Participants’ remaining questions are answered

The CleanRooms Webcast, USP 797-Facts and Fallacies, which originally aired on October 18, 2006, focused on USP 797 and raised a number of questions-so many, in fact, that several went unanswered due to time constraints. However, the panel that lead the Webcast has since reviewed the remaining questions and formulated answers based on the panel members’ familiarity with both the current and proposed changes to USP 797.

The answers provided by the panel are based on sterile product experiences in areas such as pharmacy, engineering controls and quality assurance. In some cases, the experiences of panel members resulted in differing viewpoints, which are reflected in the answers here.

In a hospital setting, how can you plan for a cleanroom if the standards keep changing?

The USP process for developing standards is one of continued change. Each year, the general chapters are open to comments and proposed changes. The chapter’s Expert Committee reviews the proposed changes and determines whether a change is warranted. This process makes it difficult for fixed facilities required to meet the standard to plan and implement changes.

The January 2004 USP 797, which is the current standard, specifies an ISO Class 8 cleanroom, though it does not specify under what conditions the air quality standard is to be met. ISO offers three choices: at rest, as built or in operation. ISO 14644-1-Part 1 defines the classifications of air cleanliness.

The proposed changes to the 2004 standard, published in 2006, upgrade the air quality to ISO Class 7 and specify that this is to be under operational conditions. It is important to remember that USP 797 is in effect today.

The pharmacy expert on our panel suggests the following approach given the uncertainty of the proposed changes. To optimize planning in a hospital setting, form a committee of stakeholders, including the infection control officer, the chief engineer, the pharmacy director and IV admixture supervisor, as well as representatives from administration, risk management and finance. This group should work together to develop a strategic plan for the cleanroom.

What is the name of the group being discussed?

The panel was discussing the U.K. (United Kingdom) Pharmaceutical Isolator Group. At the CleanRooms Boston 2006 conference last March, Brian Metcalf, a member of the group, gave a presentation on USP 797 that examined the use of isolators in hospital pharmacy in the U.K.

Why does ASHP resist regulatory or implied regulatory control of CSPs under USP 797 by saying that “persons who compound sterile preparations should exercise their professional judgment to obtain the education and training necessary to prove their competence in managing sterile compounding facilities and in sterile compounding process and quality assurance”?

In 1993, the American Society of HealthSystem Pharmacists (ASHP) was among the first to adopt professional standards for compounding sterile preparations. Since 2004, ASHP has developed many printed, electronic, online and educational program resources that explain and support USP Chapter <797>. I believe what ASHP means is that each pharmacy must examine its strengths and weaknesses in sterile compounding and train its personnel to the competence level needed in the institution.

There were two questions concerning gowning:

Does proposed USP Chapter <797> affect gowning requirements for cleanrooms? Are their any significant changes to aseptic gowning and facewear requirements?

Gowning is an essential element for product protection in a cleanroom environment. The gown and supporting items, such as head and foot coverings, act as barriers to prevent personnel shedding particulate while working in the cleanroom. Proper gowning attire and gowning sequence are critical to minimizing contamination levels.

The proposed 2006 changes to USP 797 describe the sequence for gowning. Personnel must don garb in the following order: dedicated shoes or shoe covers, head and facial hair covers, and facemasks. Eye shields are optional unless working with irritants like germicidal disinfecting agents. After this garb, personnel must clean their nails and wash their hands and arms as described in the chapter, then they must dry hands with lint-free, disposable towels or an electric hand dryer. After hands are dry, personnel must don a non-shedding gown. Once inside the buffer room, prior to donning sterile, powder-free gloves, personnel must clean their hands with an alcohol-based surgical hand scrub per manufacturer’s recommendations.

Do you foresee quantitative microbial sampling in isolators to ensure the prevention of cross-contamination in these hoods?

Microbial sampling for all ISO Class 5 environments is critical. It is important to realize that, unlike manufacturing processes, aseptic compounding environments and the outside of components are not sterile. Two articles published in AJHP have shown that contamination rates during media fill tested far above acceptable limits. In one article, a rate of 5.2 percent was reported for medium-risk conditions. The second article noted little difference between media fills in a cleanroom and those conducted in a traditional practice site. The studies point to touch contamination as the likely source for the high failure rate.

The proposed 2006 revisions to USP Chapter <797> require quantitative air and fingertip microbial sampling and recommend surface microbial sampling. The purpose is to quality control the environment inside the isolator in order to minimize the chances of contaminating preparations during compounding.

There were four questions concerning beyond use dates (BUD) for multidose vials (MDV):

What is the agreed upon expiration date we should use on commercial multidose vials? Does the 28-day BUD need to be adhered to for all MDV? Regarding MDV expirations of 28 days, what is the recommendation for insulin? There are conflicting opinions on MDV expirations once opened; please comment.

