The new bar in sterile compounding raises questions about how to achieve it
Despite the somewhat daunting physical clean-space requirements in USP 797, a bigger worry for compounding pharmacies is educating staff in proper aseptic and containment techniques.
By Bruce Flickinger
Pharmacies have been compounding, reconstituting and custom-formulating drugs for consumers for decades, but the first “post-modern” compounding pharmacy wasn’t built, inspected and ready for operation until 2004.
It is the compounded sterile preparation (CSP) facility at Advocate Illinois Masonic Medical Center of Chicago (AIMMC). It is post-modern because it is the first such facility to be built in anticipation of the then forthcoming USP Chapter 797, and the first to be inspected by the Joint Commission for Accreditation of Healthcare Organizations (JCAHO) and found compliant with the requirements of the standard. The inspection was the culmination of a two-year strategic plan by AIMMC to redesign and upgrade its CSP facility and substantially improve the quality of its sterile compounding processes.
A technican performs operational qualification testing of the core HEPA filtration system in the compounding pharmacy at Advocate Illinois Masonic Medical Center of Chicago. Courtesy Lab Safety Corp.
The plan was designed by Lab Safety Corp., a Park Ridge, Illinois-based provider of healthcare validation services, which was already involved with AIMMC’s intravenous admixtures quality assurance program. Physically, the facility was revamped to provide workspace for the compounding, distribution and redistribution of a wide range of medium-risk CSPs. Procedures were developed and validated to train staff in core aseptic techniques. Work-streaming and waste-streaming issues were addressed in the face of extreme space constraints, and to assure efficient operation and accountability approaching cGMP standards.
“A properly designed, installed, operated and maintained cleanroom is a manageable undertaking and is essential to, and constitutes best practices in, controlling potential contamination of pharmacy CSPs,” says Lab Safety President Greg F. Peters. But, drawing more broadly from his 27 years of design and operational experience with pharmacy clean spaces, he says, “Practitioners have not been given the training, information or resources, and often find themselves at odds with healthcare administration in requesting the resources to put forth their best sterile compounding efforts.”
Clean spaces are actually relatively easy and inexpensive to retrofit and maintain, and the microbiological and toxicological underpinnings of Type II Biological Safety Cabinets (BSCs) are well established in many industries. “Only in pharmacy are we experiencing exposures and widespread environmental contamination,” Peters says. “The conclusions here should be obvious.”
The bar is raised
Published in January 2004, USP Chapter 797 is built on two foundations: aseptic technique and environmental control. It is the first national pharmacy compounding standard of practice that is also enforceable by FDA. The intent of this USP chapter is to prevent harm to patients from microbial contamination (nonsterility), excessive bacterial endotoxins, large content errors in the strength of correct ingredients and incorrect ingredients in CSPs.
Compounding pharmacies traditionally have been regulated by state boards of pharmacy, but enforcement inconsistencies and mounting safety concerns brought the idea of federal oversight to the fore. A 2000 report from the Institute of Medicine (IOM) got the ball rolling. Titled, “To Err Is Human: Building a Safer Health System,” the report claimed that more than 2 million serious medical errors occur annually in the U.S., accounting for between 44,000 and 98,000 deaths. This was followed by a study conducted in 2001 by FDA’s Division of Prescription Drug Compliance and Surveillance, which found a 34 percent analytical testing failure rate among sampled compounded products-“higher than expected,” according to the report, particularly compared with the 2 percent test failure rate the agency sees among commercially produced samples.
Enter USP 797, which includes specific guidance about the preparation, storage and handling of CSPs (see Table). All guidance focuses on preadministration activities. It sets standards for microbial risk levels, expiration dating, packaging, chemical stability and CSP integrity, verification procedures and media fills, and compounding accuracy. However, it cannot dictate clinical practices and does not provide guidance for the administration of CSPs. JCAHO considers USP 797 a best practice and in those states where the board of pharmacy enforces it, JCAHO will expect compliance.
By most accounts, it is a tall, albeit feasible, order for an industry that says it is being caught short on the resources needed to comply. Notwithstanding the physical retrofitting or new construction of facilities that will be necessary, the standard has been mute in offering scientifically sound information that pharmacies can use to bring their operations up to par. The nuts and bolts of regulatory compliance are usually left to industry and government to hash out through comments, guidances and the like. Although this is changing, observers say that pharmacies caught in Chapter 797’s net are in an especially difficult situation in that the information at their disposal is inadequate, conflicting and even threatens to derail their best efforts.
