and practices of aseptic manipulations, and have knowledge of sterilization and stability. In order to perform these responsibilities in a consistent manner, a sterile compounding pharmacy must provide its personnel with well-designed cleanroom facilities and equipment, validated procedures, sterile disposables, expert training, and independent quality review. This is the true focus of USP 797.
Environmental quality and control, monitoring
Environmental quality and control depends on the amount of exposure of the CSP. A critical site for contamination is any opening providing a direct pathway between a sterile product and the environment. In order to reduce the risk of contamination, exposure time must be kept to a minimum, critical sites minimized (such as an open vial or needles), and airborne particles eliminated. Injectables also can pose great harm to patients if they are not compounded properly. In summary, a minimum level of contamination can have a serious impact on patient care, especially those with compromised immune systems.
Assessment and verification of performance within the sterile compounding environment must be done. This requires a measurement of a total number of particles (non-viable count) and a total number of viable microorganisms (viable count). Viable counts should be taken at sample sites that are most prone to contamination. Air sampling can be done using settling plates or rotary centrifugal samplers. Settling plates should be exposed for at least one hour. After exposure, they should be incubated at 30° to 35°C for 48 hours. Also, an enumeration of Colony Forming Units (CFU) should be made. The colony count is reflective of the level of contamination in the air of the particular sample site.
Environmental monitoring determines the normal baseline counts over time. It helps to determine the trend and set alert and action levels. Corrective actions should be established for counts above the action levels. These are designed to ensure the quality of the environment. Written procedures should incorporate sampling techniques, location maps, frequency, incubation parameters, alert and action levels, corrective actions, and microbial identification.
Microbial contamination risk levels
Microbial contamination risk levels are assigned according to the probability of contamination of a CSP with microbes/endotoxins and foreign chemicals/physical matter. Sources of contamination include solid/liquid matter from personnel and objects; non-sterile components that are used; inappropriate conditions within the compounding environment; prolonged pre-sterilization procedures with aqueous preparations; and non-sterile dosage forms used. Risk levels apply to the quality of CSPs immediately after the final aseptic mixing or filling, or immediately after the final sterilization.
Low-risk CSPs are those CSPs compounded with aseptic manipulations entirely within an ISO Class 5 (Class 100) hood. Furthermore, there are only sterile ingredients, product components, and devices used. And, compounding involves only the transfer, measuring, mixing, and sealed packaging system. Manipulations are limited to aseptically opening, penetrating stoppers, transferring sterile liquids to sterile devices, and so forth. There is no sterility test if the storage period before administration does not exceed 48 hours at controlled room temp and not more than 14 days at cold temperature and 45 days in solid-frozen state at ≥ -20°C.
The quality assurance requirement for low-risk CSPs is routine disinfection of the compounding environment. Environmental monitoring of air quality should be tested. Requirements also include a review of all orders and ingredients, visual inspections of CSPs, particles, leakage, and labeling, as well as annual media fills.
Medium-risk CSPs include compound Total Parenteral Nutrition (TPN) fluids, where there are multiple injections, detachments, and attachments to the device that is delivering to the final sterile container. It also includes filling reservoirs of injection and infusion devices with multiple sterile drug products, evacuation of air from reservoirs, and reservoirs of injection and infusion devices that will administer over several days at 20 to 40°C.
Figure 2: Pictured here is compounding TPN fluids at the facility.
Some other medium-risk CSPs are:
- The transference of volumes from multiple ampoule or vials into a single, final sterile container.
- Multiple, individual, or small doses of sterile products combined to prepare CSP for administration to multiple patients or one patient on multiple occasions.
- Compounding involving complex aseptic manipulations.
- Compounding that requires unusually long durations, such as dissolution/mixing.
- Sterile CSPs that do not contain bacteriostatic substances and are administered over several days-for example, implanted infusion devices.
CSPs that have storage periods of 30 hours at controlled room temperature, seven days at cold temperature, or 45 days frozen (≥ -20°C) are also considered medium risk.
Media fill proficiency for medium-risk-level CSPs should be demonstrated by the pharmacist more frequently, be performed under more challenging conditions with more complex manipulations, and take place within ISO Class 5 (Class 100).
High-risk CSPs are at a high risk to become contaminated with microorganisms. They are non-sterile ingredients or non-sterile devices that are employed before terminal sterilization. High risk can occur when exposing the ingredients to an air quality that is inferior to ISO Class 5 and when the storage of ingredients and devices occurs at an air quality that is inferior to ISO Class 5.
