Misperceptions cloud the issue of sterile drug compounding
The clamor over the requirements of USP <797> is abating, but many pharmacies and healthcare facilities still feel they are being caught short in terms of the scientific, financial, and physical resources needed to comply with the standard.
By Bruce Flickinger
Compounding pharmacies, particularly those compounding sterile products, are increasingly under the regulatory eye. Once governed by a hodgepodge of state regulations, the industry has seen USP Chapter <797>: Pharmaceutical Compounding-Sterile Preparations emerge from an amorphous effort to standardize practices to the de facto industry standard in just a few years. Now there is the specter, albeit distant, of the Safe Drug Compounding Act, a draft Senate bill that would place the federal government (namely FDA) firmly in both the compounding pharmacy and the physician’s office. At press time, the bill had not been introduced and written comments were being received from numerous industry and special interest groups.
Preferring the carrot over the regulatory stick, the compounding pharmacy industry, and the healthcare community as a whole, is moving aggressively to police itself. While USP <797> is somewhat in flux, many of those affected by it are already girding for its impact instead of watching it develop and waiting for a clear mandate to comply. One manifestation of industry initiative is the Pharmacy Compounding Accreditation Board (PCAB), a group formed in 2004 to provide a profession-wide system of standards by which individual compounding pharmacies can test their quality processes.
Formed by six national pharmacy organizations, along with the National Association of Boards of Pharmacy and United States Pharmacopeia (USP), the PCAB tests and accredits pharmacies against standards, and notifies the public about which pharmacies have achieved accreditation. Thirteen pharmacies have been accredited to date, and about another 100 are currently undergoing the process. “We’re seeing a lot of enthusiasm,” says Ken Baker, executive director of the PCAB, based in Washington, DC. “Pharmacies want a set of national standards that they can meet voluntarily.”
Clearly, the intentions behind such efforts are good, but realistically, 13 accredited pharmacies nationwide is not a substantive number. And while many more quality-focused compounding pharmacies abound, the call has gone out from all invested parties for a tangible, nationally recognized mechanism that details the way sterile and high-risk pharmaceutical products should be compounded to optimally protect the safety and health of both patients and workers. USP <797> is the critical cog in this mechanism.
It’s easy to say that there’s much grumbling about the standard, but Baker is not seeing much consternation about USP <797> among the pharmacies pursuing accreditation. “Most of them already considered it to be a nationally recognized standard and were in the process of meeting the requirements,” he says. “There was some confusion when the standard first came out, but it’s been a long time since I’ve heard any complaints about USP <797>.” He is not alone in this observation.
“National standards like USP <797> will always be moving targets,” Baker adds. “There will always be revisions and changes, and pharmacies will have to meet them.”
Doing so is not a simple matter. As for PCAB accreditation, which requires compliance to USP <797> for pharmacies doing sterile compounding, Baker minces no words in saying it is “not an easy process. There are 10 standards to be accredited to and the pharmacy has to meet all 10 of them.” Following accreditation, there is a yearly application renewal and an on-site visit every three years. The revisit can take place before the three-year period if the application renewal reveals significant change in a pharmacy’s operations.
The pharmacy visit, called a survey, looks at two elements: what the pharmacy says it is doing and whether it is actually doing what it says it is. “We’ll follow back a filled prescription to see the process it went through to get there,” Baker says. “What a pharmacy is doing on a given day is just that: a snapshot of their operations. We need to see the policies and procedures that say they’ll be doing the same thing six months from now, or when new technicians are hired and trained.”
Baker acknowledges that, for many, it is expensive to meet the equipment and infrastructure upgrades called for in USP <797>. But if it’s too expensive to do so, he says, “then you ought not to be compounding. Come back when you can meet the standards.” He adds, “We’re already seeing pharmacies getting out of the business of sterile compounding because they don’t want to make the necessary investments to comply.
“Part of our mission statement is to bring everyone up to meet quality standards,” Baker says. “Free enterprise will decide who remains in business and who doesn’t. The public should be able to decide the best place to take their prescriptions.”
Up to par
One place that patients can feel confident about their compounded prescriptions is McGuff Compounding Pharmacy Services, in Santa Ana, CA. One of the first pharmacies in California to earn PCAB’s Seal of Accreditation, McGuff is a state-of-the-art, ISO-accredited pharmacy with seven pharmacists on staff. It produces a variety of medications, including sterile injections, troches, capsules, creams, suppositories, gels, solutions, and suspensions. Compliance to USP <797> has long been part of the company’s quality assurance program.
