Revisions Continue on USP Sterile-Compounding Chapter

[September 15, 2005, AJHP News]

Cheryl A. Thompson

SAN FRANCISCO, CA, 01 September 2005—When the United States Pharmacopeia (USP) first published "Pharmaceutical Compounding—Sterile Preparations," the standards-setting organization described controls for the environment in which personnel make those medications. But the document, also known as United States Pharmacopeia chapter 797, offers few specifics on achieving such things as a buffer zone that has sufficiently clean room air.

The committee revising the chapter is considering adding details about environmental control factors, including a requirement for high-efficiency particulate air (HEPA) filters in the buffer zone or room, said Chair David W. Newton at a USP-convened workshop August 5–6 in San Francisco.

Newton, a pharmaceutics professor at Shenandoah University in Winchester, Virginia, and former practicing pharmacist, would not say when he expects the 12-member all-volunteer committee to finish the revision.

"We have to get it out there," he said, acknowledging the revision's importance to practitioners, "but haste makes waste."

Claudia C. Okeke, USP staff liaison for the committee revising chapter 797, said in a phone interview that the soonest the public could see the document would be the March–April 2006 issue of Pharmacopeial Forum, a USP journal.

USP would then allow four months for feedback, primarily from pharmacy groups, she said. Newton's committee would then decide, on the basis of the comments received, whether to further revise the chapter or publish it as is and keep the comments in mind for the next revision cycle.

Until USP formally approves the revision, chapter 797 remains as it was in January 2004, when first included in The United States Pharmacopeia and The National Formulary, Newton said at the workshop.

ISO Class 7, not 8. The committee has received hundreds of comments since publication of the chapter as an announcement in the July–August 2003 issue of Pharmacopeial Forum, Newton said.

One topic of comment, he said, concerned the air quality in the buffer zone or room where a laminar-airflow workbench resides.

Chapter 797 states that the air in this zone or room must meet or exceed the particulate-matter limit for class 8 in the International Standards Organization's (ISO's) classification of air cleanliness, equivalent to what U.S. pharmacists familiar with ASHP guidelines knew as a class 100,000 cleanroom.

That requirement will change to ISO class 7, a grade better than class 8, and specify a particle size of >0.5 micrometer, Newton said, meaning that the upper limit on airborne particles 0.5 micrometer or larger will be 352,000 per cubic meter of room air in the buffer area.

The revision will also state that the air in the buffer area must first pass through a HEPA filter and that the air-quality measurements must reflect conditions when the zone or room is in use, he said.

Still undecided by the committee, Newton said, is the number of times per hour the ventilation system for the buffer area must replace room air.

He said the decision will likely reflect the number reported in the USP informational chapter on the microbiological evaluation of cleanrooms and other controlled environments, which itself is under revision.

As with the decision to upgrade the air quality in the buffer zone or room, Newton's committee has consulted other USP chapters and material from other authoritative organizations for details on environmental controls.

Clean air. Jim Wagner, president of the Controlled Environment Testing Association and the firm Controlled Environment Consulting and a new member of the committee revising USP chapter 797, offered workshop attendees several tips for dealing with the buffer zone or room, where airflow tends to be turbulent, not unidirectional.

For one thing, pharmacists should become familiar enough with definitions, specifications, and classifications to know whether what the pharmacy needs is what the pharmacy is being sold.

"Any time there is a new standard, there's always people out there looking to take advantage" of the unwary purchaser, Wagner said.

"What we're looking to do . . . is maintain a clean level, not necessarily a superclean level," he said of the buffer area.

HEPA filters. Reduce the airborne-particle level in the buffer area, and you reduce the amount of particulates that you bring into the laminar-airflow workbench or barrier isolator, he said.

But not all HEPA filters are the same.

The Institute of Environmental Sciences and Technology recognizes six levels of performance for HEPA filters, A through F.

"My recommendation is that you specify type C filters" when outfitting the buffer zone or room, Wagner said.

A type C HEPA filter, he said, has been tested for leakage and overall penetration of particles and captures at least 99.99% of heat-generated 0.3-micrometer particles. In contrast, type A HEPA filters have not been tested for leaks.

The HEPA filter in a typical household air purifier has an efficiency of 99.97%.

Regardless of the performance level, Wagner said, a HEPA filter does not restrain the flow of gases and vapors.

Airborne particles. Airborne-particle counts should be conducted when the buffer zone or room is in use, he said.

"Your cleanroom contractor is going to want to specify either 'as built' or 'at rest,'" Wagner said. "It's the easiest way for him to count that room. You're going to want to specify 'operational' because that's what you care about."

Wagner also advised specifying the size of the airborne particles to be measured.

