12.2 Sterile Compounding & Hazardous Drug Handling: USP <797>, USP <800> & Facility Requirements

12.2 Sterile Compounding & Hazardous Drug Handling: USP <797>, USP <800> & Facility Requirements

[!NOTE] Enforceable Compendial Standards: Sterile compounding jurisprudence is anchored in United States Pharmacopeia General Chapter <797> (Pharmaceutical Compounding – Sterile Preparations) and General Chapter <800> (Hazardous Drugs – Handling in Healthcare Settings). Both chapters are incorporated into Alabama pharmacy practice standards through the Alabama Pharmacy Practice Act and ALBOP regulations. Strict adherence to cleanroom engineering, environmental monitoring, personnel asepsis, and containment protocols is mandatory to prevent microbial contamination, toxic exposure, and patient fatalities.

Compounded Sterile Preparations (CSPs) carry inherent clinical risks because they bypass the body's natural defense barriers when administered parenterally, ophthalmically, or through inhalation. Concurrently, handling hazardous drugs (HDs) poses severe occupational toxicity risks to compounding personnel, including carcinogenicity, teratogenicity, and reproductive harm.

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Cleanroom Architecture & ISO Air Classifications (USP <797>)

Air quality in compounding environments is standardized by the International Organization for Standardization (ISO) based on maximum allowable particulate counts per cubic meter of air ($0.5\ \mu\text{m}$ and larger).

+---------------------------------------------------------------------------------------------------------+
|                                 Cleanroom ISO Classification Hierarchy                                  |
+---------------------------------------------------------------------------------------------------------+
| ISO Class    | Maximum Particle Count (≥0.5 µm/m³) | Typical Compounding Facility Engineering Area      |
|--------------+-------------------------------------+----------------------------------------------------|
| ISO Class 5  | 3,520 particles/m³                  | Primary Engineering Control (PEC / LAFW / BSC)     |
| ISO Class 7  | 352,000 particles/m³                | Buffer Room (Cleanroom) & Hazardous Ante-Room      |
| ISO Class 8  | 3,520,000 particles/m³              | Non-Hazardous Ante-Room (Gown/Wash Area)           |
| Unclassified | >3,520,000 particles/m³             | General Pharmacy / Ambient Hospital Space          |
+---------------------------------------------------------------------------------------------------------+

Primary Engineering Controls (PECs)

A Primary Engineering Control (PEC) is a device that provides an ISO Class 5 environment for sterile compounding:

• Laminar Airflow Workstation (LAFW): Utilizes High-Efficiency Particulate Air (HEPA) filters delivering unidirectional airflow (either horizontal or vertical). LAFWs provide non-hazardous sterile compounding environments. Critical principle: The unidirectional airflow must never be obstructed between the HEPA filter face and critical compounding sites (ampule necks, vial stoppers, syringe needles).
• Biological Safety Cabinet (BSC): Vertical laminar flow cabinet providing product, personnel, and environmental protection. Class II Type B2 (100% total exhaust to the outside) or Class II Type A2 (vented externally) cabinets are required for hazardous sterile compounding.
• Compounding Aseptic Isolator (CAI): An enclosed glove-box system maintaining ISO Class 5 air for non-hazardous sterile preparations.
• Compounding Aseptic Containment Isolator (CACI): An enclosed glove-box system operating under negative pressure with external exhaust, dedicated to hazardous drug preparation.

Secondary Engineering Controls (SECs)

A Secondary Engineering Control (SEC) encompasses the architectural spaces housing the PEC:

1. Buffer Room (Cleanroom): The enclosed room where the PEC is physically situated. Must maintain an ISO Class 7 environment. To maintain sterility, buffer rooms must have non-porous surfaces, sealed lighting fixtures, no sinks or floor drains, and dedicated HEPA filtration.
2. Ante-Room: The staging area where personnel perform hand hygiene, garbing, order entry, and component decontamination prior to entering the buffer room.
   • For non-hazardous compounding suites, the ante-room must maintain at least ISO Class 8 air.
   • If the ante-room opens into a negative-pressure hazardous buffer room, the ante-room must maintain ISO Class 7 air to prevent particle migration.