“For our business, USP <797> simply represents what we have been doing from the beginning: good compounding practices,” says director of pharmacy services William Blair, Pharm.D. He advises pharmacies that might be holding off on facing up to USP <797>, “The best strategy is to work with knowledgeable people and get it done. The key to success will be fully understanding the regulatory, engineering, and quality concepts for CSP [compounded sterile preparation] compounding.”
Blair shares the opinion that the fuss about the financial outlay involved in USP <797> compliance is largely misplaced. He feels the standard offers options for pharmacies to overcome budgetary, space, and structural constraints to meet the requirements. “If pharmacies and physician offices cannot comply with the stated standards, they should not be in the business of compounding sterile drugs,” Blair says.
He cites as one example the fact that the standard does not mandate the use of barrier isolator systems, as some people erroneously believe, but rather indicates that unidirectional, laminar airflow workbenches (LAFWs) are equally suitable for CSP work. “So, USP strikes a balance between current accepted practice [LAFW in an ISO 7 buffer zone] and emerging technology [compounding aseptic isolator systems],” Blair says. “In either case, USP provides guidance on the proper use, precautions, and personnel interactions with the indicated engineering controls.”
Clyde Buchanan, an Atlanta-based pharmacy consultant and expert on compounding sterile preparations, points out further means to mitigate the costs involved with compliance: the “judicious use” of compounding aseptic isolators (CAIs); centralizing sterile drug compounding in pharmacy; taking advantage of USP’s “immediate use” exemption and proprietary vial and bag systems; and outsourcing selected types of sterile drug compounding.
Equipment and environmental controls alone cannot ensure a safe, sterile product. Quality systems and properly trained technicians are key ingredients as well and are addressed in USP <797>. Numerous quality procedures and safeguards are in effect at McGuff. For a sterile compounding operation, vials are first washed in a multi-step, validated wash process and receive a final rinse with water for injection. The wash process is accomplished and controlled using qualified equipment and SOPs. Washed vials are then depyrogenated in a validated depyrogenation process. During aseptic filling, the compounded medications are passed through a bacterial retentive filter into the vial in an ISO 5 environment. As appropriate, a layer of sterilized nitrogen gas is placed on top of the liquid. A sterile stopper septum is then inserted and an aluminum seal is crimped to secure the stopper to the vial.
Samples of the finished medication are then sent to the chemistry and microbiology labs to be tested for foreign matter, potency, endotoxins, and sterility. If all results come back within acceptable limits, the finished medication is dispensed according to the indicated prescription.
“Our quality systems department ensures that all policies and procedures are current and effective, and are being used,” Blair says. “This department performs the finished medication testing and will release the finished medications if test results are within acceptable limits.” The quality department also performs environmental testing and ensures that all operators maintain their skills. Audits are conducted of the compounding processes. All employees receive extensive training in quality systems, current good manufacturing practices for pharmaceuticals, good compounding practices, and individual SOPs for which they are responsible.
“Training is extremely important and is a continual process at McGuff,” Blair says.
Protecting patients and pharmacists
Personnel training and protocol, and equipment and environment are both critical to the safe compounding of pharmaceuticals.
“Technique is the most important piece of sterile compounding, be it a chemo/HD [hazardous drug] or any sterile product,” says Luci Power, senior pharmacist and manager of Parenteral Support Services (PSS) at the University of California Medical Center-San Francisco (UCSF). “All individuals involved in any aspect of sterile or chemo/HD compounding must understand the issues and the systems in place to protect the compounder and the ancillary personnel in the areas.”
Power oversees a robust training and continuous monitoring program. One component: Technicians set up their batch or dose, but nothing is injected into the final container until a pharmacist checks the drug, diluent, final container, label, all calculations, etc. Once this check has been done, the technician can complete the compounding process. “This immediate supervision and direct observation is crucial to ensure that proper handling precautions are constantly in place. It’s a safety measure for the patient as well as the personnel,” she says.
Figure 2. Sterile fill operation at McGuff Compounding Pharmacy Services. Photo courtesy of McGuff Compounding Pharmacy Services.
