Webcast wrap-up: The plain truth about USP <797>

Attendee questions from the CleanRooms Webcast are answered

On January 30, 2007, CleanRooms hosted its second Webcast focused on USP <797>. With participation from members of the USP <797> Expert Committee, now evaluating proposed revisions to the Chapter, the presentation put to rest some of the “urban legends” surrounding the standard and provided attendees with practical information and answers to the immediate and real-world challenges and questions they have today. Remaining questions that could not be answered during the one-hour Webcast are presented and answered here.

When will the final version of USP be published?

The final version will be published after the USP Sterile Compounding Committee has had time to adequately review all of the comments received.

What is the difference between validation and certification of cleanrooms?

Validation of a cleanroom or a primary engineering control is based on the specific needs of a particular facility as determined by that facility. Validation performed at one facility is often very dissimilar to that done at a different facility. Certification is the application of industry-based protocols to specific applications in an attempt to assure repeatable tests are performed using the same methods and instrumentation on every piece of equipment. Certification of primary and secondary engineering controls is often a component of an overall facility validation. Primary engineering controls should be certified to industry-based protocols such as the Controlled Environment Testing Association’s (CETA) application guides and National Sanitation Foundation (NSF) International Standard 49. The secondary engineering controls, such as cleanrooms, are often validated to the owner’s specific criteria that will include certification.

Where can we find a list of companies that are certified to validate or certify cleanrooms?

A list of qualified certifiers for validation of sterile compounding facilities currently does not exist. CETA is in the process of developing an accreditation program for this.

Where can we find a list of laboratories that measure surface contamination from hazardous drugs?

To our knowledge no such list exists. Environmental sampling is a relatively new approach used to determine the level of workplace contamination by antineoplastic agents. The procedure has been used extensively in other situations, especially for monitoring contamination from radioactive materials. Typically, work surfaces are sampled with a moistened wipe and the material is extracted and analyzed for specific antineoplastic agents. Currently, it is possible to identify and quantitate six to eight agents with this technique. Often, analytical labs will work with potential clients to incorporate new analytical methods if one can be identified, so don’t hesitate to inquire even if a particular lab doesn’t advertise this capability. There are a few labs and methods mentioned in the research literature; these might be a good place to start. Some references to aid in this search can be found at: http://www.cdc.gov/niosh/topics/antineoplastic/sampling.html#a. You might also check similar trade literature reports by certifiers, pharmacists and equipment manufacturers.

When do you think these proposed changes will become effective?

The Sterile Compounding Expert Committee is carefully reviewing and considering all comments received on or before the August 15, 2006, public commentary deadline. There are approximately 2,500 pages of comments from over 300 participants including hospitals, professional associations, vendors, stakeholders, and individual practitioners (pharmacists, nurses, physicians, etc.).

Due to the volume and criticality of these comments, it is not known when the review will be completed and the proposed revisions finalized. The committee is working hard to get a revised chapter out later this year.

How will these guidelines be enforced?

The USP has no enforcement authority. The primary responsibility of enforcement falls to the state boards of pharmacy. Many states are in the process of rewriting their laws and regulations to enhance existing sterile and nonsterile compounding regulations to harmonize with USP <797>. The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) still requires a gap analysis and action plan during survey but has neither the authority nor the trained surveyors to survey to USP chapter requirements.

Can you have an open concept in a negative room?

A negative pressure cleanroom must be maintained at a minimum pressure of 0.01 in./WC. It seems unlikely that this can be maintained in an open-concept cleanroom.

Do you need a dedicated air-handling unit (AHU) for the cleanroom or can you share one from another area? If so, must you still meet the air-changes-per-hour (ACPH) requirements?

You do not need a dedicated AHU if the existing HVAC system can handle the additional load. You still need to meet the ACPH requirements regardless of which HVAC system you employ.

Should you design the function and equipment of the room first, trying to predict the particle generation, and then design the HVAC system?

Ideally, the ACPH requirements are based on particle generators, heat load considerations, personnel traffic and other considerations and should be taken into account when determining HVAC requirements. The USP ACPH recommendations are minimum requirements and should not be looked at as specific numbers. USP states: “More air changes may be required based on the number of personnel and processes.”

Can you store supplies in the cleanroom?

Ideally, supplies in the cleanroom should be limited. The cleanroom should be as spartan as possible, containing only the supplies and inventory needed for that compounding day. Excessive amounts of supplies and inventory in the cleanroom are a hassle when performing daily, weekly and monthly cleaning procedures.

Can you compound IVs and chemo in the same room?

As stated in USP <797>: “The ISO Class 5 BSC [biosafety cabinet] or CAI [compounding aseptic isolator] shall be placed in an ISO Class 7 room that is physically separated, i.e., in a different room, from other preparation areas…”

Do you need pressure-locked doors into the anteroom and/or buffer room?


How do the standards relate to oncology offices?

