Safe Handling of Hazardous Drugs — Part 1: Drug Identification, Risk Assessment, and Engineering Controls

1. Definition and Identification of Hazardous Drugs

1.1 Definition

A hazardous drug (HD) is any drug that exhibits one or more of six specified characteristics based on established toxicological and clinical criteria. The definition encompasses far more than traditional cytotoxic chemotherapy — it includes hormonal agents, antiviral drugs, immunosuppressants, and other pharmaceutical classes that meet hazard thresholds.¹

A drug is classified as hazardous if it demonstrates any of the following properties:

1.2 National Hazardous Drug List

The national reference list of hazardous drugs in healthcare settings is maintained by a federal occupational safety research institute and is updated periodically (approximately every two years) based on ongoing literature review and expert evaluation. This list is organized into three tables that serve distinct purposes in guiding the level of precautions required.²

Table 1: Antineoplastic Drugs

Table 1 contains drugs that are confirmed antineoplastic (anticancer) agents. These drugs carry the highest level of occupational risk and require the most stringent handling precautions, including:

• Use of engineering controls (biological safety cabinets or isolators) for all compounding
• Closed-system drug transfer devices where appropriate
• Full personal protective equipment for compounding, administration, and patient care
• Dedicated negative-pressure storage and compounding areas
• Medical surveillance for exposed workers

Representative examples of Table 1 agents by pharmacological class:

Table 2: Non-Antineoplastic Hazardous Drugs

Table 2 contains drugs that meet one or more hazard criteria but are not primarily used as antineoplastic agents. These drugs require hazardous drug handling precautions that may be adjusted based on the dosage form, route of administration, and the specific activity being performed. Key considerations:

• Intact oral or topical dosage forms that are not altered (not crushed, split, or manipulated) may not require the same level of containment as compounding or parenteral preparation
• A facility-level assessment of risk determines the extent of engineering controls and PPE required
• These drugs still require hazardous drug labeling, storage considerations, and spill procedures

Representative examples of Table 2 agents:

Table 3: Drugs with Reproductive Risk

Table 3 contains drugs that primarily pose a risk to the reproductive health of workers through exposure but may not meet other hazard criteria. These drugs mainly carry teratogenic or reproductive toxicity concerns. Handling precautions focus on:

• Preventing exposure in workers who are pregnant, actively trying to conceive, or breastfeeding
• Using gloves and other appropriate PPE when manipulating dosage forms
• Providing reproductive health counseling

Representative examples include isotretinoin, acitretin, misoprostol (at lower risk thresholds), certain anticonvulsants, and other agents with established reproductive toxicity.

1.3 Institutional Hazardous Drug List

Each facility must maintain its own hazardous drug list that, at minimum, includes all drugs on the national reference list that are present in the facility’s formulary. The institutional list must be:³

• Reviewed at least every 12 months
• Updated when new drugs are added to the formulary
• Updated when the national reference list is revised
• Accessible to all personnel who handle or may be exposed to hazardous drugs
• Used as the basis for determining handling precautions, PPE requirements, and engineering controls

When a newly approved drug is added to the formulary and has not yet appeared on the national reference list, the facility must evaluate the drug’s Safety Data Sheet (SDS), package insert, and available toxicological data to determine whether it meets any of the six hazard criteria. If any criterion is met, the drug must be added to the institutional hazardous drug list and handled accordingly.

2. Exposure Routes and Health Effects

2.1 Routes of Occupational Exposure

Healthcare workers may be exposed to hazardous drugs through four primary routes:

Dermal Absorption (Most Common Route)

Skin contact is the most frequent and often underrecognized route of occupational exposure. Hazardous drug contamination has been documented on:

• Exterior surfaces of drug vials and packaging (present from the manufacturing facility)
• Countertops, floors, and work surfaces in pharmacies and treatment areas
• IV bags, tubing, and administration sets
• Doorknobs, telephones, and keyboards in treatment areas
• Glove surfaces (permeation through inadequate gloves)

Many hazardous drugs are readily absorbed through intact skin. Surface wipe sampling studies have consistently demonstrated measurable contamination on surfaces throughout drug preparation and administration areas, even in facilities with active safe handling programs.⁴

Inhalation

Aerosolization can occur during:

• Compounding and reconstitution (when vials are pressurized)
• Priming IV tubing
• Manipulating syringes (ejecting air)
• Crushing tablets
• Opening ampules
• Cleaning spills
• Patient care activities (aerosolized drug in patient exhalation)

Drugs with significant vapor pressure at room temperature (e.g., carmustine, cyclophosphamide, nitrogen mustard) may generate vapors even from intact liquid formulations. Some drugs also exist as particulate aerosols that can remain suspended in air.

Ingestion

Inadvertent ingestion may result from:

• Hand-to-mouth contact in contaminated work areas
• Eating, drinking, or applying cosmetics in drug handling areas
• Inadequate hand hygiene after glove removal

Injection / Needlestick

Direct parenteral exposure can occur through:

• Needlestick injuries during preparation or administration
• Sharps injuries from broken vials or ampules
• Cuts from contaminated glass

2.2 Documented Health Effects of Occupational Exposure

3. Facility-Level Risk Assessment

3.1 Assessment of Risk

Every entity that handles hazardous drugs must conduct a facility-specific risk assessment to determine the types of engineering controls, PPE, and procedures required. The assessment of risk must include:⁵

