Hospital pharmacy management is fraught with many overlapping priorities and over the past several years, these priorities have been complicated by the multifaceted problem of prescription drug shortages. While shortages are generally attributed to manufacturing problems, the FDA’s review of medical product shortages1 sheds more light on the problem:
- Drug shortages in the US tripled, from 61 in 2005 to 178 in 2010
- Of 127 drug shortages studied in 2010-11, 80% involved sterile injectables
- Most sterile injectables have one manufacturer that produces at least 90% of the drug
These issues point to complex problems that are not likely to resolve themselves anytime soon. Therefore, to ensure the health and safety of our patients, we must develop coherent strategies to provide high-quality care for our patients in an era where shortages have become the norm. To accomplish this, the most logical steps are to maximize the capacity of available medications, limit waste, and make use of provisions enabled through USP and TJC.
Keep Processes Close to Home
One approach to weathering a drug shortage is to maximize the utilization of the existing supply of that drug in the safest and most efficient way possible. If a new drug shortage affects an injectable product, or components of that product, one method of stretching available resources is to directly compound the product in-house. Direct compounding can be advantageous in such a situation, as it gives pharmacy control of the product, assuming the compounding activities are performed in a properly configured and maintained cleanroom. However, since drug shortages often occur without warning, determining proper beyond-use dating (BUD) and selecting a single, standard dose may not be possible. Inconsistent BUD practices and a lack of standardized dosing often leads to an increase in wasted products, further exacerbating the effects of a shortage.
Many organizations develop complex algorithms or decision trees to aid their clinical and procurement personnel in navigating the daily issues related to drug shortages. Attempting to bring standardization to the management of shortages is a worthy goal, but given that compounding sterile preparations is a complex science governed by statutes, rules, and regulations that do not allow variances simply because a drug is in short supply, these decision trees often have weak root systems. Put simply, we cannot increase our risk tolerance for CSPs in an attempt to stretch a limited drug supply.
Rather than ignore prevailing regulations and best practices, consider exploring the flexible options within existing compounding regulations to maximize limited drug supplies. One such option is to employ the immediate-use exemption of USP <797>, where appropriate. This method can be quite helpful in conserving valuable products, but does require a thorough understanding of how it can be applied to your specific situation.
The Immediate-Use Provision
The committee of experts who prepared USP <797> were acutely aware of the evolving nature of safe and effective sterile compounding. Therefore, from its inception, USP <797> contained exemptions intended to guide providers through the complex issues associated with the preparation and administration of sterile drugs in environmental conditions outside of ISO Class 5 or better. The preparation of drugs under less than ideal environmental conditions increases the likelihood of microbial contamination, and delaying the administration of a contaminated CSP by even a few hours increases the potential for clinically significant microbial colonization and thus for patient harm, especially in critically ill or immuno-compromised patients. To exert the necessary control over the practice of immediate-use CSPs, USP <797> established specific criteria for the implementation of this exemption.
Defining an Immediate-Use CSP
As stipulated in Chapter <797>, the immediate-use provision is intended only for those situations where there is a need for emergency or immediate patient administration of a CSP. Such situations may include cardiopulmonary resuscitation, ED treatment, preparation of diagnostic agents, or a need for critical therapy where preparation of the CSP under the conditions described for low-risk level CSPs would subject the patient to additional risk due to delay.
Immediate-use CSPs are not intended as a vehicle for the storage of doses or for anticipated needs, regardless of the time period of storage, nor is this exemption intended for any type of batch compounding or dividing of doses from larger packages. The chapter is quite clear that immediate-use CSPs are meant for use with a single patient with a strictly urgent need proposition and should be made using simple, low-risk manipulations. To that point, USP <797> clearly stipulates that medium- and high-risk level CSPs shall not be prepared as immediate-use CSPs.3 Furthermore, in order to comply with USP <797> and to qualify under its immediate-use exemption for low-risk level CSPs, the following criteria must be met:
- The compounding process involves simple transfer of not more than three commercially manufactured packages of sterile nonhazardous products or diagnostic radiopharmaceutical products from the manufacturers’ original containers and not more than two entries into any one container or package (eg, bag, vial) of sterile infusion solution or administration container/device.