While Kenneth Mead, research mechanical engineer with the National Institute of Occupational Safety and Health (NIOSH), concurs protocol and operator technique are of primary importance, he also believes part of that protocol and technique should include the use of properly selected engineering controls. “The best engineering control designs will provide an environment that reduces the probability of an adverse outcome when proper technique is not perfectly followed, and will do so without sacrificing the ability to reasonably conduct the work task,” he says. That being said, however, “improper technique can work counter to the protective benefits provided by engineering controls, and if the work practice is sufficiently poor, even the best engineering control design won’t help.”
Mead was involved with developing the NIOSH Safety Alert, “Preventing Occupational Exposure to Antineoplastic and Other Hazardous Drugs in Health Care Settings,” published in September 2004. Although the document does not carry regulatory weight, it incorporates the principles of USP <797>. Among its recommendations: “Prepare hazardous drugs in an area that is devoted to that purpose alone and is restricted to authorized personnel,” and “limit access to areas where drugs are prepared to protect persons not involved in drug preparation.”
These recommendations are based on evidence that potential acute and chronic health effects associated with occupational exposure to hazardous drugs, notably chemotherapy and antineoplastic agents, can be very serious, Mead says. Even with the protection of properly selected primary engineering controls, “the potential for exposure still exists due to accidents, surface contamination on products and packaging, equipment malfunctions, or lapses in proper work practice,” he says.
Not only are there concerns for the exposed worker who is handling the hazardous drug, but in a multi-occupant, multi-task environment, there is potential for secondary exposure of individuals who may not be aware of the risk. “Intervening steps that reduce or eliminate that opportunity for exposure should be considered,” Mead says. “By designating this work to occur in a specified, well-marked, access-controlled area, you reduce the number of persons potentially exposed and increase the hazard awareness of the individuals involved in hazardous drug compounding.”
This awareness extends beyond pharmacy personnel. Power, who is a member of the NIOSH Hazardous Drug Working Group that helped develop the NIOSH Alert, says there is ample evidence of hospital staff, including janitors and housekeepers, having a drug in their urine that they obviously did not mix or administer. “We think that this is touch contamination spread through contact with personnel, but a number of these drugs vaporize into the air and these could be moved through positive-pressure air handling systems,” she says. In addition, “contaminated aerosols or particles, such as in packaging or from a spill, pose a threat in a positive-pressure, recirculating environment,” even where isolators are in use.
Power is adamant that, aside from protecting patients, stringent containment controls are necessary to reduce worker exposure to hazardous drugs. With regard to product safety, the overarching recommendation for sterile compounding, she says, has been “a positive-pressure, recirculating environment that blows out of the compounding suite into the surrounding areas, and that the LAFWs are effectively sucking all the room air through their HEPAs.” However, hazardous drugs are another matter entirely, and this type of environment would allow for contamination of all equipment, supplies, and personnel if there is any contamination coming out of the primary control. “There are numerous published studies that document this surface contamination in chemo/HD compounding areas. A few of them tracked chemo/HD on floors and out into adjacent areas, onto carts, phones, computer terminals, and the like,” Power says.
The two infrastructure requirements in USP <797> generating the most comments and questions are 1) that rooms or areas for compounding chemotherapy and other hazardous drugs be segregated from the main cleanroom area; and 2) that barrier isolators-referred to as compounding aseptic isolators in USP nomenclature-do not, in themselves, provide adequate assurance of sterility and must be placed in an ISO 7 environment.
Buchanan is straightforward in addressing these areas of concern. He says that proposed changes to USP <797> require that hazardous drugs be compounded in a negative-pressure buffer room, while non-hazardous drugs must be compounded in a positive-pressure buffer room. Further, if the manufacturer of a CAI can prove that the isolator provides complete separation from the surrounding environment during dynamic operations, the isolator does not have to be placed in an ISO 7 cleanroom. “If the isolator is dedicated to hazardous drug compounding, it cannot be in the same room with other primary engineering controls used for non-hazardous drugs,” he adds.
Figure 4. A pharmacy technician loads pharmaceutical stock into the RIVA automated station. Photo courtesy of RIVA Systems.
One point of interest, particularly for equipment manufacturers, is that USP is focused on assessing and qualifying equipment performance in operation-not just out of the box or at the factory. “USP is interested in dynamic operating conditions,” Buchanan says. “This is the best way to validate that the compounding system as a whole works according to a user’s expectations. You want to know how the room performs while the work is actually being done.
