10.3 Hazardous Drugs Handling (USP <800>) in Pharmacy Practice

10.3 Hazardous Drugs Handling (USP <800>) in Pharmacy Practice

United States Pharmacopeia (USP) Chapter <800> establishes practice and quality standards for handling Hazardous Drugs (HDs) in healthcare settings. Unlike USP <795> and <797>, which primarily focus on protecting the purity, sterility, and therapeutic integrity of the finished drug preparation for patient administration, the primary objective of USP <800> is protecting healthcare personnel, patients, and the surrounding environment from the toxic, mutagenic, and carcinogenic risks associated with occupational exposure to hazardous pharmaceuticals.

In Virginia, the Board of Pharmacy incorporates USP standards into state regulations. Every pharmacy entity that receives, unpackages, stores, compounds, dispenses, transports, or disposes of hazardous drugs must maintain a comprehensive, enforceable chemical containment program. Pharmacists must designate a qualified Hazardous Drug Safety Officer, implement formal standard operating procedures (SOPs), ensure proper environmental engineering controls, and train all personnel handling hazardous agents at initial hire and at least annually thereafter.

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The NIOSH List and Toxicity Criteria

USP <800> defines a hazardous drug as any pharmaceutical agent that appears on the official National Institute for Occupational Safety and Health (NIOSH) List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings, or any novel investigational drug that satisfies one or more of the six NIOSH hazardous toxicity criteria:

1. Carcinogenicity: Documented ability to induce cancer or neoplasms in humans or animal bioassays.
2. Teratogenicity or other developmental toxicity: Ability to cause birth defects, fetal resorption, structural malformations, or embryonic harm.
3. Reproductive toxicity: Impairment of fertility, menstrual dysfunction, testicular damage, or adverse gestational outcomes.
4. Organ toxicity at low doses: Significant organ damage, bone marrow suppression, hepatotoxicity, nephrotoxicity, or neurotoxicity observed at therapeutic doses in animal models or clinical usage.
5. Genotoxicity: Mutagenic damage to DNA, chromosome aberrations, or positive Ames test results.
6. Structure and toxicity mimicry: New molecular entities with chemical structures, pharmacological actions, or toxicity profiles closely resembling existing hazardous drugs.

The Three NIOSH Groups

NIOSH classifies hazardous drugs into three distinct categories, each requiring different handling protocols:

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The Entity Assessment of Risk (AoR)

USP <800> establishes a baseline mandate: all hazardous drugs on the NIOSH list must follow full containment engineering controls (negative pressure rooms, containment hoods, chemotherapy PPE). However, recognizing the practical realities of community and outpatient hospital dispensing, USP <800> allows an entity to perform an Assessment of Risk (AoR) to implement alternative, modified containment strategies for specific dosage forms.

What May Be Exempted via an AoR

An entity may conduct an AoR solely for:

• Final manufactured dosage forms of non-antineoplastic hazardous drugs (Group 2 agents, such as intact spironolactone or carbamazepine tablets);
• Final manufactured dosage forms of reproductive hazards only (Group 3 agents, such as intact finasteride tablets);
• Final manufactured dosage forms of antineoplastic agents (Group 1) that only require counting, packaging, or pouring without any manipulation (e.g., counting intact tamoxifen tablets or pouring intact commercial oral liquids).

Under a documented AoR, the pharmacy can establish alternative procedures (e.g., dispensing intact tablets using a dedicated counting tray and spatula, wearing a single pair of chemotherapy gloves, and cleaning the tray with 70% IPA after use) without requiring negative-pressure cleanrooms.

Absolute Prohibitions from AoR Exemption

USP <800> strictly prohibits an entity from applying an Assessment of Risk to the following:

1. Hazardous Active Pharmaceutical Ingredients (APIs): Any bulk powder, chemical raw material, or API of any hazardous drug must always follow full USP <800> containment.
2. Any Physical Manipulation of HDs: Crushing, splitting, grinding, opening capsules, or compounding any hazardous drug (sterile or non-sterile) generates hazardous aerosols, dust, or vapors. These manipulations CANNOT be exempted via an AoR and strictly require full C-PEC and C-SEC containment engineering controls.
3. Annual Documentation Mandate: The entity's Assessment of Risk must be formally documented in writing, identify each specific drug and dosage form covered, delineate containment alternatives, and be reviewed and signed by the HD Safety Officer at least once every twelve (12) months.