People close to the standard, such as Eric Kastango, president and CEO of Clinical IQ, a healthcare and pharmacy consultancy in Florham Park, N.J., say thus far enforcement has been limited, although healthcare facilities are responding to the standard largely from “fear as opposed to a sense of professional responsibility.”
During the past two years, Kastango has visited more than 200 pharmacies, performing various assessments with regard to USP 797. “The general preparedness of these pharmacies ranges from actively working to comply with the requirements of the chapter to waiting to see if it is repealed,” he says. “There is a significant amount of misinformation being provided to pharmacists and technicians by vendors and others trying to sell products and services that do not comply with USP 797 and other pertinent USP guidelines.” By the same token, “there are a number of unsubstantiated practices that have developed over the years that pharmacists and technicians are hesitant to change.”
Unfortunately, one place that practitioners can usually turn to for information-published research-has lately served more to muddy the waters than provide elucidation.
In particular, two papers published last year in the American Journal of Health-System Pharmacy have ignited confusion and debate about the relative importance of aseptic technique and environmental conditions in preventing contamination of CSPs.
In the first, published in March 2005 and titled “Using a medium-fill simulation to evaluate the microbial contamination rate for USP medium-risk-level compounding,” researchers performed reconstitution of sterile dry growth medium and a complete series of USP 797 medium-risk-level transfers of the medium from vials and ampuls to intravenous bags. They report their institution’s potential contamination rate at around 5 percent (one microbially contaminated product in 20) for medium-risk CSPs under best-case testing conditions, with pharmacists faring slightly better than technicians. These rather lamentable results speak explicitly to deficiencies in aseptic technique.
A second AJHP paper published in November 2005, titled “IV admixture contamination rates: Traditional practice site versus a Class 1000 cleanroom,” is named by observers as especially problematic. The researchers found no significant difference in contamination rates between the traditional site and the cleanroom, and deduced that most contamination in the compounding environment is introduced by poor technique among operators. But this extrapolation was unwarranted given that the “research was poorly conducted, incorrect conclusions were reached, and we really don’t have any true picture of the differences in bioburden rates for the two areas tested,” Peters says. “The unfortunate result is growing confusion and apathy among practitioners.”
“The far-reaching conclusion that the environment is not important is irresponsible,” Kastango says, “because the methods used in the study are flawed and not consistent with the evidence-based science required of manufacturers. It should serve as a stimulus article to see if the findings are reproducible when conducted under measured conditions using more than a couple of operators.”
Core sterile compounding facility at Advocate Illinois Masonic Medical Center of Chicago with routine/stat pass-throughs to the ante-area at right. At left is a 192-inch ISO Class 4 work surface. Courtesy Lab Safety Corp.
Such research points to another problem facing compounding pharmacists: the concept of validation, as traditionally applied to aseptic processing, is an impractical fit in compounding pharmacy practice. A statistically significant sterility validation would require the execution of three replicates of a media-fill run of not less than 1000 products each, with results of not more than one sterility failure per 1000 units and no more than three failures in total. This type of aseptic process validation is virtually impossible in the pharmacy setting because pharmacy-prepared CSPs are not produced in any significant batches. Again, there is no official guidance on the matter.
Dearth of education
No wonder, then, that Kastango sees “a tremendous amount of urban legend about aseptic technique being used today in the training of technicians and pharmacists. Very little if any of it is based on actual validated or verified methods.”
By Peters’s reckoning, no school of pharmacy in the U.S. includes an adequate amount of quality science in the professional curriculum to foster a complete understanding of USP 797. “The result is a wide variation in the quality assurance practices and documentation that are currently incorporated into CSP programs,” he says.
“I am aware of technician training programs that do not use media fills as a routine part of the training experience,” Kastango continues. “Didactic and psychomotor skill techniques are important but media fills are by far the most valuable and telling method of validating an operator’s aseptic technique.” Observers say the media fill requirements in USP 797 are not as robust as they should be to truly validate an operator’s aseptic technique.
And yet, adequate training in aseptic and containment techniques is a core USP 797 requirement. “Good technique is as important as good workflow and outstanding facilities,” says Marian Robinson, vice president of marketing with Baxa Corp., Englewood, Colorado. “The quality of the technique and adherence to procedures are primary compliance requirements, and ones that we are working to assist our customers with through developing USP 797 compliance tools around best practice.”
