Over the last 9 months, the University of North Carolina (UNC) Medical Center pharmacy department has experienced an alarming number of controlled substances (CS) shortages, affecting most IV opioids and benzodiazepines. Certain products, such as diazepam syringes, have been completely unavailable for months; the pharmacy department is now unable to offer this product to patients. Recently, the most critical drugs on shortage include outsourced, pre-made compounds (eg, bags, cassettes, and syringes).

To ensure patients have access to critical medications, UNC Medical Center has employed multiple strategies, including purchasing from alternate manufacturers and 503B outsourcing facilities, utilizing different concentrations and delivery systems, consolidating and centralizing stock, switching patients to new therapies, and utilizing in-house compounding. Because these strategies
introduce additional risk in the medication-use process, a robust shortages management program is critical for medication safety.

What Is Causing Controlled Substances Shortages?

A combination of challenges is responsible for these CS shortages:

• Manufacturing Difficulties. Starting in late June 2017, our institution began having trouble obtaining products in Carpuject syringes, including opioids and benzodiazepines. The manufacturer distributed a letter on July 10, 2017, explaining that remediation efforts at its manufacturing facility were going to impact the supply of products distributed in Carpujects through first quarter 2018.1 A follow-up letter in late November
  updated customers that full recovery dates for Carpuject syringes had been moved to first quarter 2019, with deprioritized products predicted to be unavailable until second quarter 2019.2
• Natural Disasters. In September 2017, the island of Puerto Rico was impacted by two hurricanes, Irma and Maria. The devastation and lack of electricity in Puerto Rico from Hurricane Maria caused a series of additional difficulties, which affected product supply for a time.
• Changes in 503B Compounding Facility Production. In December 2017, following an FDA inspection, a 503B outsourcing facility temporarily halted production to make process changes in its largest facility.

The combined effect of these situations led to a dramatic decrease in product availability.

Strategies for Managing CS Shortages

Purchasing Alternate Products and Consolidating Inventory

The CS shortage situation necessitated a broad response strategy from the UNC Medical Center pharmacy. First, we attempted to purchase other products where available, expanding purchasing to include different manufacturers, concentrations, and delivery systems (eg, vial, ampule, syringe). In addition, inventory was consolidated from low-use to high-use areas and was centralized. Pharmacy utilizes a specially trained group of technicians to handle all CS drugs, including automated dispensing cabinet (ADC) inventory adjustments. Par levels for some products stored in ADCs were reduced in order to centralize stock and decrease the risk of products expiring. In addition, technicians have been moving products from ADCs without active orders to ADCs on units where active orders exist. Moving CS stock to different ADCs throughout the medical center requires constant review of the active orders report as well as dedicating technician resources to unload and load products into various ADCs. When such changes are made, keeping our nursing colleagues informed has been critically important.

Working with 503B Compounding Facilities

When we first began experiencing CS shortages, the pharmacy department delayed contacting 503B outsourcing companies to obtain products, because purchasing syringes in different sizes would significantly disrupt operations. All CS products are dispensed through ADCs, and the syringes available from a 503B facility would be larger in size compared with the Carpuject products we had been using. Because the Carpujects are small, a large quantity can fit in an ADC pocket. In addition, the Carpujects arrive bundled in packs that allow nurses and pharmacy staff to quickly verify a pocket count. Any outsourced product would be larger, would require more frequent refills, and would take longer to count to verify pocket contents. After receiving the November notification letter,2 and realizing that the shortage was predicted to last more than 1 year, we contacted 503B facilities that were already reviewed and approved by UNC to see if they could help supply products. Initially, two 503B facilities indicated that they could supply morphine and hydromorphone syringes. Unfortunately, shortly thereafter, they informed us that they would not be able to supply these medications after all.

Switching Patients to Alternate Therapies

In situations where sufficient product could not be obtained, we evaluated opportunities to switch patients to other therapies without compromising care. For example, as the supply of diazepam injection dwindled, usage was reviewed to determine the most important roles for diazepam and to consider implementing restrictions based on use. At the same time, we identified those uses wherein another agent could be substituted with equivalent results. These changes were communicated to staff, and IV diazepam orders were converted to oral diazepam or IV lorazepam when appropriate.