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Containment Engineering Controls: C-PEC, C-SEC & Pressure Regimes

To prevent hazardous chemical residues, dust, and aerosols from contaminating pharmacy workspaces and exposing personnel, USP <800> requires specialized containment engineering controls divided into primary, secondary, and supplemental levels:

Sterile Hazardous Drug Compounding Suite Engineering Layout:
┌────────────────────────────────────────────────────────┐
│         ISO Class 7 Clean Ante-Room                    │
│         • Positive Pressure: ≥ +0.02" w.c.             │
│         • Air Changes: ≥ 30 ACPH                       │
│         • Hand hygiene, garbing, staging               │
└────────────────────────────────────────────────────────┘
                           │
                  Airflow  │ (Air flows from Ante INTO Buffer
                  Barrier  │  due to negative buffer pressure)
                           ▼
┌────────────────────────────────────────────────────────┐
│         ISO Class 7 C-SEC Hazardous Buffer Room        │
│         • Continuous Negative Pressure:                │
│           -0.01" to -0.03" water column (w.c.)         │
│         • Air Changes: ≥ 30 ACPH                       │
│         • 100% Externally Vented                       │
│  ┌──────────────────────────────────────────────────┐  │
│  │ Containment Primary Engineering Control (C-PEC)  │  │
│  │ • Class II Biological Safety Cabinet (Type A2/B2)│  │
│  │ • ISO Class 5 Air Quality                        │  │
│  │ • 100% Externally Exhausted via HEPA to Roof     │  │
│  └──────────────────────────────────────────────────┘  │
└────────────────────────────────────────────────────────┘

1. Containment Primary Engineering Controls (C-PECs)

The C-PEC is the ventilated hood or biological cabinet where hazardous manipulation occurs:

• Non-Sterile HD Compounding: The C-PEC must be a Class I Biological Safety Cabinet (BSC), a Class II BSC, or a Containment Ventilated Enclosure (CVE / powder hood). It provides personnel and environmental protection. Non-sterile C-PECs should be externally vented; however, redundant HEPA filters in series are permitted only where local regulations allow.
• Sterile HD Compounding: The C-PEC must be a Class II Type A2, B1, or B2 Biological Safety Cabinet (BSC) or a Compounding Aseptic Containment Isolator (CACI). It must provide ISO Class 5 unidirectional downward laminar airflow and MUST BE 100% EXTERNALLY VENTED through dedicated rooftop exhaust ductwork.

2. Containment Secondary Engineering Controls (C-SECs)

The C-SEC is the dedicated room housing the C-PEC:

• Negative Differential Pressure: Both non-sterile and sterile C-SEC rooms must be maintained under continuous negative pressure between -0.01 and -0.03 inches water column (w.c.) relative to all adjacent surrounding areas. This negative pressure barrier ensures that air constantly flows into the hazardous room, preventing hazardous vapors and airborne particles from escaping into general pharmacy areas.
• External Venting: The C-SEC room air must be 100% externally vented to the outside atmosphere and cannot be recirculated into any non-hazardous heating, ventilation, or air conditioning (HVAC) system.
• Air Changes Per Hour (ACPH):
  • Non-sterile HD compounding C-SEC: Minimum 12 ACPH.
  • Sterile HD compounding C-SEC (Buffer Room): Minimum 30 ACPH.
  • Ante-Room serving a sterile HD Buffer Room: Must meet ISO Class 7 air quality (higher cleanliness than non-hazardous ISO Class 8 ante-rooms) with at least 30 ACPH and positive pressure relative to general spaces.

3. Dedicated Hazardous Drug Storage

• Antineoplastic HDs requiring manipulation and all HD active pharmaceutical ingredients (APIs) must be stored in a dedicated, negative-pressure storage room maintained at -0.01 to -0.03 inches w.c. with a minimum of 12 ACPH and 100% external venting.
• Antineoplastic HDs cannot be stored on the floor. Storage shelving must have front lip barriers to prevent commercial containers from rolling or falling off shelves during earthquakes or accidents.
• Refrigerated antineoplastic HDs must be housed in a dedicated refrigerator located within a negative-pressure storage room or negative-pressure buffer room.