Robinson affirms that “no definitive research has been done that would help us to identify the impact or the interplay of various contamination-control strategies. Also, because no prerelease testing is performed on most pharmacy-prepared CSPs, the practitioner must use his best efforts to control any and all factors recognized to negatively impact CSP sterility.” In addition to providing various educational and consulting services to healthcare organizations, Baxa offers the ValiMedTM Medication Validation System, a fluorescence fingerprinting system designed to help pharmacists meet USP 797 and JCAHO testing requirements for drug identity and concentration.
“We try to provide reasonable options for facilities that are unsure about how to begin the journey to compliance,” Robinson says. “Key decision factors tend to be physical limitations-there may not be enough space to create the cleanroom or anteroom required for compliance-and resources, which are primarily economic, but in some cases labor. It is possible to have a high-quality CSP without million dollar renovations.”
“The cleanroom is an essential operational baseline which is easily achieved and, with proper design, can be used and maintained in both normal and hazardous drug compounding scenarios in combination with Type II BSC technology,” Peters says. The problem is that pharmacies deem these technologies to be too daunting simply because they haven’t been properly indoctrinated and trained in their use.
Rooms and boxes
While many express concern about meeting the facility and equipment requirements stipulated in the standard, those familiar with engineering clean spaces say smart design and adherence to core principles of environmental control are good guides for even the most cash- and space-strapped facilities. The revisions contain design and performance criteria for critical environments that were not clearly defined in the first iteration of the standard. “The proposed changes now provide pharmacists with a clear set of design and performance criteria that they can use to hold vendors accountable to meeting,” Kastango says.
One piece of equipment that had no definition or performance criteria was the barrier isolator. Barriers isolators have been offered up by proponents as a practical, viable means of meeting environmental control requirements where installing and operating a cleanroom would be prohibitively expensive. “However, a cleanroom environment is beneficial for those with a much larger volume and who need more flexibility during their work procedures,” says Shari States, HYCON product manager with Biotest Diagnostics Corp., Denville, N.J. “For each there are multiple positive and negative features. It is up to the department to determine which would best fit their needs.”
Although isolators can provide a safe environment for compounding hazardous drugs, the environmental contamination risks related to their use and handling are dependent on how clean the materials are when they are placed in the isolator and how clean they are when they are removed. “That is, if you are using the isolator to provide your containment, the fact that your vial exteriors are not fully decontaminated before they are placed in the isolator contributes environmental contamination, and if the materials are not decontaminated before they are removed from the isolator, they bring hazardous drug residue with them upon removal,” Robinson says.
USP stipulates that positive air pressure be used to physically separate the isolator work area from the outside environment because it reduces the chance of introducing contaminants during product transfers to the isolator as well during the compounding process. Most isolators designed for use in sterile compounding are closed systems, which provide for the transfer of items to and from the isolator’s work area through decontaminated interfaces.
Further, while the standard requires that the compounding environment of isolators meet ISO Class 5 classification, it does not specify classification requirements for the area surrounding the compounding area. A draft guidance proffered by FDA in 2003, however, specifies that aseptic-processing isolators be placed in a classified room. Ideally, however, barrier isolators should be placed within a buffer air quality area with an ISO Class 8 environment. It also is good practice to place barrier isolators in areas with limited personnel access, control the temperature and humidity inside the room where the barrier isolator is placed, and implement a regular, monitored cleaning and maintenance schedule for the barrier isolator itself and for the surrounding area.
Despite these precautions, barrier isolators introduce a number of potential issues such as inadequate cleaning, reduced dexterity and workflow, and user discomfort and fatigue, and some say they have been prematurely introduced to pharmacy practice. “A fact often overlooked is that they need to be demonstrated to be the USP 797-mandated equivalent of the laminar airflow workstation,” Peters says. “The ambient conditions and limitations of their use need to be further demonstrated by properly designed studies.”
Something in the air
To offset some of these concerns and provide some measure of best practice for both makers and users of barrier isolators, in 2004 the Controlled Environment Testing Association (CETA) published its “Applications Guide for the use of Barrier Isolators in CSPs in Healthcare Facilities.” The product of a task force of certifiers, manufacturers, engineers and pharmacists, the guide is intended to establish a level playing field for these controls and shift the burden of proof in evaluating their performance from pharmacies to equipment vendors. “Education is a major component of establishing an environmental monitoring program. The requirements established in USP 797 have completely changed how sterile preparations are made,” States says. “Since many of the requirements are vague because they must apply to a wide range of applications, as a vendor we put a lot of time and effort into creating the HYCON solution for 797. It’s an in-depth, step-by-step guide for establishing not only an environmental monitoring plan but an overall quality control program to be applied to critical environments.”
