The same quality flaws that have come to light in Massachusetts’ crackdown on sterile compounding pharmacies also may exist in many hospital pharmacies that formulate sterile preparations, according to a recent survey by the Institute for Safe Medication Practices (ISMP).

Three out of four (74%) of 412 survey respondents—most of them pharmacists—reported that contamination could be a risk for their facilities, and 13% said that contamination actually had occurred during the past year.

Those findings came as no surprise to Darryl S. Rich, PharmD, MBA, FASHP, a medication safety specialist at ISMP. Based on hospital visits he has made, Dr. Rich told Pharmacy Practice News, hospital pharmacies are “not quite there yet” in complying with U.S. Pharmacopeia (USP) Chapter <797> standards.

For hospital pharmacies trying to upgrade their facilities to comply with USP standards, it is “mostly the facility-based issues that are the toughest” to contend with, said Dr. Rich, noting that cramped pharmacy space was often the biggest obstacle. “When hospitals do it successfully,” he added, “it’s either because the pharmacy has moved or they were able to get space next door. In some cases, it is just not a priority to improve the pharmacy’s IV room.”

As a result, he continued, “a lot of pharmacies have gone to outsource vendors because they figured they couldn’t do it themselves, particularly with regard to higher-risk compounded products.” The problem, he said, was their “level of trust” that there were “regulatory bodies out there” that were evaluating the outsourcers and making sure they remained compliant. “That obviously turned out not to be true,” he said.

More Stringent Inspections

In the wake of the fungal meningitis outbreak, the inspections carried out during the resultant crackdown in Massachusetts were extremely rigorous. Of the 40 sterile compounding pharmacies that received unannounced visits by teams of internal investigators and outside consultant experts hired by the Department of Public Health (DPH), 11 were ordered to halt all or part of their compounding activities, and 21 were cited for minor infractions that since have been corrected. The serious violations included noncompliance with required USP standards for preparation, storage and dispensing of sterile products, including some hazardous medications. Several pharmacies were cited for faulty facility design and controls.

The thoroughness of the inspections contrasted sharply with the regulatory laxity that existed prior to the multistate meningitis outbreak, attributed to contaminated methylprednisolone shipped by the now-shuttered New England Compounding Center (NECC), of Framingham, Mass.

“When you’re under the microscope, you don’t just get the walk-through, you get the fine-toothed comb,” said Michael Cotugno, RPh, the director of pharmacy patient services at Brigham and Women’s Hospital, in Boston. Mr. Cotugno was a member of the pharmacy compounding oversight commission appointed by Gov. Deval Patrick to recommend actions to strengthen the state’s regulatory surveillance in the wake of the NECC-linked public health disaster.

The oversight commission’s chairman, Christian Hartman, PharmD, MBA, the director of clinical quality and patient safety at Wolters Kluwer, said that before the meningitis outbreak, the annual budget for the volunteer state Board of Registration in Pharmacy and inspection staff was insufficient to provide comprehensive inspections. The new FY 2014 budget submitted by Gov. Patrick is for $1.3 million. “The new funding is intended to support increased inspections of compounding pharmacies and increased training of inspectors,” according to the Massachusetts Budget and Policy Center. Under the current, FY2013 budget the board received $182,600.

Additionally, the DPH hired the pharmacy consulting firm Comprehensive Pharmacy Services (CPS) to help carry out the inspections. “We were able to provide the resources needed to establish a comprehensive checklist for the pharmacy inspections,” said Edward Choy, PharmD, a divisional vice president for CPS.

“They’re using pharmacists” for inspections now, Dr. Hartman said, “and that’s a good thing. The unfortunate piece,” he added, is that there are “a lot more pharmacies that are doing medium- to high-risk compounding.” He said that it was time that all compounding pharmacies, including those operating within the state’s hospital systems, receive the same level of scrutiny as the smaller outsource pharmacies targeted in the initial inspection wave. “Raising the bar for providing high-quality and safe compounding services is something pharmacists welcome,” said Dr. Hartman.

Hospital compounding practices may be among the next in line to undergo DPH scrutiny. “We expect that to be the case,” Mr. Cotugno said. “Obviously they started with where the problem came from. But when this broke in Massachusetts, the DPH contacted all the hospitals and said we want to make sure you’re doing all you can to be compliant with USP <797>.”

