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› News › What Pharmacies Often Miss in USP <800> Compliance

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What Pharmacies Often Miss in USP <800> Compliance

By Esco Healthcare 15 May, 2026

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What Pharmacies Often Miss in USP <800> Compliance
What Pharmacies Often Miss in USP <800> Compliance

Healthcare workers handle hazardous drugs every day, but many people underestimate how many roles are actually at risk. 

From pharmacists and nurses to environmental services staff, shipping personnel, veterinarians, and laboratory workers, an estimated 8 million healthcare workers in the United States may be exposed to hazardous drugs in the workplace, according to National Institute for Occupational Safety and Health.

These drugs include not only chemotherapy agents, but also antiviral drugs, hormones, and certain bioengineered medications that can pose serious health risks when improperly handled.

This is exactly why hazardous drug safety cannot rely on a single piece of equipment alone.

While containment isolators play a critical role, true compliance with United States Pharmacopeia depends on an entire system, including facility design, airflow control, operational procedures, environmental monitoring, and staff training. Here is what the standard actually requires.

Introduction: The Most Common Misunderstanding

In many hospital and pharmacy projects, the same assumption appears early in discussions: “If we install a containment aseptic compounding isolator, we will meet USP <800> requirements.”

It is a reasonable starting point. It is also, on its own, insufficient.  According to United States Pharmacopeia (USP) General Chapter <800> Hazardous Drugs – Handling in Healthcare Settings, compliance is not defined by a single piece of equipment. Instead, it is based on how hazardous drugs are handled across the entire lifecycle, from receipt and storage to compounding, administration, and disposal.

Similarly, National Institute for Occupational Safety and Health (NIOSH) emphasizes that hazardous drug exposure risk is cumulative and can occur at multiple points in the workflow, not just during compounding. This distinction matters, while an isolator is a critical engineering control, it cannot function as a standalone compliance solution. To understand what truly drives USP <800> compliance, it is necessary to shift perspective, from equipment selection to system design.

USP <800>: A System-Level Standard, Not a Product Specification
USP <800> establishes requirements to minimize occupational, patient, and environmental exposure to hazardous drugs. The chapter is explicit: containment must be a multi-layered strategy, combining four distinct categories of control. This is also relevant to the Hierarchy of Controls from NIOSH. 



This hierarchy aligns closely with NIOSH guidance, which defines engineering controls (such as containment primary engineering controls, or C-PECs) as the first line of defense once elimination and substitution can’t be done, but not the only one.

 

USP <800> further distinguishes between:

  • C-PECs (containment primary engineering controls) such as isolators, biological safety cabinets (BSCs), and compounding aseptic containment isolators (CACIs). These form the direct physical barrier between the operator and the hazardous drug.
  • C-SECs (containment secondary engineering controls) such as the rooms, pressure relationships, and HVAC systems in which C-PECs are housed. These control the broader environment in which compounding occurs.

Both are required to work together to achieve compliance. A high-specification isolator placed in an inadequately controlled room does not satisfy the standard.


Real-world surveillance data underscore why this system-level framing matters. A 2018 multicentric study across ten Spanish hospital pharmacies (Valero-García et al.) found hazardous drug contamination on compounding surfaces in every single participating center, including those with dedicated compounding areas and established equipment. Cyclophosphamide was detected in 49% of samples, ifosfamide in 23%, and 5-fluorouracil in 10%. No hospital was free of contamination5. The implication is clear: the presence of engineering controls does not automatically translate into controlled exposure.

The Role of the Isolator (C-PEC): Critical, but Not Independent

Containment isolators for hazardous drug compounding serve several essential functions under USP <800>:1

• Providing a physical barrier between the operator and the hazardous drug

• Maintaining controlled, typically negative-pressure, airflow to prevent contaminant escape

• HEPA filtration of particulate contamination

• Supporting aseptic compounding conditions where sterile preparations are required

USP <800> specifies that C-PECs used for sterile hazardous drug compounding must be externally vented (that is, ducted to the outside. 


A 2013 study by Kopp et al., published in the Annals of Occupational Hygiene, illustrates this clearly. Researchers monitored platinum-based drug contamination in two French hospital pharmacies that both used positive-pressure isolators and similar working procedures. Despite equivalent equipment configurations, one pharmacy showed significantly higher surface contamination, traced to a vial rupture and inadequate cleaning protocols, combined with insufficient glove-changing frequency during the preparation process4. The isolator technology was identical; the outcomes diverged because of procedural and human factors.


