Anyone who has worked in health care for the last 20 plus years has seen a marked increase in the acuity level of patients being admitted to hospitals and thus the need for total parenteral nutrition (TPN) also has grown. In addition, after USP Chapter <797> mandated changes in sterile product preparation six years ago, many hospitals have considered outsourcing their TPN compounding rather than enacting the necessary measures, internally, to comply with the new standards. As one can imagine, there are many factors that go into this decision, including patient population size and makeup, materials cost and waste factors, not to mention the human resources necessary to run a compounding operation.
At Vanderbilt University Medical Center, neither outsourcing nor manually compounding TPNs has ever really been a viable option. Instead, as our need for TPN grew beyond the abilities of a manual compounding process to handle, we turned to automated compounding devices in an effort to keep this process in-house while providing safety and consistency, lower total product cost, helpful inventory management functions, and the ability to create customized preparations at will.
Determining a Need for Automated Compounding Devices
Vanderbilt University Medical Center in Nashville, Tennessee is a 916-bed teaching hospital and comprehensive medical facility. Acute care clinical services include a level I trauma center, level III burn center, the Vanderbilt-Ingram Cancer Center, as well as adjoining rehabilitation and psychiatric hospitals. The campus also includes the 243-bed Monroe Carell Jr. Children’s Hospital, which has 36 intensive care beds and an 83-bed, level IV neonatal intensive care unit. Servicing over 1000 inpatient beds at any given time, the pharmacy operation runs around the clock, and we are staffed with approximately 300 full-time employees split into 125 pharmacists, 150 technicians, and 25 ancillary personnel.
Our pharmacy dispenses an average of 60 bags of customized TPN each day to support our trauma center, NICU, and other hospital departments. Given the volume and complexity ranges of these preparations, making TPNs by hand was never an option. While we did experiment with outsourcing in the 1990s, we now prefer making TPNs in-house as it provides a level of control over our preparations and processes. To this end, we have been using automated compounding devices for about ten years.
Today we employ two 24-port devices almost exclusively for TPN compounding—one each for adult and pediatric patients—housed in a dedicated cleanroom. In addition to TPN, we do use the compounders to mix bags for a specific heart pump we use, as well as for base solutions for our syringe-filling machine. Our TPN room operates from 8:30 am to 7 pm, and in order to make the workflow as safe and efficient as possible, we instituted a 1 pm cutoff for pediatric and neonatal TPN orders and a 5 pm cutoff for general adult orders. By separating our workload into shifts, we can use both machines for either population, as needed.
The Evolution of Compounding Parenteral Nutrition
Over the past 40 years, parenteral nutrition (PN) needs have evolved to require faster preparation turnaround, increased safety measures, and the ability to deliver far more customized compounded sterile preparations (CSPs) in smaller volumes.
In the early years of PN compounding, pharmaceutical manufacturers provided 500 mL bottles of amino acids and dextrose, which pharmacists or technicians combined with electrolytes, trace elements, and vitamins to prepare a final TPN preparation. Compounding preparations in this way was labor and time intensive, offered only a limited ability to develop a preferred ratio of amino acids to dextrose, and did not enable meaningful customization. Additionally, these preparations were prone to error and microbial contamination, given that multiple source containers were often used to prepare each order and there was no bar code verification for source ingredients or to match preparations with patient orders.
The first automated compounders that came onto the market delivered only base solutions; micro ingredients still needed to be added by hand. In 1991, the first compounder that delivered both micro and macro volume ingredients became available, with the ability to dispense quantities as small as 0.2 mL. The ability of automated compounders to add micro ingredients directly to TPN preparations allowed the majority of compounding processes to be automated, which improved the accuracy and repeatability of ingredient delivery, increased productivity, and reduced the number of manipulations, thereby decreasing the potential for microbial contamination of the final product. The eventual adoption of bar code ingredient verification on some models ensured that correct source containers were set up prior to compounding.
As the physical dimensions of these devices evolved toward smaller, faster, and easier-to-clean models, so too did accompanying software programs become more sophisticated. The programs on these later models afforded the ability to alter the amount of sterile water for injection incorporated into the TPN, so the fluid volume from the electrolytes, trace elements, and vitamins could be compensated for and the final volume controlled.
Later, more advanced TPN software programs let users order specific amounts of anions and cations, and then allowed the software to determine the combinations of source ingredients necessary to meet the request. These automated compounding devices could accurately and consistently pump these solutions and, along with the introduction of two-, three-, and four-liter containers, allowed for the preparation of larger-volume TPNs. These larger volumes, comprising all the patient’s nutritional needs, allowed one TPN bag to infuse over 24 hours. These larger-volume bags also reduced the number of TPN units that had to be prepared daily, allowed a standard hang time for all patients to be established, simplified nurses’ medication administration schedules to hang the PN, and allowed lipids to be included directly in the TPN infusion (also known as 3-in-1 or total nutrient admixture).
As this technology continued to advance, pharmacy personnel gained the ability to pump specified quantities of high-concentration amino acids, dextrose, lipids, sterile water for injection, electrolytes, and other micro ingredients into the preparations. In addition, some manufacturers offered machines that measure ingredients volumetrically and verify them gravimetrically, delivering high-volume ingredients quickly while enabling small-volume accuracies.
Since we have been using this technology, compounders have gained the ability to link to automated order entry systems designed to provide calculations and issue warning limits. Eliminating the need for redundant order-entry reduces the opportunity for data entry errors, while built-in calculations help reduce human errors. At the same time, the latest software programs enable limits for incompatible elements helping to prevent clinical errors in the final solutions.