Air Pressure Differentials & Air Changes per Hour (ACPH)

• Non-Hazardous Sterile Suites: Must maintain continuous positive pressure relative to adjacent areas (buffer room positive to ante-room; ante-room positive to unclassified space). The required pressure differential is 0.02 to 0.05 inches water gauge (w.g.) (5 to 12.5 Pa) to ensure that air continuously flows outward from cleaner zones to less clean zones.
• Air Exchange Rates: An ISO Class 7 buffer room must achieve a minimum of thirty (30) Air Changes Per Hour (ACPH), of which at least fifteen (15) ACPH must be supplied from external HEPA-filtered fresh air.

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Unidirectional Garbing & Hand Hygiene Sequence

Contamination in sterile compounding environments originates overwhelmingly from compounding personnel (shedding skin cells, respiratory droplets, and hair). USP <797> enforces a mandatory, unidirectional dirty-to-clean garbing workflow:

                                    USP <797> Unidirectional Garbing Sequence

   ANTE-ROOM: Dirty Side of Demarcation               ANTE-ROOM: Clean Side of Demarcation
   ┌─────────────────────────────────────────┐        ┌─────────────────────────────────────────┐
   │ 1. Remove jewelry, watches, outer coats │        │ 4. Wash hands & forearms up to elbows   │
   │ 2. Don dedicated shoe covers            │ ─────► │    with soap & water for ≥ 30 seconds   │
   │ 3. Don head & facial hair covers        │        │ 5. Dry with lint-free disposable wipes  │
   │ 4. Don face mask & eye shield           │        │ 6. Don non-shedding gown with snug cuffs│
   └─────────────────────────────────────────┘        └────────────────────┬────────────────────┘
                                                                           │
                                                                           ▼
                                                      ISO CLASS 7 BUFFER ROOM (CLEANROOM)
                                                      ┌─────────────────────────────────────────┐
                                                      │ 7. Apply sterile 70% IPA to hands       │
                                                      │ 8. Don sterile powder-free gloves over  │
                                                      │    cuffs & sanitize with sterile 70% IPA│
                                                      └─────────────────────────────────────────┘

Step-by-Step Procedure

1. Personal Hygiene & Outer Garments: Personnel must remove all personal outer garments (jackets, sweaters), watches, rings, bracelets, and body piercings. Artificial nails, nail extenders, and nail polish are strictly prohibited.
2. Ante-Room (Dirty Side): Don dedicated shoe covers (or dedicated cleanroom footwear) one foot at a time while crossing the physical line of demarcation. Don head and facial hair covers, ensuring all hair is completely contained. Don a face mask covering nose and mouth, and eye shields if required.
3. Hand Hygiene: Wash hands, subungual areas under fingernails (using a disposable nail pick), and forearms up to the elbows with warm water and soap for not less than thirty (30) seconds. Dry hands and arms thoroughly using non-shedding disposable lint-free towels or an electronic warm-air blower.
4. Gowning: Don a non-shedding gown with snug-fitting wrist cuffs and a closure at the neck.
5. Buffer Room Entry: Enter the ISO Class 7 buffer room.
6. Sterile Gloving: Cleanse hands with alcohol-based rub containing sterile 70% Isopropyl Alcohol (IPA). Don sterile, powder-free gloves, pulling the glove cuffs completely over the gown cuffs.
7. Glove Sanitization: Spray or wipe sterile gloves with sterile 70% IPA and allow them to dry fully before initiating any compounding activity inside the ISO Class 5 PEC.

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Environmental Monitoring & Personnel Competency Verification

Sterile compounding standards mandate ongoing analytical verification of engineering controls and compounding personnel asepsis:

Environmental Monitoring Schedules

• Viable Air Sampling: Air sampling for microbial contamination (bacteria and fungi) must be conducted at least once every six (6) months in all PECs, buffer rooms, and ante-rooms using volumetric impaction air samplers.
• Total Airborne Particle Counts: Physical particle certification of all ISO Class 5, 7, and 8 zones must occur at least every six (6) months and following any major facility renovation or engineering repair.
• Surface Sampling: Surface sampling of PEC work surfaces, door handles, and staging tables using contact plates (RODAC) containing neutralizing media (e.g., lecithin and polysorbate 80) must be performed periodically at the conclusion of compounding shifts.

