As the landscape of pharmaceutical compounding continually evolves, the importance of standards for designing, implementing, and maintaining cleanrooms cannot be overstated. Central to these are the United States Pharmacopeia (USP) guidelines, specifically USP 797 / 800. These compendia ensure the provision of safe and quality pharmaceutical products by focusing on aseptic compounding and hazardous drug handling, respectively.  The integration of suitable engineering and operational measures guarantees that the compounding setting maintains a state of control, facilitating the necessary environmental conditions for sterile product preparation, preservation, and dispensing.

This article probes into the essential components of cleanroom design necessary for Category 2 drugs to adhere to the updated stipulations within USP 797 / 800 chapters.

The updated USP <797> Chapter categorizes compounded sterile preparations (CSPs) into Immediate Use (Lowest Risk), Category 1 (Lower Risk), or Category 2 (Higher Risk), hinging on several factors, including the time duration from the compounding to the patient administration.

Beyond Use Dates (BUDs): This term signifies the date or time post which a compounded preparation is deemed unusable and has to be discarded. The BUD is determined based on when the preparation was initially compounded.

Category 1 (Lower Risk): These are CSPs with a BUD of 12 hours or less at room temperature or 24 hours or less when refrigerated.

Category 2 (Higher Risk): These are CSPs with a BUD exceeding 12 hours at room temperature or 24 hours when refrigerated.

For Category 2 CSPs, USP <797> necessitates preparation within a cleanroom environment, inclusive of distinct buffer and ante areas, and mandates compliance with all relevant USP standards for Category 2 sterile preparations.

The ISO 7 CSP sterile drug compounding area or buffer area will house an ISO 5 primary engineering control device for compounding operations.

Types of Primary Engineering Control (PEC) Devices

Vertical or Horizontal Laminar Airflow Hoods (LAFS)

Class II Biological Safety Cabinet (BSC)

Restricted-Access Barrier System (RABS)

Hazardous CSPs and Containment Primary Engineering Controls

The ISO 7 CSP hazardous drug compounding area will house an ISO 5 primary engineering control device for compounding operations.

Types of Containment Primary Engineering Control Devices (C-PEC)

Class II Biological Safety Cabinet (BSC) externally ducted and HEPA filtered exhausted

Compounding Aseptic Isolator (CAI)

Compounding Aseptic Containment Isolator (CACI)

CSP and Hazardous CSP Secondary Engineering Controls

Secondary engineering control spaces are the areas where the PEC is placed (e.g., a cleanroom suite). It incorporates specific design and operational parameters required to minimize the risk of contamination within the compounding area.  Critical parameters are monitored in the space each day manually or automatically including:

▪ Temperature at approximately 20 degrees Celsius (68 degrees Fahrenheit)

▪ Relative humidity below 60%

USP 797 and 800 provide specifications for area classification based on the type of activity performed.

USP <797> Compounding Sterile Products Spaces

Compounding Category II sterile drugs requires segregation into designated spaces, namely: the unclassified anteroom area, the ISO Class 8 Buffer Area, and the ISO Class 7 Cleanroom.  The personnel flow entering the facility transitions from ‘dirty’ to ‘clean’ with progressive gowning and operating procedures. The facility is positive pressure which transfers air from clean to dirty as a means of reducing contamination risk. Refer to Figure 1 below.

The Anteroom Area serves as a transition room, where staff don their personal protective equipment (PPE). The Buffer Area is where non-hazardous sterile compounding takes place.  Environmental monitoring air, personnel and surfaces is critical to continuous contamination risk management.

Compounding hazardous drugs according to USP <800> necessitates the allocation of dedicated areas, specifically: the non-classified space, ISO 8 anteroom, the ISO Class 7 Containment Secondary Engineering Control (C-SEC) HD Buffer Cleanroom. Personnel movement within the facility is engineered from ‘dirty’ to ‘clean’, incorporating sequential gowning and operating procedures. In order to minimize the risk of contamination, the facility maintains a negative pressure, directing airflow from ‘dirty’ to ‘clean’ areas. Refer to Figure 2 below.

The anteroom in the facility functions as an intermediary space, where staff don their personal protective equipment (PPE). Hazardous compounding operations are carried out in the HD Buffer Cleanroom. The continuous management of contamination risk pivots on rigorous environmental monitoring of air, personnel, and surfaces.

Antineoplastic hazardous drugs (HDs), which necessitate manipulation beyond repackaging of final dosage forms, along with any HD active pharmaceutical ingredient (API), must be segregated from non-HDs to preclude contamination and personnel exposure. This storage should occur in an externally ventilated room under negative pressure, necessitating a minimum of 12 air changes per hour (ACPH).

USP Chapter <800> stipulates that the Containment Primary Engineering Controls (C-PECs), the devices used for compounding hazardous drugs (HDs), must be externally vented through High-Efficiency Particulate Air (HEPA) filtration. The objective is to capture and contain hazardous particles to minimize the risk of environmental contamination and personnel exposure.

HEPA filters are critical components in maintaining air quality as they can capture at least 99.97% of airborne particles of 0.3 micrometers (µm) in diameter. These filters are thus effective in limiting the spread of HDs, ensuring cleaner and safer air within the cleanroom and the surrounding areas.

Furthermore, any area that is externally vented, such as rooms used for HD storage or the Containment Secondary Engineering Controls (C-SECs), must employ proper exhaust ventilation. This exhaust air should ideally be expelled outside the building, but if it is to be re-circulated, it must pass through a redundant HEPA filtration system before returning to the general circulation, as a precautionary measure to prevent potential contamination.

These filtration requirements, combined with other stringent controls on air quality, airflow patterns, and pressure differentials, help to create a safer compounding environment compliant with USP <800> guidelines.