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Personal Protective Equipment (PPE) Standards

Personnel compounding, handling, unpacking, cleaning, or disposing of hazardous drugs must don certified Personal Protective Equipment (PPE) designed to resist chemical permeation:

1. Chemotherapy Gloves: Must be tested to ASTM D6978 standards (specifically evaluated against chemotherapy permeation). Regular nitrile, latex, or vinyl examination gloves are prohibited.
   • Two Pairs Mandatory: When compounding hazardous drugs, cleaning C-PECs, or remediating spills, personnel must wear two pairs of ASTM D6978 chemotherapy gloves.
   • Glove Cuffs: The inner glove is worn under the cuff of the chemotherapy gown sleeve; the outer glove is worn over the gown sleeve cuff.
   • Replacement Frequency: Outer gloves must be changed at least every thirty (30) minutes, or immediately if torn, punctured, or contaminated.
2. Chemotherapy Gowns: Must be disposable, non-linting, and demonstrated to resist permeation by hazardous drugs (polyethylene-coated polypropylene). Must feature a closed back closure, long sleeves with elastic or knit cuffs, and no seams or closures in the front. Gowns must be changed every two (2) to three (3) hours, or immediately following a splash, spill, or suspected contamination.
3. Eye and Face Protection: Must be worn whenever there is a risk of splashing or aerosolization. Goggles and a full-face shield are required. Standard prescription eyeglasses or safety glasses with side shields do not provide adequate protection against chemical splashes and are legally non-compliant.
4. Respiratory Protection:
   • Routine sterile/non-sterile HD compounding: An N95 respirator provides particulate protection but does not protect against hazardous vapors or gases.
   • Spills, cleaning C-PEC exhaust, or handling volatile antineoplastics: Personnel must wear a Powered Air-Purifying Respirator (PAPR) or an elastomeric half-mask respirator equipped with a multi-gas and P100 combination chemical cartridge.
5. Shoe and Hair Covers: Two pairs of shoe covers are required when compounding sterile hazardous drugs: the outer pair is donned upon entering the negative buffer room and removed upon stepping out across the demarcation threshold.

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Surface Decontamination, Cleaning, and Spill Remediation

Cleaning surfaces contaminated with hazardous drug residues requires a strict, sequential 4-step chemical protocol. Using standard alcohol alone is ineffective because alcohol does not destroy or neutralize hazardous chemical molecules.

Four-Step Hazardous Drug Surface Cleaning Protocol:
┌──────────────────────┐     ┌──────────────────────┐     ┌──────────────────────┐     ┌──────────────────────┐
│   1. DEACTIVATION    │────►│  2. DECONTAMINATION  │────►│     3. CLEANING      │────►│   4. DISINFECTION    │
│                      │     │                      │     │                      │     │ (Sterile Compounding)│
│ • Renders chemical   │     │ • Dissolves and      │     │ • Removes dirt,      │     │ • Destroys viable    │
│   inert and inactive │     │   removes residual   │     │   dust, and organic  │     │   microorganisms     │
│ • Bleach (sodium     │     │   HD molecules       │     │   matter             │     │ • Sterile 70%        │
│   hypochlorite) or   │     │ • Alcohol, water, or │     │ • Germicidal         │     │   Isopropyl Alcohol  │
│   EPA peroxide oxidizer    │   hydrogen peroxide  │     │   detergent solution │     │   (IPA)              │
└──────────────────────┘     └──────────────────────┘     └──────────────────────┘     └──────────────────────┘

Dedicated HD Spill Kits and Remediation

• Readily Available Spill Kits: Dedicated chemical spill kits must be physically present in all areas where hazardous drugs are received, stored, compounded, or dispensed.
• Spill Kit Contents: Must contain ASTM D6978 chemotherapy gloves, an impermeable gown, chemical splash goggles, an N95 or elastomeric respirator, absorbent hazardous spill towels/pads, neutralizing absorbent powder, non-metallic disposable scrapers/dustpans, puncture-resistant yellow hazardous waste disposal bags, and incident reporting forms.
• Immediate Containment: When a spill occurs, personnel must immediately restrict access to the area, post warning signs, don full PPE from the spill kit, cover liquid spills with absorbent pads (or dry powder with moist towels), clean from the perimeter inward, place all contaminated waste into yellow chemotherapy disposal containers, and notify the Hazardous Drug Safety Officer.