Recent developments in outsourced compounding reinforce the need for immediate and complete compliance with the provisions of USP <797>. The USP anticipated the possibility of such events when it stated in the chapter that “it is generally acknowledged that direct or physical contact of critical sites of CSPs [compounded sterile preparations] with contaminants, especially microbial sources, poses the greatest probability of risk to patients.”1 To address these risks, USP <797> contains provisions for performance standards for CSPs as well as compounded sterile hazardous drug preparations. Likewise, NIOSH and the ASHP have recommendations for ventilated equipment standards for preparation of compounded sterile hazardous drugs.2,3
Engineering and industrial hygiene—ie, health-based engineering and monitoring—can help pharmacy directors achieve compliance with USP <797> standards, as well as NIOSH and ASHP recommendations. Industrial hygiene, which traditionally has focused on worker exposure assessments, provides the interface between engineering and pharmacy to help the latter with implementing the proper equipment and procedures to achieve compliance with USP <797> and minimize staff exposure to hazardous drugs. A successful USP <797> compliance program, therefore, will utilize information gleaned from industrial hygiene/engineering surveys, including gap analysis, a ventilation checklist, and employee training and competency testing.
While USP <797> may appear stringent at first glance, it presents minimum goals that must be met. For example, the expectation for twice-a-year environmental testing does not preclude the possibility that an intervening event may occur that will elevate particulate and/or microbial levels. Thus, many hospital pharmacies have instituted more frequent environmental testing, based partly on the premise that a six-month interval between environmental sampling is too long, in order to ascertain that no adverse impacts are causing exceedances.
Designing a USP <797>-Compliant Pharmacy
Pharmacy industrial hygiene and engineering starts with the facility design. When a new or renovated pharmacy facility is being planned, it is critical that pharmacy staff participate on the hospital committee that addresses design and construction with regard to TJC Environment of Care and USP standards dealing with sterile compounding. The pharmacy needs to have a team in place to interface with facilities and engineering in the proper design and planning of the compounding workspace, including the primary engineering controls (PECs) (ISO Class 5), buffer areas (ISO Class 7) and ante areas (ISO Class 8). While engineering will take the lead in HVAC compliance issues, and facilities will head the architectural design process, pharmacy’s role is to provide input regarding workflow requirements. The pharmacy director must be involved with the layout and design starting in the design phase, not the construction phase, because once the construction commences it will be much more difficult, and more expensive, to make changes in the facility. For example, we witnessed a case where a disconnect between the hospital pharmacy and the engineering design team led to a change in placement of supply air diffusers and HEPA filters, resulting in an increased burden of particulates and microbes in the chemotherapy compounding area.
The best designed and most compliant pharmacies tend to be those where knowledgeable pharmacy personnel have had input in the design, workflow, and cleaning procedures. To achieve this, begin by creating a workflow diagram showing the facility layout with regard to the stocking, filling, compounding, transfer, and waste management operations. Focus on designated storage and supply procurement areas, as well as personnel selected to bring in the supplies. The procured products should be accessible to the anteroom or designated storage area, in which the assigned staff passes the products through to the compounding personnel. At no time should compounding personnel come out of an ISO Class 5 area to an ISO Class 7 or 8 area to procure product. Personnel always must flow from more clean to less clean, and not vice-versa. When planning a renovation or constructing a new pharmacy, it is helpful to role play work scenarios with staff regarding the storage and disposal areas, as well as traffic routes.
Engineering Requirements of USP <797>
An understanding of the engineering requirements of USP <797>, including both the devices and the engineering principles involved, provides pharmacy directors with the information needed to make important layout and design decisions for the pharmacy facility. In addition, this information helps pharmacy present a case to hospital administration in support of facility improvements. Start with the practical application and placement for compounding usage of laminar airflow workbenches (LAFWs), biological safety cabinets (BSCs), barrier isolators, compounding aseptic isolators (CAIs), and compounding aseptic containment isolators (CACIs).
