6.3 Sterile Compounding (USP 797 & GA Board Rules)

Sterile Compounding (USP 797 & GA Board Rules)

Introduction to USP Chapter 797

Sterile compounding is one of the most highly regulated and critically important areas of pharmacy practice. It involves the preparation of medications that bypass the body's natural defense mechanisms, such as intravenous (IV) infusions, intramuscular injections, epidurals, and ophthalmic drops. Because these Compounded Sterile Preparations (CSPs) are administered directly into the bloodstream or other sterile areas of the body, any contamination—whether microbial, chemical, or physical—can result in catastrophic patient harm, including severe infection, sepsis, or death. The Georgia Board of Pharmacy stringently enforces the standards established in the United States Pharmacopeia (USP) Chapter 797 to minimize these profound risks. USP 797 provides a comprehensive set of regulations dictating the environmental controls, facility design, personnel training, garbing protocols, and quality assurance procedures that must be adhered to in order to ensure the absolute sterility and integrity of CSPs. For the MPJE, candidates must demonstrate an exacting knowledge of cleanroom classifications (ISO classes), the specific engineering controls required, the sequence of garbing, the parameters for personnel competency testing (such as media-fill and gloved fingertip testing), and the complex rules for assigning Beyond-Use Dates (BUDs) based on the revised USP 797 Categories (1, 2, and 3).

Facility Design and Environmental Controls

The core principle of USP 797 is the creation and maintenance of a rigorously controlled environment designed to eliminate airborne particles and microorganisms. This is achieved through a combination of Primary Engineering Controls (PECs) and Secondary Engineering Controls (SECs).

The Primary Engineering Control (PEC) is the actual device or workstation where the sterile compounding takes place. Examples include Laminar Airflow Workbenches (LAFWs), Biological Safety Cabinets (BSCs), and Compounding Aseptic Isolators (CAIs). The air quality within the PEC must meet ISO Class 5 standards, which means the air is highly filtered (using HEPA filters) and contains an extremely low number of microscopic particles. The critical site—the area where the sterile product is exposed to the environment, such as the tip of a syringe or the injection port of an IV bag—must always be bathed in unidirectional, first-air from the HEPA filter.

The Secondary Engineering Control (SEC) refers to the cleanroom suite that houses the PEC. A traditional cleanroom suite consists of two distinct areas: the Buffer Room and the Anteroom.

• The Buffer Room (also known as the cleanroom) is the space where the PEC is located. To provide a high level of air quality surrounding the PEC, the Buffer Room must meet ISO Class 7 standards. It must maintain positive pressure relative to the adjacent Anteroom to ensure that cleaner air pushes outward, preventing dirtier air from entering.
• The Anteroom is the transitional space located just outside the Buffer Room. It is used for personnel garbing, hand hygiene, and staging of materials. The Anteroom must meet ISO Class 8 standards (or ISO Class 7 if it opens into a negative pressure buffer room for hazardous drugs). The Anteroom must maintain positive pressure relative to the unclassified general pharmacy area.

Routine environmental monitoring, including viable air testing, surface sampling, and continuous monitoring of temperature, humidity, and pressure differentials, is legally required to verify that these strict environmental conditions are constantly maintained.

Garbing Protocols and Hand Hygiene

Humans are the most significant source of contamination in a cleanroom environment, shedding millions of skin cells and microorganisms every hour. Therefore, USP 797 dictates an exacting, step-by-step garbing protocol designed to contain this contamination. The garbing process must proceed in a specific order, generally moving from the "dirtiest" items to the "cleanest" items, taking place primarily in the Anteroom on the "dirty" side of the line of demarcation.

1. Remove Personal Items: Personnel must remove all cosmetics, visible jewelry, artificial nails, and nail polish.
2. Don Dedicated Shoes/Shoe Covers: Shoe covers must be donned one at a time as the individual crosses the line of demarcation from the dirty side to the clean side of the anteroom.
3. Head and Facial Hair Covers: Hairnets, beard covers, and face masks are donned to completely contain all hair.
4. Hand Hygiene: Personnel must perform a meticulous hand washing procedure, cleaning the hands and forearms up to the elbows with antimicrobial soap and warm water for at least 30 seconds, using a specialized nail pick to clean under the fingernails. Hands are then dried completely using lint-free disposable towels.
5. Gown: A non-shedding, sterile gown is donned.
6. Hand Sanitizer: An alcohol-based hand rub is applied to the hands.
7. Sterile Gloves: Upon entering the Buffer Room, sterile, powder-free gloves are donned. The gloves must be routinely sanitized with sterile 70% isopropyl alcohol (IPA) throughout the compounding process.

Personnel Competency Testing

To ensure that compounding personnel have mastered aseptic technique, USP 797 requires rigorous competency evaluations before they are allowed to compound independently, and at regular intervals thereafter.

Media-Fill Testing: This test simulates the most challenging compounding procedures using a microbiological growth medium (e.g., soybean-casein digest medium) instead of actual medications. The personnel perform a complex compounding simulation. The resulting "products" are then incubated for a specified period (typically 14 days). If the medium remains clear, the test is passed. If the medium becomes cloudy (turbid), it indicates microbial growth and a failure of aseptic technique, meaning the personnel must be retrained and successfully repeat the test before returning to compounding duties.

Gloved Fingertip Testing: This test assesses the individual's ability to garb and sanitize their hands without contaminating their sterile gloves. Immediately after garbing, but before compounding, the individual presses all ten fingertips onto agar plates. The plates are incubated, and to pass the initial test, there must be zero colony-forming units (CFUs) of microbial growth. This test must be passed initially (three successive times) and subsequently in conjunction with the media-fill test.

Categories of CSPs and Beyond-Use Dates (BUDs)

The revised USP 797 has transitioned away from the old "Low, Medium, High Risk" classifications and now utilizes a category system (Category 1, 2, and 3) based primarily on the environmental conditions under which the CSP is prepared, rather than just the complexity of the compounding process.

• Category 1 CSPs: These are prepared in an unclassified Segregated Compounding Area (SCA) rather than a full cleanroom suite. Because the environment is less controlled, the BUDs are severely restricted to minimize risk. The maximum BUD for a Category 1 CSP is 12 hours if stored at controlled room temperature, or 24 hours if refrigerated.

• Category 2 CSPs: These are prepared in a fully compliant cleanroom suite (an ISO Class 5 PEC located within an ISO Class 7 Buffer Room, with an ISO Class 8 Anteroom). These CSPs are eligible for longer BUDs. The exact BUD depends on the sterility of the starting ingredients, whether sterility testing is performed, and the storage temperature. For example, a Category 2 CSP made from sterile starting ingredients without sterility testing can have a BUD of up to 4 days at room temperature, 10 days refrigerated, or 45 days frozen.

• Category 3 CSPs: These are CSPs prepared in a cleanroom suite that undergo rigorous sterility testing and require the pharmacy to implement additional, exceptionally strict quality assurance measures and more frequent environmental monitoring. Category 3 CSPs are eligible for the longest possible BUDs, potentially up to 90 days or more, depending on the specific testing and storage conditions.

Table: Air Quality ISO Classifications for Sterile Compounding