November 8, 2005 - ASM Comments on U.S. Pharmacopeia (USP), Proposed Changes to Chapter

Dr. Claudia Okeke
US Pharmacopeia
12601 Twinbrook Parkway
Rockville, MD 20852-1790

Dear Dr. Okeke:

The American Society for Microbiology (ASM) appreciates the opportunity to comment on the proposed 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 more than 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 such as those listed in this Chapter. Overall, we commend the USP for implementing the quality assurance program outlined in . However, there are some areas, particularly regarding microbiological and aseptic technique practices, that we feel need clarification or harmonization with other USP guidelines; these are outlined below:

1. Environmental monitoring (Page 18):

ASM agrees that microbial monitoring of the clean rooms, anterooms, laminar flow hoods (LFHs) and biological safety cabinets (BSCs) is warranted. However, ASM does not believe that a trending analysis over time to identify increasing numbers above baseline can be adequately determined using settling plates. In 1999, the American Conference of Governmental Industrial Hygienists published a book entitled “Bioaerosols: Assessment and Control.” In it they state that gravity samples, i.e., settling plates, are not suitable substitutes for volumetric air samples, i.e., impaction using electric air samplers. Further, they note that settling plates should not be used even to determine the relative air concentrations of different microorganisms because of the method’s collection bias. In fact, in USP Chapter , the same admonishment is made regarding the limitations of settling plates and the superiority of electric air samplers relying on impaction. Thus, there appears to be a contradiction; ASM believes that the more stringent recommendation in for sampling in anterooms, clean rooms, LFHs and BSCs should also be required in USP . This is the only way that accurate comparisons or trending can be done since pharmacies will collect the same volume of air (the same flow rate for the same amount of time) each time sampling is performed. Further, although an increasing trend is defined as 50% above the baseline, we suggest that the USP add specified individual action limits as outlined in the article, “Quality Assurance for Sterile Products” published in the International Journal of Pharmaceutical Compounding, Vo. 5 No 4 July/August 2001. One of the most confusing components of implementing the environmental monitoring process is the lack of clear guidance on tolerance ranges. Unfortunately, vendors to the pharmaceutical industry are already selling settling plates that contain inappropriate media for the detection of both bacteria and fungi as well as limited surface area and limited capacity for accurate results. Until scientific side-by-side analysis with these devices is performed, ASM believes that environmental air sampling should only be done by electric air samplers (impaction) and using media that is already standard in the bioaerosol testing community for the recovery of both significant bacteria and fungi.

2. Environmental monitoring (Page 19):

ASM does not agree with doing bioburden testing on hood surfaces or gloves. In fact, the Centers for Disease Control and Prevention (CDC) eliminated surface testing in hospitals more than 30 years ago, and there are no requirements for such routine testing in current guidelines for healthcare institutions (See Guidelines for Environment Infection Control in Health-Care Facilities, MMWR 52(RR10), June 2003). In fact, no correlation between routine surface sampling and improved patient outcome (i.e., morbidity or mortality) has been demonstrated. However, if the purpose is to demonstrate individual instances in which compounding personnel may contaminate surfaces and glove fingertips, ASM suggests performing this testing once at the time of the media-fill competency to demonstrate any problems with sterile technique an individual compounding technician or pharmacist may have.

3. Sterility testing (Page 21):

ASM recommends that this section be more robust. An individual unfamiliar with USP will not realize that there are actually at least 3 different tests that may be necessary based on volume of the product and whether the product is an antimicrobial with a beta-lactam ring. A testing laboratory might simply add 1 ml of product to the tryptic soy broth (TSB) and thioglycollate broth (thio) in any circumstance. However, as shown in Table 1/Chapter , the processing of CSPs is dependent on the volume of the product, where larger volumes must be processed by membrane filtration. Further, it would be unlikely that any testing lab not intimately familiar with the USP monographs would know that penicillins and cephalosporins must be neutralized using their respective beta-lactamases prior to sterility testing. Additionally, ASM stands ready to assist in suggesting other, more rapid methods currently available for microbiological blood culture technology. This could allow real time detection of contaminated CSPs.

4. Bacterial endotoxin (pyrogen) testing (Page 21):

It is ASM’s opinion that most testing labs called upon to perform endotoxin testing are unfamiliar with USP Chapter , which describes the use of specific USP monographs for individual drugs to determine the permissible level of endotoxin units (EUs)/ml in CSPs. It is our belief that this section would benefit from an example using a product such as morphine or heparin lock flush solution so that the appropriate testing decisions are made. Unfortunately, vendors currently selling to the pharmaceutical industry are providing a one tube endotoxin assay that is not FDA–cleared for pharmaceuticals and is intended for use in the hemodialysis industry. This section would be strengthened by adding information on how to perform and interpret the test correctly including how to determine the sensitivity of the pyrotell needed in individual assays. Additional information is critical to adequately demonstrate how laboratories should assist compounding pharmacies in testing CSPs for endotoxin.

5. Examples of media-fill test procedures for low- medium- and high-risk compounded sterile products (CSPs) (Pages 5-6):

The statement that each person should be tested “under conditions that closely simulate the most challenging or stressful conditions encountered during compounding” appears to indicate that all testing should be performed in empty, sterile clear vials; indeed, ASM agrees that this is the most rigorous test. However, vendors selling to the pharmaceutical industry are using transfers in IV bags, which is clearly not as robust as the USP intended. Therefore, if the USP intent is to simulate the most challenging or stressful conditions, ASM recommends the USP specify sterile vials and give no other option.

6. Garbing of personnel (Page 16):

As currently written, personnel are donning their tight-fitting gowns, coats etc., prior to scrubbing their hands and arms. Shouldn’t the order be reversed?

7. High-risk media-fill test procedure (Page 7):

ASM questions the reason for changing the incubation temperature from 25°C-35°C to 20°C-25°C. Does the USP subcommittee believe that 20°C-25°C is more realistic because fungi are more likely contaminants than bacteria or, is the USP simply looking for psychrophilic bacteria? It is our experience and opinion that a range of 32°C ± 2°C covers a broader spectrum of potential contaminants and pathogens.

8. Finally, ASM recommends adding °F or °C as appropriate when specific temperatures are listed throughout the text.

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


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