Barrier isolators incorporate either unidirectional airflow, which is standard in laminar airflow workstations (LAFWs), or turbulent airflow to remove contaminants from material. Positive air pressure is used to keep external airborne particles out of the isolator. The CETA guide says unidirectional airflow is the preferred design in most applications because turbulent airflow is dependent upon the volume of air that is cycled into the environment and larger volumes of air require more time to process. During this process, particles can be suspended in the air, some of which could become stagnant and harbor contamination. Still, turbulent airflow designs are well-suited for aseptic environments, such as those environments that surround the ISO 5 primary engineering control.
Microbial air sampling and particle counting, along with surface sampling, are the core components of a USP 797-compliant environmental monitoring program. Principally, surface and air sampling should be performed in or adjacent to areas with product or component contact under dynamic conditions. Critical sites include surface samples of processing equipment, LAFWs, personnel gowning (including fingertips) and gowning areas, and the walls and floors of sterile compounding areas. Supporting areas also should be monitored at an appropriate frequency. Test results can be used to detect drifts in processes or lapses in control by comparing them to historical data from the area sampled.
Air monitoring encompasses the measurement of both the total number of particles and the number of viable microorganisms in the controlled environments of the compounding area. For some environments, government regulations or published reports and guidelines exist. Federal regulations for total particle monitoring of controlled areas can be found in ISO 14644-1 “Airborne Particulate Cleanliness Classes.” In the case of viable monitoring, some guidance is provided for cleanrooms (USP 27 1116). “These numbers should only be a guide and more specialized statistical analysis of each facility’s historical data should be used,” States says.
States says many facilities use an active air sampler for monitoring the microbial levels within their critical environments. “Such testing is performed at least monthly for low- and medium-risk preparations and at least weekly for high-risk preparations,” she says. In addition to microbial air samplers, particle counters can be used for spot checking to verify that your system remains in proper operation. Biotest’s HYCON 797 package includes the APC Airborne Particle Counters, RCS Microbial Air Samplers, contact slides for surface sampling, and the Biotest Agar Strips for use with the microbial air sampler. The company also provides guidelines for validation, which include and IQ (installation qualification), OQ (operation qualification) and PQ (performance qualification).
There are multiple options for the analysis of microbial air samples. “Some facilities rely on their internal microbiology labs while others will send samples to an outside source,” States says. “A third option is to simply purchase an incubator such as those already available in most pharmacies. However, we recommend that you use a skilled microbiologist for identification purposes.”
Sampling technicians should be thoroughly trained prior to the commencement of monitoring. “The RCS Microbial Air Sampler and APC Particle Counter can be operated by anyone in a compounding facility following a half-day training session,” States says. In addition to the pharmacy department performing the air monitoring, some larger hospitals turn to their infection control department, a dedicated quality unit, biosafety officer, or the health and safety department for assistance with this task. “In smaller operations, we typically find that managers do not have time to perform this function. They’ll train all staff members on using the instruments so the actual sampling can be done by whoever is available at the time. However, time is of the essence with compounding pharmacists no matter what the size of the operation is.”
“You can create a product free of microbial and/or particulate contamination in a controlled area only if you are using proper aseptic techniques and routinely monitoring the environment,” States says. A sterile preparation performed in an ISO 5 environment alone does not guarantee product sterility; this requires a combination of a controlled environment and well-trained staff. “However, you must keep in mind that low contamination rates one day does not guarantee that they’ll be at the same level the next day, which is why monitoring and proper technique is a continual requirement,” she says. “Pharmacists must establish internal guidelines that are designed to keep the product safe every single time.”
American Society of Health-System Pharmacists (ASHP), Bethesda, MD. Tel: (301) 657-3000; Web site: www.ashp.org
Baxa Corporation, Englewood, CO. Tel: (303) 690-4204; Web site: www.baxa.com
Biotest Diagnostics, Denville, NJ. Tel: (973) 625-1300; Web site: www.biotestusa.com
Clinical IQ, Florham Park, NJ. Tel: (973) 765-9393; Web site: www.clinicaliq.com
Controlled Environment Testing Association (CETA), Raleigh, NC. Tel: (919) 861-5576; Web site: www.cetainternational.org
Lab Safety Corp., Cumberland, WI. Tel: (800) 433-7698; Web site: www.valiteq.com