According to USP <797>, BSCs are defined as cabinets for CSPs that provide personal, product, and environmental protection. They have an open front for inward airflow, downward HEPA laminar airflow, and HEPA-filtered exhaust. Inflow and downflow velocities should remain constant. BSCs typically meet NSF/ANSI Standard 49 requirements for biosafety cabinetry.4 A CAI is defined as an isolator for compounding pharmaceutical ingredients or preparations, with an aseptic compounding environment maintained throughout the process. Incoming air must pass through a microbially retentive filter, which shall at a minimum meet HEPA filter standards. A CACI is designed to protect both the sterile compounding solution as well as the worker. Because volatile drugs are prepared in this apparatus, exhaust air must be removed by proper building exhaust ventilation. Placement of all of these devices should reflect a logistical consideration of pharmacy workflow requirements and exhaust configurations.
HEPA filtration principles for control of particles also are important. USP <797> requires HEPA-filtered air to be supplied in ISO Class 5 areas at a velocity sufficient to move particles away from the compounding area and to maintain unidirectional airflow during the compounding process, and that PECs maintain at least ISO Class 5 conditions for 0.5 μm-diameter particles throughout the compounding of CSPs. Pharmacy should verify with engineering that the appropriate specifications for velocity and airflow have been achieved, and request data on air exchange rates and particle counts from the certifiers and engineering on a regular basis in order to confirm that the appropriate ISO class areas are compliant, and to help ensure the health and safety of pharmacy staff.
It is essential that both pharmacy and engineering maintain policies and procedures (P&Ps) for meeting the requirements of USP <797>; these should include guidelines on operation, maintenance, and inspections of the various types of ventilation controls (LAFWs, etc), as well as a log of any exceedances or downtime. This forms a redundant system to ensure that any ventilation-related problem can be cross-referenced with the appropriate action and date.
While creating protocols through P&Ps is an excellent starting point, ensuring that they are followed consistently is equally important. Be sure your P&Ps include training on how engineering controls operate, include a checklist that assists in tracking PEC certification dates (see sidebar, Jump-start <797> Compliance), and confirm staff competency in proper use of personal protective equipment and safe operation of cleanroom devices.
Leveraging Internal Resources
Creating P&Ps to ensure the maintenance of industrial hygiene standards may seem a daunting task. However, by drawing on the existing expertise in your hospital—engineering, facilities, microbiology/infection control—a team approach can address these challenges. For example, in addition to regular maintenance and cleaning, filtration monitoring is necessary to ensure engineering controls are operating effectively. Look to your certifier to provide advice on the operation, cleaning, and replacement of HEPA filters. Water should be tested and treated for organisms such as Legionella, Pseudomonas, Sphingomonas, and Acinetobacter, all of which can potentially contaminate pharmaceutical compounds. The pharmacy director should refer to hospital P&Ps for water testing, but should provide his or her input as well.
While pharmacy is responsible for cleanroom cleaning and following the detailed USP <797> direction regarding cleaning products (eg, 70% sterile isopropyl alcohol [IPA] to clean surfaces), the engineering and/or facilities departments must maintain a P&P manual to address cleaning procedures and verification of such procedures for the larger engineering-related items such as air handling units, chillers, etc, that might impact pharmacy, as well as smaller related items such as diffusers for supply and return air in pharmacies. Working with engineering, pharmacy can develop a simple checklist of items to inspect on a routine basis, including LAFWs, BSCs, barrier isolators, and supply and return air diffusers.
USP <797> provides excellent sampling protocols and procedures for surface and air sampling. Likewise, NIOSH is an outstanding resource for sampling for exposure to hazardous drugs. It is essential to have a quality assurance/quality control (QA/QC) plan for verifying that appropriate concentrations of particulate matter and microbes are maintained, and what measures to take if limits are exceeded. Pharmacy can join with microbiology and/or infection control on monthly rounds to discuss cleanliness levels, which can only be verified by direct surface testing for microbes. Outside labs can serve as a resource for analyzing surface and air samples, if you do not have this expertise in house.
It is important for compounding staff to review the USP <797> listing of critical sites that could become contaminated during sterile compounding. These may include vial septa, injection ports, and opened ampules. All compounding staff should demonstrate familiarity with the processes of cleaning and sanitizing of workspaces and surfaces, as well as the deactivation of hazardous drugs. When employees understand how the cleanliness of engineering controls and other sites impacts sterile compounding, they are more likely to accept the measures needed to achieve USP <797> standards.
