USP Chapter <797> provides beyond-use date (BUD) limitations in the absence of passing a sterility test for each compounded sterile preparation (CSP) risk level (see Table 1); these limitations are based on the probability of contamination and bacterial growth rates under various storage conditions. While reasonable, the BUD limitations present operational challenges—especially when dealing with products such as pain medications and OR syringes that must be readily available in patient care areas.
To comply with the USP <797> BUD limits, some facilities opt to produce most of their CSPs on-demand, with limited dating for the remaining preparations. This has proven an effective model for many facilities; however, it can mean an increase in turnaround time or drug waste in situations where CSPs need to be readily available. Other hospitals choose to outsource the production of commonly used CSPs to achieve extended dating.
Our 1300-bed acute care facility needed to provide extended beyond-use dating for many pain management and OR preparations for distribution in our automated dispensing cabinets while complying with <797> requirements. As outsourcing was not really an option for us because of restrictions our state imposes on the outsourcing of CSPs, we explored sterility testing options as a means of meeting our extended dating needs.
Working with the Microbiology Lab
Given that testing for contamination is not a typical pharmacy task, we initially sought assistance from our microbiology lab. We already had been sending samples to them, but the holding period and growth media used were not in line with USP <71> requirements for sterility testing. Once the lab began holding our samples for 14 days, we quickly realized that their job is to grow bugs—not to see if they can avoid growing bugs.
If you intend to use your clinical microbiology lab for sterility testing, make sure that they are set up for this type of testing. The lab should have segregated storage for sterility testing samples in order to limit the risk of cross contamination with clinical samples. It also is a good idea to choose media that can be inoculated in the pharmacy and stored and read in the microbiology lab. It is important to determine whether the lab has the space to hold pharmacy samples for 14 days and the resources to read them at specified intervals. Keep in mind, the operational impact to the lab may increase their fees to the pharmacy for the sterility testing.
Assigning Extended Dating
In order to determine what CSPs would be assigned BUDs, we closely evaluated our production history and distribution patterns for all products that historically had been assigned extended dating.
For low-use products and those with limited and predicable distribution, we simply changed our beyond-use dating to comply with <797> requirements. In this way, we are able to limit waste by adjusting production to match demand on a continuing basis. Because we planned to implement CSP quarantine during the testing period as part of our program, we also decided to stay with the <797> BUD limits for any product with stability data of 30 days or less since sterility testing would increase costs but not gain significant shelf life past the <797> limits.
For OR syringes and pain management CSPs (eg, fentanyl and hydromorphone infusions and various epidural preparations), decreasing the expiration dates to <797> BUD limits or adopting an on-demand system would have resulted in significant increases of waste or unacceptable delays in patient care and/or an increase in compounding by nursing and anesthesia staff. We chose instead to review production history to determine the most appropriate batch size for these products in order to maximize efficiency while minimizing the costs of sterility testing.
Testing with Limited Resources
While we were able to obtain funding for materials to conduct the sterility testing, we were not able to acquire additional space or increase personnel resources to manage this program. Approximately 12 to 16 hours of pharmacist time weekly is dedicated to the sterility-testing program, which is incorporated into the regular workflow in the production area. To manage this additional workload without adding staff, we had a few of our pharmacists develop their microbiology knowledge through research, study, and trial and error; and we rearranged some of their tasks to allow sufficient time for processing samples and completing the necessary record keeping. In addition, we assigned the responsibility to a particular position designated on the schedule as opposed to a set staff member to ensure testing responsibilities are completed daily. As part of batch production, our compounding technicians are inoculating and labeling samples at the end of each batch. For our largest batches, we inoculate up to 24 samples (12 in each media). Most of these are quite easy to do and do not add significant time to the compounding process.
To help staff better execute testing and understand these new expectations, we developed standard operating procedures, including procedures for early release from quarantine and addressing positive results. We worked with our Infection Control department to develop definitions of false positive and true positive results and appropriate methods for reporting both situations.
As we did not acquire additional space for sterility testing purposes, we designated space and storage shelves for samples and for products in quarantine within our existing cleanroom. Six shelves of a five-foot shelving unit are used for quarantined product, a three-foot shelving unit and three incubators (about 8 cubic feet, total) are dedicated to samples. All of the testing equipment is in our lab room, which is part of the controlled environment but separate from the compounding area. We also designated two doors of refrigerator space for quarantined products.
On average we test 70 to 80 batches (with batches varying from 25 to 600 items) per month with 1200 to 1300 inoculated samples. Typically we have anywhere from one to four samples show evidence of contamination per month. False positives provide an opportunity to address testing technique with staff and provide assurance that the media we are using will indeed grow microorganisms. By quarantining the products for the duration of testing, we ensure patients are not exposed should a true positive occur.
Evaluating Testing Materials
In order to perform sterility testing in the pharmacy, we had to purchase the appropriate materials, including incubators and growth media. Growth media products designed for pharmacy-based sterility testing are commercially available from several companies, and we evaluated products based on cost and ease-of-use in our setting. The materials should be pharmacy friendly (ie, you should not have to be a microbiologist to use them correctly), not too bulky, readily available, and certified for required organisms. Since the available growth media products provide a result as turbid (growth or possible growth) or clear (no growth), we specified in our standard operating procedures that all turbid samples are to be sent to the clinical microbiology lab for species identification.
In general, modifying operations to comply with USP <797> beyond-use dating is a much easier solution than implementing a pharmacy-based sterility-testing program. However, if you determine such a program is necessary, a careful evaluation of current and historical usage will allow you to limit your testing program to those preparations where the need for extended dating is greater than the risks associated with testing. The time and energy spent evaluating our product list; modifying our batch sizes; working on product scheduling; and carefully examining every process to assure that it was safe, reproducible, and least likely to result in contamination was essential to our success in implementing a compliant sterility-testing program.
Angela W. Yaniv, PharmD, has been the sterile products manager at Cleveland Clinic in Cleveland, Ohio, since 2007. She also serves as the interim manager for the Taussig Cancer Institute pharmacy.
Pyrogen Testing Options
Pyrogen testing is required when preparing batches of more than 25 units from a non-sterile ingredient or when using non-sterile equipment (ie, high-risk compounding). Since we compound a few products that require pyrogen testing, we evaluated options for this. In larger academic medical centers, research labs on campus may be able to run the required tests. There are commercially available test kits that are easy to use, but require short-term incubation at a specific temperature. Another option is to purchase lab equipment specifically designed for endotoxin testing. We chose a commercially available kit to keep the testing in the pharmacy without adding equipment.