“Manufacturers of compounding aseptic isolators embraced the first version of USP <797> because it tended to encourage the use of isolators as alternatives to building cleanrooms,” Buchanan says. “But I am not aware of any makers of compounding aseptic isolators that have advertised that their units provide complete separation from the surrounding environment during dynamic operations.”
Isolation or open architecture
In many respects, which primary engineering control to use-a LAFW or a CAI-is the key guide to budgetary and engineering decision making for most compounding operations. Uniform equipment testing standards have not yet been adopted industry wide, although testing guidelines have been advanced by several associations and industry groups, such as the Controlled Environment Testing Association.
“I believe most, but probably not all, of the available CACIs [compounding aseptic containment isolators] currently on the market would meet the performance recommendations in the NIOSH alert,” Mead says. “The response among equipment manufacturers has been terrific in quickly bringing effective CACIs to the marketplace. The main thing lacking at this point is a uniform performance or testing standard by which all CACIs would be evaluated.” Such a standard ideally would address both the containment issues of the NIOSH alert as well as the asepsis requirements of USP <797>.
Power opines, “There is no question that isolators require more technician training and constant monitoring of work practices, and are not as efficient as open workstations.” However, “barrier isolators can prevent some of the corner cutting that compounders can get away with in open workstations. They enforce organization and prevent jumping from one task to another.” A technician at a biological safety cabinet (BSC), for example, can stop to answer the phone and then go back to compounding without cleaning their gloves; this couldn’t happen with an isolator because the gloves are attached to the unit. On the other hand, “the gloves in an isolator must be changed regularly and this is an expense as well as a potential breach of the integrity of the equipment,” Power says.
“Barrier isolators are a good technology when they are truly necessary,” says Daniel Jacobs, executive director of Haddad-Wylie Industries, LLC (HWI), in Pittsburgh, PA. “Pharmacies are looking at the cost of renovating or upgrading, and saying, ‘Instead of spending $300 a square foot to build a cleanroom, we’ll just spend $8,000 on an isolator.’ But the isolator still needs to be in an ISO 7 room that is buffered by an ISO 8 anteroom,” according to proposed revisions to the standard.
“We recommend isolators only where people are compounding very low amounts of chemo or other toxic drugs,” Jacobs continues. “If you’re compounding more than 15 drugs each day, the isolator can be cumbersome for the technicians. Compounding is a long, arduous process, and the operator doesn’t want to have his hands in an isolator all day long.”
Jacobs’ company takes an “open-architecture” approach to sterile compounding rooms that eliminates the need for LAFWs. Instead, a bay of HEPA filters is built into the ceiling grid above the compounding work table, with a suspended air return running behind the wall. The cleanroom walls are coated with a product called Bioguard, an 80-mil thick PVC laminate commonly found in pharmaceutical facilities.
“The approach eliminates the need for bulky hoods that can harbor microbial growth,” Jacobs says. “We have been able to achieve ISO 4 and 3 certification on the workbench, where only ISO 5 is required.” HWI has installed cleanrooms at several pharmacy facilities, including the Duke University Medical Center and the University of Pittsburgh Medical Center.
Chemotherapy and other hazardous drugs obviously call for additional precautions. Jacobs’ experience has been that many of the hospitals that are compounding chemotherapy drugs have incurred considerable costs complying with USP <797> and NIOSH requirements. Per NIOSH, BSCs are to be vented (100% HEPA filtered) to the outside with no windows located above the exhaust, which usually means the vent is exhausted through the roof. “Often times the BSCs are located in the basement of the hospital, which can lead to a very cost-prohibitive exhaust system,” he says. An alternative according to Jacobs is an oxidizing (scrubbing) system that is in accordance with NIOSH requirements and thus complies with USP <797>. “This can save the hospital a lot of money by eliminating the exhaust system, and at the same time actually scrubs the toxic chemicals and better protects the public from the otherwise exhausted chemo,” Jacobs says.
The HVAC system is the cornerstone to any clean environment, Jacobs and others say. “We ideally want to see a dedicated HVAC system for the cleanroom, and while there may be an initial expenditure for the hospital to achieve this, there are savings in the long run,” he says. “A facility can save $10,000 to $12,000 a year with a well-engineered HVAC system.”
