Since 2011, the National USP <797> Compliance Survey has provided an annual measure of the degree of self-reported compliance with the requirements of <797> by US pharmacies performing sterile compounding. With <797> nearing one decade since it became the official and enforceable sterile compounding standard in 2004, the investigators hoped that this third year of survey measurement would reveal significant improvement, especially in light of the NECC tragedy; however, compliance trends for the overall study population, as well as the hospital cohort, remain predominately unchanged from last year.
This article provides a description of the 2013 study population, highlights of the findings, as well as a discussion of particular areas of ongoing concern. It is recommended that the reader review the findings and recommendations from the articles published on the 2011 and 2012 National USP Chapter <797> Studies, which can be found here at www.pppmag.com/2012survey and www.pppmag.com/2011survey since they continue to be pertinent. Readers of the 2011 and 2012 study findings were provided free resources, including forms and policies and procedures, as well as detailed recommendations to address specific areas of non-compliance that posed significant risks to both patients and employees. Because the areas with deficiencies were work practice–related, the recommended improvements could be implemented without significant financial impact. These resources remain available, current, and can be used to implement compliant sterile compounding practices.
Since most of this year’s findings demonstrated little or no improvement in compliance, many opportunities remain to implement increased patient safety practices through improved compliance with <797>. Figure 1 shows what participants identified as their location’s biggest challenge to <797> compliance. Similar to previous years, financial constraints/budgetary limitations (29%) and physical plant challenges (21%) were cited as the primary barriers to compliance this year; however, there also has been little improvement in the many work practice–related areas for which solutions can be implemented at little cost, regardless of physical plant issues. Nineteen percent (19%) of the participants cited a lack of available competency and training resources as the primary barrier to compliance with the chapter; this is difficult to understand given the vast amount of published literature and Web-based sterile compounding training products available. Likewise, 16% identified the time required to implement the changes as their location’s primary barrier to compliance. Certainly time management is challenging with the many competing priorities pharmacy faces; nonetheless, given that preventable patient injury and death has occurred and received significant media coverage, continued lack of compliance with sterile compounding standards of practice is a risky approach to take. Although this year’s participants still identify their primary motivation for <797> compliance as the simple fact that it is a practice standard that should be implemented, a growing number of participants identified negative publicity as the most influential factor driving their compliance (see Figure 2).
As this year’s findings underscore, pharmacies performing sterile compounding must gain improved traction in their effort to comply with USP Chapter <797>. There is no excuse that justifies waiting; instead, pharmacy must focus on the opportunities immediately at hand to change attitudes and improve work practices. It may seem to be a large undertaking, but it is important to begin. As we all know, the journey of a thousand miles starts with the first steps. If you have yet to take the USP <797> Compliance Survey, we strongly recommend you do so today; there is no need to wait until the study opens again next year. This is a free resource. Please use it to identify your facility’s areas of non-compliance with <797>. If there are multiple areas of non-compliance at your location, target one or perhaps two or three areas, but please get started. A focus on compliance will deliver results, which is clearly demonstrated by higher compliance scores in the groups that have taken the survey in multiple years versus a single year (Figures 3 and 4). Use the Action Plan generated upon survey completion, published articles, and free resources provided in this publication and others to reshape your sterile compounding practice. The change you embrace today will improve your current sterile compounding practices and reduce patient risk tomorrow.
Purpose, Methodology, and Limitations
The survey opened on May 1, 2013 and data was collected through June 30, 2013. No changes were made to the 2012 survey questions. The 1045 participants in this year’s survey represented a 254% increase over last year’s 412 study participants and is similar in size and composition to the 2011 study population (1184 respondents). It was encouraging to note that there were 705 new locations that had not participated in 2012 (these locations may have participated in 2011 but that data was not collected). Also encouraging is that of the 412 locations that participated in 2012, 334 (81%) participated again this year. For a comprehensive discussion of the purpose, methodology, and limitations of this survey refer to the discussion published in the 2011 survey results at www.pppmag.com/2011survey, which continues to be relevant.
Description of Study Population
Hospital pharmacies (790) represented the overwhelming majority (79%) of the total sample population of survey respondents (1045) with home infusion/ambulatory infusion suites comprising the next largest group (117). Though there was representation from other settings, their sample sizes were significantly smaller, so this article will limit its discussion to the overall population, and where appropriate, to hospital-based participants (see Figure 5).
Similar to last year’s results, the 2013 survey had geographic representation from every state as well as the District of Columbia. There was a range of participants per state from one (District of Columbia and Wyoming) to 135 (California) with a mean of 20 and a median of 13 respondents per state (see Figure 6).
13.2% (138) of the locations reported that at least one outside agency has had negative findings about their sterile compounding practices. Negative findings reported at the locations are described in Table 1.
Of the 709 hospitals participating, 68% reported that the location they were reporting for was the only sterile compounding location at their organization. Fifteen percent (159) had one other compounding location and 177 had two or more compounding locations with 19 (2%) having greater than 5 compounding locations.
The following tables and figures on page S8 summarize some of the important characteristics of the overall or hospital study populations (see Figures 7-11 and Tables 2-3).
This year the overall compliance score for the entire study population was 77.2%, essentially unchanged from last year’s overall compliance of 77.7%. (see Figure 12). The average hospital compliance score increased from 72.4% to 76.3%. Notably, those who participated in the 2011 survey had a higher compliance score than those who did not. This finding was true for the overall population as well as for the hospital and alternate site groups (Figures 3 and 4).
The overall compliance score for the entire population is trending up; however, the trend line for both the overall population and the hospital population made its major improvements between 2011 and 2012 with little change between 2012 and 2013. Keep in mind that the sample size in 2012 was significantly smaller (412) than the 1148 and 1045 in 2011 and 2013, respectively. The findings are not likely to be statistically significant; however, that examination has not yet been performed. As predicted, the alternate site data did not demonstrate any improvement. Though this part of the sterile compounding industry is newer (therefore using newer physical plants) and practitioners seemed to be early adopters of the USP Chapter <797> standards, it appears that there has not been a significant push by this population to further improve compliance. Figure 13 summarizes the overall compliance scores for the entire sample population, as well as the hospital and home infusion cohorts.
In 2011, it appeared that there was a trend for larger pharmacies (based on the number of CSPs compounded per week) to have higher compliance scores. We assumed this was due to the significant economies of scale available to larger organizations. In 2012, that trend line appeared to flatten out; however, the sample that year was about 40% of the 2011 sample size, so it might be less likely to reflect reality. In 2013, the compliance results tend to indicate that larger compounding operations tend to have slightly higher <797> compliance scores, as illustrated in Figure 14.
In 2011, there also was a trend for hospitals with higher numbers of beds to have higher compliance scores. Figure 15 illustrates that although hospital size (based on the number of beds) may influence compliance scores, it no longer appears to be a significant influence.
Specific Compliance Findings
While there has been only incremental improvement in overall compliance, some practice areas, or domains, have seen more substantial improvements (see Table 4). Note that while the Patient/Caregiver Training domain appears to have improved by 32%, the compliance score in 2011 was due to a study defect. The logic of the tool should have limited these items to certain populations (eg, alternate site, prescribers, etc) but it was asked of the entire population, making the findings in 2011 incorrect. Also, note that there has been a steady and marked improvement in the domain Radiopharmaceuticals as CSPs, which is encouraging; however, that population sample size is relatively small: in 2013 only 31 providers stated that they dispense radiopharmaceutical CSPs.
Table 4 presents a comparison of the compliance scores for each domain for the entire sample population over three years (2011-2013), including a summary of the delta change from 2011 to 2013. Other domain and item summary analyses are available online at www.pppmag.com/usp2013onlinetables.
