FDA Outlines Conditions for Pharmacies to Repackage Drug Products
A guidance issued by FDA on January 12 makes clear that the agency does not favor some long-standing habits of pharmacy personnel related to the repackaging of drug products.
First Breach of Manufacturer's Container
Take, for example, the beyond-use date (BUD) for tablets taken from a manufacturer's large container and repackaged into smaller containers.
According to the guidance, FDA wants the BUD for those repackaged tablets to be the earliest of
- 6 months from the first time the large container is opened,
- A date in accordance with the "in-use" time stated in the product's FDA-approved labeling, and
- The expiration date on the large container.
The BUD of 6 months agrees with the time frame for expiration dating stated by FDA in a decades-old compliance policy guide for unit dose repackaging firms, said Dennis Tribble, an expert in pharmacy operations automation who works for medical device maker BD.
But referencing the date of the original container's first opening in determining the BUD is not what pharmacists usually do when repackaging tablets or capsules, he said.
Tribble, expressing his own opinion and not that of his employer, said "FDA doesn't see any difference—or doesn't appear to see any difference—between perforation of a [sterile] vial for removing its contents and the opening of a bottle of 100 pills."
That regulatory view by FDA agrees with what the agency has said over time, he said. "But it's certainly not consistent with the way that we have practiced traditionally, either in retail or in health-system pharmacy."
Implementation of Compounding Law
In issuing the guidance, FDA explained that the BUDs for pharmacy-repackaged drug products reflect the BUDs for compounded drugs in 2 United States Pharmacopeia (USP) chapters: chapter 795 ("Pharmaceutical Compounding—Nonsterile Preparations") and the proposed revision to chapter 797 ("Pharmaceutical Compounding—Sterile Preparations").
Jillanne M. Schulte, ASHP's director for federal regulatory affairs, said FDA views the activity of repackaging a drug product as a manipulation that presents a risk and fits into the "larger discussions" about the quality of drug compounding.
Those discussions, she said, have their legal basis in the Drug Quality and Security Act (DQSA) and its Title I, also known as the Compounding Quality Act.
The DQSA does not exempt repackaged drugs from any of the drug-production provisions of the federal Food, Drug, and Cosmetic Act (FD&C Act), FDA stated 2 years ago.
However, FDA said it "does not intend to take action" against state-licensed pharmacies and federal facilities for violating certain provisions of the FD&C Act if those pharmacies and facilities repackage drug products in accordance with the conditions specified in the January 12 guidance.
Repackaging Without FDA Registration
The official title of the guidance is "Repackaging of Certain Human Drug Products by Pharmacies and Outsourcing Facilities."
As the title suggests, the guidance does not apply to the repackaging of all pharmaceuticals.
A guidance specific to biological products, such as therapeutic monoclonal antibodies, is in the works. In January, FDA released a revised draft version of "Mixing, Diluting, or Repackaging Biological Products Outside the Scope of an Approved Biologics License Application."
A draft guidance on the compounding and repackaging of radiopharmaceuticals by state-licensed nuclear pharmacies was released in December.
Footnote 13 in the January 12 guidance on drug product repackaging by pharmacies suggests that the agency may develop a version specific to hospitals and health systems.
The footnote reads as follows: "FDA is considering the applicability of the policies described in this guidance to hospitals and health systems and intends to address these issues in separate guidance."
Schulte described ASHP as "cautiously optimistic" that FDA will release repackaging guidance specific to the hospital and health-system settings.
Further, she said, ASHP will work to ensure that such guidance, if developed and finalized, harmonizes with the competing requirements of the USP chapters and the Centers for Medicare and Medicaid Services.
In-Use Time for Sterile Drug Products
At pharmacies that repackage sterile drug products, FDA's incorporation of "in-use time" in the BUD for those products will present the biggest challenge to pharmacists, said Eric Kastango, head of the consulting company Clinical IQ LLC.
"As a profession, we don't think about what in-use time means," Kastango said. "That's kind of a new concept . . . that was introduced in the proposed revision of [USP chapter] 797."