Notably, the study found contamination inside the isolators themselves (maximum: 198.4 pg cm⁻²), predominantly attributable to inadequate over gloving practice. Nitrile gloves used during handling outside the isolator showed the highest platinum concentrations (maximum: 5.86 ng per pair)4. Engineering controls alone could not compensate for deficits in work practice. This shows even a fully compliant C-PEC does not ensure overall compliance. The isolator operates within an environment, and its performance depends heavily on that environment and administrative control.

The Facility Matters: Secondary Engineering Controls (C-SEC)


USP <800> requires that hazardous drug compounding areas be located in rooms designed to support containment. These are known as secondary engineering controls (C-SECs).

Configuration

C-PEC

C-SEC

ISO Class 7 buffer room with an ISO Class 7 anteroom

Externally vented (e.g: BSC Class II or CACI)

Externally vented, 30 ACPH, negative pressure between 2.5 to 7.5 Pa relative to adjacent areas

Unclassified SCA

Externally vented, 12 ACPH, negative pressure between 2.5 to 7.5 Pa relative to adjacent areas

This means that the isolator must be installed within a properly designed room.
A common compliance gap occurs when:
• A high-quality isolator is installed
• But the room lacks proper pressure control or ventilation
In such cases, in the case of breach, hazardous drug vapors or particulates may still escape into surrounding areas, especially during maintenance, cleaning, or failure scenarios. NIOSH has repeatedly highlighted that engineering controls must be implemented as a system, noting that improper ventilation design can compromise even well-designed containment devices.
Procedures and Work Practices: The Human Factor
Even with properly designed engineering controls, compliance can fail without correct procedures. USP <800> places strong emphasis on standard operating procedures (SOPs), including:
• Deactivation, decontamination, cleaning, and disinfection (DDCD)
• Proper donning and doffing of PPE
• Workflow control to prevent cross-contamination
• Spill management procedures
For example, the DDCD sequence is essential for reducing hazardous drug residue on surfaces. 
NIOSH studies have demonstrated that surface contamination can persist in facilities with functioning engineering controls when cleaning protocols are incomplete or inconsistently applied.2 The Kopp et al. data reinforces this: in one of the two monitored pharmacies, contamination in the drug vial storage area (outside the isolator entirely), was attributed to an undetected vial rupture combined with inefficient cleaning procedures4.

USP <800> explicitly requires two pairs of chemotherapy-rated gloves during compounding of sterile and non-sterile hazardous drugs. The Kopp et al. findings suggest that even this requirement is insufficient without appropriate frequency of glove changes and overgloving discipline within the isolator4. Training is equally critical. Personnel must understand not just what to do, but why it matters. Improper techniques such as incorrect glove use or poor aseptic practices can compromise both sterility and containment. 

The integration of Closed System Drug Transfer Systems (CSTDs) into compounding workflows also illustrates a broader principle: adding an engineering control without procedural adaptation can introduce new risks alongside the ones it mitigates. De Jong et al. (2025) highlight that CSTD components, including vial adaptors, syringe adaptors, and bag spikes, each carry hold-up volumes that vary between device brands. Without accounting for these volumes in compounding procedures, pharmacies risk under-dosing patients when CSTDs are used, or over-dosing when flush procedures are applied inconsistently. The authors recommend a structured, product-specific risk assessment before any CSTD is incorporated into a compounding workflow, covering molecule type, dosage form, route of administration, and site-level infrastructure6. This reinforces the broader point: every layer of engineering protection must be matched by an equivalent layer of operational discipline.


PPE Requirement by Activity Type

The following table, adapted from NIOSH guidance,2 summarizes recommended PPE and engineering control requirements across different hazardous drug formulations and activities. These requirements apply independently of, and in addition to, the C-PEC in use.

Table 2. Control Approaches for Safer Handling of Hazardous Drugs, by Activity and Formulation (NIOSH, 2023)

Activity

Formulation

Control Approaches

Engineering Controls

Personal Protective Equipment

Ventilated Engineering Control (BSC or CACI)

Closed system drug transfer device

Other

Double chemo-glove (ASTM-rated)

Protective gown (single use, impervious)

Eye, face, hair, sleeve and shoe cover

Respiratory protection

Receiving, unpacking, and placing in storage

All types of hazardous drug

No, unless a leak is observed or suspected

NA*

NA*

No (single pair of gloves)

No, unless a leak is observed or suspected

Consider protective sleeves; add additional protection if a leak is observed or suspected

No, unless a leak is observed or suspected

Transportation within facility

Intact tablets or capsules, manufacturers’ prefilled syringes

No

NA*

Transport in containers that minimize the risk of break- age or leakage; Double bag or place in a sealed container