Fostering a Safe and Efficient Workflow
Our current automated compounding device technology incorporates safety checks directly into our pharmacy workflow. Our cleanroom has two devices, one for pediatrics and one for adults. The pediatric machine is set up to handle 18 ingredients—including specialized amino acids—and the adult machine is equipped to handle 14. This setup follows national recommendations that all pediatric and neonate formulations be prepared separately from adult formulations, a measure designed to help reduce errors.
Although the process of making a TPN dose may sound complex, the entire sequence takes just 15 minutes using our compounder. The process starts when a physician enters a TPN order into our computerized order entry system. The order prints out in our TPN room and our technicians then enter the order by hand into the compounder’s software system. At the same time, the order entry PN software uses pre-loaded warning limits to check the order. The PN software can issue warnings for electrolytes, calcium/phosphate curves, and osmolarity cutoff limits for peripheral administration, and they are customized to match our clinical guidelines. Although rare, these warning limits trigger review by a clinician and have prevented a handful of adverse drug events from occurring. Last of all, the TPN pharmacist verifies the TPN order entry; once verified and transmitted to the clean room, a third person—either another technician or a pharmacist—again verifies the order.
In such a busy compounding room, the use of bar codes creates a secondary level of verification security. To prepare the dose, a technician affixes the bar-coded label to the container and attaches it to the compounder. Then, he or she scans the label’s bar code, which tells the compounder which formula to load. At this point the label is placed on the compounder’s touch screen, which is compared to a real time video feed to ensure that the proper label is matched to the compounded dose. Outside the cleanroom, a pharmacist can view the TPN as it is being made. Earlier in the process, bar coding will have already helped us safely set up the compounders, as each ingredient bag is bar coded and then hung on a corresponding port. Bar code verification is a critical step in ensuring safe compounding, as it prevents the technician from hanging—and subsequently compounding with—an incorrect ingredient.
One of the most important elements of our compounding workflow is that our compounding devices also are programmed to dispense ingredients in the proper order to avoid precipitation. Without the correct amount of dilution, drugs such as calcium and phosphorus can form crystals when mixed, so our compounders will insert enough dextrose or water as base solution to prevent this interaction. Also, while the ingredients are being dispensed, the device performs another set of checks; it uses volumetric controls to measure how much of each ingredient is being delivered, as well as gravimetric controls to weigh the final bag. Finally, once the bag is complete and sent outside the cleanroom, our pharmacists check it against a report generated through the software that provides complete information for each bag and verifies that any manual additions have been performed correctly.
Staff Training and Validation
Safety is not simply confined to the machinery and workflow, it also is dependent upon proper staff training and validation. We staff our TPN room with one dedicated pharmacist and a subset of 12 specially trained technicians. Four pharmacists on our staff have been trained to supervise the TPN room and because there are four different compounding shifts each day, we train new technicians for a week in each shift. Given this, it takes a month to become competent in using the automated compounding devices and the order entry software.
To ensure that proper compounding knowledge and skill sets remain current, pharmacists and technicians take an annual competency evaluation on both the machine and the software, administered through a Web-based interface that was developed in-house. We also perform blind and random checks of technicians’ aseptic technique. Pharmacy leadership oversees annual media-fill challenge tests with observation for USP <797> compliance, and every month observes one technician throughout the day. At the end of that technician’s shift, we provide written and verbal feedback to improve any perceived flaws in process or technique.
Of note, we do not perform sterility testing on individual TPN bags because all of our TPNs are hung within 12 hours. USP <797> requires that any medium-risk CSP that is not tested for sterility be hung within nine days under refrigeration.
In the past year, we have experienced shortages of almost every ingredient used in TPN. Fortunately, our compounders can produce a report that totals the quantity of every ingredient used each day. We then can compare against existing stock to determine how many days’ supply are on hand. This has helped us stay ahead of our ingredient needs and avoid running out completely. Two to three times a week, our pharmacy orders a list of set ingredients from our wholesaler. If the wholesaler is out of a specific ingredient, we turn the problem over to our procurement manager, who is responsible for finding another vendor. He or she checks with other sources daily to stay ahead and minimize the impact of shortages.
Outsourcing vs Automated Compounding
When evaluating whether to invest in automated compounding device technology, a pharmacy director needs to weigh financial and non-financial factors. From my perspective, if a pharmacy is making more than ten TPNs per day, the director should consider purchasing such a device. If one’s volume ranges from five to eight TPNs a day, the director may want to perform a complete ROI analysis on the types of compounded preparations needed based on population (eg, CRRT patients, critical patients with high protein needs, etc).
Another important consideration is patient mix and whether you have a high percentage of pediatric or neonate patients. In our case, 40 percent of the TPNs we prepare each day are for neonates, and 20 percent are for pediatric patients. It has been our experience that in-house automation of our TPN compounding takes away the challenges associated with complex calculations and provides a consistent product.
Making the decision to keep TPN compounding in-house through the use of automated compounding devices is more than just a financial decision. In our case, we see the clinical benefits of custom TPNs and the increased control over the process as the key decision factors.
First and most importantly, outsourcing companies may not be able to develop formulations for pediatric, neonatal, or premature patients—a significant part of our patient volume. Second, while outsourced products may meet a high quality standard because their laboratories can be tightly controlled, the risk of contamination remains. In our case, I would rather take responsibility for ensuring proper aseptic technique and retain overall control of the compounded preparations we administer.
Richard Osteen DPh, has worked at Vanderbilt University Medical Center for 25 years as a pharmacist and pharmacy supervisor before assuming his current role as the Manager of Narcotics, Sterile and Non-Sterile Compounding. He received his BS in pharmacy from Samford University in 1976 and is a member of ASHP.
Questions to ask when doing a financial comparison between outsourcing and compounding TPN in-house: