Proposed changes to USP 797: Where is the good science?
08/01/2006
By Hank Rahe, Containment Technologies Group
In early May 2006, USP published the proposed changes to General Chapter <797>: Pharmaceutical Compounding-Sterile Preparation. Because the original chapter contained a number of errors and points needing clarification, the proposed changes have been long awaited.
However, the proposed changes to the chapter, instead of bringing clarification and an improved focus on the intended purpose of patient safety, have fallen far short of the mark. The areas needing the most improvement-such as definitions, meaningful references, expanded information on disinfection, and less prescriptive facility design and engineering controls-are notably missing. To add to the confusion and frustration, the proposed revisions include a section on hazardous drugs, which has nothing to do with patient safety.
In this article, I will explore each of the deficient areas, identifying the shortcomings and suggesting ideas that the expert committee that created the recommendation should consider as USP <797> moves forward.
Definitions
The proposed revisions do add several definitions that cause concern about the intent of the document. For example, the definition of disinfection seems to exclude spores that have been identified as the cause of death of patients infected by nonsterile compounded products. The intent of this is not certain but would seem to support the continued use of nonsterile alcohol, which is prevalently mentioned in the proposed changes.
Other definitions seem out of place in a chapter in a document intended to support the safe compounding of sterile products. The definition of airlock, for example, references a nonaseptic laboratory rather than FDA guidance associated with aseptic manipulation of sterile products.
Perhaps most out of place is the inclusion of the definition of a negative pressure room, when the concept of a negative pressure area within aseptic facilities is inconsistent with the basics of contamination control for sterile products-and most of all patient safety.
References
Turning to the references provided throughout the document, I found more confusion and questions as to the intent of a document that should improve the sterility assurance of compounded sterile products.
References for negative pressure rooms include a CDC guide called CDC Guidelines for Environmental Infection Control in Healthcare Facilities - 2003 that, on closer inspection, gives references to intended usage for an examination room or morgue room-nothing to do with compounding sterile products. When asked at a recent meeting about the intent of the negative pressure room, an expert committee member indicated it was “in case of a spill.” Even in the case of a spill, a negative pressure room would not protect the individual working in the area and would likely do little to prevent the spread of contamination. It would seem a spill control kit would cost much less than the thousands of dollars a negative pressure room would add to the already taxed budgets of healthcare facilities.
Another surprise is the reference to the Controlled Environment Testing Association (CETA) as the source of definitions and testing standards, rather than simply using ISO standards. A look at the referenced CETA documents raises some questions: If these standards were required, how much would the cost of testing increase, and would the testing place prescriptive limitations on improved aseptic compounding technology?
Intent of the chapter
The intent of the chapter is clearly stated as protection of patient safety and is only focused on preparation, not administration. Yet the proposed revisions clearly contain cost-increasing requirements in the area of administration. One has to question again the intent of violating the stated bounds of the chapter. Of the over twenty individuals involved in the preparation of compounded sterile products with whom I have spoken concerning the proposed changes to the chapter, a couple of quotes stand out. First, “USP needs to ban consultants and special interests from the compounded sterile products committee.” Another, “The proposed revisions to the chapter sound like a Washington spending bill, full of pork and special interest.”
Immediate use
I was heartened to see the inclusion of an “Immediate Use” exemption in the proposed revisions to the chapter. This is extremely necessary in order to deal with the practical requirements of responding to patients in immediate need of treatment. The glow of hope that there may be some salvation in the proposed changes is dimmed, however, by the addition of a hazardous drug exclusion from this exemption. The truth is, some of the drugs that need to be compounded for immediate use are on the NIOSH hazardous drug list, which is cited as the guide to what can be compounded under this exemption. If the NIOSH list is kept as the official guide in this document, individuals will once again find themselves outside the regulation.
Hazardous drugs
The inclusion of hazardous drugs in the proposed changes is the most perplexing detail. Not only are the proposed changes in many cases in direct conflict with accepted facility practices for aseptic manipulations of sterile products, but go far beyond the NIOSH hazardous drug recommendation. The capital cost and engineering challenges that adopting the proposed changes would bring could easily cost healthcare facilities millions of dollars. The changes would also increase the potential for contamination during compounding while not improving the protection of the healthcare workers involved in the compounding. Who benefits? Companies marketing the proposed required device would stand to increase sales by over one hundred million dollars.
Facility design and environmental controls
This key section for control of contamination provides some insight into the committee’s mindset. The committee comprises primarily pharmacists, but in more recent times has expanded to include other professions. One major missing link, however, is engineering expertise in facilities and environment control design and implementation. As a result, sections addressing the proper primary ISO Class 5 environments lack continuity and contain a number of prescriptive “how-to” requirements. The proposed changes call for dynamic testing, which is a good step-except that the physical act of compounding even a low-risk product generates more than ISO Class 5 particles.
Another example is the surrounding environments the proposed changes identify for isolators. In one section, isolators are not required to be in a controlled cleanroom environment if it meets certain conditions. But in other locations in the document, isolators are required to be in either an ISO Class 8 clean space, an ISO Class 7 cleanroom, or be used in conjunction with a device that adds nothing to either aseptic quality or personnel protection if used in an isolator. It would seem, based on pharmaceutical experience, that if the isolator can be validated to meet ISO Class 5 requirements and containment expectations are met, the isolator can be placed in a conditioned environment as first indicated in the 2004 chapter. The many different conditions are either justified or can be supported by good science.
Another example is the prescriptive requirement for the number of air changes in the cleanroom. It seems a cookie-cutter approach has been taken without consideration of the layout or load created by personnel working in the cleanroom. Both of these factors support the contention that qualified engineering professionals familiar with cleanroom design should have been involved with the document.
Cleaning and disinfection
The concept of minimization of micro-organisms by proper disinfection is not emphasized in the proposed revisions to USP <797>. Disinfection is the cornerstone of aseptic preparation of sterile products, yet the committee seems to ignore FDA guidance. It seems the practice of using nonsterile alcohol is reinforced throughout the document. Alcohol is mentioned in over ten places in the proposed recommendation, with no recognition given to better, more effective agents.
Conclusion
If any of the observations or comments strike a note with the reader, please contact USP and offer your feedback on the proposed changes. Hopefully, by pointing out the lack of good science demonstrated in the proposed revisions to USP <797>, the organization will work with its committee to bring the situation back under control.
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Hank Rahe is director of technology for Containment Technologies Group and is a member of the CleanRooms Editorial Advisory Board. He can be contacted at [email protected].