Pharmacy workers must undergo training, retraining, and competency testing regarding the provisions of USP <797>, including handling of hazardous drugs as CSPs. QA/QC procedures must be in place to ensure that CSPs are not and cannot become contaminated with bacterial endotoxins and/or particulate matter, per USP <797>, regardless of whether such preparations are low-, medium-, or high-risk. Given the risk of particulate airborne concentrations and microbial levels to adversely impact CSPs, it is important to outline the levels of particulates and microbes that are causes for action and educate your staff on these parameters. Also include a policies and procedures section for verification of the environmental sampling mandated by USP <797>, as well as fingertip sampling.
Control of environmental conditions is vital for full compliance with USP <797>; this includes hazardous drugs as well as CSPs. Engineering and industrial hygiene checklists can help ensure that these conditions are achieved, both in terms of protecting the sterility of the compounds as well as protecting the health of employees.
Farrell Melnick, PhD, MS, is president and founder of Melnick Scientific, a consulting firm focused on reducing infections in health care due to contaminated pharmaceutical products and microbial growth and proliferation in water and ventilation systems in health care facilities. Melnick Scientific also focuses on toxicological and industrial hygiene evaluations to assist in protecting workers in health care and other industries. Farrell received a PhD in environmental engineering from Columbia Southern University, an MS in pharmaceutical chemistry from Duquesne University, and an MS in industrial hygiene from the University of Pittsburgh. He is trained in toxicology (particularly inhalation) and has performed both toxicological and cancer research.
Batya Moses van Messel, MS (Hyg.), is executive assistant and senior project manager with Melnick Scientific, specializing in chemical hazard assessment. She has performed environmental assessments, facilities audits, laboratory analysis of contaminated environmental media, and regulatory consulting for a wide variety of clients. Batya attended the University of Pittsburgh Graduate School of Public Health where she worked identifying immune responses of workers exposed to industrial allergens.
Bernard D. Silverstein, MS, CIH, is a senior consulting industrial hygienist at Melnick Scientific. He is a certified industrial hygienist (CIH) with over 30 years of experience working for both government and private industry, specializing in regulatory compliance, risk assessment, and health and safety management systems. Bernard is a member of the American Industrial Hygiene Association (AIHA) Exposure Assessment Strategies Committee and an AIHA Distinguished Fellow. He is a contributing author of A Strategy for Assessing and Managing Occupational Exposures 3rd Ed, and principle author and editor of The AIHA Value Strategy Manual.
Limiting Hazardous Drug Exposure*
To keep workplace exposure to hazardous drugs at a minimum, conduct a hazard analysis of such drugs, as found in the 2012 NIOSH list, to identify ways by which exposure may occur, and perform an assessment to estimate potential and actual staff exposure to hazardous drugs. Include a provision for assessing acceptable air quality and associated ventilation controls to ensure that the environmental quality objectives in USP <797>, along with NIOSH recommendations, are met. The key components of a hazardous drug assessment program are:
*CDC (NIOSH). NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2012. http://www.cdc.gov/niosh/docs/2012-150/pdfs/2012-150.pdf. Accessed January 18, 2013.
Relying on Outside Expertise
> Ventilation equipment should be commissioned prior to operation to confirm that the systems meet the expected objectives. A certification contractor is an excellent resource for pharmacy, given their expertise in ensuring proper function of the cleanroom engineering controls. Consider including your certification contractor in the design phase, as they may have valuable input regarding the proper layout and coordination of demarcated areas, such as the ISO Class 7 buffer with the associated PEC and ISO Class 8 ante areas. When choosing a certification contractor, consider the standards followed; for example, certification of Class 2 BSCs adheres to NSF/ANSI Standard 49. Ensure your field certifiers are currently accredited through NSF International. In addition, certifiers should be accredited through the Controlled Environment Testing Association (CETA) certification program to ensure they possess baseline qualifications. (See James Wagner’s “Choosing a Certification Professional to Evaluate Your Cleanroom and Engineering Control” in the July 2009 issue of PP&P for more information.)
It is also helpful to be comfortable interpreting the basics of a hood certification report. For example, a report of a Class 2 BSC would include tests for downflow and inflow velocity, HEPA filter leaks, airflow smoke patterns, cabinet integrity, etc. Keep in mind that a noncommissoned or improperly certified piece of equipment provides a false sense of security and is a potential disaster waiting to happen.
Jump-start <797> Compliance
Pharmacy directors can boost compliance with USP <797> and its associated engineering and industrial hygiene aspects by adopting the following measures:
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