Gloveboxes are commonly utilized in cleanrooms and laboratories for the manufacturing and testing of pharmaceuticals, live biologics, chemicals, and microelectronics. Terra offers an industry-leading selection of glovebox systems, accessories, and add-ons online, including containment isolators and specialty gloveboxes for radiopharmaceuticals, precision climate control, or hazardous substances.

In this article, we'll discuss considerations for gloveboxes and isolator designs used in aseptic cleanroom environments. These environments are governed by a combination of regulatory bodies, such as the State Board of Pharmacy, and industry standards set by the US Pharmacopeia (USP). As a result, equipment requirements for these use cases can be particularly challenging and not always perfectly harmonized.

As a rule of thumb, gloveboxes and isolators must demonstrate the following capabilities:

  • Shield products from external environmental contamination
  • Safeguard operators from hazardous materials within the container; or both.
  • Continuous supply of HEPA or ULPA filtered air
  • Provide a contained exhaust route for the exhaust of dirty air

In a previous article, we outlined updated USP descriptions for compounding aseptic isolators among two classifications: Restricted Access Barrier Systems (RABS) and Isolators.

An isolator is defined as an ISO 5 enclosure that meets the following criteria:

  • Uses rapid transfer ports or another type of decontaminated, high-integrity interface to transfer compounding materials into the isolator
  • Uses an automatic sporicidal decontamination system
  • Constantly maintains a significant overpressure relative to the surrounding environment
  • Manufacturer provides documentation verifying that the isolator can maintain ISO 5 at all times

Any CAI that does not meet all of the isolator criteria would be classified as a restricted access barrier system (RABS). RABS placed within an ISO 5 enclosure provide a physical separation from the compounding area through the use of glove ports, but the openings for transferring materials would not provide the same level of protection as an isolator.

Since USP standards are subject to change, it's important to evaluate the most recent and up-to-date documentation to address any changes that affect your facility requirements.

The most significant changes in recent years include:

  • Exclusion of certain (hazardous) compounds from USP 797 classifications
  • Creation of USP 800 classifications for hazardous drugs
  • Creation of USP 825 classification for radiologicals
  • Categorization of Compounded Sterile Preparations (CSPs)

Introduction to Aseptic Environment Engineering Controls (C-SEC | PEC | SEC)

When discussing pharmaceutical isolator configurations, you may find references to broader control and containment terminology, such as Primary Engineering Controls (PEC) and Secondary Engineering Controls (SEC).

Containment Secondary Engineering Controls (C-SEC) and Containment Primary Engineering Controls (C-PEC) function as two unique components within the cleanroom framework, each fulfilling distinct but complementary roles in safeguarding against hazardous drug (HD) exposure and contamination.

Containment Primary Engineering Controls (C-PEC) serve as a front-line apparatus designed to minimize direct exposure to hazardous drugs for both workers and the immediate environment. This is often a ventilated device like a fume hood, biological safety cabinet, or isolator that is specifically engineered to capture and contain harmful drug particles. It acts as the immediate zone where the compounding or manipulation of hazardous substances takes place, rendering it the first line of defense against potential hazards.

Primary engineering controls refer to specific workstations where direct manipulations are conducted. For sterile compounding, this refers to a glovebox, isolator, or flow hood that maintains ISO Class 5 cleanroom air to support direct compounding, mixing, or packaging of sterile preparations.

  • High-efficiency particulate air (HEPA) filtration, rated 99.97% of particles ≥ 0.3 microns.
  • Unidirectional airflow ensures a consistent flow of air to prevent contamination.
  • Controlled environment: Temperature, humidity, and air quality are strictly regulated
  • ISO Class 5 cleanroom air quality for sterile and aseptic workflows

Secondary engineering controls are systems that surround the primary control as an added layer of protection from the exterior environment, such as a cleanroom-rated suite with designated partitions for the internal production areas, as well as anterooms, buffer rooms, and gowning areas. In some cases, unclassified areas, such as segregated compounding areas (SCA), are suitable alternatives to a complete cleanroom suite for certain compounds where cleanroom exemptions are offered under USP/FDA guidelines.

Aseptic Glove Box Isolators for Sterile Compounding

Compounding Aseptic Isolators (CAI): Mandated under USP 797 standards for pharmaceutical compounding, aseptic isolator designs are built to maintain an aseptic environment in which sterile products and sterile packaged goods can be safely manipulated, packaged, or distributed without encountering contamination from non-sterile air or surfaces. These systems feature HEPA/ULPA filtered air supply to the internal chamber that maintains laminar air flow and ISO Class 5 air quality, which is generally synonymous with definitions for 'sterile-grade air'.

