Clinical Microbiology Newsletter

Vol. 30, No. 14

$88
July 15, 2008

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USP Chapter 797 and Environmental Monitoring

Eric S. Kastango, MBA, RPh, FASHP, Clinical IQ, Florham Park, New Jersey

Abstract
Over the last 10 years, there has been increasing morbidity and mortality resulting from infections caused by intravenous or intrathecal preparations sterilely compounded in hospitals or freestanding pharmacies. Although individual state boards of pharmacy have oversight of these activities, prior to 2004 there were no universal guidelines to ensure that all compounded products were aseptically prepared. That year, the United States Pharmacopeia (USP) developed such guidelines, which resulted in an outcry from pharmacists across the country. Over 500 comments were submitted to the USP. Three years later, the guidelines are about to take effect, and all the comments have been addressed. In light of the continuing number of deaths from contaminated preparations, the infection control implications are huge for all patients who receive these products. Do not be surprised if you are asked to support pharmacy environmental monitoring programs in your hospital in the near future.

Editors Note
I asked Eric Kastango to write the following paper to give microbiologists, hospital epidemiologists, and infection control practitioners a chance to understand how the regulations for environmental monitoring in pharmacies were developed and how the committees of The American Society for Microbiologys Public and Scientific Affairs Board, specifically the Professional Affairs Committee, play key roles in advising individuals across the spectrum of health care about issues that involve the practice of microbiology. Alice S. Weissfeld, PhD, D(ABMM), F(AAM) Editor

Background
The preparation of drug products to fill prescriptions for specific patients is considered pharmaceutical compounding. There are two types of compounded
Mailing Address: Eric S. Kastango, MBA, RPh, FASHP, Clinical IQ, 184 Columbia Turnpike, #282, Florham Park, NJ 07932. Tel.: 973-765-9393. Fax: 973-966-8720. Email: ekastango@clinicalIQ.com

sterile preparations, i.e., extemporaneous ones that are compounded for a single patient and batch preparations that are compounded for multiple patients in anticipation that physician orders will be forthcoming. In January 2004, the United States Pharmacopeia (USP) published a chapter dealing with the requirements for pharmaceutical compounding. This chapter has since been known by its chapter number, i.e., 797 (1). The USP was first recognized as the official compendium of drug standards in the United States in 1938 under the Federal Food, Drug and Cosmetic Act. Chapters 1 to 999 are considered official monographs enforceable by the FDA. However, the requirements in chapter 797 have been slow to be implemented. Although there have been multiple incidences of morbidity and mortality following improper compounding of sterile preparations (2-8), the FDA, the Centers for Disease Control and Prevention (CDC) and the 50 individual state boards of pharmacy have been active in investigations only after the fact. Furthermore, only 19 states have incorporated 797 into their state board
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of pharmacy regulations and actually inspect for compliance with the chapter. One of the more controversial sections of chapter 797 is the section on environmental monitoring. The CDC, the Society for Healthcare Epidemiology of America (SHEA), and the Association for Professionals in Infection Control and Epidemiology (APIC) do not believe that routine environmental surveillance in hospitals is warranted. They also point to the fact that there is no literature that shows that such a program for bioaerosol sampling affects patient safety. Anecdotal evidence suggests otherwise, and in fact, environmental monitoring is the cornerstone of

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quality systems employed by pharmaceutical manufacturers. The FDA is adamant that this program should be in place, and because of the high visibility of patient injury and death associated with compounded sterile preparations, Senator Edward Kennedy (D-Massachusetts) has introduced a bill in Congress known as the Safe Drug Compounding Act of 2007 that would give the FDA regulatory oversight of pharmacy compounding and limit compounding of sterile preparations in hospitals and other venues (e.g., freestanding retail pharmacies, home infusion pharmacies, and physician office pharmacies).

Appointment to the USP Expert Panel

Routine air and surface sampling had been a staple of my quality control motto since 1985, when I was compounding large volumes of parenteral nutrition products from nonsterile ingredients (high-risk-level compounding). In hindsight, however, I realize today that I was performing a series of rote activities (very well, I might add) with little understanding of the utility of the information. Company policies dictated what needed to be done, i.e., collect, count, and document the CFU. If counts exceeded alert or action levels, there was a defined remediation plan that needed to be executed. In all of the aseptic compounding pharmacies I had been responsible for, we never once identified the genus or species of the microorganisms that were recovered from culture. We did not have access to microbiologists, industrial hygienists, or infection control professionals. I have authored a number of articles extolling the virtue and necessity of environmental monitoring. My mantra was as follows: It is important to monitor the microbial bioburden of controlled

