FDA Starts Showing Its Plans for Oversight of Pharmacy Compounding
This spring and summer, FDA revealed in several guidance documents what the agency thinks pharmacy compounding should look like now that the relevant provisions in federal law are firmly in place and the agency has a budget for oversight.
Some of FDA's ideas, if incorporated into the final versions of the guidances, could be challenging for hospitals and health systems to implement, said Mark Sullivan, executive director of pharmacy operations for Vanderbilt University Hospital and Clinics (VUHC), based in Nashville.
Other hospitals and health systems, such as Tufts Medical Center in Boston, may not be immediately concerned about FDA's ideas. But as hospitals continue to affiliate or form multihospital systems, said Melissa Ortega, director of the medical center's inpatient pharmacy operations, a plan to centralize compounding activities may need to be reconsidered.
Guidances, Not Regulations
Other than removing the unconstitutional prohibition on advertisements about specific compounded drug products, the Drug Quality and Security Act (DQSA) did not change section 503A of the federal Food, Drug, and Cosmetic Act (FDCA).
Section 503A, which exempts pharmacy-compounded products from three subsections of the FDCA, went into effect in 1998 but was invalidated by the U.S. Supreme Court in 2002.
Afterward, FDA used a compliance policy guide and an enforcement policy guidance to communicate its tack of preserving the traditional pharmacy practice of compounding and identifying when a pharmacy's practice resembles conventional manufacturing.
But soon after enactment of the DQSA in 2013, FDA withdrew both policy documents, leaving section 503A—"Pharmacy Compounding"—in the federal law but without guidance to compounders or regulations for enforcement.
That situation began to change in December 2014 when Congress started incorporating funds for the oversight of pharmacy compounding into FDA's annual budget.
"I think they're trying to get the biggest pieces in place first," said Jillanne M. Schulte, ASHP's director of federal regulatory affairs. "So they did the initial 503A guidance and 503B guidance. . . . Now we're getting the guidances that have a lot more detail."
One of those initial guidances, "Pharmacy Compounding of Human Drug Products Under Section 503A of the Federal Food, Drug, and Cosmetic Act Guidance," explains that compounded drug products can qualify for section 503A's exemptions yet still prompt FDA to act against the pharmacy.
That's because section 503A does not exempt compounded drug products from the entire FDCA.
Details on pharmacy contamination conditions that would render compounded drug products adulterated under federal law (e.g., visible mold in the production area) were presented in part in the draft guidance "Insanitary Conditions at Compounding Facilities," issued on August 3.
As for guidances related to section 503B, "Outsourcing Facilities," FDA has issued final versions explaining the agency's "current thinking" on registration, fees, and facilities' duty to report adverse events.
"We support the idea that there needs to be regulation around compounding," Schulte said. "We want to see something that actually is tailored [and] appropriate to the setting."
Compounding activities in a community pharmacy differ from compounding activities in a hospital or health system, she said.
"We need a guidance that . . . takes that into account," Schulte said. "Hospitals and health systems are already extremely heavily regulated."
Limits on Anticipatory Compounding
The draft guidance "Prescription Requirement Under Section 503A of the Federal Food, Drug, and Cosmetic Act," issued on April 15, presents FDA's view regarding how much of a compounded product can be prepared before receipt of a patient-specific order from a prescriber for the product. Included in FDA's idea is the existence of earlier orders for the same product from a known prescriber or prescribers.
Sullivan said FDA's idea puts VUHC's anticipatory compounding "potentially at risk, depending on the interpretation."
Patients in VUHC's perioperative services area and emergency department have acute, emergent needs for commercially unavailable sterile drug products whose composition is standard at the facility, he said. The prescribers are licensed independent practitioners—anesthesiologists and emergency medicine physicians with credentials to practice at the hospital.
"We can make that product in a sterile products room with appropriate validation of BUD [beyond-use date] in a batch according to the USP standards," Sullivan said, referring to United States Pharmacopeia chapter 797, "Pharmaceutical Compounding—Sterile Preparations." The product is then stored in the perioperative area or emergency department and available for immediate use.
Ortega said Tufts Medical Center's batch compounding qualifies as anticipatory. When interviewed in mid-August, she said the pharmacy was preparing to go live with i.v. workflow technology that will enable personnel to "track the anticipatory compounding to a patient."
