August 15, 2006 - ASM Comments on USP Proposed Revisions to Chapter

USP Executive Secretariat
U.S. Pharmacopeia
12601 Twinbrook Parkway
Rockville, MD 20852-1790

RE: Comments

Dear USP Executive Secretariat:

The American Society for Microbiology (ASM) appreciates the opportunity to comment on the May 1, 2006 draft revisions to The United States Pharmacopeia (USP) Chapter . The ASM is the largest scientific society dedicated to the advancement of the microbiological sciences and their application for the common good. The Society represents approximately 42,000 individual members who work as researchers, educators, clinicians, administrators and technical personnel in academic, industry, government, clinical and public health laboratories and institutions. As such, our members are often asked to consult with or assist infection control, risk management and pharmacies in the implementation of their requirements for microbial monitoring such as those listed in this Chapter. The importance of this document in insuring safe patient care practices, as highlighted in the August 8, 2006 USA Today article, “Deaths spur debate about drugs made in pharmacies,” can not be underestimated. In fact, the Food and Drug Administration warnings issued on August 10 to three firms compounding large quantities of products for mass distribution serve to highlight the potential for extremely serious consequences should a contamination event occur.

We commend the USP for developing the quality assurance program outlined in and we thank the Sterile Compounding Expert Committee members for thoughtfully reviewing the previous ASM comments and incorporating many of them into the current revision. However, there are a few remaining areas that we feel could benefit from further clarification or harmonization with other guidelines. Our comments are based on the review of the May 1, 2006 draft document by an ad hoc committee of ASM members with particular interest and expertise in environmental microbiology in the healthcare environment. This group operated under the direction of Alice S. Weissfeld, Ph.D., previous chair and a current member of the Professional Affairs Committee who represented ASM at the recent USP Pharmacy Stakeholder’s meeting.

Based on the committee’s input, we offer the following additional comments:

1.  The ASM would like to suggest a harmonization of terminology so that the pharmacy community and the microbiology community clearly understand the methods described for air-sampling. We suggest that the Definitions Section include the following:

a. Volumetric air sampling should be used to define the use of an electronic air sampler.
b. Gravimetric air sampling should be used to define the previously recommended use of settling plates (which ASM does NOT recommend).
c. Active sampling should be used to define volumetric air sampling under conditions where a pharmacist or pharmacy tech is actively compounding (i.e. occupied space and activity occurring).
d. Passive sampling should be used to define volumetric air sampling under conditions where no compounding activities are occurring (i.e. unoccupied space with no activity occurring).

It is currently unclear to us whether active sampling means that a person is compounding or that someone is simply using a volumetric air sampler. Further, these standard definitions should be incorporated into the Environmental Monitoring Section to achieve the desired harmonization of terminology.

2.  The ASM continues to strongly disagree with the performance of any surface sampling, including glove fingertip samples. This is in accordance with the CDC Guidelines for Environmental Infection Control in Health-Care Facilities (MMWR Volume 2, Number RR-10, June 3, 2003) which discourages such testing unless conducted as part of an epidemiologic investigation or during assessment of hazardous conditions. Regarding glove fingertip cultures, it is unclear what information will be gained from culture of sterile gloves used in a LAFW. It is also unclear what information will be gained from culture of nonsterile gloves used by an individual in a compounding aseptic isolater (CAI). Further, it is markedly unclear why nonsterile CAI gloves would be repetitively used without specific instructions for decontamination prior to re-use. Similarly, if surfaces are decontaminated regularly as recommended, it is unclear what information will be gained from recommended surface testing. Rather, we reiterate our former suggestion that random sterility tests of compounded sterile products (CSPs) should be expanded to include low and medium risk products. In many cases, there are compounded products remaining that would be discarded anyway and could be used to meet compliance standards. At a minimum, a small portion of CSPs should be saved by storing at 4-8C for microbial testing in the event of a suspected CSP associated infection, an approach which is used for many blood banking products.

3.  The environmental monitoring plan should be an on-going monitoring system to confirm, by secondary methods, that the engineering controls and personal hygiene practices do not contribute to or cause any failed CSPs. It also allows the sterile compounding facililty to trend any “out-of-range” results, determine the cause of any upward fluctuations in viable airborne contaminants, and initiate immediate corrective action. However, the volume of air sampled and the type of volumetric air sampling equipment will determine baseline and action limits. Therefore, it needs to be emphasized that establishment of this baseline is method dependent. For example, the Andersen N-6 Sampler (Thermo Electron Corporation, East Greenbush, NY) pulls 28.3 lpm (liters per minute) of air which is equivalent to 1 ft3/min. The SKC Quick 30 (SKC Inc, Eighty Four, PA) pulls 30 1pm which is approximately the same as the Andersen N-6. However, the SAS (Bioscience International, Rockville, MD) can be set to pull either 500 or 1000 liters of air. Thus, 1 colony growing on a plate collected for 10 minutes using an Andersen N-6 or SKC Quick 30 represents 3.5 cfu (colony forming units)/m3 (cubic meter) of air whereas 1 colony growing on a plate set to collect 1,000L of air with the SAS represents 1 cfu/m3. Thus, if a pharmacy were using an Andersen or SKC sampler, any colony would represent a failure. However, in point of fact, ASM believes that laminar air flow workbenches (LAFWs), biological safety cabinets (BSCs), or CAIs should have their action limit set at 0 cfu/m3. In actual practice, if these primary engineering controls are functioning properly, it will be no problem to achieve 0 cfu/m3 of air.