- Unless required for the preparation, the compounding procedure is a continuous process not to exceed one hour.
- During preparation, aseptic technique is followed and, if not immediately administered, the finished CSP is under continuous supervision to minimize the potential for contact with nonsterile surfaces, introduction of particulate matter or biological fluids, mix-ups with other CSPs, and direct contact of outside surfaces.
- Administration begins not later than one hour following the start of the preparation of the CSP.
- Unless immediately and completely administered by the person who prepared it or immediate and complete administration is witnessed by the preparer, the CSP shall bear a label listing patient identification information, the names and amounts of all ingredients, the name or initials of the person who prepared the CSP, and the exact one-hour BUD and time.
- If administration has not begun within one hour following the start of preparing the CSP, the CSP shall be promptly, properly, and safely discarded.
TJC and Immediate-Use CSPs
TJC’s accreditation standards for medication management (MM) cover the practice of emergency preparation of a drug product under MM.05.01.07, which focuses on an organization’s ability to safely prepare medications for its patients. Specifically, MM.05.01.07, EP 1, prohibits non-pharmacist staff from mixing CSPs in non-emergency situations, especially on nursing patient units, and EP 2 states that regardless of urgency, staff must use sterile technique and maintain clean, uncluttered, and functionally separate areas for product preparation. Despite this, examples of physicians, anesthesiologists, and other allied health professionals being cited under this standard during a survey are common and this trend continues to grow. The uptick in the number of such citations can be attributed to such factors as TJC’s overall focus on patient safety, well known media reports of medication errors due to contaminated CSPs, as well as health care organizations’ expanding utilization of automated dispensing cabinets (ADCs).
Increasing dependence on ADC technology has had a monumental impact on daily pharmacy practice, specifically on how drugs, devices, and supplies are provided to patients. In December 2008, TJC issued a Sentinel Event Alert4 confirming that of all the technologies discussed, ADCs had the largest installed base with 83% of US hospitals employing some form of these systems. In their own survey, the Institute for Safe Medication Practices (ISMP) found an even higher adoption rate (94%) of ADCs, and of those facilities, over half (56%) use ADCs as their primary means of drug distribution.5
ADCs and Immediate Use
While utilizing ADCs can help facilities comply with TJC regulations regarding the safe and secure storage of medications, often TJC will find issues with the implementation and configuration of these cabinets. For example, if ADC configuration does not allow routine CSPs to be stored as finished units (ie, unit-of-use) that a physician or nurse can remove and administer directly to a patient without further compounding, then the only alternative is to remove the drug vial, diluent, and syringe from the ADC and compound it at the patient’s bed side. If this latter scenario is enacted in response to a true immediate-use situation, then it should conform to the prevailing statutes, rules, and regulations of USP <797>, as well as TJC standards. However, if compounding at the bedside—outside of ISO Class 5 or better conditions—in this manner is routine practice, then it is, by definition, inappropriate. Ultimately, CSPs must be stored in ADCs as finished units unless the components are to be used in a true immediate-use scenario. Although reconfiguring ADC dispensing drawers will require a commitment of time and perhaps expense, the benefits in efficiencies and compliance to prevailing regulations justify the effort.
Ensure True Immediate-Use Processes
True immediate-use administration of CSPs carries with it some degree of risk, so careful review of existing policies and procedures (P&Ps) governing the overall production of these CSPs should be executed to mitigate risk. An overall CSP contamination risk-reduction strategy should include the following elements:
- A comprehensive hand hygiene training program: Touch contamination is a primary concern for all CSPs, so all compounding personnel must be trained and evaluated in avoiding touching critical sites, especially during immediate-use situations. Training procedures, employee evaluation, and process documentation of these activities must be reviewed annually.
