Sterile compounding technology is used to identify, reduce, or eliminate compounding errors and ensure that a patient receives the correct prescribed medication and dose within an acceptable tolerance. This is of the utmost importance as deviations (ie, wrong medication, wrong dose) during the sterile compounding process can cause severe patient harm or even death.
In the current environment, minimum practice standards for sterile compounding (eg, USP <797>) have no requirement to use compounding technology during sterile compounding, and instead provide an emphasis on manual processes.1 Thus, the use of sterile compounding technology in today’s environment is seen as a best practice, rather than a requirement, which has led to slow adoption rates and ultimately results in patients being vulnerable to harm from inappropriately compounded sterile preparations (see TABLE 1).
Current Best Practices
In 2016, the Institute for Safe Medication Practices (ISMP) revised the ‘Guidelines for Safe Preparation of Compounded Sterile Preparations’ following a summit that emphasized the use of IV admixture technologies to enhance safety. ISMP now recommends that institutions providing IV admixture services incorporate technology solutions to aid in manual preparation and verification of compounded sterile preparations. At a minimum, it is recommended that barcode scanning verification be incorporated into the workflow to verify base solutions and ingredients. For locations providing parenteral cancer chemotherapy or products for pediatric use, gravimetric verification should also be incorporated for quality control to ensure the weight of ingredients meets the expected weight for the given compounded sterile preparation.2
Technology and Automation Adoption
The results from PP&P’s 2021 national survey on the State of Pharmacy Automation demonstrate that the adoption rate of technology and automation for sterile compounding remains relatively low across the nation (see TABLE 2). IV workflow management systems (WMS) are utilized by 36% of facilities, which was a 10% increase from 2020. The adoption rate for IV robots remains at just 7%, and this utilization is mainly concentrated in the largest facilities (>400 beds).3
The current USP <797> (2008) states “The use of technologies, techniques, materials, and procedures other than those described in this chapter is not prohibited so long as they are not inferior to those described herein.”1 Apart from this statement, there is no specific mention of the use of compounding technology and automation outlined within the minimum standard. This represents a significant safety gap and a need for revised and modernized standards. In the absence of directly addressing compounding technology and automation within minimum practice standards, the rate of adoption will continue to remain low.
Need for Compounding Technology
Data captured from ISMP’s National Medication Errors Reporting Program (MERP) have outlined that national efforts are needed to identify and eliminate or reduce errors and their causative factors. In addition, an observational study for sterile compounding across five hospitals showed a mean error rate of 9%.1 While this study was performed over 2 decades ago, with the current low rate of adoption of technology this error rate most likely persists today. In 2009, a compounding survey showed that 30% of hospitals experienced a serious patient event involving a compounding error in the past 5 years.2 To address these ongoing errors and events, sterile compounding technology must be accurate, precise, and safe, while also maintaining preparation sterility and delivering efficiency.
Accuracy and Precision
The term ‘accuracy’ is defined as the freedom from mistake or error, and conformity to a truth or standard.4 Precision refers to the consistency or repeatability of a given measurement. The standard for compounding accuracy can be defined at the medication level as outlined by a USP monograph acceptable assay range. While this is generally recognized as +/- 10%, it can be different for certain medications, especially those with a narrow therapeutic index. Achieving a high degree of accuracy and precision can be challenging given the volume variability in medication vials and fluid bags due to manufacturer overfill, coupled with limitations in accuracy using syringes as volume measurement tools. Cumulatively, these variations may lead to a preparation that is outside of the acceptable accuracy range and in some cases may impact patient care. While these variations may exist even with the use of compounding technology, they are less likely to be detected when using manual methods, and thus not corrected.
Safety considerations must encompass the final preparation, compounding personnel, and the environment. A CSP should be free from contamination (microbial and non-microbial), cross-contamination of other medications, and errors. Compounding personnel and the environment should not be unnecessarily exposed to medications, especially those that pose health hazards. Many technologies provide safety features that focus on accuracy and precision but do not provide features to maintain sterility or avoid cross contamination. The safety of the person preparing the compound is an important consideration for the preparation of hazardous drugs, which can be addressed by technologies that prepare the compound within a closed system. Eliminating human interaction with sterile compounded products further reduces the potential for cross-contamination.
In 2012, the New England Compounding Center (NECC) was responsible for a multi-state fungal meningitis outbreak that resulted in 753 infected patients, more than 64 deaths, and prison sentences for the individuals deemed responsible.5 This was a pivotal moment in the state of compounding which led to the creation of numerous new laws and regulations surrounding sterile compounding. This compounding disaster underscores the need for future sterile compounding technology and automation to focus on ensuring sterility.