USP Chapter <51>, Antimicrobial Effectiveness Testing, requires that commercial sterile multidose product manufacturers not perform sterility and stability testing beyond 28 days after the vial has been punctured with a needle. USP chapters, such as Chapter <797>, must remain consistent with other USP chapters. Manufacturers do have the option, however, of testing their products’ sterility and stability beyond 28 days. If their FDA-approved labeling specifies a BUD longer than 28 days, you may adhere to the manufacturer’s labeling and use the longer date. Adhering to the 28-day BUD means that some expensive multidose drugs, like insulin, will be wasted.

With regard to disinfectant efficacy and wet contact times, are pharmacies relying on the disinfectant manufacturer’s EPA-registered label claims or are they validating them internally?

USP Chapter <797> only mentions one disinfectant, 70 percent isopropyl alcohol. Rather than perform their own efficacy and wet contact time testing, most pharmacists rely on labeled disinfectant manufacturer claims.

Will ultraviolet cabinets remain an acceptable method for sterilizing goggles?

USP 797 (current or proposed) does not discuss methods for sterilizing goggles or eye shields.

What furniture is allowed in the cleanroom (i.e., buffer room) and how much storage is allowed in this space?

Both the current and proposed USP 797 address fixtures and support materials in the cleanroom (i.e., buffer room). According to the chapter: “Only the furniture, equipment, supplies, and other material required for the compounding activities to be performed should be brought into the room. The fixtures should be nonpermeable, nonshedding, cleanable, and resistant to disinfectants.”

Items that are brought into the room should first be cleaned and disinfected. Storage space in the buffer room is limited to working components and supplies needed for compounding. No long-term storage is permitted in the cleanroom.

Regarding preparing medications on a nursing unit, must administration begin within 1 hour of preparation and then administration be no longer than 12 hours? Will this be the standard?

The official 2004 USP 797 does not address immediate use. Although interim communications from USP have mentioned an administration period of no longer than 12 hours, the published proposed changes for 2006 do not. This is because USP 797 is not intended to govern drug administration, only sterile drug preparation and storage before medication administration begins.

Currently there do not appear to be uniform testing standards for compounding isolators. How is the consumer supposed to select one product over another without relying totally upon manufacturers’ own promotional literature and statements?

The question seems to have two parts. First, regarding testing standards, USP 797 requires ISO Class 5 conditions for isolators and other primary engineering controls. ISO has published a series of relevant documents (ISO 14644-1 through ISO 14644-7): ISO 14644-1 defines classifications of air cleanliness; ISO 14644-2 describes specifications for testing and monitoring to prove continued compliance with ISO 14644-1; ISO 14644-3 provides test methods; ISO 14644-7 covers separative devices (clean air hoods, gloveboxes, isolators and minienvironments).

ISO is the worldwide federation of national standards bodies. The work of preparing international standards is normally carried out through ISO technical committees. These standards are internationally recognized and represent the thinking of experts in the field. Referencing the ISO standard (e.g., ISO 14644-1) would seem to indicate testing to meet this standard. Manufacturers should use the ISO 14644 series for testing of the isolators used in pharmacy compounding.

The proposed 2006 changes to USP 797 include a reference to the Controlled Environment Testing Association’s (CETA) recently published guidelines for testing sterile compounding isolators. Susan deMars, Chief Legal Officer for USP, has indicated that the proposed language does not specifically require the use of the CETA testing guide, rather it simply lists the guide as an example of a suitable certification procedure. She further cautions that the language in the proposed revisions is still under review by USP. She also points out that USP produces public standards and has no authority to establish law or regulations.

Regarding the second part of the question, manufacturers should be able to provide user references as well as studies of their equipment. Check out the company history and the individuals representing the company. Product testing should always be conducted to the USP standard, which in the case of pharmacy isolators is ISO Class 5 air cleanliness.

The pharmacy community has a variety of communication forums, and information about products that do not meet expectations soon becomes common knowledge.

Allergists state that they adhere to the Practice Parameters for the expiration dates for allergen dilutions and that nothing can grow in the allergy extract because of the high phenol content. What is your recommendation for the preparation of allergens given the above facts?

Technically, the preparation of allergenic extracts and dilutions is covered by the standards set in USP Chapter <797>. It is good compounding practice to assure that these products meet their purported characteristics of sterility, purity, accuracy of strengths, and non-pyrogenicity. This means purchasing allergenic extracts from FDA-approved manufacturers when possible or, if such extracts are not available, having a pharmacy compound the extracts using USP Chapter <797> standards.

The manufacturers should provide written documentation concerning their sterility claims.

CleanRooms would like to thank the experts who served on the Webcast panel: Jack Lysfjord, vice president of consulting for Valicare; Russell E. Madsen, president of The Williamsburg Group, LLC; and E. Clyde Buchanan, M.S., FASHP, pharmacy consultant, private practice. Please visit www.cleanrooms.com for information on the next CleanRooms Webcast, as well as access to USP 797-Facts and Fallacies in its entirety.