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Compounding pharmacies, equipment suppliers, and educators are all working to prove that USP <797> compliance is an attainable goal.
By Bruce Flickinger
Early in her career, Mary Monk-Tutor, PhD, spent many years as a home infusion pharmacist and for 12 years was a Joint Commission Home Care Surveyor. She remembers the time when home care patients were trained to mix total parenteral nutrition (TPN) formulations in their kitchens, and when nurses in hospitals compounded intravenous solutions on countertops. “We did this in the industry for years without infectious complications,” she says. “Obviously, these are not the safest or most appropriate environments, but it does show that it is possible to prepare at least low volumes of CSPs in uncontrolled environments without contamination.”
Things have changed in the past 20 years. Although avoiding contamination may be possible in such uncontrolled conditions, nobody now would admit to mixing intravenous and other sterile preparations on an open countertop. Doing so could cost a pharmacist his license and his livelihood, not to mention potentially compromise the safety of his patients and employees. Expectations for the handling and disbursement of compounded sterile preparations (CSPs)–loosely defined as manufacturer-supplied medicines (high-risk compounding can now involve non-manufacturer-supplied materials such as non-sterile bulk chemicals) that need to be mixed or modified by a pharmacist for patient use–have risen steadily among consumers, practitioners, and regulatory bodies. Standards for sterility and safety now have been codified in USP Chapter <797>, a federally enforceable standard introduced in 2004 and published in revised and updated form just this month.
Monk-Tutor, who is now professor of pharmacy administration and director of assessment with the McWhorter School of Pharmacy at Samford University (Homewood, AL), is among industry observers who say USP <797> is a long time in coming but still has a long way to go in terms of even, effective implementation. The standard, formally titled “USP General Chapter <797> Pharmaceutical Compounding–Sterile Preparations,” details the way sterile and high-risk pharmaceutical products should be compounded to optimally protect the safety and health of both patients and workers. It is incorporated to varying degrees in pharmacy accreditation programs and by individual state boards of pharmacy.
Like any federal mandate worth its salt, USP <797> initially prompted apprehension and procrastination in the pharmacy compounding industry, responses that have proved largely unwarranted and are for the most part dissipating. “While USP requirements are likely to become more stringent over time, they should be achievable for those organizations that have already put basic guidelines in place for compounding sterile preparations,” Monk-Tutor says.
In the wake of earlier consternation about USP <797>, two realities have emerged. The first is that the standard makes a clear demarcation between those pharmacies that want to do sterile compounding and those that do not. It is simply and primarily a business decision, one that expands the reach of care provided to patients but that requires a significant investment in training and infrastructure. The second is that education and training in sterile compounding needs to improve for those who do fall under the purview of USP <797> to achieve and maintain compliance.
Figure 1. State boards of pharmacy’s current USP <797> compliance status (direct, indirect, or no reference). Colors indicate whether the state’s pharmacy laws are harmonized with USP <797> (direct, green); include regulations for sterile compounding and/or parenteral nutrition but do not directly cite USP <797> (indirect, yellow); or currently include no regulations referencing USP <797> or sterile compounding/parenteral nutrition (no reference, red). Adapted with permission from ClinicalIQ.Click here to enlarge image
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Compliance clearly entails more than simply adding sterile compounding to a pharmacy’s slate of services or for the pharmacy to continue to compound CSPs the way it did five or 10 years ago. “Sterile compounding is a complex practice; it is not a simple matter to add sterile compounding to a hospital or community practice that dispenses manufactured products and compounds non-sterile dosage forms,” says Timothy McPherson, PhD, associate professor of pharmaceutical sciences in the School of Pharmacy at Southern Illinois University Edwardsville. “Rather, complying with USP <797> becomes a full-time, resource-intense commitment.
“I’ve spent some time with one pharmacy in the Midwest that specialized in non-sterile compounding for both humans and animals,” McPherson offers as an example. “A decision was made to add sterile product compounding, so they expanded their facility and added a state-of the-art cleanroom suite. They added a partner pharmacist to be in charge of the sterile compounding business, including all QC. I don’t see how a single pharmacist could reasonably handle the responsibility for both parts of this practice.”
