A revised version of the United States Pharmacopoeia (USP) 797 “Pharmaceutical Compounding—Sterile Preparations” regulation has been issued this year. All health facilities that prepare compounded sterile preparations (CSPs)—pretty much all hospital pharmacies and many off-site pharmacies—should be aware of this new regulation, whether or not it is adopted within the facility’s particular state.

The 2008 version of the USP 797 regulation is the second formal issue of the regulation by USP. The first formal issue was in 2004. The new 2008 version contains important, new requirements that differ substantially from the now-superseded 2004 version.

Minimize risk, maximize safety

The regulation is named after a chapter published by the United States Pharmacopoeia-National Formulary (USP-NF). Starting with the first edition of USP 797 in 2004, and carrying over into the current edition, USP 797 spells out a comprehensive quality system for the design and operation of sterile compounding areas and their support spaces. The intent of USP 797 is twofold: to minimize the risk of contamination of CSPs as well as to maximize the safety of the environment for staff working in these areas.

Looking now at the details of the 2008 edition of USP 797, the general intent of the regulation remains the same. In the words of the first sentence of the 2008 regulation: “The objective of this chapter is to describe conditions and practices to prevent harm, including death, to patients” that could result from improper compounding practices done in an improper environment.

The standards of the regulation are intended to apply to “all persons who prepare CSPs and all places where CSPs are prepared (e.g., hospitals and other health care institutions, patient treatment clinics, pharmacies, physicians’ practice facilities and other locations and facilities in which CSPs are prepared, stored and transported).”

The regulation classifies five types of compounding environments: low-risk CSPs with 12-hour beyond use dating (BUD), low-risk, medium-risk, high-risk and immediate use. The classification of the compounding environment influences its required characteristics, so it is important that clients determine their compounding risk as part of the initial planning of any USP 797-compliant project.

Design and construction

There are 25 sections in the 2008 regulation, as well as four appendices, and the regulation has far-reaching goals in terms of the design and operation of a facility involved with CSPs. However, the focus of this article is the design and construction of a USP 797-compliant environment, which is addressed in the section of the regulation entitled: “Facility Design and Environmental Controls.”

A good place to start is the two key areas of the 2008 requirements that differ substantially from the 2004 requirements. They include the following:

ISO standard for buffer area. In the 2008 standard, the buffer area (the room or area where the compounding work is done) must meet a minimum ISO 7 cleanroom standard (equivalent to a Class 10,000 cleanroom). In the 2004 standard, the buffer area only had to meet ISO 8 (the lower the ISO number, the higher the standard).

ISO standard for ante area. In the 2008 standard, the ante area (the room or area that one passes through on the way to the buffer area) must meet a minimum ISO 8 cleanroom standard (equivalent to a Class 100,000 cleanroom). In the 2004 standard, the area did not have to meet an ISO standard.

A central element in a USP 797-compliant facility is the primary engineering control (PEC). The PEC is the piece of equipment, such as a laminar airflow workbench or biological safety cabinet, where the actual aseptic compounding activities are performed.

The PEC is typically located within the buffer area, and the internal work chamber within that equipment that must equal ISO 5. In the low-risk level CSP with 12-hour BUD section, the PEC is permitted to be located in a segregated area (unclassified space). An example of this type of facility configuration would be a satellite pharmacy.

In the planning process, attention should be given to placing these devices “out of the traffic flow and in a manner to avoid disruption from the HVAC system and room cross-drafts.” Selecting that piece of equipment—or pieces, as larger compounding rooms may have several—is an important early stage decision in the pharmacy planning process.

Also central to the design of a USP 797-compliant facility is the physical relationship between the buffer area and ante area. This physical relationship hinges around hazardous versus non-hazardous compounding as well as the classification of the nonhazardous compounding room as low, medium or high risk (hazardous compounding rooms are always classified as high risk).

There must be a physical separation (i.e., wall and door) between the buffer area and ante area in high-risk environments. No physical separation is required in the other facility classifications, however, there are daunting HVAC requirements that come into play for “open” facilities (no wall/door between buffer and ante areas), as we shall see shortly.