ISO class 7 means the presence of no more than 352,000 particles 0.5 micrometer or larger per cubic meter of room air, no more than 83,200 particles 1.0 micrometer or larger per cubic meter, or no more than 2,930 particles 5.0 micrometers or larger per cubic meter.

Newton appeared confident that the new chapter 797 would specify 0.5 micrometer as the key particle size for air classification.

Airflow. Well-designed airflow, Wagner said, can make it possible, without erecting a physical barrier, to divide a sterile-compounding room into a buffer zone and what chapter 797 calls an "ante area."

"I can make a room that has very poor [HEPA] filter layout work well if I have good [air] returns," he said. With well-placed air returns, which pull out air, he explained, the direction of airflow can be better controlled than when air is pushed into the space.

As for the number of HEPA filters that should service a given area or room, Wagner said it depends foremost on the number of air changes per hour that need to be achieved—something that Newton's writing group, the USP Sterile Compounding Committee, has not settled on yet.

Recent changes to revision. The Sterile Compounding Committee met most recently July 7–8 in Rockville, Maryland, at which time new members Wagner and Eric S. Kastango, president of Clinical IQ LLC, officially joined the group, Okeke said.

Newton said the group changed or deleted some of the proposed revisions that he had described months earlier in a document on the USP Web site (www.usp.org/healthcareInfo/pharmInfo/revisions797.html).

These changes, which are still just proposals, are as follows:

• Chapter 797 practice standards will continue to apply to all manipulations of sterile products, even manipulations that adhere strictly to the instructions in the manufacturer's FDA-approved labeling. (The committee had initially planned to exempt sterile products that were prepared, packaged, and stored in accordance with information in their labeling.)
• A compounded sterile preparation that would normally qualify for "low-risk conditions" will be exempt from the requirement for an ISO class 5 or better air-quality environment if (a) the compounding procedure involves no more than three sterile products, including the diluent, (b) there is no "direct contact contamination," and (c) administration begins within one hour. (The initial proposal for the "immediate use" exemption had also stated a 12-hour maximum from time of preparation to completion of administration, but chapter 797 does not pertain to the clinical administration of compounded sterile preparations.)
• Compounded sterile preparations at medium risk of contamination and in the absence of passing a sterility test may be stored for no more than nine days at a cold temperature. (Newton said this change was made at the request of home infusion pharmacists who expressed concern that the original seven-day limit does not allow adequate time for the delivery of total parenteral nutrient preparations.)
• Chapter 797 will not delineate the conditions for the use of single-dose containers. (The committee had initially planned to state that single-dose vials continuously exposed to an ISO class 5 or better air-quality environment could, after the first needle puncture, be used again for up to six hours. But, Newton said, this statement would conflict with the definition of single-dose container in USP chapter 1, "Injection.")
• Hazardous drugs in compounded sterile preparations shall be "contained, enclosed, isolated, measured, packaged, prepared, spill-protected, and vented" in accordance with their FDA-approved labeling and applicable state and federal guidelines and standards. (A subcommittee is working on statements that may address unidirectional airflow, the exhausting of air from the ISO class 5 or better air-quality environment to outside the facility, and whether the air pressure in the ISO class 5 or better environment must be less, not more, than the surrounding environment.)
• Certain procedures in compounding radioactive sterile preparations may need to be done in an air-quality environment not as clean as ISO class 5. State and federal regulations must be followed.
• Exposure of a "sterile critical site" for more than one hour to an air-quality environment not as clean as ISO class 5 creates a high-risk condition. The ingredient or compounded preparation must undergo sterilization or be proven sterile before administration.
• Before entering the buffer zone or room, personnel must remove cosmetics that may shed as flakes and particles and jewelry that interferes with the fit of gloves or cuffs. (Chapter 797 currently requires the removal of all makeup and jewelry.)
• The sequence for garbing and cleansing will be (a) don shoe covers, (b) don head and facial hair covers, (c) don a face mask if the laminar-airflow workbench lacks a transparent shield that extends at least six inches below the person's mouth level, (d) scrub hands and arms to the elbows with an antiseptic cleanser and dry with lint-free towels or a clean-air blower, (e) don a coat, gown, or coverall that has a closed front and snug-fitting wrists and that does not shed particles, and (f) don sterile gloves and avoid contaminating them. (Newton said this sequence of events was changed in response to comments from the public.)

Also, a subcommittee is studying specifications for construction materials, surface-contact sampling methods, chemical disinfectants, and whether the environment in which a barrier isolator is located needs to be of a certain air quality or even tested.

As Newton emphasized during his presentation, none of the above changes are firm until publication of the revision of USP chapter 797.

Comments regarding the revision of chapter 797 should be directed to USP's Okeke, at cco@usp.org.