- An aseptic technique competency evaluation and training program: All compounding personnel must be evaluated for proper aseptic technique and related practice competency upon hire and annually thereafter. Documentation of these activities also is required by USP <797>.
- Maximizing the use of commercially available or ready-to-use (RTU) dosage forms: Utilization of these dosage forms will minimize the need to produce CSPs in-house, thereby reducing risk. To enable this, a thorough formulary review should be conducted, including care protocols and standard dosing, to maximize stocking of available RTU products. RTU options include outsourced CSPs, pre-filled syringes, dual chamber doses only requiring activation, as well as any other commercially available pre-mixed dosage forms.
An organization’s use of proprietary bag and vial systems also qualify as RTU dosage forms, as activation of these systems is not considered compounding; rather, according to USP <797>, use is guided by the manufacturer’s recommendations for each proprietary system. RTU dosage forms are highly viable options for the provision of therapy, especially where ADCs are the primary source of drug distribution.
[Note: Careful review of manufacturer documentation prior to preparation of proprietary RTU systems is essential for safe use. If manufacturer documentation does not specifically address under what environmental conditions the proprietary RTU system is to be prepared, then USP <797> guidance must be followed for their preparation and BUD determination.]
- Employing needleless connection devices: For drug therapies that cannot be acquired in RTU form, or for therapies that must be compounded immediately before patient administration, the use of commercially available vial adaptor and connector systems should be considered as a lower-risk alternative to traditional mixing methods (eg, reconstitution or mixing with a needled syringe).
Implementing a comprehensive, organization-wide immediate-use training program, which takes into account all of these factors, will help your organization reduce the risk of patient harm from contaminated CSPs, as well as comply with all prevailing government statutes, rules, and regulations.
Selecting an Appropriate Vial Adapter and Connector System
Selection of the most suitable connection system for your facility must be a careful, comprehensive, and multidisciplinary process. Since no system can account for every immediate-use or emergency situation you may encounter, the final system selected should cover a variety of applications and be the most user-friendly for your operation.
Key Considerations For Vial Adapter and Connection Systems
- Device quality and safety record
- Overall system ease-of-use (based on safety, efficiency, and ease of operation)
- Type and number of parts required to operate system
- Flexibility to use device in multiple situations without having to purchase additional parts or pieces
- Overall cost to operate the system, including per-device cost
- Manufacturer support for customer service and training
Once implemented, periodic usage evaluations will ensure all end-users are happy with a system that meets all organizational needs. These evaluations should be included in annual training and review processes to prevent compliance exposures for the organization and to ensure the best possible patient care and employee satisfaction.
It is important to remember the choice of RTU dosage forms for immediate-use ADC stocking may not be the same devices chosen for use in the pharmacy department. Most proprietary bag and vial systems are intended to be initially prepared by the pharmacy in a controlled environment as a regular part of their RTU drug distribution. The nurse then activates the system immediately before administering the product to a patient. Therefore, it is not a requirement that the vial adapter and connector system used for immediate-use compliance throughout the organization be the same as what is in use for pharmacy distribution. In fact, there is a rationale that using different systems for these two very different applications may help avoid confusion in determining BUDs for CSPs.
Keep in mind that USP General Chapter <797> does not endorse any specific drug product, compounding method, or medication administration device. However, it does cover the use of these proprietary systems within the Storage and Beyond-Use Dating section of the chapter.7 It is quite clear in this section that any of these administration systems should be used according to manufacturer instructions for handling and storage, especially when determining correct general use and proper beyond-use limits. Similarly, TJC is not in the business of approving or endorsing any specific devices or supplies; rather, TJC develops performance standards to assist its 19,000 plus members in providing the highest quality care. Ultimately, if used properly, each of the currently available proprietary systems can offer a measure of compliance to the overall quality of a CSP program, but none have been approved or endorsed by either the USP or TJC.