work areas by monitoring air and surface samples. The total amount of airborne particles (viable and nonviable) under static conditions should be determined twice a year during routine hood and cleanroom certification. This is referred to as a room particle count. Routine ongoing environmental monitoring involves establishing baseline data for the microbial bioburden of the controlled work areas. Air and surface sampling involve collecting environmental snapshots on tryptic soy broth (TSB)/agar (TSA) plates that support the growth of many types of microorganisms. Air sampling is accomplished by placing air settling plates at various locations throughout the controlled environment according to the types of activities performed or the number of personnel and extent of product movement in the area. (9) Unbeknownst to me, this particular article, which I co-authored in 2001 (long before USP chapter 797 was published in 2004) would bring me together with Keith St. John and Alice Weissfeld in 2005. During one of my first meetings as a member of the 2005 to 2010 USP Sterile Compounding Committee (SCC) in July 2005, I had the chance to sit next to Keith and we spoke about environmental monitoring. In particular, we spoke about ASMs position on this subject and the leadership of Alice Weissfeld in writing ASMs position on the USP chapter on environmental monitoring. This statement included a description of gravimetric versus volumetric sampling (not active or passive sampling, as I called it then) and the process for establishing the action and alert levels or limits. Although I did not realize it at

the time, my understanding of environmental monitoring and all of my published support of settling plates and other aspects of environmental monitoring were about to fundamentally change.

Reaction to Chapter 797

When USP chapter 797 was published in January 2004, the only environmental monitoring that was required was monthly air sampling for low and medium risk levels and weekly air sampling for high-risk compounding. Risk levels were defined in the original document. The chapter did not specify the collection method, so settling plates, paddles, and other methods were not prohibited. On 1 May, 2006, USP initiated the public review process for General Chapter Pharmaceutical CompoundingSterile Preparations 797, inviting the public to comment on sweeping proposed changes to this first enforceable sterile-compounding practice standard. Almost immediately, the proposed revisions precipitated a significant response from dozens of professional organizations including ASM, FDA, CDC, APIC, and the American Society for Healthcare Engineering (ASHE). In an effort to address the submitted responses, Roger Williams, USP Executive Vice-President and CEO, sponsored an invitation-only Compounding Stakeholder Forum in June 2006. One outcome of this meeting was the creation of two ad hoc advisory panels, one tasked with addressing radiopharmaceuticals and the other with environmental monitoring, cleaning, and disinfection. The radiopharmaceutical ad hoc advisory panel worked to address the outstanding issues and submitted consensus recommendations to the SCC for consideration. The SCC reviewed the recommendations of the panel and

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voted to accept the modified language without change.

Environmental Ad hoc Advisory Panel

The ad hoc advisory panel tasked with addressing the other two sections of USP chapter 797 set to work reviewing the language in the proposed revision and submitted consensus recommendations to the SCC for consideration. This ad hoc advisory panel was chaired by Keith St. John, who assembled a group of recognized experts in microbiology, infection control, disinfection, public health, and pharmacy. The controversial parts of the proposed environmental-monitoring section included replacing the use of settling plates with electronic impaction air samplers when performing viable air sampling. The advisory panel also recommended the elimination of surface and glove fingertip sampling. The recommendations of the environmental ad hoc advisory panel were submitted to the SCC in May 2007. The consensus recommendation for the cleaning and disinfection section was reviewed by the SCC and, with very minor modifications, we voted to accept it. The consensus recommendation for the environmental-monitoring section from the ad hoc advisory panel was significantly different than the proposed revisions published in May 2006 and the standards followed by many of the SCC members and the FDA. It resulted in lively discussions among committee members. However, the final chapter was accepted in late November 2007 and published on the USP website the first week of December (10). The FDA was extremely unhappy with the outcome. Environmental monitoring is approached very differently by the two governmental organizations that provided comment to the SCC, i.e., the CDC and the FDA. The FDA requires pharmaceutical manufacturers to have a comprehensive environmental-monitoring plan that involves daily sampling of air, surfaces, and personnel. Within the FDAs 2004 aseptic processing guidelines (11) are published recommended action levels of microbiological quality, and these action levels were used to model those written into the chapters proposed revision of May 2006. The
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CDC, however, was diametrically opposed to the FDAs position and the proposed revisions drafted by the SCC. Unbeknownst to the SCC, prior to 1970, hospitals were performing routine microbiologic sampling of the environment as described in the proposed revisions of USP chapter 797. In the 1970s, the CDC began to advocate the discontinuation of this practice, because there was no association between infection rates and levels of environmental contamination and because there were no standards for permissible levels of environmental microbial contamination. The issue of routine microbiologic sampling of the environment in health care facilities is specifically addressed in the evidencebased document Guideline for Environmental Infection Control in Healthcare Facilities, 2003 (12). The CDC pointed out that the proposed requirements for routine environmental sampling in chapter 797 would create a double standard in all health care facilities where sterile preparations are compounded. The CDC environmental guidelines specifically recommend against this practice in all practice settings within the hospital and would likely create confusion and resistance in health care facilities. The SCC used the standards followed by pharmaceutical manufacturers and enforced by the FDA as its basis for the proposed revisions. The SCC believed that sterile compounding was more like the aseptic processing done by pharmaceutical manufacturers, and all of the legacy documents used to create USP chapter 797 were based on current good manufacturing practices. However, when pharmacists started requesting assistance from hospital infection control professionals and clinical microbiologists to start environmental air and surface testing, there was a great deal of resistance. Until now, the basis for this resistance was misunderstood and frustrated many pharmacists, pharmacy technicians, and directors of pharmacy. In trying to reconcile the differences between the environmental-monitoring recommendations of the ad hoc advisory panel and the CDC and those of the FDA, the SCC had to answer some fundamental questions. Was there value in requiring environmental monitoring? If so, what was the rationale for requiring it? If there was a basis for requiring
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environmental monitoring, what type of monitoring would be required and how often would it be required? Would alert or action levels be established? If yes, what would those levels be and how would those values be determined?

