6.4 USP <800> Hazardous Drug Compounding & Closed System Drug-Transfer Devices (CSTDs)

Scope and Core Purpose of USP General Chapter <800>

While USP <797> focuses on protecting the patient from receiving contaminated CSPs, USP General Chapter <800> Hazardous Drugs—Handling in Healthcare Settings focuses primarily on protecting healthcare workers and the environment from exposure to hazardous drugs (HDs). Exposure to antineoplastic agents and other hazardous drugs is linked to secondary malignancies, spontaneous abortions, congenital malformations, genetic damage, and organ toxicities.

The NIOSH List of Hazardous Drugs

USP <800> relies on the National Institute for Occupational Safety and Health (NIOSH) to identify hazardous drugs, using six criteria: carcinogenicity, developmental toxicity, reproductive toxicity, organ toxicity at low doses, genotoxicity, and structure or toxicity similar to existing HDs. The current list is the NIOSH List of Hazardous Drugs in Healthcare Settings, 2024, published in December 2024. It replaced the 2016 list's three groups with two tables:

• Table 1: Drugs that carry manufacturer's special handling information (MSHI) and/or meet the NIOSH definition and are classified as known or probable human carcinogens (NTP "known"; IARC Group 1 or 2A). Most antineoplastics are here, along with some non-antineoplastics; for example, azathioprine and cyclosporine moved into Table 1.
• Table 2: Other drugs that meet the NIOSH definition, including some antineoplastics and many drugs with reproductive or developmental risk.

For USP <800>, "antineoplastic" means an antineoplastic drug in NIOSH Table 1 (revision bulletin official July 1, 2020). The entity must keep its own list of HDs it handles and review that list at least every 12 months.

Assessment of Risk (AoR)

A facility may perform a documented Assessment of Risk (AoR) for dosage forms of other HDs, and for NIOSH Table 1 antineoplastic final dosage forms that need no manipulation beyond counting or repackaging. The AoR considers the type of HD, dosage form, risk of exposure, packaging and manipulation. It must list each drug and dosage form individually and be reviewed at least every 12 months. USP's FAQ says reconstituting and diluting NIOSH Table 2 drugs may be covered by an AoR. However, any HD API (including hormone concentrates) and any NIOSH Table 1 antineoplastic that needs manipulation must follow full USP <800> containment.

Engineering Controls for Sterile HD Compounding

1. Containment Primary Engineering Control (C-PEC)

Sterile HDs must be compounded in a ventilated enclosure providing ISO Class 5 air with vertical downflow:

• Class II Biological Safety Cabinet (BSC): Type A2 (canopy-connected), Type B1, or Type B2 (total exhaust).
• Compounding Aseptic Containment Isolator (CACI): Negative-pressure glove box.
• External Venting: Every C-PEC used for sterile HDs must be externally vented. If the C-PEC supplies some or all of the room's negative pressure, or is used for sterile compounding, it must run continuously. After a power loss, repair or move, work stops. The unit is then decontaminated, cleaned and disinfected, and the manufacturer's recovery time is allowed before compounding resumes.

2. Containment Secondary Engineering Control (C-SEC)

• Negative Air Pressure: The hazardous cleanroom buffer suite must maintain continuous negative pressure between -0.010 and -0.030 inches water column relative to the adjacent ante-room.
• Air Changes: Minimum of 30 Air Changes Per Hour (ACPH) from HEPA supply.
• Ante-Room: Must be ISO Class 7 (not ISO 8), with at least 30 ACPH and at least +0.02 inch water column relative to adjacent unclassified areas. The hand-washing sink is in the anteroom, at least 1 meter from the entrance to the HD buffer room.
• Alternative: C-SCA: An unclassified, externally vented room with fixed walls, negative pressure of 0.01 to 0.03 inch water column, and at least 12 ACPH. HD CSPs made there are limited to the SCA (Category 1) BUDs.

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.

Operational Mandates for CSTDs

• Compounding: CSTDs are recommended but not required during HD compounding under USP <800>. They supplement the C-PEC and do not replace it.
• Administration: CSTDs are required when administering NIOSH Table 1 antineoplastic HDs if the dosage form allows, for example when connecting secondary IV tubing to a patient's primary line.
• Compatibility: A CSTD known to be physically or chemically incompatible with a specific HD must not be used for that HD. NIOSH has never finalized a universal CSTD performance test protocol.
• Mechanisms: Physical barrier technologies (airtight elastomeric seals and interlocking double membranes) or air-cleaning filtration technologies (activated carbon and hydrophobic HEPA filters).