Recent nationwide drug shortages have impacted the compounding of sterile drug preparations as profoundly as any area in the modern health care continuum. However, the development of safe and compliant strategies for maximizing limited resources cannot come at the expense of increased patient risk or regulatory non-compliance. Maximizing the immediate-use exemption within USP <797> may alleviate some of the pressure of managing shortages, but only when executed within a properly designed and implemented CSP program. As a safer alternative to expanding BUD determinations of compounded CSPs beyond where they are supportable and appropriate, the proper employment of the immediate-use provision of USP <797> can assist in providing vital drug therapy to patients.
References—All Web addresses accessed August 6, 2012
- US Food and Drug Administration. A Review of FDA’s Approach to Medical Drug Product Shortages. October 31, 2011. www.fda.gov/DrugShortageReport
- USP <797> Guidebook to Pharmaceutical Compounding—Sterile Preparations. <797> Pharmaceutical Compounding—Sterile Preparations. Introduction, p. 27. © 2008 The United States Pharmacopeial Convention.
- <797> Pharmaceutical Compounding—Sterile Preparations. Immediate-Use CSPs, p. 36. © 2008 The United States Pharmacopeial Convention.
- The Joint Commission. Sentinel Event Alert. Safely implementing health information and converging technologies. Issue 42, December 11, 2008. www.jointcommission.org/assets/1/18/SEA_42.pdf
- ISMP. Medication Safety Alert! ADC survey shows some improvements, but unnecessary risks still exist. January 17, 2008. www.ismp.org/newsletters/acutecare/articles/20080117.asp
- Centers for Disease Control and Prevention. Guideline for Disinfection and Sterilization in Healthcare Facilities, 2008. www.cdc.gov/hicpac/pubs.html
- <797> Pharmaceutical Compounding—Sterile Preparations. Storage and Beyond-Use Dating: Proprietary Bag and Vial Systems, p. 59. © 2008 The United States Pharmacopeial Convention.
Lou Diorio, RPh, (left) and Dave Thomas, MBA, RPh, (right) are the principals of LDT Health Solutions, Inc (LDT). A nationwide medication safety and total quality management firm, LDT specializes in controlled process and quality management strategies for the health care community. LDT also provides consulting services for USP <795> and <797>, and regional compounding service models including hazardous drug compounding, nuclear medicine, and automated compounding devices. Lou and Dave can be reached at LSDiorio@LDTRx.com and DThomas@LDTRx.com, respectively.
Tenets of USP General Chapter <797>
It is important to note that the objective of USP General Chapter <797> Pharmaceutical Compounding – Sterile Preparations is to describe conditions and practices to prevent harm, including death, to patients that could result from:
- Microbial contamination (nonsterility)
- Excessive bacterial endotoxins
- Variability in the intended strength of correct ingredients that exceeds either monograph limits for official articles or 10% for nonofficial articles
- Unintended chemical and physical contaminants, and
- Ingredients of inappropriate quality in compounded sterile preparations (CSPs).2
To achieve these five objectives, Chapter <797> provides minimum practice and quality standards for CSPs based on current scientific information and best sterile compounding practices. These objectives must be taken into account when performing any type of sterile preparation compounding, as they are enforceable by State Boards of Pharmacy and the FDA. Accreditation organizations will uphold these standards during the survey process as well.
Immediate-Use Training Program Basics
A well-designed immediate-use training program should include the following key elements:
Competency-based learning modules for the following skills:
- Standard Precautions6
- Hand hygiene, garbing, and gowning
- Aseptic technique for drug handling
Educational resources for all RTU and proprietary bag and vial systems in use in the organization
- Instructional wall charts
- Directions for use
An organizational P&P covering proper use of any vial adapter and connector systems in use
- Directions for proper, safe use and disposal
- Instructional wall charts
- Organizational P&Ps for staff, including a competency checklist to record successful completion of employee training
An immediate-use training program, along with an annual formulary review intended to reduce the number of CSPs that can only be mixed at bedside, will form the nucleus of a USP <797> immediate-use compliance program.
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