4. The ASM also recommends clarification and differentiation of the use of the terms Clean Room and IV/Buffer Zone, particularly as they relate to action or baseline levels. Clean Rooms should have 0 cfu/m3 as well as positive pressure, HEPA filtration and laminar air flow if possible. It is our understanding that a buffer zone is an ISO Class 7 Room containing a CAI as its primary engineering control. IV/Buffer Zones could have low numbers of cfu/m3 while still maintaining 0 cfu/m3 in the CAI. If a CAI were placed in this environment, one runs the risk of bringing contamination from the IV/Buffer Zone into the chamber on non-sterile PPE or while changing filters. If, however, the CAI maintains positive pressure as required, risk should be minimal.

5. Use of appropriate PPE is a critical element of any infection control program. While PPE is mandated for use in preparing most CSPs, we are concerned that personnel preparing Immediate Use Compounding are not subject to a reasonable requirement for PPE use. At a minimum, personnel preparing IUCSPs should be required to wear sterile gloves. In addition, all personnel involved in CSP preparation should not be permitted to eat, drink, apply cosmetics, or smoke in the area in which the compounding is occurring.

The ASM also noted several issues of a more editorial nature that you might wish to consider for revision:

  1. Item 1 under High-risk level CSPs refers to “c” in the Introduction. Item “c” has been deleted and reassigned as item “1.” 
  2. For Immediate Use CSPs (IUCSP), it is recommended that labeling (item 5) be a standard required practice. In laboratory medicine, strict adherence to labeling requirements for specimens and reagents is a standard which we believe should be applied across the healthcare sector, including for IUCSP’s. 
  3. For Cleaning and Disinfecting the Sterile Compounding Areas, trained personnel have the responsibility “for developing and practicing written procedures for cleaning and disinfecting the DCCAs.” While IPA is subsequently referred to, it is desirable to more clearly delineate what constitutes appropriate cleaning and disinfecting procedures. The ASM does not consider IPA to be an effective stand-alone disinfectant. 
  4. The paragraph in the section, Sampling Plate Incubation Period, implies that both the TSA and MEA are to be inverted and incubated. In fact, fungal culture plates such as MEA are not inverted. 
  5. Table 4, Action Levels (Counts) of Microbial Colony-Forming Units (cfu) per Cubic Meter of Air or Contact Plate should be corrected to include appropriate denominators in the Table headings. It appears that Active Air levels are “per cubic meter,” glove fingertip levels are “per 10 fingertips,” and inanimate surfaces are “per surface area of 24 – 30 cm2.” 
  6. The last paragraph in the section, The Quality Assurance Program, says “for example, the trending of an indicator such as settling plate counts.” We believe this is probably an error as settling plates are no longer allowed in the environmental monitoring section and should read “such as volumetric air sample microbial counts.” 
  7. There are a number of additional USP Chapters referred to throughout the USP Chapter. An Appendix which lists these USP Chapters and cross-references them to the corresponding section of Chapter would assist those who prepare CSPs to comply with ALL standards and guidelines.

Finally, USP’s Executive Director asked Dr. Alice S. Weissfeld, who attended the recent USP Pharmacy Stakeholder’s Meeting as a representative for the ASM, to provide some references regarding past instances of patient morbidity or mortality resulting from non-sterile compounded products. Three such articles are attached to this letter:

Exophiala infection from contaminated injectable steroids prepared by a compounding pharmacy – United States, July – November 2002. MMWR Volume 51, Number 49, December 13, 2003 (http://www.cdc.gov/mmwr/PDF/wk/mm5149.pdf). 

  1. Pseudomonas bloodstream infections associated with a heparin/saline flush – Missouri, New York, Texas, Michigan. MMWR Volume 54, Number 11, March 25, 2005 (http://www.cdc.gov/mmwr/PDF/wk/mm5411.pdf).
  2. Perz, Craig, et al. 2005. Pseudomonas putida septicemia in a special care nursery due to contaminated flush solutions prepared in a hospital pharmacy. J Clinical Microbiology 43(10): 5316 – 5318.

Additional published documentation of such events can be provided on request.

Again, ASM appreciates the opportunity to comment on these most recent revisions and would be pleased to answer any questions you may have regarding these or our previous recommendations. We stand ready to assist the USP with any consultative services required.

Sincerely,

Vickie S. Baselski, Ph.D., Chair
Committee on Professional Affairs
Public and Scientific Affairs Board

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