Attention Turns to Nonpharmacy Sterile Compounding Activities

In the year since investigators entered a New York City oncology clinic in search of the source of an outbreak of fungal bloodstream infections involving 17 patients, information has emerged suggesting that healthcare facilities without a pharmacy professional go unmonitored for adherence to sterile compounding standards.

Three of the 17 patients, all with cancer, died less than 90 days after diagnosis with Exophiala dermatitidis or Rhodotorula mucilaginosa bloodstream infection, said investigator Amber M. Vasquez of the Centers for Disease Control and Prevention (CDC).

Whether the infections contributed to the patients’ demise may never be known, she said.

What is known, Vasquez said during a CDC-hosted webinar, is that all 17 patients had a central venous catheter that had been flushed at least once with fluid from a 1-L bag of heparin-vancomycin-ceftazidime lock solution compounded at the clinic on February 7, 2016.

Inspections of nonpharmacy settings. FDA has “recently done a couple of inspections” at physician offices in response to complaints about compounding activities, the agency’s Sarah Rothman told the Pharmacy Compounding Advisory Committee on May 8.

One of those inspections occurred because of an outbreak of infections at a physician office in New York, she said.

“We haven’t been focusing on physicians,” Rothman said of the more than 350 inspections conducted since enactment of the Drug Quality and Security Act through November 27, 2016.

But because FDA knows there are concerns about compounding in physician offices, she said, the agency has been considering how best to focus its resources and has been speaking with state medical boards, the National Association of Boards of Pharmacy, and CDC.

“Egregious” practice conditions. Vasquez said investigators learned that the single-physician oncology clinic had the following routine for preparing syringes of heparin-antimicrobial lock solution: Compound the 1-L bag. Store it in a refrigerator. Use 10-mL syringes to access the bag multiple times each morning to prepare a batch for use throughout the day. Continue accessing the bag until empty, which could be up to 8 weeks after the day on which the solution was compounded.

Unfortunately for the investigators, she said, nothing remained of the bag involved in the February 7, 2016, compounding incident when they arrived on the scene in late May. Their initial clue came on May 24 from an infectious diseases physician who notified the New York City Department of Health and Mental Hygiene that 2 patients with E. dermatitidis bloodstream infection admitted to the same hospital had received care at the same oncology clinic.

Through whole genome sequencing, Vasquez said, the team identified a single source of the outbreak: the compounded lock solution.

“So we performed an infection-control assessment to determine what might have gone wrong with the i.v. flush solution,” she said.

Joel Ackelsberg, with the New York City health department, said he had “never [before] heard the word egregious used so many times by so many people to describe” conditions in a healthcare provider’s office.

“An i.v. flush solution that was stored in the refrigerator for up to 2 months was improperly prepared in a biological safety cabinet that was last tested and failed inspection in 2014 and which was situated next to a refrigerator and in which improper technique was used to prepare parenteral medications,” he said during the webinar.

Problems aplenty. Among the slides of the clinic shown by Vasquez was a photo of the biological safety cabinet. It had a sticker stating “REJECTED” in red and a date roughly 2 years before the outbreak.

Another photo showed the interior of the refrigerator used to store the 1-L bag and flush syringes. There was grime on the floor of the refrigerator. A self-sealing bag held moldy-looking materials. The same refrigerator, Vasquez said, had reportedly also been used to store the staff’s food items.

“Not good at all,” declared Nitika Agarwal, director of specialty, oncology, and infusion pharmacy for DuPage Medical Group in Illinois, in assessing the clinic’s sterile compounding practices after viewing the slides.

Agarwal, who was not part of the investigation and was not speaking on behalf of her employer, said the slides showed the clinic had obvious problems.

“No wonder things didn’t work out,” she said.

Among the problems mentioned by Agarwal was the lack of any onsite pharmacy professional—“critical pieces of the sterile compounding [operation].”

Vasquez had reported that sterile compounding activities at the clinic were performed by a nurse who had no pharmaceutical training and whose performance had not been assessed before the investigators’ arrival.

Agarwal said any pharmacy technician trained in sterile compounding who walked into a work area like the one shown in the photos would sense that the conditions were inappropriate.

“Even at home, you would not leave anything [in the refrigerator] with the moldy stuff around it”—let alone store i.v. medications alongside food rather than in a refrigerator dedicated to drug storage, she said. “You can’t even fathom that anybody would practice in that situation.”

DuPage Medical Group, she said, has a pharmacy technician working at every infusion site where sterile compounding activities occur and separates each site’s sterile compounding area from the other work areas in accordance with United States Pharmacopeia chapter 797.

“It’s very, very important—no matter what the setting is—that patient safety comes first,” Agarwal said.

Changes needed. Willis Triplett, a principal with the group known as Comply 797 and a consultant with ASHP’s consulting services unit, said many of the nation’s oncologists do not believe they need to handle sterile products in the same way that hospital pharmacies do.

“I’ve been at many, many oncology practices in the last year,” Triplett said. “And every one of them has had a biological safety cabinet, but they don’t know how to use it. I’ll walk into an oncology practice and the rear air return [grill] on the biological safety cabinet will have vials sitting on it,” disrupting the unidirectional airflow.

But his concern is not restricted to oncology practices.

“There’s infusion clinics everywhere,” Triplett said, noting the ones operated by allergists and immunologists to administer i.v. immune globulin and others operated by rheumatologists and gastroenterologists to infuse tumor necrosis factor inhibitors.

Nine states have laws, regulations, or policies that specifically apply to compounding activities by healthcare practitioners who are not pharmacists, according to the results of a 2015 survey by the Government Accountability Office; 23 states had no such law, regulation, or policy, and representatives of the remaining states either did not know the answer (17) or did not respond (1).

New York, where the outbreak occurred, lacks laws specific to compounding, the survey report states.

That lack of specificity frustrates Ackelsberg.

“After speaking with the New York State Department of Health, which has an office that addresses clinical misconduct, it became clear that there was a considerable regulatory gap in regard to pharmacy-related and infection-prevention practices by outpatient physicians, specifically oncologists,” Ackelsberg said during the webinar. “They could rescind the provider’s license if an investigation uncovered maleficence, but there was no ongoing oversight of outpatient provider settings other than a requirement for them to take an online infection-control course every 4 years.”

The city’s health department commissioner on May 31 issued a cease-and-desist order to the oncology clinic, relying on the department's authority to abate public nuisances, Ackelsberg said.

On October 5, the department lifted the order, Vasquez said. The clinic had completed remediation efforts under the guidance of an infection control practitioner and pharmacist, demonstrated workers’ ability to safely prepare and deliver medications, and stopped compounding.

A recording of CDC’s April 18 webinar, with slides, is available online.

[This news story appears in the July 1, 2017, issue of AJHP.]