Final Document
All of these questions and others would be answered when USP published the final version of chapter 797, which is currently posted on the USP website (http://www.usp.org). What can be said is that the SCC believed that environmental monitoring was an important quality assurance procedure required of all compounders (pharmacists, technicians, nurses, physicians, and others) but it had to be tied to activities that posed the greatest risk of contamination to the compounded sterile preparation, such as hand hygiene, garbing and gloving, cleaning, and aseptic compounding procedures. The frequency of environmental monitoring, and sampling, as well as the methods and materials used to collect the samples, had to be consistent with the recommendations of ASM and the CDC. There was less concern about routinely sampling the compounding environment because it is required that primary engineering controls (laminar airflow workbenches and biological safety cabinets or isolators) which provide unidirectional airflow be used for all compounding activities except in emergencies and that the buffer (ISO class 7) and ante area (ISO class 8) are designed and built to meet the architectural and performance criteria stipulated in the chapter. These environments are routinely monitored, cleaned, and tested semi-annually in accordance with the Controlled Environment Testing Association Guidance (CAG-003-2006). Since the start of the 2005-to-2010 term of the SCC, 30 months have elapsed and over 1,000 pages of comments from 500 contributors have been received and reviewed, producing a revised USP chapter 797 that has integrated evidence-based science and best practices from a myriad of expert organizations. It will be a standard of practice that can be embraced by all compounders and enforced by state boards of pharmacy having the expressed goal of ensuring patient and compounder safety.
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References 1. U.S. Pharmacopeial Convention. 2004. Pharmaceutical compounding: sterile preparations, p. 2461-2477. In U.S. pharmacopeia 27 national formulary 22. U.S. Pharmacopeial Convention, Rockville, MD. 2. Myers, C.E. 1996. Needed: serious attention to sterile products. Am. J. Health Syst. Pharm. 53:2582. 3. Patel, R. et al. 2006. Hepatitis C virus infections from a contaminated radiopharmaceutical used in myocardial perfusion studies. JAMA 296:2005-2011. 4. Civens, R. et al. 2005. Outbreak of Serratia marcescens infection following injections of betamethasone compounded at a community pharmacy. Clin. Infect. Dis. 43:831-837.

5. Mattner, F. and P. Gastmeier. 2004. Bacterial contamination of multiple-dose vials: a prevalence study. Am. J. Infect. Control 32:12-16. 6. Centers for Disease Control and Prevention. 2002. Guidelines for the prevention of intravascular catheter-related infections. MMWR Recomm. Rep. 51(RR-10):1-32. 7. Centers for Disease Control and Prevention. 2002. Exophiala infection from contaminated injectable steroids prepared by a compounding pharmacy. MMWR Morb. Mortal. Wkly. Rep. 51:1109-1112. 8. Centers for Disease Control and Prevention. 2005. Pseudomonas bloodstream infections associated with a heparin/saline flushMissouri, New

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York, Texas, and Michigan, 2004-2005. MMWR Morb. Mortal. Wkly Rep. 54:269-272. Kastango, E.S. and K. Douglass. 2001. Quality assurance for sterile products. Int. J. Pharm. Compd. 5:246-253. U.S. Pharmacopeial Convention. 2007. Revision bulletin, December 2007. Chapter 797 pharmaceutical compounding sterile preparations. http://www.usp.org/pdf/EN/USPNF/ generalchapter797.pdf. U.S. Food and Drug Administration. 2004. Guideline on sterile drug products produced by aseptic processing. FDA, Rockville, MD. http://www.fda.gov/ Cder/guidance/5882fnl.pdf. CDC website. http://www.cdc.gov/ ncidod/dhqp/gl_environinfection.html.

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