In-House Compounding

The pharmacy department previously relied on a 503B facility to obtain a significant number of CS infusions, including fentanyl IV bags and fentanyl, morphine, and hydromorphone CADD cassettes for patient-controlled analgesia (PCA) infusions. Due to the outsourcer’s subsequent shutdown and the decrease in product availability, we were forced to shift from using outsourced products to in-house production. This introduced additional challenges into the shortage response plan, such as the need to quickly increase staffing levels, obtain the supplies needed for these compounds, and alter the distribution model to accommodate refrigerated storage of these products, rather than room-temperature storage.

Strategies to Overcome Obstacles

Each of these strategies has affected operations and presented challenges to overcome. As the shortages unfold, our strategies have evolved and we have learned valuable lessons.

Include the IT Team

Because purchasing alternative products requires frequent updates to pharmacy information systems and technology platforms, it is important to include the hospital’s informatics team in implementing shortage response plans. Updates to our electronic health record (EHR) were necessary to minimize the safety risk associated with changing products and to facilitate efficient product interchanges. The UNC Medical Center’s EHR pharmacy informatics team is actively engaged with pharmacy leadership to apply changes as they occur.

The EHR links the product order and dispense to a specific product NDC. Therefore, products that might be considered equivalent or interchangeable, such as a 1 mg/1 mL syringe and a 1 mg/1 mL vial, are separate products in the EHR. Therefore, EHR updates had to be implemented, including the following:

• Building EHR entries that connect equivalent products (such as syringes and vials that are otherwise the same strength and volume) and then
  linking the order to the product available in each unit’s ADC, to ensure
  interchangeability of different products in different areas
• Updating dispense locations in the EHR for products now being
  compounded internally
• Ensuring labels are printed with the correct information, such as expiration dates

To achieve success, it was critical to keep the informatics teams abreast of the shortage status and work together to identify efficient, safe methods to update the EHR.

Maximize IV to PO Switches

Clinical interventions, including therapeutic substitutions and optimization of IV to oral conversions, have been utilized to manage the CS shortages. UNC Medical Center’s policies allow pharmacists to convert IV medications to the oral route of administration under certain circumstances. These clinical interventions offer multiple benefits for patient safety, while also lowering costs, and can help conserve limited IV fluid stock. Support for pharmacists and other providers in pursuing clinically appropriate alternatives to IV medications should be adopted, especially when an equally efficacious oral option exists.

Insourced Compounding

Insourcing production of a small group of products had a profound impact on our operations. Before the shortage, the central IV room at UNC Medical Center compounded approximately 40 CS compounds per day. The number of doses prepared since the shortages began has increased by >1200% per week, as we have taken on additional workloads: preparing batches of morphine, hydromorphone, and fentanyl IV bags, including filling pump cassettes, elastomeric pump devices, and IV syringes to meet patient care needs. The time-intensive process of compounding these medications also impacts the sterile products workload, as compounding 50 fentanyl epidurals requires approximately 4 hours of technician work time.

As pharmacy departments across the country work to respond to these shortages, other supplies, such as sterile water for injection, bulk vials of drugs for compounding, cassettes, syringe pumps, and other items have also experienced shortages or delays in availability as their use unexpectedly increases. The impact of the IV fluid shortage, caused by the devastation of Hurricanes Irma and Maria, further complicated our transition to insourcing production, as small volume parenteral fluids and empty IV bags were both in limited supply. Because small volume parenteral fluids are a high-use material for CS compounding of standard concentration continuous infusions and PCA infusions, the addition of insourcing multiple products into the fluid allocation equation was an unexpected strain on already low stock. Fortunately, per an April 19th, 2018 letter, production of small volume parenteral and empty bags from our manufacturer in Puerto Rico has returned to pre-hurricane levels, and since that time, UNC Medical Center has been able to access these products again.3

Many products received from our 503B outsourced compounder were stable at room temperature for at least 30 and often up to 90 days, and were stored in unit ADCs. Because the pharmacy department does not have in-house testing data to support extended beyond-use dates (BUDs) for our insourced products, these medications are assigned shorter BUDs and stored in refrigerators in the central pharmacy rather than room-temperature ADCs on the nursing units. This has resulted in a significant increase in the number of on-demand CS deliveries to the nursing units, requiring increased staffing levels to avoid patient care delays.