The greatest source of microbial contamination during sterile compounding is personnel. Aseptic assembly, aseptic technique, and material transfer are all associated with either a high or very high risk of microbial contamination which results from personnel involvement.6,7 Certain compounding automation devices can reduce human interaction during the aseptic processing to reduce this potential for contamination.
The introduction of technology and automation within the process of sterile compounding should not only increase safety but also efficiency. Carelessly adding a series of additional steps into the compounding process has the potential to extend the length of the process, which could lead to delays in care for acute care settings. Technology should only be added to areas where it addresses a specific problem, and seamlessly becomes part of the workflow. In some cases, additional added steps may add downstream efficiencies, such as reducing the risk of having to re-make a CSP due to a detected error or optimizing the final product verification steps.8,9 Waste can also be decreased via more efficient tracking of medications to determine when items should be used based on the earliest expiration.10
Key Technology Components
Compounding technology and IV WMS are comprised of interrelated safety features and components. Each component adds a specific safety benefit, and when used in combination with other components, aids in reducing the risk of an undetected compounding error reaching a patient.
Barcode verification uses a machine-readable, visually printed code on an object to determine whether the drug base, diluent, or additives are correct based on a medication’s NDC, order number, or other identifiers. This technology is relatively inexpensive, provides an immediate safety benefit, and alleviates potential errors resulting from human distraction (eg, look-alike and sound-alike medications). This technology is limited in that it requires the barcode to be readable (ie, free from damage) and requires programming of the barcode scanner based on the type of barcode being used.
Image recognition uses camera technology coupled with software to confirm that the correct product (eg, medication vial, syringe size) is being used by comparing the product in use against a stored image of the correct product in the database. This process requires programming of all new products by taking numerous pictures of the new product for future comparison, a process that may lead to some efficiency loss if not performed in advance.
Gravimetrics uses highly accurate and precise weight scales coupled with known or measured specific gravity values of a medication to provide a more accurate method of medication dosing during compounding. To use gravimetrics, a specific gravity value must be determined for each medication and fluid used in compounding. The limitation of this component is that specific gravity values are not widely available, which requires expensive testing or error prone mathematical theoretical calculations. Further, due to limitations in balance technology used within compounding hoods, small volumes and highly potent medications may not benefit from this technology.
Multichannel pumps are devices that are commonly used to prepare total parenteral nutrition (TPN), continuous renal replacement therapy (CRRT), cardioplegia, and base solutions. They allow a compounder to safely pool a multitude of ingredients together, depending on the device and configurations. These devices utilize barcode scanning of products, barcode scanning of patient specific labels for preparation, software interfaces, and volumetric and gravimetric checks. A report is produced for each product prepared, which can be utilized to maintain and audit accuracy and precision. These devices are limited by the inability to pump very small volume medications (usually <0.2 mL) and there is a risk of cross contamination of ingredients due to the use of common central tubing.
During the sterile compounding process, there may be multiple steps requiring volume transfer from one container to another. In the absence of technology, the ‘syringe pull-back’ method is used, which relies on human memory to serve as a retrospective proxy method of verifying the volume that was transferred by pulling the empty syringe’s plunger back to indicate the measured volume. This method is prone to error, and ISMP states that this form of volume verification should never be used.2
Technology, such as cameras, can be used to verify a given volume. Camera technology can capture the volume of medication or diluent in a syringe prior to addition to the final container. Saved images can be added to the compounding record and used to verify the final preparation; in addition, they can aid in the investigation of a suspected compounding error. Sufficient camera resolution is required to ensure detailed images are captured using software enhancement features (eg, zoom, contrast, brightness). A well-lit environment with a solid color background can aid in quality image capture.
A USB controlled foot pedal provides hands-free access that allows the compounder to keep their hands in the ISO class 5 space. These devices can have multiple pedals with macros programmed to keystrokes that are linked to specific features in the electronic health record (EHR). During sterile compounding within a hood utilizing a camera system, the programmable foot pedal can be mapped to take a picture, delete a picture, or save a picture during the compounding process. This can be performed without requiring compounding personnel to remove their gloved hands from the ISO class 5 environment. The main disadvantage associated with this technology is the introduction of additional objects into the cleanroom that require frequent cleaning and disinfection.