The standards in USP Chapter 797 are intended to apply to all persons who prepare compounded sterile preparations (CSP) and all places where CSPs are prepared, e.g., hospitals and other healthcare institutions, patient treatment clinics, pharmacies, physicians’ practice facilities, and other locations and facilities in which CSPs are prepared, stored, and transported. Persons who perform sterile compounding include pharmacists, nurses, pharmacy technicians, and physicians. These terms recognize both that most sterile compounding is performed by or under the supervision of pharmacists in pharmacies and that this chapter applies to all healthcare personnel who prepare, store, and transport CSPs. In Virginia, the Board of Medicine adopted emergency regulations requiring all physician offices that engage in compounding (which is broadly defined) to meet USP Chapter 797-Sterile Compounding Rule emergency regulations. Oncology offices that don’t have a licensed pharmacy area are regulated by the state board of medicine and may be required to comply with other local, state and federal (e.g., OSHA, NIOSH) requirements.

Will JCAHO, FDA or state boards of pharmacy survey my facility for compliance?

Possibly any or all of those organizations will survey your facility, depending on your state. You should contact your state board of pharmacy directly for more information.

Can two people work and compound under the same laminar bench and still maintain ISO 5?

If that device has been designed for that operation and particle count testing confirms that ISO Class 5 is maintained, two people can work at the same time.

How many of the changes in the proposed revisions will be accepted and become a requirement?

That will be determined by the committee based on the review of the comments received.

In chemo rooms, how can you maintain ISO 5 on the bench if you are pulling dirty air (ISO 7 or 8) across the bench, based on airflow? Shouldn’t the chemo bench be in an ISO buffer room as well?

Work in a chemo room should only be done in a BSC or compounding aseptic containment isolator (CACI) specifically designed to provide ISO Class 5 and to contain at the same time. Work should never be performed on a bench in a chemo application.

How often do you need to do particle and bioburden counts?

Particle counting or nonviable sampling occurs every six months. Depending on your risk level, you are required to sample either monthly (low- and medium-risk level) or weekly (high-risk level). If you haven’t already, download a copy of the proposed changes to USP Chapter 797. Visit http://www.usp.org/USPNF/pf/generalChapter797.html to obtain a copy. The specifics can be found in this document.

State boards of pharmacy have full legal compliance such that fines can be imposed. Should we not have to follow their laws, regardless of USP <797>?

There are some state laws that are not harmonized with USP Chapter 797. The principle of preemptive law applies and pharmacists have to follow the stricter of the two laws (state vs. federal). It is best to contact your state board of pharmacy for more complete guidance. USP standards have been used in lawsuits as national standards of practice.

Can you elaborate on viable sample requirements?

Viable sampling is the collection of air, surface or personnel samples with the express purpose of detecting microbial contamination.

How are HEPA filters tested after installation (in situ)?

For cleanrooms, every application is slightly different. Ideally, the cleanroom contractor has made accommodations for field-testing. An aerosol challenge (typically polyalphaolefin [PAO]) is introduced upstream of the HEPA filters and the filters are scanned downstream with an aerosol photometer. Ceiling-mounted HEPA filters are usually easier to test than remotely located banks of filters.

What are the deadlines for facility implementation?

Technically, USP Chapter 797 has been in effect since January 1, 2004. JCAHO initially published 2008 deadlines but has since backed down on those dates, unless mandated by state boards of pharmacy.

Is there any historical data to justify 30 ACPH vs. the normal 60 ACPH for ISO 7 areas?

The rate of 30 ACPH is based on the minimum suggestions in the ISO 14644-4 document. Remember, USP specifically states: “More air changes may be required based on the number of personnel and processes.” It is interesting to note that, when discussing this document with people familiar with cleanrooms, they invariably comment on the concern that 30 ACPH might not be adequate to maintain ISO Class 7. When you discuss this with people less familiar with cleanrooms, they wonder why we require so much air. The final number of air changes will need to be determined on an individual basis but, with the amount of HEPA-filtered air added to the room from the primary engineering controls (except for an exhausted chemo hood), 30 ACPH will be a good starting point.

Is it true that all work surfaces and storage surfaces must be stainless steel in the cleanroom?

No, as long as they are smooth, impervious, free from cracks and crevices, nonshedding, cleanable, and will stand up to the disinfectants.

What is a reasonable date to expect the completed revision of USP <797>?

All USP chapters are dynamic and subject to change. The goal of the USP Sterile Compounding Committee is to get through the comments from the proposed changes and issue a revised chapter as soon as feasible.

Is coving necessary in a cleanroom?

Coving is ideal, but as long as cleaning can be accommodated and seams are sealed and caulked, it should be sufficient.

Please comment on the ability of an operator to shut off a laminar flow bench (LFB) and therefore change the effective ACPH. Wouldn’t it be better to have the primary airflow be at a minimum of 30 ACPH or, even better, 60 ACPH?