To facilitate shifting production of the products from the 503B outsourced compounder to our IV room staff, the CS technicians began using a spreadsheet to keep track of inventory counts of products previously received from the outsourced compounder. The spreadsheet is updated daily and shared with IV room staff so they can develop and adjust their batch-compounding schedule. The spreadsheet includes the following information:

• Current inventory counts of CS medications
• Shortest expiration date of product on hand
• Average daily use
• Calculated days’ supply on hand
• Estimated runout date

Insourcing production of certain medications created a physical space challenge in the IV room and the CS storage area. Thus, batch compounding is now distributed throughout the medical center’s IV rooms, and additional refrigerators have been purchased for the CS storage area.

Quantifying the Financial Impact

The financial impact of utilizing alternate acquisition strategies may prove significant. The pharmacy department and hospital leadership have met to monitor potential budget variances due to more expensive products being purchased and increased staffing levels in order to meet patient care needs.

Unique Considerations with Controlled Substances Shortages

Diversion

Managing the risk of diversion is essential when developing strategies around CS shortages. Because CSs are often targets for diversion, managing these shortages presents unique challenges compared with shortages of non-controlled medications. For example, organizations must develop a strategy for handling multi-dose vials (MDVs). At UNC Medical Center, single dose CS vials or syringes are traditionally the only option delivered to nursing for patient administration, due to the risk for diversion and the need to document and check expiration dates once an MDV is initially opened. However, diazepam MDVs were available when single dose vials were on shortage. The organization had to decide whether or not to allow MDVs to be used for repeat administrations, which would require nursing to document use and indicate how much medication remained in the vials. Due to the significant diversion risk this would carry, we decided to treat the available MDVs as a single dose option, which resulted in wasting >50% of each vial.

Purchasing Complexity

Addressing CS shortages can be a complex, time-consuming process, as additional steps are required for processing CS orders. DEA222 forms must be exchanged between the buyer and the seller, which can add an extra day or two to the process. Even if handled electronically through a CS ordering system, purchasing typically requires signoff by a pharmacy manager prior to the order being processed and filled by the seller. Early identification of CS shortages is critical, since the turnaround time from order placement to receipt of the drug is longer than for non-controlled substances.

Strategies for Ensuring Medication Safety

Communication

Active communication is imperative for organizations when managing drug shortages. The pharmacy department has implemented several recurring calls to address the various shortages in the medical center and throughout the health system. Currently, these include single-hospital calls related to fluid shortages, calls focused on CS and oncology shortages, as well as a system-wide shortage call that includes all facilities in the health system. These calls, which are facilitated by a dedicated drug shortages pharmacist, include pharmacy purchasing agents, informatics representatives, operational and clinical members of the pharmacy department, and supply chain leaders from pharmacy and materials management. Regular communication with all impacted staff, including pharmacy technicians, pharmacists, nurses, physicians, and other providers, is also essential.

Staff Education

Providing appropriate education for technicians, pharmacists, nurses, and physicians is a prerequisite to proper handling of new CS products. Pharmacists should receive education on which medications are on shortage as well as the recommended clinical and operational interventions for conserving supplies. Nurses must be educated on practice changes, including the potential use of MDVs as single dose vials, and the use of ampules. Physicians must be educated on any changes in the ordering process as well as product utilization restrictions. Educational documents outlining the required changes can be posted in common areas for easy access and reinforced with communication strategies, such as weekly shortage update emails, to inform all staff of changes that will affect their practice.

Collaboration

When significant changes are required, ensure patient safety and avoid treatment delays by including medication safety officers, nursing representatives, clinicians, and other impacted staff in decision-making processes. Go-live dates for all strategies should be decided in conjunction with operational and clinical staff, as well as the informatics team, to verify appropriate education has occurred and systems are in place to facilitate drug preparation and administration and to safeguard patient safety. Proactive evaluation of clinical and operational plans is critical to successful implementation when shortages occur. Organizations must recognize the increased risks associated with shortage management and keep patient safety at the forefront when making decisions to introduce changes.

Monitoring

After all parties are properly educated, clinical staff should monitor practice for efficacy and safety, especially when using equivalent doses of alternative medications. In addition, closely monitor staff for the diversion risk some of these strategies introduce (eg, use of larger vial sizes and increased waste, use of MDVs instead of single dose vials, etc). Over the past 18 months, UNC Medical Center has worked to develop a robust diversion-monitoring program. Without this infrastructure in place, any significant changes that could put the organization at risk for diversion should be approached with caution.