Terra Universal is a manufacturer of several glovebox isolator designs, as well as an authorized dealer of several leading brands that support aseptic compounding and USP 797 requirements:

Aseptic Containment Isolators for Hazardous Drugs (HDs) and Substances

For materials that fall under specific hazard classifications, redundancy in safety mechanisms is obligatory. Closed-loop isolators and glove box workstations are typically utilized for direct interactions with hazardous substances. These apparatuses are specialized enclosures that afford a controlled environment for safely handling volatile or dangerous materials.

Hazardous Drugs (HD) include drugs that are identified as hazardous or potentially hazardous by the National Institute for Occupational Safety and Health (NIOSH) on the basis of at least one of the following six criteria: carcinogenicity, teratogenicity or developmental toxicity, reproductive toxicity in humans, organ toxicity at low doses in humans or animals, genotoxicity, and new drugs that mimic existing HDs in structure or toxicity.

Compounding Aseptic Containment Isolators (CAIC): The major difference between an isolator and a containment isolator is that a containment isolator is designed for use with potentially hazardous medicines and therapies that pose significant exposure risks to operators and administrators. With the addition of special protection mechanisms, such as airtight, hermetically sealed internal chambers and negative pressure exhaust systems, operators can safely manipulate high-risk substances. Importantly, these systems also require the same product protection mechanisms found among general aseptic isolators, such as HEPA filtration, to maintain sterile air quality within the glove box chamber.

USP 800 Hazardous Drug Isolators

USP 800 Drug Preparation: The handling and manipulation of hazardous drugs require a secondary negative-pressure containment cleanroom to prevent the escape of room air when conducting activities that generate hazardous aerosols:

  • Receipt and unpacking
  • Storage of HDs
  • Nonsterile HD compounding (if performed by the entity)
  • Sterile HD compounding (if performed by the entity)
  • USP 800 hazardous pharmacy compounding
  • Cytotoxic chemotherapy compounding
  • Hazardous, non-radioactive cancer therapies
  • Superior solution to class II BSC’s

USP chapter <800> requires prepare HDs to have a containment secondary engineering control (C-SEC) that is:

  1. Externally vented
  2. Physically separated from parallel areas
  3. Maintains appropriate air exchange rates
  4. Achieves negative pressure between 0.01 and 0.03 inches of water column relative to all adjacent areas.

USP 800 BioSafe® All-Steel Cleanrooms include reverse-flow exhaust fans and negative-pressure plenums, which rapidly evacuate hazardous air from the room to prevent operator exposures. Room-to-room pressure is maintained at precise levels to ensure that all room air is ported to an external exhaust or returned to a dedicated air handling system for further processing.

Radiopharmaceutical Glove Box Isolators

Radiopharmacy Glove Box Isolators: Gloveboxes for radiology, nuclear medicines, and manipulation of radioisotopes entail several protective mechanisms ensure operator safety and the integrity of purse products. Negative pressure containment is required to prevent the escape of radioactive or hazardous particles that become irradiated and aerosolized during manipulations. Stainless steel enclosures allow the installation of lead shielding to protect the operator from radiation particles that could otherwise penetrate stainless steel layers.

  • USP General Chapter <825> Radiopharmaceuticals
  • Use of radionuclide generators
  • Preparation of commercially-manufactured radiopharmaceutical kits
  • Patient-specific radiopharmaceutical doses

RadioSafe applications: Terra RadioSafe glovebox families offer lead lined chambers that protect operators for radioactive substances, which can support environments for handing radioactive chemotherapy drugs, or broader applications for handling radioactive substances or inspection of items and materials exposed to radiation. Examples of sterile radiopharmaceuticals include injectables (e.g., intravenous, intrathecal, intraperitoneal, subcutaneous, and intradermal), inhalations, ophthalmics, and intra-organ instillations.

Hazard Controls such as Bag-in-Bag Out systems, Bag Out Ports, molecular filters, and integrated disposal receptacles are essential for glovebox applications that require disposal of contaminated items, both hazardous and non-hazardous.

