NEWS

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 ex-

Downloaded from https://academic.oup.com/ajhp/article-abstract/74/7/453/5103365 by Iowa State University user on 18 January 2019

ample, 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 compli-
ance policy guide for unit dose repackaging firms, said
Dennis Tribble, an expert in pharmacy operations auto-
mation 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 perfora-
tion 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 tradition-
ally, 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 com-
pounded 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 regula-
tory 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 Hu-
man Drug Products by Pharmacies and Outsourcing
Facilities” (available at www.fda.gov/downloads/
Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM434174.pdf).
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 repackag-
ing of radiopharmaceuticals by state-licensed nuclear
pharmacies was released in December.
Footnote 13 in the January 12 guidance on drug prod-
uct 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

AM J HEALTH-SYST PHARM | VOLUME 74 | NUMBER 7 | APRIL 1, 2017  453

 NEWS
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
New drugs and dosage forms
Brodalumab injection (Siliq, Valeant Pharmaceu-
ticals North America): The interleukin-17 receptor A
antagonist is indicated for the treatment of moderate-
to-severe plaque psoriasis in adults who are can-
didates for systemic therapy or phototherapy and
whose disease has not responded or no longer
responds to other systemic therapies. The drug is
subject to FDA risk evaluation and mitigation strat-
egy and Medication Guide requirements.
Dapagliflozin and saxagliptin tablets (Qtern,
AstraZeneca): The combination product, contain-
ing a sodium–glucose cotransporter 2 inhibitor and
a dipeptidyl peptidase-4 inhibitor, is indicated as
an add-on therapy for use in combination with diet
and exercise measures to improve glycemic control
in adults with type 2 diabetes mellitus who have
had inadequate control with dapagliflozin alone or
are already using single-agent formulations of both
drugs. The product is subject to Medication Guide
requirements.
Ganciclovir injection (no brand name, Exela Pharma
Sciences): The ready-to-infuse formulation of the
nucleoside analog cytomegalovirus (CMV ) DNA
polymerase inhibitor is indicated for the treatment
of CMV retinitis in immunocompromised adults
and prevention of CMV disease in at-risk adult
transplant recipients.
Telotristat ethyl tablets (Xermelo, Lexicon Pharma-
ceuticals): The tryptophan hydroxylase inhibitor
is indicated for use in combination with a soma-
tostatin analog (SSA) for the treatment of carcinoid
syndrome diarrhea in adults whose disease is inad-
equately controlled by the SSA alone.
454    AM J HEALTH-SYST PHARM | VOLUME 74 | NUMBER 7 | APRIL 1, 2017
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 liq-
uid drug product as the maximum allowable interval from
penetration of the container or closure system to the start
of administration to the patient.
Downloaded from https://academic.oup.com/ajhp/article-abstract/74/7/453/5103365 by Iowa State University user on 18 January 2019
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 pharma-
cies 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 chlo-
ride 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 environ-
ment with International Organization for Standardization
class 5 or better air quality.
“This is where we have these disconnects” in the lan-
guage appearing in FDA-approved product labeling ver-
sus 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 stor-
age. 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
Maine pharmacists eye legislation to end drug plans’ retroactive fees
D irect and indirect remuneration (DIR) fees are a
“dragon” that pharmacists in Maine are trying to
slay, says Felicity Homsted, chief
pharmacy officer for Penobscot Com-
munity Health Care (PCHC) in Bangor
and president of the Maine Society of
Health-System Pharmacists (MSHP).
Companion bills to prohibit payers
from assessing retroactive DIR fees on
pharmacies after the submission of a
Felicity Homsted
clean claim were introduced in Maine’s
House and Senate on January 5. The
bills have the support of MSHP and the Maine Pharmacy
Association and are similar to federal legislation that was
introduced in February.
The Medicare program for years has required Medicare
Part D prescription drug plans to report DIR received as
rebates and other price concessions from drug manufac-
turers that affect the cost of Part D–covered medications.
But the drug plans have put their own imprint on DIR
in the form of performance-related assessments charged
to pharmacies.
Homsted said the fees can quickly reach alarming
totals. DIR fees are applied retroactively to claims that
AM J HEALTH-SYST PHARM | VOLUME 74 | NUMBER 7 | APRIL 1, 2017  455
NEWS
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
Downloaded from https://academic.oup.com/ajhp/article-abstract/74/7/453/5103365 by Iowa State University user on 18 January 2019
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 men-
tioned in the January 12 guidance.
The provision pertains to adulterated drugs.
Rephrased by FDA, the provision means that “if a con-
tainer 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.
—Cheryl A. Thompson DOI 10.2146/news170021
weren’t flagged during adjudication, so the pharmacy
cannot intervene at the point of sale to resolve the issue
in real time.
Homsted first became aware of the problem last sum-
mer, when one of PCHC’s contract pharmacies for the fed-
eral 340B Drug Pricing Program asked for help. She said the
pharmacy was seeing “a very high frequency” of DIR fees
from Medicare Part D plans and their pharmacy benefit
managers (PBMs) and could no longer afford to continue
the 340B contract with PCHC.
“They were going to be losing money on every prescrip-
tion that they dispensed for us,” Homsted explained.
To solve the problem, PCHC increased the pharmacy’s
dispensing fee by $10 per prescription.
“We have a good partnership. We’ve been working with
them for at least 5 years,” Homsted said of the contract
pharmacy. “This was a big change within the last year, . . .
and we’re fully in support of making the adjustment.”
Homsted said DIR fees have since spread to PCHC’s
own pharmacies and are of growing concern. The fees most
frequently relate to patients’ refill rates, she said.
“So if you’ve got people on blood pressure medications
that they’re not filling as regularly as they should, you could
see fees attached there,” she said.