Kastango chaired the United States Pharmacopeial Convention (USP) subcommittee tasked with revising USP chapter 797. His membership on that subcommittee and the overarching Compounding Expert Committee ended in 2013.
Revision of the chapter, USP announced on January 27, is still in process.
FDA defines in-use time for a compounded sterile liquid drug product as the maximum allowable interval from penetration of the container or closure system to the start of administration to the patient.
That definition appears in the draft guidance "Current Good Manufacturing Practice—Interim Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act," which FDA issued in July 2014 as part of implementing the DQSA.
The January 12 repackaging guidance advises pharmacies to take into account the in-use time stated in an FDA-approved drug product's labeling when assigning a BUD to a repackaged sterile drug product.
If the labeling does not specify an in-use time or if the sterile drug product being repackaged is an unapproved product on FDA's drug shortages list, the guidance advises pharmacies to assign a BUD according to the standards in the 2015 proposed revision of USP chapter 797 or the expiration date on the original container, whichever results in the shortest time frame.
"How do I repackage, say, a [large] vial of potassium chloride that's on drug shortage?" Kastango asked, presenting a possible predicament for pharmacists trying to make the most of limited supplies.
Potassium chloride injection has been on FDA's drug shortages list for nearly 5 years. As of February 28, the list showed that 1 manufacturer of FDA-approved 2-meq/mL, 250-mL potassium chloride pharmacy bulk packages had a manufacturing-related delay in supplying the product while the other manufacturer was allocating the product to current customers.
Neither manufacturers' labeling states an in-use time per se; rather, users are instructed to discard the original container no more than 4 hours after first penetrating its closure.
The 2015 proposed revision of USP chapter 797—the apparent next source of information on assignment of the BUD in this case—says the in-use time for a pharmacy bulk package is "[a]s specified by the manufacturer" if opened, stored, and used for sterile compounding in an environment with International Organization for Standardization class 5 or better air quality.
"This is where we have these disconnects" in the language appearing in FDA-approved product labeling versus USP chapter 797 and other guidance, Kastango said. "Everybody has a slightly different understanding of the terms being used."
No Deviations From Instructions on Handling and Storage
Among FDA's other expectations of pharmacies is that they repackage drug products in accordance with the handling and storage instructions in FDA-approved labeling.
That may be easier said than done in some cases.
Propofol injectable emulsion, the guidance explains in a footnote, has labeling stating that the drug "undergoes oxidative degradation in the presence of oxygen and is therefore packaged under nitrogen."
Thus, a pharmacy that repackages propofol and exposes it to oxygen during the process is producing a drug product that conflicts with FDA-approved labeling, the guidance states.
FDA in 2014 cited an outsourcing facility, formerly a compounding pharmacy, for misbranding propofol. The warning letter said the agency's investigators found that the facility did not repackage propofol in "tight containers under an atmosphere of inert gas, which is the standard for packaging and storage of propofol established in the monograph by [USP]."
Containers Suitable for Storage
Another expectation by FDA, the guidance states, is that pharmacies repackage a drug product into containers "suitable for storage of the drug product" through its BUD.
Problems with the use of syringes as storage containers arose in 2015 [see November 1, 2015, AJHP News]. FDA stated at the time that it had "not cleared or approved any syringes for stand-alone use as ‘closed container systems.'"
Asked after issuance of the January 12 guidance how pharmacy personnel would search an FDA database to discover the containers suitable for repackaging liquid drug products, the agency referred to footnote 20 in the guidance.
The footnote, in part, reads as follows: "[i]nformation provided by the container's manufacturer could indicate that the container is suitable for drug products repackaged in accordance with this condition."
FDA also referred to an FD&C Act provision not mentioned in the January 12 guidance.
The provision pertains to adulterated drugs.
Rephrased by FDA, the provision means that "if a container contains a poisonous substance that causes the drug to be harmful, or if material from a container adversely interacts with the drug, the drug could be adulterated in violation of federal law."
The guidance lists a total of 12 conditions for pharmacies.
[This news story appears in the April 1, 2017, issue of AJHP.]