Reporting - Radiopharmaceutical Compounding and Repackaging by Outsourcing Facilities GFI, Repackaging GFI

Repackaging of Certain Human

Drug Products by Pharmacies

and Outsourcing Facilities

Guidance for Industry

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

January 2017

Compounding and Related Documents

Repackaging of Certain Human

Drug Products by Pharmacies

and Outsourcing Facilities

Guidance for Industry

Additional copies are available from:

Office of Communications

Division of Drug Information, WO51, Room 2201

Center for Drug Evaluation and Research

Food and Drug Administration

10903 New Hampshire Ave., Silver Spring, MD 20993

Phone: 301-796-3400; Fax: 301-847-8714

[email protected]

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

January 2017

Compounding and Related Documents

Contains Nonbinding Recommendations
TABLE OF CONTENTS

I.

INTRODUCTION AND SCOPE..................................................................................... 1

II.

BACKGROUND ............................................................................................................... 2

A.

Repackaging, Generally ................................................................................................................ 2

B.

Regulatory Framework for Repackaging .................................................................................... 3

III.

POLICY ............................................................................................................................. 4

A.

General Policy ................................................................................................................................ 4

B.

Establishment Registration and Drug Listing........................................................................... 10

Contains Nonbinding Recommendations
• Repackaging by entities that are not State-licensed pharmacies, Federal facilities, or
outsourcing facilities (e.g., repackers registered with FDA under section 510 of the
FD&C Act).
• Removing a drug product from the original container at the point of care (e.g., patient’s
bedside) for immediate administration to a single patient after receipt of a valid patientspecific prescription or order for that patient (e.g., drawing up a syringe to administer
directly to the patient). FDA does not consider this to be “repackaging,” for purposes of
this guidance document.
• Upon receipt of a valid patient-specific prescription, a licensed pharmacy removing from
one container the quantity of non-sterile drug products 5 (e.g., oral dosage forms)
necessary to fill the prescription and placing it in a different container to dispense directly
to the patient.
• Investigational new drugs being studied under an investigational new drug application.
This guidance does not alter FDA’s existing approach to regulating investigational new
drugs.
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
as recommendations, unless specific regulatory or statutory requirements are cited. The use of
the word should in Agency guidances means that something is suggested or recommended, but
not required.
II.

BACKGROUND
A. Repackaging, Generally

FDA regards repackaging as the act of taking a finished drug product from the container in
which it was distributed by the original manufacturer and placing it into a different container
without further manipulation of the drug. 6 Repackaging also includes the act of placing the
contents of multiple containers (e.g., vials) of the same finished drug product into one container,
as long as the container does not include other ingredients. If a drug is manipulated in any other
way, including if the drug is reconstituted, diluted, mixed, or combined with another ingredient,
that act is not considered repackaging. 7
Repackaging is performed by a range of entities, including pharmacies and other facilities that
specialize in repackaging drug products. FDA is aware that repackaging is done for a variety of
5

For purposes of this guidance, a sterile drug is a drug that is intended for parenteral administration, an ophthalmic
or oral inhalation drug in aqueous format, or a drug that is required to be sterile under Federal or State law.

6

For example, if tablets are removed from a blister pack and placed into a different container, that would be
repackaging. However, if the blister packs containing tablets are placed into a different container for later use
(without opening the individual blister packs), that would not be repackaging.

7

This guidance does not apply to the compounding of drug products. Compounding is addressed in other guidance
documents. See, for example, the guidances Pharmacy Compounding of Human Drug Products Under Section
503A of the Federal Food, Drug, and Cosmetic Act and For Entities Considering Whether to Register as
Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act.