Power can attest to the importance of an optimally functioning HVAC system. “We’re set up to do batch chemo but have had continuing problems with our exhaust system that have delayed implementing this service,” Power says. “We added two floors to our three-floor building; our motor-blower, HEPA bank, and ductwork that support our negative-pressure HD compounding room are on the roof, so this has been problematic. The motor and ducts had to be upgraded and the system has not yet been re-balanced to operate.”
The UCSF PSS facility, which is USP <797> compliant, employs two pharmacists and three technicians, who compound total parenteral nutrition (TPN) solutions, continuous renal replacement therapy (CRRT) solution bases, batch intermittent IV antibiotics, batch electrolyte replacements, and other batch preparations. Output is an average of 40 TPNs per day and 50 CRRT bags, with other compounding amounting to roughly 2,200 units per month.
The negative-pressure (chemo or HD) room is designed as an ISO 8 room housing 2x6-foot exhausted CACIs. Elsewhere in PSS, the positive-pressure cleanroom is ISO 7 and contains a 2x8-foot and a 2x6-foot horizontal laminar airflow hood, and one 6-foot positive-pressure, recirculating isolator. The two cleanrooms share a HEPA-filtered anteroom. “All air technically goes into the HD room, but as it is filtered and controlled by sliding glass doors, the room stays at ISO 8,” Power says.
PSS is certified by an independent agency every six months, including all the equipment and the cleanrooms. Technicians are tested yearly for aseptic technique using a tryptic soy broth (TSB) test system of multiple manipulations. All compounding technicians perform a QC test bag daily with the automatic compounding device, and that test bag is filtered and inoculated with TSB as part of ongoing quality assurance.
Future plans for UCSF’s pharmacy system include the use of two automated, robotic compounding stations from RIVA Systems, in Winnipeg, Canada. The RIVA is an enclosed, ISO 5 robotic system for preparing IV admixtures. It fully automates the preparation of syringe and bag doses in multiple combinations and sizes, producing up to 800 labeled, patient-specific or batch doses per eight-hour shift. “The system requires that syringes have needles attached and placed into a carrier in an ISO 5 environment before being placed into the carousel,” Power says. “From there it draws the compound and completes all the remaining steps.”
Such equipment could well figure into the future of many pharmacies that compound sterile and high-risk drugs. But equipment and engineering are only one aspect of USP <797>’s current iteration that has generated comment and is being addressed. Other areas include beyond-use dating and appropriate storage parameters for compounded drugs, and standardized definitions and terminology. People involved in the revision process almost unanimously agree that definitive statements are needed most urgently on these topics.
As USP <797> is a work in progress, preparedness for and perception of it varies among compounding pharmacies throughout the country. Observers say it is a good sign that those adopting a “wait and see” posture are becoming the minority. They will likely be caught wanting-both technologically and economically-as the standard undergoes further refinement and becomes further ingrained in best pharmacy practice.
“Some hospitals tend to get out in front of the requirements, while others take a reactive approach, watching the revisions and waiting until something becomes concrete and enforceable,” Jacobs says. To this latter group he cautions, “Each revision to the standard is only going to get cleaner. It’s not going away, and the requirements aren’t going to get any dirtier.”
Resources and contacts
Haddad-Wylie Industries, LLC (HWI)
4143 Brownsville Rd.
Pittsburgh, PA 15227
Pharmacy Compounding Accreditation Board
1100 15th St. NW
Washington, DC 20005
12-75 Scurfield Blvd.
Winnipeg, Manitoba R3Y 1G4, Canada
The current version of USP <797> marked up with proposed revisions is available on the USP web site, at http://www.usp.org/pdf/EN/USPNF/PF797redline.pdf.
The NIOSH Safety Alert, “Preventing Occupational Exposure to Antineoplastic and Other Hazardous Drugs in Health Care Settings,” is available on the NIOSH web site, at http://www.cdc.gov/niosh/docs/2004-165/.
Three CETA standards for pharmaceutical compounding (CAG-001-2005 “Use Of Compounding Isolators in Compounding Sterile Preparations in Healthcare Facilities,” CAG-002-2006 “Compounding Isolator Testing Guide,” and CAG-003-2006 “Certification Guide for Sterile Compounding Facilities”) are available on the Controlled Environment Testing Association web site, at http://www.cetainternational.org.