Taking up the challenge
The independent community pharmacist is one of several players feeling the impact of USP <797>. Pharmacy compounding is a diverse practice that also encompasses hospital pharmacies, chain pharmacies, home health-care pharmacies, and specialty infusion companies, among others. Uptake of USP <797> varies among these establishments. Some of the best facilities in terms of compliance and overall quality practice are in community and specialty pharmacies “because they can implement changes much faster than hospitals can, provided they have budgets to work with,” says Loyd Allen, Jr., PhD, editor-in-chief of the International Journal of Pharmaceutical Compounding and professor emeritus of the University of Oklahoma HSC College of Pharmacy (Oklahoma City, OK).
“Some of the best facilities I have seen are in small- or medium-sized cities and even in some smaller towns. Most of the population lives in smaller cities and towns, and they require the same medical services as people in larger cities,” Allen says. Still, he notes that some pharmacists opt to forego their sterile compounding practice and focus on non-sterile compounding if it is not economically beneficial to invest in the necessary changes in their pharmacies. Some hospitals, too, are “outsourcing more sterile compounding to specialized companies, even to local pharmacies that have the required facilities,” he says.
One snapshot of the pharmacy landscape comes from a survey conducted by McPherson and his colleagues, results of which appeared in 2006 in the Journal of the American Pharmacists Association. His team surveyed 370 pharmacies in the Midwest and found that 94 percent of them provided compounding services. However, prescriptions requiring compounding represented less than 1 percent of total prescriptions filled for the majority (58.3 percent) of respondents. Overall, only 2.3 percent of prescriptions dispensed were compounded preparations, and “only about 5 percent of our respondents offered sterile product compounding,” McPherson says.
So while there is a market for sterile compounding, McPherson senses it is being met by businesses dedicated to the practice. “Most compounders we have come into contact with avoid sterile products. They generally refer patients requesting sterile products to a qualified pharmacy in the area,” he says.
One independent pharmacy that made the decision to specialize in compounding is The Compounding Shoppe, based in Homewood, AL. The Compounding Shoppe earned the Pharmacy Compounding Accreditation Board’s (PCAB) Seal of Accreditation in September 2006 and in the process became USP <797> compliant.
“Our goal was to become PCAB-accredited, so meeting USP <797> was mandatory for achieving this,” says Scott Wepfer, a registered pharmacist and owner of The Compounding Shoppe. “The commitment for any pharmacy that wants to bring itself up to USP <797> standards is significant, both in time and money. But if you are really serious about compounding and being in business 10 years from now, then it is simply a must-do.”
Wepfer adds, “I think that with the increased regulations and the increased costs of keeping up with these regulations, we will see fewer compounders doing more compounds and doing a better job of it than today.”
The Compounding Shoppe prepares capsules, creams, ointments, gels, suppositories, enemas, oral solutions and suspensions, sublingual (under-the-tongue) tablets, nasal sprays, ear drops, transdermal pain gels, and sterile injectables. A policy and procedure manual provides step-by-step instruction on every activity performed in the compounding lab for making these dosage forms.
“Definitely, the greatest amount of time was spent in writing policies and procedures,” Wepfer says. “We purchased non-sterile and sterile policies and procedures from a vendor, then combined the two and organized them in a way that was better for us.”
Chemicals used in compounding come from FDA-inspected chemical suppliers. Upon receipt, they are placed into quarantine until their certificate of analysis is verified by a pharmacist, who then creates a barcode to place on the container and adds it into inventory, Wepfer explains. “Formulas are stored electronically in our pharmacy computer system,” he says. “When we need to compound one of the formulas, we pull up an electronic log sheet in the lab where the barcode reader and even the electronic balance are all integrated into the computer system to literally create an error-proof compounding lab.”
Any compounding that involves working with powders is done in one of four containment hoods in the lab. Policy dictates that hoods are cleaned between each project to prevent cross-contamination. For sterile compounding, a Class 10 barrier isolator, from Containment Technologies Group (CTG; Indianapolis, IN), is used. “Rather than investing in the typical cleanroom setup with open-faced hoods, we decided to invest in a sterile isolation barrier. While the upfront cost was higher, the daily consumables cost is much lower,” Wepfer says.
Clear choices
Facilities and equipment requirements, including deciding among barrier isolators, laminar airflow workbenches (LAFWs), and enclosed cleanrooms, were cause for much confusion when USP <797> was introduced. People said they were unclear about the chapter’s requirements regarding equipment, positive and negative air pressure, and the segregation of hazardous and non-hazardous drugs, among other things. And if they weren’t unclear, practitioners were concerned that the infrastructure upgrades were too expensive for the typical pharmacy. A popular position at the time was to “wait and see”–that is, to do nothing until the standard wended its way through the comment and revision process and became more widely applied by regulators.