1. Inventory of all hazardous drugs present in the facility (the institutional hazardous drug list)
2. Identification of all activities involving hazardous drugs:
   • Receiving and unpacking
   • Storage
   • Compounding (sterile and non-sterile)
   • Dispensing
   • Administration
   • Patient care activities (handling body fluids, linen)
   • Spill response
   • Waste handling and disposal
   • Transport
   • Maintenance and repair of contaminated equipment
3. Determination of the dosage form (injectable, oral solid, oral liquid, topical, inhaled)
4. Assessment of manipulation required (intact dosage forms vs. crushing, splitting, compounding)
5. Frequency and volume of hazardous drug handling
6. Number of workers potentially exposed
7. Current control measures in place and their adequacy
8. Review of any exposure incidents, spill events, and surface contamination monitoring data

3.2 Hierarchy of Controls

Protective measures must follow the established hierarchy of controls, prioritizing engineering and administrative controls before relying on personal protective equipment:⁶

1. Elimination/Substitution — Use of less hazardous alternatives when clinically appropriate (rarely applicable, as drug selection is driven by clinical need)
2. Engineering controls — Physical containment devices and ventilated environments (highest priority for implementation)
3. Administrative controls — Policies, procedures, training, signage, work practice modifications, medical surveillance
4. Personal protective equipment (PPE) — The last line of defense; necessary but never sufficient alone

4. Engineering Controls

4.1 Biological Safety Cabinets (BSCs)

Biological safety cabinets are the primary engineering control for sterile and non-sterile compounding of hazardous drugs. The specific BSC type required depends on the activity and the regulatory framework in the facility’s jurisdiction.⁷

Class II Type B2 BSC (Required for HD Compounding)

The Class II Type B2 BSC is the standard of care for hazardous drug compounding. Its specifications:

Class II Type A2 BSC

A Class II Type A2 BSC may be considered when the following conditions are met:

• The BSC is connected to the outside through a canopy connection or thimble (snorkel) connection
• This type recirculates approximately 70% of HEPA-filtered air to the room and exhausts approximately 30% through a HEPA filter; therefore, it provides less protection than a B2
• Acceptable only for low-volume HD compounding in some jurisdictions or when a B2 is not feasible, provided the facility’s assessment of risk supports its use and the exhaust is appropriately vented
• Not acceptable for volatile hazardous drugs (those with significant vapor pressure) because HEPA filters do not capture vapors or gases

Key BSC Operational Requirements

• Allow the BSC to operate for a minimum purge time (manufacturer-specified, typically at least 5 minutes) before beginning work and after completing work
• Do not place materials or equipment within 6 inches of the air intake grilles on the work surface
• Work at least 6 inches inside the front opening
• Do not disrupt airflow by rapid arm movements, opening/closing doors, or foot traffic in front of the BSC
• Place a plastic-backed absorbent pad (chemo-rated) on the work surface; change when visibly contaminated, after a spill, and at the end of each compounding session
• Clean and decontaminate the BSC using appropriate agents (see Part 3) before and after compounding and when contamination is suspected
• Do not use the BSC for non-hazardous compounding simultaneously with hazardous drug compounding

4.2 Compounding Aseptic Containment Isolators (CACIs)

CACIs are sealed, negative-pressure isolator units that provide an alternative to BSCs for hazardous drug compounding. They provide both product protection (ISO Class 5 environment) and personnel/environmental protection.⁸

4.3 Closed-System Drug Transfer Devices (CSTDs)

A closed-system drug transfer device (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.⁹

CSTD Requirements

Types of CSTD Mechanisms

Important considerations regarding CSTDs:

• CSTDs do not eliminate the need for BSCs or CACIs during compounding; they are used within these devices as an additional layer of containment
• Not all CSTDs have been equally validated for vapor containment; facilities should evaluate published performance data
• CSTDs do not maintain sterility of the drug product unless the device is specifically designed and tested for this purpose
• Staff must be trained on proper CSTD technique; improper use negates the containment benefit
• CSTD connections must be verified as secure before each drug transfer

4.4 Ventilation Requirements

Compounding Area Ventilation

The area where hazardous drug compounding occurs must meet specific ventilation standards:¹⁰

Containment Segregated Compounding Area (C-SCA)

For facilities where a full negative-pressure cleanroom suite is not required (e.g., low-volume HD compounding of non-sterile preparations or when allowed by the facility’s assessment of risk for certain dosage forms), a Containment Segregated Compounding Area (C-SCA) may be used:¹¹

Storage Area Ventilation

4.5 Supplemental Engineering Controls

5. Facility Design Considerations

5.1 Workflow and Layout Principles

Facility design for hazardous drug handling should incorporate the following principles:

• Unidirectional workflow: Movement of drugs, materials, and personnel should follow a logical, one-directional path from receipt through compounding to dispensing, minimizing backtracking that increases contamination risk
• Physical separation: Hazardous drug compounding areas must be physically separated from non-hazardous compounding areas. Ideally, HD compounding occurs in a separate room with its own anteroom
• Minimize traffic: The HD compounding area should be designed to minimize non-essential personnel traffic through the space
• Surfaces: Walls, ceilings, floors, and work surfaces in HD handling areas should be smooth, impervious, non-porous, and resistant to chemical damage to facilitate decontamination
• Sink access: Handwashing sinks and emergency eyewash stations must be readily accessible in all HD handling areas
• Emergency equipment: Spill kits must be available in all areas where hazardous drugs are handled, including compounding, administration, storage, and waste handling areas

5.2 Signage Requirements

All areas where hazardous drugs are stored, compounded, administered, or disposed of must be clearly identified with:

• Hazardous drug warning signs at all entry points
• Labeling of individual drug storage locations (bins, shelves, refrigerators)
• Location signs for spill kits and emergency equipment
• PPE requirement signs indicating the minimum PPE needed for entry and specific activities
• Waste stream identification signs to guide proper disposal

References