No (single pair of gloves)

No

No

No

Compounding

Oral liquid drug

Yes

NA*

NA*

Yes¶

Yes

Hair and shoe covers. Added eye and face protection if not done in ventilated engineering control

Yes, if not using a ventilated engineering control

Topical drug

Yes§ (note: some drugs can be volatile)

NA*

NA*

Yes¶

Yes

Hair and shoe covers. Added eye and face protection if not done in ventilated engineering control

Yes, if not using a ventilated engineering control

Injections withdrawn from a vial

Yes§

Yes, when dosage form allows

NA*

Yes¶

Yes

Hair and shoe covers. Added eye and face protection if not done in ventilated engineering control

Yes, if not using a ventilated engineering control

Mixing injections form a vial

Yes§

Yes, when dosage form allows

NA*

Yes¶

Yes

Hair and shoe covers. Added eye and face protection if not done in ventilated engineering control

Yes, if not using a ventilated engineering control

Solution from irrigation

Yes§

Yes, when dosage form allows

NA*

Yes¶

Yes

Hair and shoe covers. Added eye and face protection if not done in ventilated engineering control

Yes, if not using a ventilated engineering control

Powder/solution for aerosols treatment

Yes§

Yes, when dosage form allows

NA*

Yes¶

Yes

Hair and shoe covers. Added eye and face protection if not done in ventilated engineering control

Yes, if not using a ventilated engineering control

Administering

Intact tablets or capsules from unit dose package

NA*

NA*

NA*

No (single glove)

No

Eye and face protection if vomit potential**

No

Crushing or manipulating tablets or capsule

Yes

NA*

Consider crushing tablet in pill pouch

Yes¶

Yes

Hair and shoe covers. Added eye and face protection if not done in ventilated engineering control

Yes, if not using a ventilated engineering control

Cut, crushed, or uncoated tablets or capsule

NA*

NA*

NA*

Yes

Yes

Eye and face protection if vomit potential**

No

Subcutaneous or intramuscular injections from manufacturer’s supplied prefilled syringe or injector

NA*

NA*

NA*

No (single glove)

Yes

Eye and face protection if likely to splash**

No

Subcutaneous or intramuscular injections from a prepared syringe or injector

NA*

NA*

NA*

Yes

Yes

Eye and face protection if likely to splash**

No

Intravenous injections from prepared syringes††

NA*

Yes, when dosage form allows

NA*

Yes

Yes

Eye and face protection if likely to splash**

No

Intravenous solution for infusion

NA*

Yes, when dosage form allows

NA*

Yes

Yes

Eye and face protection if likely to splash**

No

Ophthalmologic applications

NA*

Yes, when dosage form allows

NA*

Yes

Yes

Eye and face protection if likely to splash**

No

Oral liquid drug: PO*/feeding tube/NG* tub

NA*

NA*

NA*

Yes

Yes

Eye and face protection if likely to splash**

Yes, if inhalation potential

Topical drug (ointment, cream)

No (Note: some drugs are volatile and may need to be administered in an enclosure)

NA*

NA*

Yes

Yes

Eye and face protection if likely to splash**

Yes, if inhalation potential

Irrigation solution, bladder instillation, HIPEC*, limb perfusion

NA*

Yes, when dosage form allows

NA*

Yes

Yes

Eye and face protection

Yes

Powder/ solution for inhalation/ aerosol treatment

Yes, when applicable; Note that some treatments may need to be administered in an enclosure

Yes, when dosage form allows

NA*

Yes

Yes

Eye and face protection if likely to splash**

Yes, full facepiece or PAPR* with combination particulate/ chemical cartridges if inhalation potential

Disposal and Cleaning

Drugs and metabolites in body fluids

NA*

NA*

Fold soft materials (sheets, hygiene care products) inward to prevent leakage Place in sealed bag

Yes

Yes

Eye and face protection if likely to splash

Yes, if inhalation potential

Drug-contaminated waste

NA*

NA*

void creating dust; Place in sealed bags; Use caution when closing bags; Pushing waste down may force hazardous drug dust up into face.