The current set of revisions, two years in the making and incorporating more than 500 comments, allows the use of both LAFWs and barrier isolators (called compounding aseptic isolators) in an ISO Class 7 buffer zone. However, if the manufacturer of a barrier isolator can prove that the isolator provides complete separation from the surrounding environment during dynamic operating conditions, the isolator does not have to be placed in an ISO Class 7 room. In total, the revisions “emphasize the personnel training and testing as well as the air quality and equipment and facilities necessary to meet the standard,” University of Oklahoma’s Allen says.
In his travels, Allen has noted a mix of cleanrooms with LAFWs and barrier isolation technology being used. “Generally, if a large volume of sterile preparations or IV admixtures is prepared, then workbenches with laminar airflow are easier to work with. If economics is an issue and the workload is low, then isolator systems are often selected,” he says.
Figure 2. The MIC-EDU barrier isolator from Containment Technology Group is the result of four years’ collaboration with STERIS Corp. and is offered in both single- and dual-chamber models. It has a static airlock that allows for residence time for decontamination agents and for performing automatic decontamination of the compounding environment. Photo courtesy of CTG.Click here to enlarge image
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The isolator at The Compounding Shoppe is one of CTG’s MIC units, a line of equipment that incorporates a static airlock, which allows for residence time for decontamination agents. “Our documentation package for compliance to the 2008 revisions to USP <797> contains a study showing that the static airlock approach results in at least [a 30 percent reduction] of microorganisms compared to a dynamic airlock when using 3 percent non-sterile hydrogen peroxide,” says Hank Rahe, technical director with CTG. “We attribute the reduction of microorganisms to the airlock design and the airflow pattern within the isolator chamber.”
Rahe points to two primary factors that influence a pharmacy director’s decision to choose a cleanroom instead of isolator technology: the perception that compounding in a cleanroom is more efficient and that it requires less change or disruption to familiar staff routines. “The idea that an isolator represents change and tends to slow down compounding activities is the most common reason cited for not using isolator technology,” he says. “We addressed this issue early on and published a study that concluded that, when proper procedures are followed, an isolator is as productive as conventional engineering controls.”
Figure 3. A pharmacy technician uses a Class 10 barrier isolator for sterile preparations. Photo courtesy of The Compounding Shoppe.Click here to enlarge image
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Another criticism is that, when using barrier isolators, people tend to relax their vigilance of protocol and other environmental controls because they feel the isolator will compensate for them. While isolators are less procedurally dependent than open cleanrooms, “good aseptic technique still needs to be practiced, and a properly trained staff understands the importance of maintaining the integrity of the environment in which sterile preparations are compounded,” Rahe says. “The isolator simply does not allow inadvertent touch contamination that can occur in open hoods.”
Monk-Tutor of the McWhorter School adds an important point: “Technique is always the key. The best equipment and cleanroom in the world will not make up for poor technique; they can only enhance correct technique,” she says.
On the pro-isolator side, reasons such as cost, flexibility, staff preference, safety, and increased sterility assurance typically are cited by pharmacy directors as reasons to use barrier isolators, Rahe says. Space utilization issues are common in hospital sterile compounding areas, and equipment design must accommodate these concerns. “Even though isolators are a less costly option, the flexibility an isolator offers is many times the deciding factor in selecting an isolator over a cleanroom,” Rahe says. “Cleanrooms represent a fixed asset and do not have the flexibility to relocate within a given facility or between facilities.” Furthermore, as opposed to being restrictive, isolators can actually be seen as enhancing the movement of pharmacists and technicians among different jobs, he says.
Other stipulations
Both isolators and LAFWs are referred to generically as primary engineering controls, or PECs, in USP <797>. Both must provide ISO Class 5 levels of cleanliness, but equipment specifications are just one part of the chapter’s scope. The net outcome of the chapter is that all CSPs be prepared in a manner that “maintains sterility and minimizes the introduction of particulate matter” and that final compounded products “maintain their labeled strength within monograph limits for USP articles, or within 10 percent if not specified, until their BUDs [beyond use dates].”1
The chapter addresses a number of different scenarios and types of products under the CSP umbrella. Hazardous drugs are one example. Using any PEC, hazardous drugs must be compounded in a negative-pressure buffer room, while non-hazardous drugs must be compounded in a positive-pressure buffer room. In addition, hazardous drugs must be stored separately from other inventory in a negative-pressure area.