  • Requires robust construction with pressure-tight seals to maintain negative pressure.
  • Cuff rings must allow hypalon sleeve changes without compromising the work zone.
  • Exhaust air from the isolator must be HEPA filtered before being expelled into the surrounding environment.
  • HEPA filtration with ISO 5 rated air quality
  • Exhuast air must undergo HEPA filtration before release

Gloveboxes with HEPA Filtration Modules: Inlet and outlet particulate (HEPA or ULPA) filters provides a leak-tight environment preventing contaminants from entering or exiting chamber. For radiopharmaceutical glovebox applications, an externally exhausted negative pressure system is deployed to ensure that contaminated air is safety routed to a dedicated hazardous air handling system, or routed directly to an outdoor environment if permitted.

Closed-loop filtration glove box isolators continuously filter and recirculate air inside the glovebox, without introducing any ambient air. They are suitable for applications that require both a low-particle and controlled gas atmosphere. They can be combined with a process gas such as nitrogen to maintain a low-moisture, low-oxygen atmosphere inside the enclosure.

Integrated Waste Ports and Bag-In-Bag-Out systems allow disposal of contaminated filter media or interior objects with fewer risks for exposures and cross contamination of the environment and internal enclosure.

Bag-in-bag-out systems are specially designed to allow for safe and simple disposal of contaminated filters without requiring a complete shutdown of the local environment. In high risk hazardous environments, its an essential mechanism to allow replacement of filters impregnated by radioactive materials, hazardous agents, biowaste, or mold and bacteria spores.

Lead Lined: Lead is a highly effective material for radiation shielding due to its high density and atomic number. In glovebox isolators, lead lining provides protection against ionizing radiation, ensuring that operators and the surrounding environment are shielded from harmful exposure. This is particularly important in nuclear, medical, and research settings where handling radioactive isotopes or other radiation-emitting substances is common.

Biological Safety Cabinets

Biological safety cabinets, also referred to as BSCs, have similar features to sterile containment glovebox isolators for hazardous sterile products but are described, named, and used differently. Biosafety Cabinets feature glovebox containment systems that are designed specifically for use with high-risk biological agents and must comply with Biosafety standards under Microbiological and Biomedical Laboratories (BMBL) specifications.

Compare Styles

Class II biosafety sub-types include A1, A2, B1, B2, and C1 configurations. A2 cabinets recirculate 70% of the air back into the work area while exhausting the remaining 30%. B2 cabinets immediately exhaust 100% of the air leaving the work area. C1 cabinets are capable of toggling between A2 and B2 configurations.

Class II, B2 Biological Safety Cabinets by Labconco
Class II A2 Biosafety Cabinets
Class III Biological Safety Cabinets by Germfree

Class I Biological Safety Cabinets are appropriate in the presence of microbes that do not consistently cause disease, such as E. coli. A negative-pressure hood draws air from the room into the enclosure and recirculates the air internally after UV-C and HEPA filtration. Ducted designs allow routing of noxious chemicals to an outside environment. Class I biosafety cabinets do not have HEPA-filtered supply air.

Class II Biological Safety Cabinets provide both HEPA filtered supply air and HEPA filtered exhaust air. Class II biosafety cabinets are required in the presence of moderately hazardous microbes, such as Staphylococcus aureus.

Class III Biological Safety Cabinets by Germfree, available at Terra Universal, offer robust containment solutions for handling highly pathogenic samples. An airlock with passive HEPA filtration and electronically interlocked doors is available, with options for left- or right-side mounting. For monitoring, both digital and mechanical pressure gauges with low-pressure alarms are included. The main chamber features an externally mounted fluorescent light fixture and two interior electrical outlets.

Read More: View Biosafety Cabinet Pricing and Configurations Online

BioSafety Cabinet Applications:

  • Gene Therapy
  • Viral Vector
  • Vaccines
  • Aerobiology
  • Biosafety & Biosecurity
  • Disease Response & Surveillance
  • Category 1 or Category 2 HD CSPs if placed in a C-SCA zone

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Contact us or request a quote for custom orders including custom glove box chamber designs, gas purge solutions, vacuum systems, feedthroughs, custom gauges, and more. With over 45+ years in designing specialized containment glove boxes and isolators, Terra's glove box designs offer unrivaled performance, endless customization options, and a host of accessories and add-ons that are built with modular principles in mind.

Learn More: Terra's Glovebox Comparison Guide offers a complete overview of glovebox and isolator accessories, configurations, and add-ons.