Yes

Yes

Eye and face protection if likely to splash

Yes, if inhalation potential

Routine Cleaning

All types of hazardous drugs

NA*

NA*

Use wet wiping methods; Avoid creating dust; Disinfection, deactivation, or decontamination agents may be necessary; Place in sealed bags for disposal

Yes

Yes

As needed‡‡

As needed‡‡

Spill Cleanup

All types of hazardous drugs

NA*

NA*

Limit access to area. Use absorbent pads for liquid spills; Disinfection, deactivation, or decontamination agents may be necessary; Avoid creating dust; Place in sealed bag

Yes

Yes

Yes, as needed

Yes, full facepiece or PAPR* with combination particulate/ chemical cartridges may be needed
Note: 
The Table of Control Approaches provides general approaches that should be adapted to facility-specific conditions. For more detailed information on safe handling practices, see the reference list for this table [ASHP 2006; NIOSH 2004a, 2008; ONS 2011, 2018; OSHA 2016; Power and Cyne 2018]. 
*Abbreviations: BSC: biological safety cabinet; CACI = compounding aseptic containment isolator; CSTD = closed system drug-transfer device; CVE = containment ventilated enclosure; HIPEC = hyperthermic intraperitoneal chemotherapy; NA = not applicable; NG = nasogastric; PAPR = powered air-purifying respirator; PO = per os (by mouth). 
†Respiratory protection must be selected on the basis of the hazardous drug and its physical form (particulate, vapor, etc.) and other exposure factors. For general activities, a N95 may suffice. Use a surgical N95 respirator if there is potential for splashes of bodily fluids or liquid drugs. When performing activities such as cleaning the BSC or CACI or responding to large spills, a combination particulate/chemical cartridge respirator may be needed. 
‡Compounding is the process of combining, mixing, or altering ingredients by or under the direct supervision of a licensed pharmacist or physician to create a prescribed medication tailored to the needs of an individual patient. See FDA: https://www.fda.gov/drugs/human-drug-compounding/section-503a-federal-food-drug-and-cosmetic-act and https://www.fda.gov/drugs/human-drug-compounding/compounding-and-fda-questions-and-answers. 
§For nonsterile preparations, a ventilated engineering control such as a fume hood, Class I BSC or CVE is sufficient if the ventilated engineering control exhaust is either (1) HEPAfiltered and appropriately exhausted to the outside of the building (preferred) or (2) filtered with redundant HEPA filters in series and recirculated back into the C-SCA. Although these activities are recommended in ventilated engineering controls, they may not be possible under some treatment scenarios (e.g., time-sensitive activities in the emergency department). If the activity is performed in a ventilated engineering control that is used for sterile intravenous preparations, thorough cleaning and disinfecting is required following the activity. 
¶ Sterile gloves are required for aseptic drug preparation in a BSC or CACI. 
**Needed if the patient might resist (infant, unruly patient, patient predisposed to spitting, patient with difficulty swallowing, or veterinary patient) or if the formulation is hard to swallow. 
††Intravenous tubing already attached and primed. 
‡‡Activities such as cleaning floors may not require eye or respiratory protection but cleaning a BSC or CACI may require it. 
Monitoring and Control: Detecting Failure Before Exposure
Effective hazardous drug containment depends not only on engineering controls, but also on the ability to continuously verify that those controls are functioning as intended. Facilities handling hazardous drugs must monitor critical containment conditions, which may includes:
• Room pressure differentials 
• Performance of containment engineering controls 
• Environmental wipe sampling as part of a surface contamination control program 
Environmental wipe sampling plays an important role in evaluating the effectiveness of cleaning, decontamination, and overall containment practices by identifying hazardous drug residue on surfaces.
Alarm systems and monitoring devices are equally critical. They help alert personnel when operating conditions fall outside acceptable ranges, allowing facilities to respond before containment is compromised.
This is especially important because containment failures are most likely to occur during abnormal operating conditions, not during routine operation.
Examples include:
• Loss of exhaust airflow 
• HVAC system imbalance 
• Power interruptions 
• Breach of isolator integrity, such as glove damage or improper transfer procedures 
Without proper monitoring and alarm systems, these failures may go unnoticed until hazardous drug exposure has already occurred. National Institute for Occupational Safety and Health also emphasizes the importance of ongoing evaluation, early detection, and corrective action as part of a comprehensive hazardous drug safety program.
Where Facilities Often Fall Short
Despite the clarity of regulatory guidance, several recurring deficits appear in real-world implementations. These gaps typically reflect fragmented decision-making, where equipment procurement, facility design, and operational planning are handled by separate teams without coordination.

Gap 1: Over reliance on equipment

Assumming that a high spec isolator alone fulfills the compliance obligation

Gap 2: Inadequate room design

Lack of appropriate pressure differentials or exhaust capacity

Gap 3 : Poor system integration

Lack of coordination between the C-PEC, HVAC, and BMS

Gap 4: Incomplete SOPs

Missing or incosistently implemented procedures

Gap 5: Limited monitoring

Absense of real-time alerts for deviation that could indicate system failure

These gaps are not due to lack of intent, but often due to fragmented decision-making, where equipment, facility, and operations are considered separately rather than as a unified system.