“Hazardous drugs are a part of a pharmacist’s life: As long as a patient needs a hazardous drug that has been prescribed by a physician, pharmacists have the obligation to prepare it,” Allen says. “Safety precautions are now addressed in much more detail than they were years ago, so we now have good standards, practices, and new equipment to better handle hazardous drugs.”
Figure 4. Cintas offers the same cleanroom garments and services to compounding pharmacies that it offers pharmaceutical manufacturing companies. These include sterile reusable coveralls, hoods, boots, and frocks constructed of its Integrity 1800 antimicrobial fabric. The company also supplies technician suits (cleanroom undergarments), sterile consumable products, and sterile disposable garments. Photo courtesy of Cintas Corp.Click here to enlarge image
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The concept of a segregated area is new in the revised chapter. Along with hazardous drugs, the chapter includes a section on compounding low-risk-level CSPs with 12-hour beyond-use dating in an ISO Class 5 PEC within a segregated area. The chapter similarly provides an Immediate Use Exemption from ISO Class 5, in which compounding with direct contact contamination in an environment lower than ISO Class 5 is permitted when no more than three sterile ingredients are prepared or combined for administration that begins within one hour and is completed within 12 hours of completing the CSP.
Realistically, Allen notes, “some pharmacies may be able to do low-risk but most probably end up doing low- and medium-risk work. High-risk is more limited but is necessary in many situations; it just depends upon the workload and market the pharmacy serves as to which risk level is utilized.”
Jan Eudy, corporate quality assurance manager with Cintas Corp. (Cincinnati, OH), affirms that building a cleanroom capable of handling the variety of CSPs encountered is a key challenge to achieving both USP <797> compliance and good quality systems in the pharmacy setting. “Examples include separate areas for chemotherapy or hormonal mixtures in a closed cleanroom system vs. nutritional mixtures in a laminar flow hood system,” she says. “These require proper segregation of product and processes.” The pharmacy must also be ready to “make the financial commitment to maintain the calibration of the equipment and the cleanroom cleanliness levels required,” she adds.
“Cross-contamination is constantly a concern due to the number of people working in the cleanroom and the variety of products and processes in the cleanroom,” Eudy says. “This issue is addressed by creating a comprehensive cleanroom cleaning/sanitizing program that addresses the contamination from personnel working in the cleanroom, the products and processes in the cleanroom, and any mechanized equipment used in the cleanroom.”
Back to school
Although USP <797> devotes extensive attention to the provision, maintenance, and evaluation of air quality, it is clear the avoidance of direct contact between gloves and surfaces in ISO Class 5 areas is paramount. The chapter states unequivocally, “Compounding personnel must be meticulously conscientious in precluding contact contamination of CSPs both within and outside ISO Class 5 areas.”1
This speaks directly to aseptic technique and the proper preparation of sterile drugs. The chapter specifies that compounding personnel must be adequately skilled, educated, instructed, and trained in the following activities: antiseptic hand cleansing and disinfecting of non-sterile compounding surfaces; selecting and appropriately donning protective garb; maintaining or achieving sterility of CSPs in ISO Class 5 PEC devices; protecting personnel and compounding environments from contamination by radioactive, cytotoxic, and chemotoxic drugs; identifying, weighing, and measuring ingredients; manipulating sterile products aseptically; sterilizing high-risk-level CSPs; and labeling and quality inspecting CSPs.
So where does one become educated and trained in these skills? University curricula, continuing education, and on-the-job training are options, but none of them, individually or in concert, are doing a particularly good job in filling the knowledge void created by USP <797>. Efforts are underway to improve the situation, of course, and most recently the American Pharmacists Association published its official education and training policies that reflect many of the issues raised by USP <797>.
“The level of training has been a problem for at least 20 years,” Allen says. “Pharmacy students today do not have the scientific and laboratory background that they used to obtain during their education. So many of them attend specialized training programs to obtain the education required to meet the <797> standards. This is one reason that the <797> committee is emphasizing personnel training and especially personnel testing in performing operations such as media fills and fingertip testing. This is a good and necessary step for ensuring proper procedures are followed.”