The primary engineering controls should never be turned off in a cleanroom. They are designed for continuous operation. I understand your concern that an operator can make a mistake and therefore affect the operation of the cleanroom. If you feel that concern is real for your institution, I recommend you bypass the on/off switch on the hood. That will be a much cheaper solution than ignoring the value of the HEPA-filtered air delivered to the cleanroom. This allowance by USP was intended as a cost-saving consideration.

Are open-concept cleanrooms a better alternative to traditional design? Where can I find more information on open-architecture designs?

Open architecture cleanrooms are not a better design, nor are they cheaper. Factoring in the air needed to achieve 40 FPM across the interface between two spaces, this becomes an expensive option. The open architecture design is acknowledged in ISO 14644-4, thus it is acknowledged by USP. There is not a lot of precedent in the U.S. for this type of design outside the pharmacy industry. You will also find that most of the early discussions regarding open architecture cleanrooms were conducted without consideration for engineering criteria: Just place a line on the floor, and the room magically works. Once criteria become part of the discussion, the costs seem to make this design impractical.

Which particle counter flow rates are applicable for environmental monitoring?

Most particle counters are available in 0.1 CFM, 1.0 CFM, and sometimes even larger sample volumes are available. Any sample volume will work depending on how much time can be allocated to particle counting. I assume most professional certifiers will use at least a 1.0 CFM counter, simply based on the amount of time needed when using a 0.1 CFM counter. A pharmacy looking for a particle counter might value the lower cost of a 0.1 CFM counter more than the implications of sample time. In this case, the particle counter can be set up for longer sample times while pharmacists go about their day.

What media requirements do you recommend for viable sampling?

Proposed revisions in USP recommend tryptic soy agar (TSA) and malt extract agar (MEA).

When it states that a cleanroom must meet the specification for 0.5 micron or greater, does that mean that more than one particle size should be monitored, or is monitoring only 0.5 micron sufficient?

Setting the counter for the cumulative mode will count all particles that size and larger. Reading in the differential mode will count that specific size range.

Are there any studies indicating the impact of venting hazardous drugs to the outside air?

I assume the questioner is concerned about negative impact to the outdoor environment or positive impact (in terms of disease reductions) to the indoor environment. In either case, I am unaware of any studies that enacted this change and then evaluated the results upon the respective environments.

I understand that cleanroom certification for nonviable particles is recommended every 6 months at a minimum: How do I know I’m in compliance between certifications?

Technically, you only “know” for a fact that you are in compliance when you perform the counts. However, with a properly designed unidirectional-airflow primary engineering control, you know what control points (proper velocity, unidirectional airflow, leak-free HEPA filter, good return locations) provided the ISO Class 5 conditions that were observed while you took the counts in dynamic operating conditions. If you know your control points and you prove that you will maintain class when those control points are maintained, you should have confidence that you will maintain class reliably between tests. The same is true for the room itself: If you know that your control points (adequate ACPH of HEPA-filtered air) provided ISO Class 7 when the test was performed, you will likely maintain ISO Class 7 between tests. Continuous monitoring is the best solution but it is often outside the realm of possibility for most compounding operations.

How can isolators be advocated for use with hazardous drugs when little third-party validation of this equipment has been performed? At least BSCs have third-party review through NSF.

The adoption of containment isolators as an acceptable primary control for protection against hazardous drug exposures was based upon a number of factors, including their similarity of design with respect to Class III BSCs, the use of similar protective concepts within the pharmaceutical manufacturing industry, a small number of research studies favorably reporting their use for hospital pharmaceutical compounding, and the announced intention to reference the use of isolators in USP <797> as an alternative primary engineering control for CSP compounding. Admittedly, the big risk with this reference is a lack of industrywide performance and testing standards for pharmacy compounding isolators. Unlike Class II BSCs, isolators do not have the advantage of an independent industry organization setting the standards, testing the designs, and setting criteria for field certification. There are many different isolator designs and not all of them perform the same. This lack of testing standards can result in a potentially dangerous situation in which consumers are limited in their ability to compare and select such equipment, thus becoming potentially vulnerable to selective performance claims unverified by independent testing organizations. Until performance and testing standards are adopted, consumers are encouraged to insist that their new isolator, as a procurement requirement, meet the test and performance criteria in CETA’s application guide CAG-002-2006. Hopefully, manufacturers will begin to voluntarily and uniformly adopt this or a similarly rigorous and comprehensive test and performance protocol.

Should we wait to renovate our pharmacy until the new regulations are finalized?

That is a decision each facility must make based on the needs of their operation.

CleanRooms would like to thank the experts who served on the Webcast panel: Jim Wagner, president of Controlled Environment Consulting; Eric Kastango, president and CEO of Clinical IQ; and Kenneth R. Mead, MS, PE, research mechanical engineer at the Centers for Disease Control and Prevention. Please visit www.cleanrooms.com for information on the next CleanRooms Webcast, as well as access to The plain truth about USP <797> in its entirety.


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