Workflow Management Systems
IV WFMS use a software interface to standardize and automate the steps in the compounding process. Although these systems vary by vendor, most offer the capability to integrate various technology components into the system and some offer bidirectional interfaces with the EHR. These systems offer numerous benefits including extensive documentation during the sterile compounding process, standardization, error detection, and tracking capabilities. Limitations that impact some of these systems include poor ergonomics, the potential to contaminate sterile gloves (with systems that incorporate a touch screen), or the risk of increasing contamination opportunities by repeatedly moving gloved hands in and out of the hood (for systems that use a computer outside of the PEC). Currently, the cost of many of these systems limits widespread adoption, which is another area that must be addressed.
The informational chapter USP <1211> Sterility Assurance provides concepts and principles for the preparation of materials that must be sterile. There is a focus on the inherent limitations with the term sterile, as the strict definition—no viable microorganisms—cannot be applied to actual items labeled as sterile due to irresolvable limitations in sterility testing. Therefore, it is essential to focus on the implementation of interrelated controls to deliver confidence and assurance that items are sterile, rather than the results of in-process or finished goods testing. Because operating personnel pose the most significant contribution to microbiological risk during sterile operations, separating personnel from the aseptic environment and limiting their interactions with sterilized components and product(s) are essential.11
Value of IV Robotics
One of the main safety features of automation is the removal or minimization of the human element (ie, the primary source of contamination) from the compounding process. As USP <1211> Sterility Assurance outlines, this can be achieved through both automation and separative technologies (see TABLE 3). Incorporating these principles into sterile compounding follows the Quality by Design (QbD) approach, which has been widely adopted in current good manufacturing (cGMP) operations.11 Further, the use of automation can increase accuracy and precision, while also performing lengthy batching operations without fatigue.
Restricted Access Barrier System
Some IV robotic devices can be classified as a closed restricted access barrier system (RABS). These devices provide ISO class 5 unidirectional air within the barrier and are located within an ISO class 5 to 7 cleanroom. Closed RABS are designed to minimize human intervention within the ISO class 5 area by using material transfer ports coupled with air overspill that prevents the ingress of contamination. All drugs and materials are fed into the device using these ports, and the device is never opened until the end of the operation for cleaning or maintenance.
One of the main features of these devices is a multi-axis robotic arm that articulates its movements to maintain first air and minimize particle contamination by removing the human element in performing all aseptic transfer steps. These articulating arms operate entirely in the RABS ISO class 5 environment. The pincher on the end of the robot arm must be programmed to correctly hold each type of syringe, bag, medication vial, or use adaptors that are compatible with the system. One limitation is that the robotic arm must be supplied with oil to ensure smooth movements during use.
A comprehensive IV robotic device will perform all aseptic manipulations and dispense a final preparation. For syringe preparations, this includes applying a sterile cap using the robotic arm upon completion of the withdrawal. These devices have the capacity to entirely remove the needle from a syringe and secure a syringe cap within the ISO class 5 device. One limitation is that not all syringe caps are compatible with each device, which is determined by the cap holding mechanism.
Some automation technology includes the ability to autonomously label each preparation that is produced. This is highly advantageous—compared to the manual application of a label—as it eliminates opportunities for inadvertently labeling the improper preparation. Label information can be patient specific or generic (for batch preparation). Currently, label customization options are somewhat limited; thus, some organizations may choose to apply a manually created label post-production which can be used to ensure safety and compliance (eg, ASTM-D4774 Standard Specification for User Applied Drug Labels in Anesthesiology, USP <7> Labeling requirements); however, this approach may be prone to mix-up errors.
Volume Withdrawals and Additions
Certain automation devices have the capability to perform fluid withdrawals from bags or vials that can be used for lyophilized powder reconstitution, dilutions, or to create a specific total volume admixture. Further, volume additions to bags, syringes, or vials can be performed using a calibrated dosing mechanism, usually with a sterile empty syringe. For either withdrawals or additions, each must be calibrated to a specific accuracy using either volumetric or gravimetric verifications.
When using automation for sterile compounding, it is essential to minimize contamination during drug and material transfer into the device. There is potential for contamination to occur during the assembly of a sterile needle and syringe. Best practice is to purchase and use syringes with manufacturer attached needles pre-assembled and ready for use. This minimizes opportunities for personnel contaminants compared to manually attaching a syringe and needle using aseptic technique.
A benefit of using automation for sterile compounding is the resulting robust documentation. These devices maintain data logs that users and engineers can access to troubleshoot issues with the automation, provide quality and compliance documentation, or use for continuous quality improvement. The devices can track highly detailed information using a serialized tracker down the specific preparation of each dose.