“Some states require CSP certification through a CE program that includes a test and a skills demonstration, but, in my experience, these programs only cover very basic skills and are not sufficient to provide any proficiency,” Monk-Tutor says. “Some involve as little as 10 or 15 minutes “under the hood.’ So, I do see a national skills certification program coming some time in the future, either through a national pharmacy organization or through a private company.”
For an assessment of the current state of affairs among U.S. schools of pharmacy, Monk-Tutor conducted a survey to assess the extent of didactic and laboratory instruction related to CSPs. Results published last November in the American Journal of Health-System Pharmacy showed that, overall, instruction varied widely and only about a sixth of respondents believed that their students were adequately trained in CSPs before graduation.
“Ideally, every school of pharmacy would have a state-of-the-art cleanroom and at least one faculty member who is experienced in infusion therapy and knowledgeable about USP <797> to teach students,” Monk-Tutor says. “Unfortunately, few schools have the financial resources and/or space available to build out a cleanroom, not to mention maintain it.” Another deficiency in her mind is that many pharmacy schools “do not seem to have an expert in infusion on faculty.”
Further findings from the study seem to put the onus on continuing and on-the-job education: Although only 13 percent of schools felt that their students had adequate CSP training before graduation, nearly 90 percent of them believed that students could only become fully competent in these skills over time in actual practice.
“In my experience and based on the literature I have seen, most continuing education programs on infusion are minimal and on-the-job learning varies drastically by site,” Monk-Tutor says. “Even though great resources, like those provided by ASHP [American Society of Health-System Pharmacists] and NHIA [National Home Infusion Association], are available to help train employees, not all organizations use these tools. One great way to get appropriate training in all schools of pharmacy is for schools to partner with local hospitals or infusion providers.”
Learning by doing
Equipment and service suppliers are also an important educational resource. Many of them also work with biopharmaceutical manufacturers and can apply the knowledge and experience from this industry to their clients in sterile compounding.
Cintas, for example, includes education and site assessments as part of its overall offering. A supplier of cleanroom garments and disposables, Cintas provides an education program based on IEST recommended practices and ISO 14644 guidelines on cleanroom protocol. This includes design of cleanroom linear product flow with line clearance; donning and doffing cleanroom garments; behavior/working in the cleanroom; cleaning of the cleanroom; environmental monitoring and testing of the cleanroom; and documentation and auditing of the cleanroom management program.
A sterile garment/gowning program should not be overlooked. “A cleanroom garment program that is USP <797>-compliant needs to replicate the cleanroom garment program currently in use by pharmaceutical manufacturers,” Eudy says. “This includes the recommended garment items, the validated laundry process, the validated sterilization process, and the assurance of consistent quality of product and services required by USP <797>.” Cintas’ Cleanroom Resources Division currently provides sterile consumable garments and supplies to a large compounding pharmaceutical company with 23 different locations throughout the United States, as well as to smaller compounding pharmacies.
CTG also offers a pharmacy assessment service that provides two types of information to the pharmacy. The first helps them understand the number and types of isolators that will best fit their given needs, and the second advises them how to configure the isolators economically to meet the facility’s volume of work. “Using the data the pharmacy provides, we can determine with our database the proper configuration of isolators and provide an economic analysis comparing the cost of a cleanroom to the isolators. This includes both capital and operating costs,” Rahe says.
To be sure, numerous companies design and build compliant cleanrooms for the various compounding risk levels; programs are available for training pharmacists and technicians and for providing continuing education; services exist to certify cleanrooms and laminar flow hoods; and analytical labs provide product QC including sterility and pyrogen testing.
“None of these are free, of course, but the essential component is a commitment by the pharmacist in charge to avail him/herself of these services and conscientiously carry out the QC program,” McPherson of Southern Illinois University says.
On this point, some observers find disconcerting the apparent reluctance to reach out to the pharmaceutical manufacturing community and translate some of its accumulated knowledge to pharmacy sterile compounding. “Some pharmacy consultants seem to have taken the position of “NIH’–“not invented here’–because they feel compounding is somehow different,” Rahe says. “While some aspects of compounding sterile products are different, a great deal of knowledge could be transferred from manufacturing experience-based individuals. One wonders what is the true motivation in not taking advantage of an outreach to other communities of knowledge.”
Reference
- United States Pharmacopeia, “USP General Chapter <797> Pharmaceutical Compounding–Sterile Preparations.” The revised USP <797> is available online at www.usp.org/pdf/EN/USPNF/generalChapter797.pdf.