Non-sterile preparations are exposed at least six hours before being sterilized, and chemical purity and content is not verified to meet original specifications. CSPs that have storage periods of not more than 24 hours at controlled room temperature, not more than three days at cold temperature, or 45 days frozen (≥ -20°C) are also a high-risk level. Some examples of high-risk compounding are dissolving non-sterile bulk drug and nutrient powders to make solutions, which will be terminally sterilized, and mixing sterile ingredients in non-sterile devices before sterilization.
Figure 3: A scene from a major Boston hospital pharmacy undergoing 797 compliance activities.
The quality assurance for high-risk CSPs is more acute than low-risk CSPs. Environmental monitoring of air and surfaces is performed weekly. Media-fill proficiencies are more strenuous and time-consuming.
Cleaning and sanitization
Cleaning and sanitization must follow written procedures, and are the responsibility of the pharmacists and technicians. Cleaning and sanitization is performed at the beginning of each shift and include horizontal surfaces, floors, walls, carts, and shelving. Work surfaces near the compounding area should be disinfected more frequently. Approved agents must be used to perform all cleaning and sanitization. In addition, cleaning logs must be kept. Non-shedding wipes, sponges, and mops are to be used, and appropriate contact times should be observed. And, a rotation of disinfectants is advisable.
Personnel cleaning and gowning
All personnel should be trained and educated in contamination-control principles. Written procedures in the form of Standard Operating Procedures (SOPs) are required. Personnel should not wear makeup or jewelry, and hands and arms should be completely covered. Hair covers, disposable lab coats, shoe covers, and gloves must be worn. Routine re-sanitization of gloves should be frequent and performed upon re-entry into the sterile field. Personnel are advised to change into new cleanroom garments upon each entry.
Training should be performed by expert personnel, and should be in the form of audio-video instruction and classroom instruction. All personnel must demonstrate an understanding of contamination control, media-fill proficiency, and gowning certification before being allowed to perform sterile compounding activities.
Media-fill proficiency training should occur at least annually by each compounding person. It should be designed to mimic the “worst-case scenario” for the most complex CSP at the particular risk level. Sterility and endotoxin results of this media-fill proficiency testing must exhibit no contamination.
Sterility-test requirements, endotoxin
All high-risk CSPs for IVs into the vascular and the central nervous system that are prepared in groups of more than 25 identical but individual single-dose packages (for instance, vials, bags, and so forth) require sterility testing by USP 71 standards. Sterility testing is also required for multiple-dose vials for multiple patients and CSPs that are exposed more than 12 hours at 2° to 8°C or exposed for 76 hours at 8°C or warmer before they are sterilized. Testing, if possible, should be complete before the CSPs are administered. Moreover, membrane filtration is recommended for aqueous solutions; direct transfer, if not filterable, is the alternative. And, sterility tests are checked for contamination over a 14-day period.
Figure 4: Shown here are pharmacists in the prep room.
In addition, sterilization methods should be verified with written documentation and the use of biological indicators (BIs). Sterilization methods include steam (autoclaving) and filtration. Steam sterilization is the preferred method for aqueous preparation. The material must be heat-stable at 121°C for a verified amount of time (20 to 60 minutes). Filtration is done by using a 0.22 micron absolute rated porosity. A certificate of analysis should be requested from the manufacturer and filed with the batch record. Furthermore, filtration must be chemically and physically compatible with the CSP. Filters can become damaged during processing and should be integrity-tested at the completion of the processing procedure.
The current USP 797 regulations emphasize the need to maintain high-quality standards for processes, components, and environments for sterile compounding preparations. The benefits of USP 797 compliance include the minimization of contamination of CSPs, improved aseptic proficiency of hospital pharmacy personnel, and increased drug quality levels. These benefits should translate into lower noscomial infection rates and overall better patient care.
United States Pharmacopeia and National Formulary (USP-NF), 29th Edition, US Pharmacopeia Convention, Inc.: Rockville, MD, 2004.
Fran McAteer is vice president at Microbiology Research Associates, Inc. Located in Acton, Massachusetts. Microbiology Research Associates is an FDA-registered microbiology testing laboratory specializing in USP 797 compliance, consulting, and testing of compounded sterile preparations. The author has expertise and experience in USP 797-compliance programs, and acts as a consultant for many hospitals.