Personnel Competency: Gloved Fingertip Testing & Media Fills

+---------------------------------------------------------------------------------------------------------+
|                              Personnel Aseptic Competency Requirements                                  |
+---------------------------------------------------------------------------------------------------------+
| Assessment Modality           | Initial Qualification Standard          | Ongoing Re-Evaluation Frequency|
|-------------------------------+-----------------------------------------+--------------------------------|
| Gloved Fingertip Testing (GFT)| THREE (3) consecutive samples with      | Annually (Category 1 & 2 CSPs) |
|                               | ZERO (0) CFUs on both hands (6 plates)  | Semi-Annually (Category 3 CSPs)|
| Media-Fill Simulation Testing | ZERO growth (turbidity) after 14 days of| Annually (Category 1 & 2 CSPs) |
|                               | incubation (soybean-casein digest)      | Semi-Annually (Category 3 CSPs)|
| Surface & Aseptic Cleaning    | Passing written exam and practical audit| Annually (Every 12 Months)     |
+---------------------------------------------------------------------------------------------------------+

• Initial Gloved Fingertip Testing (GFT): Before being authorized to compound sterile preparations independently, personnel must successfully pass three (3) consecutive post-garbing fingertip samplings yielding zero (0) Colony-Forming Units (CFUs) on both hands.
• Ongoing Gloved Fingertip Testing: Conducted in conjunction with the media-fill test. The passing threshold for ongoing testing is no more than three (3) CFUs total across both hands.
• Media-Fill Testing: The compounding practitioner simulates the most complex, stressful aseptic manipulation using sterile microbiological growth media (soybean-casein digest / tryptic soy broth). The compounded media units are incubated for fourteen (14) days (typically 7 days at $20^\circ\text{C to } 25^\circ\text{C}$, followed by 7 days at $30^\circ\text{C to } 35^\circ\text{C}$). The failure threshold is any visible microbial turbidity (growth).

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Hazardous Drug Handling Under USP <800>

USP <800> applies to all healthcare personnel who handle Hazardous Drugs (HDs) identified on the NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings. HDs include antineoplastics (e.g., paclitaxel, cyclophosphamide, doxorubicin), immunosuppressants, and teratogenic antivirals.

Facility & Engineering Controls for Hazardous Drugs

1. Containment Primary Engineering Control (C-PEC):
   • Must be a Class II or III Biological Safety Cabinet (BSC) or CACI.
   • External Venting Mandate: C-PECs used for sterile hazardous drug compounding must be 100% externally vented through dedicated ductwork to the outside atmosphere. Recirculation of air back into the cleanroom or building is strictly prohibited.
2. Containment Secondary Engineering Control (C-SEC):
   • The C-SEC (hazardous buffer room) must be physically separated from non-hazardous compounding areas.
   • Continuous Negative Pressure: Must maintain continuous negative pressure between -0.01 and -0.03 inches water column (w.c.) (-2.5 to -7.5 Pa) relative to all adjacent areas to prevent hazardous fumes and aerosols from escaping.
   • Air Exchange: Must provide a minimum of thirty (30) ACPH for sterile hazardous compounding (or twelve [12] ACPH for non-sterile hazardous drug compounding).
   • Must be externally vented to the outside atmosphere.
3. Closed System Drug-Transfer Devices (CSTDs):
   • A CSTD is a drug-transfer device that mechanically prohibits the transfer of environmental contaminants into the system and the escape of hazardous drug or vapor concentrations outside the system.
   • Administration vs. Compounding Rule: Under USP <800>, CSTDs are recommended during sterile hazardous compounding, but are MANDATORY for healthcare personnel during the administration of antineoplastic hazardous drugs when the dosage form allows.

Personal Protective Equipment (PPE) for Hazardous Drugs

• Chemotherapy Gloves: Personnel must wear two (2) pairs of chemotherapy gloves meeting ASTM D6978 standards. The inner glove is worn under the gown cuff; the outer glove is worn over the gown cuff. Gloves must be changed every thirty (30) minutes or immediately if torn, punctured, or contaminated.
• Chemotherapy Gowns: Must be non-linting, non-permeable, disposable, and close in the back. Gowns must be changed every two to three (2–3) hours or immediately following a spill.
• Shoe Covers: Two (2) pairs of shoe covers are required when handling hazardous drugs. The outer shoe covers must be discarded in a yellow chemotherapy waste container upon exiting the negative-pressure C-SEC.
• Spill Kits and Eyewash Stations: A specialized hazardous drug spill kit must be immediately accessible. An emergency eyewash station must be located within ten (10) seconds of unobstructed travel from any hazardous compounding area.