Looking Forward

Given that approximately 10% of all pharmaceuticals in the United States are produced in Puerto Rico,4 Hurricanes Irma and Maria had a significant impact on the supply chain processes for hospitals across the country. Fortunately, a report released by the FDA Commissioner in early 2018 indicated the shortage of IV saline fluids began to improve in the second quarter of 2018, and full resolution is expected by July.5 Likewise, in December 2017 our vendor’s manufacturing facilities in Puerto Rico returned to the commercial power grid,5 and production of small volume parenteral and empty bags has returned to normal as of late April 2017.3

A letter from our 503B outsourced compounder in mid-January 2018 states that they are in the process of restoring operations and developing new processes.6 However, thereafter we learned that the compounding plant’s reopening is indefinitely delayed. In addition, once the plant is fully operational, the FDA will require product be held for at least 7 days while testing results are received. This new quarantine process will effectively shorten the BUD. For products such as hydromorphone, we expect the outsourced products to arrive at our facility with 14-20 days remaining on the BUD, which may impact product waste.

At this time, it remains unclear when full supply capacity will be restored; thus, the UNC Medical Center Pharmacy Department plans to continue its current course to acquire and maximize use of CSs on shortage. Future directions include pursuing extended BUDs for products that we prepare in the IV room. As drug shortages continue, it is essential for organizations to consider a variety of approaches to limit operational inefficiencies, minimize risk, promote clear and frequent communication across all staff, and ensure patient safety.

References

1. Pfizer Inc. Notification of upcoming Pfizer injectables opioid and non-opioid prefilled syringe shortage. mms.mckesson.com/content/wp-content/uploads/2017/06/Pfizer-Injectables-Opioid-and-Non-Opioid-Prefilled-Syringe-Shortage.pdf. Accessed April 16, 2018.
2. Pfizer Inc. Update to Pfizer injectables opioid and non-opioid syringe portfolio. www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM586737.pdf. Accessed April 16, 2018.
3. Baxter Dear Valued Customer Letter. Scott P. Luce, General Manager, U.S. Hospital Products, Baxter Healthcare Corporation. April 19, 2018.
4. United States General Accounting Office. Briefing report to the chairman, special committee on aging, us senate pharmaceutical industry tax benefits of operating in Puerto Rico.
   www.gao.gov/assets/80/78407.pdf. Accessed April 16, 2018.
5. United States Food & Drug Administration. Statement by FDA commissioner Scott Gottlieb, MD, update on recovery efforts in Puerto Rico, and continued efforts to mitigate IV saline and amino acid drug shortages. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm591391.htm. Accessed April 16, 2018.
6. PharMEDium Customer Service. Update on FDA Inspections at PharMEDium’s Four 503B Outsourcing Facilities. January 11, 2018.

Mary G. Petrovskis, PharmD, BCPS, is a PGY2 administration/MS resident at the UNC Medical Center and the UNC Eshelman School of Pharmacy and the resident manager for the controlled substances area. She received her pharmacy education from The Ohio State University College of Pharmacy, graduating in 2016. Mary’s professional interests include clinical practice management, data analytics, and the integration of education and research into practice.

Mary-Haston Leary, PharmD, BCPS, is a PGY2 administration/MS resident at the UNC Medical Center and the UNC Eshelman School of Pharmacy. She received her pharmacy education at the University of Mississippi School of Pharmacy. Mary-Haston’s professional interests include transition of care services, practice advancement and pharmacy practice models, and practice-based outcomes research.

Daniel Schenkat, PharmD, MS, is the clinical manager of central inpatient pharmacy at UNC Health Care. He received his Doctor of Pharmacy degree and MS in health-system pharmacy administration from the University of Wisconsin School of Pharmacy. Daniel’s practice interests include pharmacy leadership, automation and technology, data analytics, and pharmacy technician role advancement.

Maryann Oertel, PharmD, BCPS, is the coordinator for pharmacy contracts and shortages at the UNC Shared Services Center Pharmacy and an adjunct professor at the UNC Eshelman School of Pharmacy. She attended University of Michigan College of Pharmacy and completed a PGY1 pharmacy practice residency and PGY2 drug information specialty residency at Rush Medical Center in Chicago. Maryann served as the director of drug information for UNC Hospitals for 20 years, and is currently leading the UNC Health Care System Pharmacy Strategic Sourcing Team, which identifies, negotiates, and implements contracting as well as other clinical and purchasing-based strategies to improve the cost-effectiveness of drug therapy within the health system. Her interests include formulary management, medication safety, cost-effectiveness, drug shortages, and pharmacy contracting.