Selected Areas Requiring Improvement
Compliance scores have improved slightly across the board in the past year, with those locations demonstrating an increased focus on compliance reaping the greatest improvements. Nonetheless, the overall compliance for many items is lower than expected. While progress is being made, it is slow and some compliance elements experienced no improvement at all. The discussion that follows reviews selected activities required by the chapter where significant focus is needed.
Personnel and Facility Environmental Sampling Metrics
A written environmental sampling plan and associated policies and procedures are fundamental to ensuring an effective environmental sampling program; however, only 49% of hospitals in 2011 stated that they had a written environmental sampling plan. Though this one item has demonstrated consistent improvement in both populations (as noted in Table 9), the annual gain is small. Far too many pharmacies still do not have a formal environmental sampling plan. Environmental sampling is a tool that is designed to measure the extent to which the primary and secondary engineering controls, disinfecting procedures, and work practices result in a suitable environment for sterile compounding. The results of facility and personnel sampling indicate whether the pharmacy is maintaining an adequate state of control.
In 2011, only 30% of hospitals complied with the requirement for all compounding personnel (including supervising pharmacists) to successfully complete at least three gloved fingertip/thumb sampling procedures (success is 0 CFUs for both hands) before being allowed to compound CSPs. This initial gloved fingertip sampling is designed to verify that compounding personnel can properly donsterile gloves without contaminating them. There was significant progress measured in 2012, but 2013 saw just incremental improvement (Figure 16).
After the initial gloved fingertip sampling, ongoing gloved fingertip sampling is accomplished in association with the preparation of media fill units. Interestingly, these ongoing gloved fingertip samples have a significantly higher compliance rate than the initial gloved fingertip samples associated with the garbing competency (Table 10). Nonetheless, there has not been significant improvement over previous years; just over half of respondents are compliant with this requirement.
Table 11 displays the discouraging results of compliance with one of the surface sampling items. The chapter does not specify the exact frequency of sampling; nonetheless, it is distressing that only half of the pharmacies in the sample are performing surface sampling as required. Surface sampling can be considered a personnel metric as the results provide information about the quality of the aseptic practices of the compounding staff in terms of frequent glove and compounding surface disinfection. One way to perform sampling is in association with routine media fills. Media fills should be developed to mimic each pharmacy’s most complex compounding methods and be performed at the end of the compounding day to simulate worst-case scenarios. At the time of the media fill, the operator must perform gloved fingertip testing (inside of the hood or isolator), so this is a great time to perform surface sampling as well.
Participants who indicated that they had both an ante and buffer area were asked if they measured their pressure differential or airflow velocities daily. Figure 17 compares hospital compliance for this item across the years. Though there was significant improvement in compliance in 2012, there appears to be no further improvement, at least in the study population. Compliance in the overall population was slightly higher at 59%; however, that is likely due to the alternate site population, which tends to have newer facilities. Please refer to the 2011 study findings for information on an easy, inexpensive solution to this issue.
Regardless of physical plant limitations, a line of demarcation can be added to the facility at almost no cost (see Figure 18). The purpose of the line of demarcation is to mark the area beyond which street shoes do not cross. It also serves as the point beyond which the “dirty” cart does not pass carrying the heavy particle load picked up in travels through the storage areas and general pharmacy preparation area. This is a simple but effective way to reduce the introduction of particles into the controlled environment and the segregated compounding area. The line of demarcation may be marked with something as simple as cleanroom tape on the floor.
Final Release Tests
For the third year is a row, Filter Integrity Testing remains the item with the lowest compliance overall. Participants who use a 0.22 micron filter to sterilize solutions during the compounding process were asked if they perform filter integrity (bubble point) testing. Of those who do use 0.22 micron filters to sterilize solutions, only 20% (2011), 22% (2012) and 27% (2013) report that they routinely perform the required filter integrity (bubble point) after the filter is used to sterilize a solution in the overall population. Hospital compliance was even lower, as seen in Figure 19.
While some areas of USP Chapter <797> may lack clarity, this requirement is clear. The chapter states “filter units used to sterilize CSPs shall also be subjected to manufacturers’ recommended integrity test, such as the bubble point test.”1 All filters used for sterilization must be subjected to the bubble point test against the filter’s respective bubble point PSI rating. Failure to pass a bubble point test requires that sterilization by filtration and subsequent bubble point testing be repeated using another filter.
In another troubling finding, only 131 locations (in the overall population) reported that they perform high-risk compounding; however, 353 locations stated they sometimes did use a 0.22 micron filter to sterilize a solution (see Figure 20). Certainly locations may filter a solution to remove particulates, but that does not provide sterilization. This finding is difficult to interpret, leaving the study team to wonder if compounders understand the microbial risk level categories. If a solution requires sterilization with a filter, then it is a high-risk CSP by definition. Perhaps those locations using a 0.22 micron filter without conducting any high-risk compounding may be doing so to compound intrathecal injections or neonate CSPs; however, the discrepancy between the two numbers seems too large to be explained by this rationale only.
Sterility testing and bacterial endotoxin testing also seem to be poorly understood, as they are on the low end of item compliance. In order to identify those who should perform sterility testing and/or bacterial endotoxin testing, the following question was included in the survey:
Which of the following statements are true for your compounding location? Please select all that apply.
Table 12 summarizes the number of locations required to perform these final release tests across all survey years. If a participant answered any single or combination of a, b, and/or c, then sterility testing is required of that location based on those conditions, and so they were asked if they performed sterility testing. In addition, if any combination of a and/or b was selected, then they should be performing—and were asked questions about—bacterial endotoxin testing (see Figure 23).
It is clear is that there has been little improvement in compliance with sterility testing. Figure 21 shows that less than half of the study population who should perform sterility testing does so, and although there was improvement in compliance findings from 2011 to 2012, the 2013 findings are essentially unchanged from the previous year. Figure 22 breaks down the data further into the subset of those who should perform sterility testing, and examines pharmacies who answered “c” only, indicating that the only condition that existed at their location was occasions when the assigned BUDs exceed the storage times published in <797> (regardless of risk level). Only 25% of the hospitals and 31% of the entire study population engaged in the practice of performing sterility testing. Thus, it seems that it may not be clear to pharmacies that they are required to perform sterility testing under these conditions. This information may be missed when the chapter is reviewed since the information is not included in the Sterility Testing section of the chapter; rather, it is included in the section titled CSP Microbial Contamination Risk Levels. It states the “pre-administration storage duration and temperature limits specified in the following subsections apply in the absence of direct sterility testing results that justify different limits for specific CSPs.”1
The microbial contamination risk levels are assigned to a particular type of CSP according to its potential for the introduction of contamination during the compounding process and consideration of the potential for microbial growth during storage. The assignment of risk level is based on multiple factors including the type of components and equipment used, the environment in which compounding occurs, and the complexity of the compounding process. The study directors have observed that BUDs are extended too often without sufficient reason, or perhaps understanding, of the increased risk this introduces.
Sterility testing according to USP Chapter <71> (as required by Chapter <797>) is not a simple procedure. It is an industrial (ie, pharmaceutical manufacturing) test used as a means of meeting the compendial and regulatory requirements of the FDA. It is important to recognize that the pharmaceutical manufacturing industry does not rely on the results of sterility testing the way pharmacy does. The pharmaceutical industry creates systematic process control to monitor the critical control points of their manufacturing processes. They create validated processes, procedures, and methods, as opposed to simply incorporating end product testing at the conclusion of production. Such an approach is beyond the scope of most pharmacies, and therefore sterility testing should be contracted out to qualified laboratories to perform. The test itself requires a 14-day incubation period to complete, so it delays batch release. Certainly batches can be released prior to completion of the full 14-day incubation period; however, this is a risky endeavor that requires the pharmacy to ensure they can track each dispensed CSP to the patients who received the items from the affected lot. In addition, the sterility test media samples must be inspected on a daily basis. While sterility testing by direct inoculation is easier to perform, it is only appropriately performed on CSPs that can not be filtered and have a total volume of 40 mL or less; thus, membrane filtration is required in the vast majority of cases. USP <71> does allow other methods to be used that have demonstrated equivalency as long as “the verification results demonstrate that the alternative is at least as effective and reliable as the USP Membrane Filtration.”1 The emerging Rapid Micro Methods may be used, but only when they have demonstrated equivalency to membrane filtration through a robust validation procedure. To date, no commercial laboratory has successfully demonstrated equivalence or completed the necessary validation procedures. In addition, method suitability testing must be performed for each type of CSP being tested. This type of testing ascertains whether microbial contamination can grow and ensures that the CSP ingredients do not interfere with the growth of the test microorganism, as this could result in false negative results.
Clearly, USP Chapter <797> has had a positive influence on patient safety, as acknowledged by 97% of the participants in this year’s study. Many cited budgetary constraints and physical plant limitations as the primary barrier to their location’s full compliance with <797>. Previous study reports have acknowledged the strides made toward improved compliance. These reports also provided detailed information, as well as access to free quality tools, to assist pharmacists and technicians in their efforts to improve sterile compounding practice. This year, it is difficult to acknowledge improvements, as the data demonstrate that much of the growth was incremental only.
<797> is the gold standard of practice, and it is also almost 10 years old. While there have been previous compounding misadventures, 2012 brought with it the single, largest—and likely preventable— sterile compounding misadventure in compounding history, now responsible for 64 deaths and 750 total cases.2 More than 50 sterile compounding pharmacies have since been visited by the FDA.3 On the senate’s legislative calendar is the Pharmaceutical Compounding Quality and Accountability Act (s.959), which will amend the Federal Food, Drug, and Cosmetic Act with respect to compounding and create a new category called “compounding manufacturers” that will receive oversight from the FDA. The National Association of Boards of Pharmacy is working closely with many state boards of pharmacy to assist them in evaluating sterile compounding practice within their state according to Chapter USP <797> requirements.
If you have not visited the FDA Web site to review the posted inspection observations (Form 483s) made by the FDA for each visited location, we suggest you do so. Though visits by the FDA require the pharmacies to be inspected as though they were registered FDA manufacturers (consequently applying cGMP requirements that are not appropriate to pharmacies), what becomes immediately apparent from the 483s is that many of the shortcomings identified are not cGMP issues, rather they relate to hand hygiene, garbing, aseptic technique, cleaning, environmental sampling, and other aspects of work practice that are directly addressed in <797>.
Compliance with all aspects of the chapter are necessary, and though full compliance certainly is not a simple endeavor, it seems as though further progress should have been achieved over the past nine years. To employ proper sterile compounding practices requires leadership, persistence, a willingness to learn, and a commitment to achieving a measurable state of control that removes patients, practitioners, organizations, and pharmacy practice from a state of risk. For some facilities, a complete change in the compounding quality culture may be required. What will it take for you to improve the quality of your compounded sterile preparations?
The study team wants to extend their appreciation to those who participated in this and previous surveys. We would also encourage every pharmacist to take advantage of this free resource to assess their compliance with the chapter and generate a detailed Action Plan customized to the survey responses. CriticalPoint’s USP <797> Gap Analysis tool is available throughout the year at http://797study.criticalpoint.info/
Kate Douglass, MS, RN, APN,C, CRNI is the President, CEO and principal of Performance Strategies, LLC and serves as the Study Director for the USP <797> Compliance Survey.
Eric S. Kastango, MBA, RPh, FASHP is the President, CEO, and principal of Clinical IQ, LLC and CriticalPoint, LLC. He also serves as the Study Director for the USP <797> Compliance Survey.
Peter Cantor (COO and Managing Partner of CriticalPoint, LLC) is the Study Coordinator.
Address correspondence to Kate Douglass at email@example.com.