Personal Protective Equipment (PPE) & Cleaning Protocols

PPE for Sterile HD Compounding

• Chemotherapy Gloves: Must be tested against ASTM D6978. Personnel must wear two pairs of chemo-rated gloves: the inner pair under the gown cuff and the outer pair (which must be sterile) pulled over the gown cuff. Gloves must be changed every 30 minutes or immediately if torn or contaminated.
• Chemotherapy Gown: Disposable and shown to resist HD permeability (for example, polyethylene-coated), closing in the back, long-sleeved, with closed elastic or knit cuffs and no seams that let drug through. It is changed according to the manufacturer's permeation data, or every 2 to 3 hours if no data exist, and immediately after a spill or splash. ASTM F3267-22 is the newer standard for chemotherapy gowns.
• Head, Hair and Shoe Covers: Required for sterile and nonsterile HD compounding. A second pair of shoe covers goes on before entering the C-SEC and comes off when leaving it, together with the gown, in the doffing area.
• Eye, Face and Respiratory Protection: Required when there is a risk of splashes or inhalation, for example when working outside a C-PEC, unpacking a damaged shipment, or cleaning a spill. Goggles are used (safety glasses are not enough), and a face shield may be added. A surgical mask gives no respiratory protection. A fit-tested N95 protects against particles but not vapors, so a large spill calls for a full-facepiece chemical cartridge respirator or a PAPR. Routine compounding inside a properly working C-PEC does not by itself require a respirator.
• Disposal: Outer gloves (and sleeve covers) are removed inside the C-PEC into a trace-waste container. Disposable HD PPE is never reused.

Four-Step Cleaning & Decontamination Sequence

[1. Deactivation] ──► [2. Decontamination] ──► [3. Cleaning] ──► [4. Disinfection]
(EPA Oxidizer /        (Rinse / Inactivate      (Surfactant /     (Sterile 70% IPA)
 2% Hypochlorite)       Neutralizer)             Detergent)

1. Deactivation: Oxidize or inactivate hazardous molecules (e.g., sodium hypochlorite, hydrogen peroxide, or peracetic acid).
2. Decontamination: Inactivate, neutralize, and physically remove chemical residue (surfactants or sodium thiosulfate neutralizers).
3. Cleaning: Remove organic and inorganic soils using a sterile neutral detergent.
4. Disinfection: Inhibit or destroy microbial bioburden using sterile 70% IPA.

Medical Surveillance & Environmental Surface Wipe Sampling

Environmental Surface Wipe Sampling Protocols

USP <800> recommends, but does not require, environmental wipe sampling for HD residue (USP FAQ). The suggested schedule is at baseline and at least every 6 months, or more often as needed. Common marker drugs are cyclophosphamide, ifosfamide, methotrexate, fluorouracil and platinum agents. There is no standard for acceptable surface contamination, so results are used to establish a baseline and to confirm containment.

• Typical Sampling Locations:
  1. Interior work surface of the C-PEC (including intake grilles and work tray)
  2. Pass-through chambers and doors connecting the C-SEC to ante-room
  3. Staging and packaging surfaces directly adjacent to the C-PEC
  4. Floor areas immediately beneath and surrounding the C-PEC operator chair
  5. Outside surface of finished CSP containers and delivery transfer bins
• Response to Measurable Residue: The designated person identifies, documents and contains the cause. That may mean reevaluating work practices, retraining personnel, deactivating, decontaminating and cleaning thoroughly, or improving engineering controls. Sampling is then repeated to confirm the cleanup worked.

Personnel Medical Surveillance Programs

USP <800> recommends, but does not require, a medical surveillance program as part of the workplace health and safety plan (USP FAQ). Recommended elements include:

• Initial Baseline Health Assessment: Detailed reproductive history, occupational exposure questionnaire, physical examination, and baseline laboratory panels (complete blood count with differential, liver function tests, and renal function).
• Ongoing Surveillance: Periodic health assessments, exposure history (which HDs, quantities and dosage forms, and hours handled per week), and prompt post-exposure evaluation after spills or skin or mucosal contact.
• Exit Evaluations: Comprehensive health and exposure documentation maintained for at least 30 years post-employment per OSHA standards.