From Equipment to System Thinking

To achieve USP <800> compliance, pharmacies must move beyond the idea of “buying an isolator” and instead focus on designing a containment system.

This system includes:

• A properly selected and configured isolator (C-PEC)

• A compliant room environment (C-SEC)

• Robust HVAC and airflow design

• Clear and enforced SOPs

• Continuous monitoring and alarm integration

Each component must support the others. A weakness in one area can undermine the entire system. This integrated approach reflects both USP <800> requirements and NIOSH recommendations, which consistently emphasize layered protection strategies.

Supporting System-Level Compliance: HPI-G3 Healthcare Platform Isolator
Esco Healthcare's HPI-G3 is designed from the ground up to function as a component within a compliant system, not as a standalone compliance device. Its configuration options and integration capabilities are intended to address the gaps that most commonly undermine USP <800> compliance programs.


Flexible airflow configuration

Support external ducting to match facility exhaust strategies

BMS integration

Designed for connection to send signal for external fan and sending alarms

Real-time alarms

Continuous monitoring with audio-visual capabilities

Ergonomic design

Reduced operator fatigue during extended compounding sessions

Cleanability

Smooth interior surfaces with SS316L and coved corners to support DDCD

Efficient H14 filtration

Double exhaust filtration with HEPA H14 filters system

Product protection

Unidirectional airflow with 0.4 m/s in process chamber

Type D2 Pass Chamber

With sliding tray and electromagnetic interlocking doors

Air cleanliness

ISO Class 3 in process chamber


The HPI-G3 supports the transition from equipment-centric to system-centric compliance planning, providing the engineering foundation on which a complete USP <800> program can be built. To explore how a platform-based isolator can support system-level compliance: Esco Healthcare Platform Isolator – G3
Conclusion: Compliance Is Built, Not Bought
USP <800> compliance cannot be achieved by specifying the right product alone. It is the result of integrated decisions across multiple domains:
• Thoughtful facility and room design (C-SEC)
• Appropriate selection and configuration of primary engineering controls (C-PEC)
• Coordinated HVAC and pressure management
• Consistent, well-trained operational practices and SOPs
• Continuous monitoring with defined response protocols
An isolator is a vital component of this system but understanding it as one component among several is the precondition for building a program that genuinely protects personnel, ensures compliance, and sustains long-term operational reliability.
References
  1. United States Pharmacopeia <800>
  2. NIOSH [2023]. Managing hazardous drug exposures: information for healthcare settings. By Hodson L, Ovesen J, Couch J, Hirst D, Lawson C, Lentz TJ, MacKenzie B, Mead K. Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2023-130, https://doi.org/10.26616/NIOSHPUB2023130
  3. NIOSH [2024]. NIOSH list of hazardous drugs in healthcare settings, 2024. By Ovesen JL, Sam­mons D, Connor TH, MacKenzie BA, DeBord DG, Trout DB, O’Callaghan JP, Whittaker C. Cin­cinnati, OH: U.S. Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2025-103 (Supersedes 2016-161), https://doi.org/10.26616/NIOSHPUB2025103
  4. Kopp, B.; Crauste-Manciet, S.; Guibert, A.; Mourier, W.; Guerrault-Moro, M.-N.; Ferrari, S.; Jomier, J.-Y.; Brossard, D.; Schierl, R. . (2013). Environmental and Biological Monitoring of Platinum-Containing Drugs in Two Hospital Pharmacies Using Positive Air Pressure Isolators. Annals of Occupational Hygiene, 57(3), 374–383.                    doi:10.1093/annhyg/mes073 
  5. Valero-García S, Poveda-Andrés JL, et al. Hazardous drugs levels in compounding area surfaces of Hospital Pharmacies Services: multicentric study. Farm Hosp. 2018;42(4):152–158. doi:10.7399/fh.10935
  6. De Jong, I., Tan, D. C. T., Lehermayr, C., Daugherty, M., Filipe, V., Winzer, M., Kwok, S. C., Medina, A., Guy, A., Christian, T., Singh, S. N., Bhattacharya, S., & Jabary, S. (2025). Current industry practices on closed system drug-transfer devices for parenteral drug products. Journal of Pharmaceutical Sciences, 114(3), 1535–1547. https://doi.org/10.1016/j.xphs.2025.01.019

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