Cleanroom interior fit and finishes must support sanitization efforts. Surfaces, including walls, ceilings, and floors, must be smooth, impervious, and easy to clean. Coved or rounded corners can prevent the accumulation of dust or other particulates. The use of seamless and crack-resistant materials minimizes bacterial growth and aids in maintaining the required cleanroom conditions.

Equipment and case work should be easy to clean, and should not generate particles or microorganisms. Germfree’s equipment products, such as their compounding aseptic isolators and laminar flow workstations, are designed with these considerations in mind. For example, work surfaces should be made of smooth, non-shedding materials, such as stainless steel, and should be easy to disinfect.

USP <797> necessitates a positive pressure differential for non-hazardous compounding areas, ensuring that air flows from clean areas to less clean ones, minimizing contamination risk. In contrast, hazardous compounding areas according to and USP <800> should maintain a negative pressure differential to confine contaminants within the area.

Ventilation rate, air change rates, HEPA filtration and proper airflow patterns are paramount in controlling airborne contaminants. It is important to incorporate unidirectional airflow for critical areas, such as ISO 5 compounding aseptic isolators or containment aseptic compounding isolators.

USP <800> provides detailed instructions on containment systems. It mandates the use of Containment Primary Engineering Controls (C-PECs) for manipulating hazardous drugs (HDs). C-PECs, like Biological Safety Cabinets or Compounding Aseptic Containment Isolators, should maintain negative pressure to ensure HD containment. Furthermore, Containment Secondary Engineering Controls (C-SECs), consisting of the room design and the general HVAC system, must be incorporated to augment the containment provided by C-PECs.  C-PECs should be externally vented.

Control of temperature and relative humidity within the compounding areas is vital for staff comfort, preservation of products, and minimizing microbial proliferation. Both USP <797> and <800> require specific temperature and humidity parameters for compounding spaces.

• 20 degrees Celsius (68 degrees Fahrenheit) or cooler
• Relative humidity below 60%

Monitoring and controlling these parameters helps maintain drug stability and sterility.

Cleanrooms should have appropriate lighting levels that enable pharmacists and other healthcare workers to perform tasks safely and effectively. Lighting should be non-glare, non-flickering, and should not generate heat or ultraviolet radiation that may affect drug products.

Cleanroom flooring should be non-porous, non-shedding, and easy to clean. The flooring should be compatible with the cleaning agents and disinfectants used in the cleanroom, and should be able to withstand frequent cleaning and disinfection.  Suppliers of cleaning agents have detailed material information on the compatibility of their products.

Cleanroom doors should have self-closing mechanisms and are designed to withstand the cleanroom regimen needed. Pass-throughs both active and note active, are used to transfer materials and equipment into and out of the cleanroom.  Pass-throughs should be designed to prevent the escape of contaminants, and should be easy to clean and disinfect.

Cleanrooms should have monitoring and control systems that enable pharmacists and other healthcare workers to monitor and maintain the cleanroom environment. These systems should include temperature and humidity sensors, pressure sensors, particle counters, and alarm systems that alert personnel to deviations from acceptable conditions.

An efficient workflow and personnel flow must be established to minimize cross-contamination and optimize productivity. The design must encourage a logical progression of movement from ‘dirty’ to ‘clean’ areas. Staff should enter through the gowning area, proceed to the ante area, and finally into the compounding areas. There should be clear demarcations and indications for ‘first air’ zones and pass-through chambers for materials.

USP 797 / 800 emphasize regular cleaning and disinfection USP 797 and 800 emphasize regular cleaning and disinfection schedules for cleanrooms, which are essential for maintaining the appropriate cleanliness level and minimizing microbial and particulate contamination. Cleanroom design should facilitate these activities.

The choice of disinfectants and detergents should be compatible with the surface materials used in the room and they should not contribute to worker exposure to HDs. Procedures should outline deactivation, decontamination, cleaning, and disinfection processes.

Continuous monitoring and validation of the cleanroom environment are crucial in assuring the compounding areas’ compliance with the defined standards. Environmental monitoring includes viable and non-viable air and surface sampling, pressure differentials, temperature, and humidity measurements. The monitoring frequency depends on the room classification and the risk level of the compounded preparations.

Moreover, validation of air handling systems, including HEPA filters, is required initially and periodically. A smoke study can validate the airflow patterns and turbulence that may lead to contamination. In terms of equipment validation, the functionality and safety of primary engineering controls should be shared.

Both USP <797> and <800> emphasize the segregation of hazardous and non-hazardous drug compounding areas. USP <800>, in particular, underscores that containment strategies must be in place to minimize personnel and environmental exposure to hazardous drugs. Designing separate, dedicated areas for receiving, storing, compounding, and deactivating/decontaminating, cleaning, and disinfecting hazardous drugs is essential.

Finally, the human factor cannot be disregarded. The personnel’s role is vital in maintaining the cleanroom environment. Hence, regular training and competency assessments are required as per USP <797> and <800>. Staff should be well-trained in proper garbing procedures, aseptic techniques, cleaning, disinfection, hazardous drug handling, and emergency procedures.

The design and maintenance of cleanrooms for pharmaceutical compounding are complex tasks, necessitating a thorough understanding of USP <797> and <800> standards. From room construction and air quality control to containment systems, personnel flow, and continuous monitoring, each element requires detailed planning and careful implementation.

While the USP guidelines serve as a benchmark, the pursuit of quality and safety in compounding practices should not be limited to mere compliance. It’s about creating an environment that consistently promotes the production of safe, high-quality compounded medications, ultimately ensuring the wellbeing of patients and healthcare providers.