Constant Monitoring Required

That requires constant vigilance, Mr. Cotugno noted. “Just because you look good today, doesn’t mean that you’re going to look good tomorrow. That’s why you have to keep monitoring because you never know when someone is going to cut a corner. All it takes is one day for a break in technique” to occur, he said.

So far eight of the 11 Massachusetts pharmacies whose compounding activities were halted have submitted corrective plans. But the DPH said that cease-and-desist orders would remain in place until pharmacies come into compliance with USP <795> and <797>.

“That is all for the greater good of patients,” Mr. Cotugno said. “We will get a better quality compounding pharmacy, and maybe we’ll have fewer of them. Some of them are behind the times and won’t want to invest the resources” needed to upgrade to the new standards. “If that’s the case, they need to get out,” he said.

In the ISMP survey, most respondents (74%) said that accrediting agencies, such as the Joint Commission, should be responsible for monitoring external compounding pharmacies’ compliance with USP <797>.

“I think that’s great,” Dr. Rich said, “but it’s just that it’s not what the accrediting agencies are doing.” He added that most accrediting agencies’ surveys cover only their own standards, and in the case of the Joint Commission, although compliance with state law and regulation is required, USP <797> compliance is neither part of its standards nor surveyed.

One answer, he said, might be for regulatory bodies to mandate accreditation for external compounding pharmacies, just as the Centers for Medicare & Medicaid Services (CMS) requires Joint Commission accreditation for hospitals. The regulatory bodies then could mandate compliance with <797> and the accrediting agencies would have to survey for that. Also, if CMS mandated that the agencies that accredit hospitals comply with USP <797>, then those agencies would have to survey for it.

However, he said, “right now if it is just going to be left up to the accrediting agencies and the states, it doesn’t become mandatory unless it becomes law.”

FDA Tightens Reins on PharMEDium

In a policy reversal that could strain some hospitals’ ability to meet demand for compounded sterile preparations, the FDA has informed PharMEDium that it will no longer be willing to exercise an earlier “enforcement discretion” that allowed PharMEDium to ship the preparations without a valid patient-specific prescription. Under the earlier arrangement, the compounder was allowed to use bar-coding and other tools to link patients to its batch-prepared products after they had been shipped and dispensed.

The agency’s tougher new enforcement approach, which comes in the wake of the fungal meningitis disaster, overturns the more flexible attitude toward the patient-specific requirement, which has existed since Jan. 2005. It was detailed in a Feb. 5 letter from Janet Woodcock, MD, director of the agency’s Center for Drug Evaluation and Research (CDER).

“We have determined that, going forward, we are no longer willing to accept” PharMEDium’s post-shipment linking of patients to compounded drugs, Dr. Woodcock wrote.

Hospital pharmacies’ ability to prepare batches of sterile compounded products in anticipation of patient need—or obtain them from outsourcers—is key to providing safe and effective patient care, particularly for hospitals unable to meet USP 797’s exacting standards. Outsourced compounded products can also be crucial as alternatives when critical medications are in short supply.

Dr. Woodcock appeared to acknowledge that fact in her letter to PharMEDium. “In 2012 Congressional testimony,” she wrote, “the agency recognized that the industry has involved to include firms such yours that engage in large-volume compounding of sterile drug products for distribution to health care facilities without patient-specific prescriptions.” She added that “new legislation is needed” to “facilitate effective oversight of such firms.”

New federal legislation could allow nontraditional compounders such as PharMEDium to operate at a new point in the medication-production continuum between traditional compounding for specific patients and large-scale manufacturing for specific diseases.

At press-time, PharMEDium was preparing a response to Dr. Woodcock’s letter, but the company’s chairman, David Jonas, told Pharmacy Practice News in an email message that “we believe that the FDA is seeking to establish a new category more fitting with the FDA oversight.”

In the meantime, at least one pharmacy director said he is concerned about the impact that the FDA’s decision will have on compounded drug supplies. “I understand the need to increase regulation of compounders that manufacture and bulk-ship products without enough regulatory oversight,” said the director, who asked to remain anonymous due to the sensitive nature of hospital-vendor relations. “But until we figure out a new category for these companies, effectively shuttering a supplier as large as PharMEDium could really put a strain on our access to sterile compounded medications. And I can tell you right now, you don’t want hospitals suddenly picking up the slack and trying to compound these meds themselves. Complying with [USP] 797 is hard—that’s why so many hospitals outsource in the first place.”

—B.B.