When using automation, it is important to ensure organizations have a routine preventative maintenance plan, in addition to procedures for expected or unexpected downtime events. Regular preventative maintenance is performed as outlined by the automation manufacturer, but unexpected downtime can occur through normal wear and tear and use. Depending on the manufacturer, engineers can resolve some issues remotely and diagnose and resolve issues promptly. When physical maintenance is performed, engineers must be properly trained on cleansing and garbing procedures for entering the cleanroom suite, and ensure work is not interfering with adjacent operations. When possible, these maintenance events should occur on days or times when the devices are not operational and must be followed with a complete cleaning and disinfection protocol prior to resuming operations.
Limitations to automation devices on the market center on how personnel interact with the loading process for labels, syringes, vials, fluid bags, and any other consumables placed in the device. Organizations should use their material disinfection protocols prior to loading any material into the device’s ISO class 5 areas. A significant consideration for organizations adopting automation is the allocation of space within a cleanroom suite. The size of each device on the market varies drastically. For exceptionally large devices, it is important to review whether the device can be separated into smaller pieces to allow for adequate clearance at the loading dock, through the hallways, and into the cleanroom suite without significant infrastructure modifications. Once the space is determined, consider whether the specs for power, network links, and other device requirements (eg, compressed air, coolant) will require additional build steps or line drops.
Human and Automation Vulnerabilities
Data has shown there are various physical attributes that impact human job performance in the workplace. Some of these attributes include noise levels, variable illumination, and other distractions.12 While technology is used during sterile compounding to reduce errors, as long as humans are involved heavily in manual processes, errors are inevitable. Coupling human distractibility with sterile compounding can lead to significant patient harm or death from unintended errors. As such, the introduction of automation into sterile compounding may offer significant benefits—compared to manual compounding—as automation does not fatigue or become distracted by the physical environment.
The Failure Mode & Effects Analysis (FMEA) is an essential tool to help identify and address vulnerabilities and failures or potential failures in technology or automation. Adding a Corrective Action and Preventive Action (CAPA) plan is key to addressing detected issues while also preventing issues that have not yet occurred. For each step in a given process, an FMEA should take into account the probability, severity, and detectability of a specified event. These events should be quantified numerically, using a risk priority number (RPN) to help identify areas of focus and prioritization to ensure preparations are safely produced. This method also helps identify potential workarounds that can be addressed prior to an error occurring.13
In today’s current state, patients remain vulnerable to harm from compounded sterile preparations through antiquated manual admixture methods. However, compounding technology and automation are available that can provide immediate safety benefits. These systems are currently viewed only as best practices, which has resulted in low adoption rates across the nation. Significant opportunities exist to elevate these systems to be viewed as minimum practice standards; thus, providing safer compounds to patients.
While each technology has its limitations—including cost—compounding safety can be made immediately safer through introducing a low-cost barcode scanner, which is a minimum practice standard in other healthcare settings (eg, barcode medication administration). Further, there are additional inexpensive technologies that have been around for decades but have not yet been marketed for sterile compounding use. Consider Radio Frequency Identification (RFID) processes, which have been extensively used in industries outside of healthcare. While some drug manufacturers have begun adding RFID tags to manufactured products, opportunities abound for expanding this technology into sterile compounding processes. To truly ensure patient safety, the use of compounding technology and automation must be prioritized and become minimum practice standards.
Austin Paytes grew up in Charlotte, North Carolina, and obtained a BS in nutrition science from NC State University. He is currently completing his fourth year of pharmacy school at the UNC-Eshelman School of Pharmacy and hopes to enter into a PGY-1 Acute Care residency following graduation. Austin’s current clinical interests are in infectious diseases and ambulatory care.
Kevin N. Hansen, PharmD, MS, BCPS, BCSCP, is the assistant director of pharmacy at Moses H. Cone Memorial Hospital in Greensboro, North Carolina. He received a doctor of pharmacy degree from the Lake Erie College of Osteopathic Medicine and received an MS in pharmaceutical sciences from the University of North Carolina Eshelman School of Pharmacy. Kevin provides oversight and leadership for pharmaceutical compounding and perioperative services pharmacy.
Christopher J. Boiallis, PharmD, BCSCP, the quality assurance pharmacy coordinator at Moses H. Cone Memorial Hospital, graduated from St. John’s University College of Pharmacy with a doctor of pharmacy degree and was one of the first to obtain his board certification in sterile compounding.