Many pharmacies compound substances, such as chemotherapy drugs, referred to as hazardous drugs as defined in the National Institute for Occupational Safety and Health (NIOSH) publication on “Preventing Occupational Exposure to Antineoplastic and Other Hazardous Drugs in Health Care Settings.” These drugs are extremely toxic and dangerous to staff if not transported, stored and handled properly. Hazardous compounding should be done in a separate hazardous buffer area. Some hospital pharmacies will have two buffer areas—a hazardous buffer area and a nonhazardous buffer area—often served by one common ante area. One point worth mentioning here is that any ante area serving a hazardous buffer area must be a minimum of ISO 7 (because the air from the ante area is being drawn into the hazardous buffer area).

For a nonhazardous buffer area, where there is a separation between the buffer area and the ante area, the buffer area should be pressurized to be positive relative to the ante area (i.e., the air should flow from the buffer area to the ante area, so the cleaner buffer area environment is not contaminated by the less clean ante area environment). The regulation specifies that nonhazardous buffer areas that have a physical separation should have a minimum, differential, positive pressure of 0.02- to 0.05-inch water column. Within the nonhazardous buffer area, the PEC is a device that recirculates air within the room.

All hazardous buffer areas must have a separation between the buffer area and the ante area. The buffer area should be pressurized to be negative relative the ante area (i.e., the air should flow into the buffer area from the ante area, so the potentially more hazardous air of the buffer area is contained and it does not contaminate the cleaner ante area environment). The regulation specifies that for these hazardous buffer areas, there should be a minimum, differential, negative pressure of a minimum of 0.01-inch water column between the buffer area and ante area. Within the buffer area, the PEC must be 100 percent exhausted (no recirculation of air) directly to the exterior through a high-efficiency particulate air (HEPA)-filtered exhaust.

For pharmacies that are low or medium risk, and do not compound hazardous drugs, and where the facility has elected not to have a physical barrier between buffer and ante areas, the regulations specify that a system of “displacement airflow shall be employed … (which) utilizes a low pressure differential, high airflow principle … (which) requires an air velocity of 40 feet per minute or more from the buffer area across the line of demarcation into the ante area.” It should be noted that this HVAC benchmark, which is required of all “open” USP 797 facilities (i.e., facilities that do not have a wall/door between buffer room and ante room), has been historically difficult to achieve.

There are additional HVAC factors to be considered in the facility design. The first is air changes, where the regulations specify that there be a minimum of 30 air changes per hour (ACPH) in an ISO 7 space supplied by HEPA-filtered air. That number of air changes could be split between the PEC contributing no more than 15 ACPH and the HEPA-filter supply air to the area at least 15 ACPH. 

The minimum requirement for ACPH for the buffer area is 30 ACPH and should be based on compounding activities in the area. Compounding processes that generate a significant amount of particles may increase the ACPH requirements. Also, the regulation proscribes an OR-type, unidirectional airflow design, where the HEPA-filtered air is distributed from supply grills in the ceiling and returned through return grills mounted low in the wall.

Moving on to the architectural regulations for the buffer area, only items absolutely essential to compounding should be brought in. Items like refrigerators, computers and printers can be placed in a buffer area as long as there is an accommodation for the particles they may generate. Typically, the placement of low-wall returns behind these devices will help sweep away any particles.

Any furniture or equipment should be “nonpermeable, nonshedding, cleanable and resistant to disinfectants.” All surfaces (e.g., ceilings, walls, floors, fixtures, shelving, counters and cabinets) should be “smooth, impervious, free from cracks and crevices, and nonshedding.” Junctures of ceilings to wall “shall be coved or caulked.” Wall construction can be either epoxy-coated gypsum board, or heavy gauge polymer panels locked together and sealed. No sinks or floor drains are allowed in the buffer area.

Work surfaces should be made of smooth, impervious materials such as stainless steel or molded plastic. Carts should be made of stainless steel wire, nonporous plastic or sheet metal construction. Storage shelving, counters and cabinets should also be “smooth, impervious, free from cracks and crevices, nonshedding, cleanable and disinfectable.”

To learn more

This article provides a general overview on the portions of the new USP 797 regulation that pertain most to the planning, design and construction of USP 797-compliant facilities.

General questions can be addressed to USP at http://usp.org. Additionally, a selection of some of the most commonly asked questions and answers provided by industry experts also can be accessed at http://usp797.org/Questions_and_Answers.htm.

William N. Bernstein, ACHA, AIA, is a principal of Bernstein & Associates Architects in New York. He can be contacted via his e-mail address at wb@bernarch.com.