The pharmacy had already been doing some tracking of compounded sterile preparations, she said.
When large-scale compounder Ameridose LLC ceased operations nearly four years ago, the medical center's pharmacy had to start preparing about 31 formerly outsourced line items, Ortega said. "We did a lot of analysis on utilization—taking a look at our pharmacy systems, historically looking at what was ordered—to help us decide what our production will be for these batches."
Geographic Limit on Distribution
The draft guidance "Hospital and Health System Compounding Under the Federal Food, Drug, and Cosmetic Act," issued on April 15, acknowledges hospital pharmacies' need to compound and distribute drug products "without first receiving a patient-specific prescription or order."
This acknowledgment contains a caveat that limits to one mile the distance between the compounding pharmacy and the healthcare facilities receiving non-patient-specific compounded drug products.
Ortega said none of the four hospitals with which Tufts Medical Center is affiliated through Wellforce, a two-year-old healthcare system, is within one mile of the medical center.
"There would be no way to set up a central [compounding] operation" that conforms to what FDA describes in the draft guidance, she said.
Sullivan said the one-mile limit, if incorporated into the final guidance, would present "a big concern" for VUHC, which owns several clinics in mid-Tennessee.
"We do have a practice currently of providing products [made] in a centralized compounding facility to those off-campus facilities," he said.
The facilities enable patients to receive the same high level of care provided at VUHC's main campus without traveling to downtown Nashville, Sullivan said.
In comments to FDA, ASHP urged the agency to replace the geographic limit with a time-based limit derived from the USP chapters on sterile pharmaceutical compounding and hazardous-drug handling.
Address-Dependent Facility Definition
The draft guidance "Facility Definition Under Section 503B of the Federal Food, Drug, and Cosmetic Act," issued on April 15, conveys FDA's desire for pharmacy compounding activities and outsourcing facility activities not to occur near each other.
To Sullivan, such a desire would likely quash any proposal at VUHC to establish a hospital pharmacy location dedicated to section 503B–level compounding. That location would have the same address as the locations where compounding activities under section 503A take place, he said. Thus, FDA would require that all drug products made at the hospital address, including in the satellite and operating room pharmacies, meet the requirements for outsourcing facilities.
No Copycats of Commercially Available Products
A draft guidance issued on July 7 presents FDA's idea of what constitutes a compounded drug product that is essentially a copy of a commercially available drug product and thus ineligible for section 503A exemptions.
Tufts Medical Center already eschews compounding copycats, Ortega said. "If it's commercially available, we don't compound it."
She said the decision not to replicate a manufacturer's product was made a couple of years ago when the pharmacy worked to enhance its sterile products services.
FDA's idea, if incorporated as is into the final guidance, "potentially could" be an issue in the VUHC intensive care unit, Sullivan said.
There, patients with an enteral feeding tube may be receiving a histamine H2-receptor antagonist or proton pump inhibitor through that tube. Although those drugs are available commercially in solution form, he said, "there's evidence [of] a clumping issue" when they are administered via a feeding tube.
By compounding a liquid formulation known to be associated with less clumping when delivered via feeding tubes, Sullivan said, the pharmacy can provide the same active ingredient as the commercial solution but with fewer complications.
Some sterile drug products, such as cefazolin, are commercially available as both a premixed solution and a powder for reconstitution and dilution. Schulte indicated that ASHP expects FDA to clarify that commercial availability of a premixed solution does not preclude pharmacies from using the powder in accordance with the labeling's instructions for reconstitution and dilution.
ASHP Submits Comments, Awaits Final Guidance
Schulte coordinated ASHP's submission of comments on the three draft guidances that were issued on April 15.
She said ASHP would also comment on the July 7 draft guidance "Compounded Drug Products That Are Essentially Copies of a Commercially Available Drug Product Under Section 503A of the Federal Food, Drug, and Cosmetic Act."
As for when FDA will release final versions of the guidances, the agency has not stated and its general administrative procedures do not mandate a deadline.
Ortega said it will be interesting to compare and contrast the FDA guidances on pharmacy compounding and modifications to USP chapter 797, which are currently in development.
[This news story appears in the Sept. 15, 2016, issue of AJHP.]