2

Contains Nonbinding Recommendations
reasons including: to meet the needs of specific groups of patients (e.g., pediatric patients or
patients receiving drugs for ophthalmic use) who require smaller doses of approved sterile drug
products that may not be available commercially; to reduce medication errors associated with
drawing up a dose from a vial at the point of patient care; to reduce the availability of drug
products that could be abused when controlled substances are left over in a vial after a dose is
drawn out; to provide a particular sized container to fit into a particular device to administer the
drug (such as a particular pain medication pump); for convenience for the practitioner
administering an injection to a patient; to reduce waste and conserve drug supplies; and in some
cases to reduce cost. Some repackagers repackage both sterile and non-sterile drug products.
Examples of repackaging include tablets and capsules that are repackaged from large containers
into smaller containers or blister packs, and creams and lotions are sometimes purchased in bulk
and repackaged into smaller tubes or containers.
As part of the drug application review and approval process, FDA evaluates the container closure
system and the packaging into which the drug will be placed, as well as the conditions under
which the drug will be packaged. The container closure system and packaging can affect the
quality of the drug product when it is on the market. In particular, during the approval process,
FDA reviews whether the container closure system and the packaging are appropriate for
maintaining the stability of the drug product through its expiration date, as long as the containerclosure and package are not breached, and the drug is stored according to the conditions
specified in the application. For drug products required to be sterile, FDA also considers
whether the container closure system and packaging are adequate to ensure that the drug product
will remain sterile until its expiration date, as long as the container closure is not breached and
the drug product is stored appropriately.
When a drug product is repackaged, its characteristics may change in ways that have not been
evaluated during the FDA approval process and that could affect the safety and efficacy of the
drug product. Improper repackaging of drug products can cause serious adverse events. Of
particular concern is repackaging of sterile drug products, which are susceptible to contamination
and degradation. For example, failure to properly manipulate sterile drug products under
appropriate aseptic conditions could introduce contaminants that could cause serious patient
injury or death. Repackaging practices that conflict with approved product labeling could result
in drug product degradation and adverse events associated with impurities in the product or lack
of efficacy because the active ingredient has deteriorated.
B. Regulatory Framework for Repackaging
Repackaged drug products are generally not exempt from any of the provisions of the FD&C Act
related to the production of drugs. For example, repackaged drug products are generally subject
to the premarket approval, misbranding, adulteration, and drug supply chain security provisions
of the FD&C Act, including section 505 (concerning new drug applications), 8 section 502(f)(1)

8

But see U.S. v. Kaybel, 430 F.2d 1346 (3d Cir. 1970) (holding that repackaging of approved Enovid (estrogen)
tablets from large bottles into small bottles did not require pre-approval under section 505 of the FD&C Act).

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Contains Nonbinding Recommendations
(concerning labeling with adequate directions for use), section 501(a)(2)(B) (concerning current
good manufacturing practice (CGMP)), and section 582 (concerning drug supply chain security).
Drugs that are repackaged are not subject to sections 503A and 503B of the FD&C Act. 9
Therefore, drug products repackaged by State-licensed pharmacies, Federal facilities, or
outsourcing facilities are not eligible for the exemptions provided under those sections. In this
guidance, FDA describes the conditions under which it does not intend to take action regarding
violations of certain requirements of the FD&C Act, in the context of drug repackaging.
III.

POLICY
A. General Policy 10

As discussed above, repackaged drug products are generally subject to the adulteration,
misbranding, and approval provisions of the FD&C Act. 11 FDA does not intend to take action
for violations of sections 505, 502(f)(1), and 582 if a State-licensed pharmacy, a Federal facility,
or an outsourcing facility repackages drug products in accordance with the conditions described
below, and any applicable requirements. 12, 13 In addition, FDA does not intend to take action for
violations of section 501(a)(2)(B) of the FD&C Act if the drug product is repackaged by a Statelicensed pharmacy or a Federal facility in accordance with the conditions described below, and
any applicable requirements. 14
The conditions referred to in the preceding paragraph are as follows:
9

Section 503A of the FD&C Act exempts compounded drug products from sections 505, 502(f)(1), and
501(a)(2)(B) of the FD&C Act provided certain conditions are met, including that the drug product is compounded
pursuant to a valid prescription for an individually identified patient from a licensed practitioner. The Drug Quality
and Security Act added a new section 503B to the FD&C Act. Under section 503B(b), a compounder can register as
an outsourcing facility with FDA. Drug products compounded by or under the direct supervision of a licensed
pharmacist in an outsourcing facility qualify for exemptions from the FDA approval requirements in section 505 of
the FD&C Act, the requirement to label drug products with adequate directions for use under section 502(f)(1) of the
FD&C Act, and the Drug Supply Chain Security Act requirements in section 582 of the FD&C Act, if the conditions
in section 503B are met. Drug products compounded in outsourcing facilities are not exempt from CGMP
requirements under section 501(a)(2)(B).
10

Portions of this guidance are shaded in gray to indicate that they constitute collections of information that are
subject to review by the Office of Management and Budget under the Paperwork Reduction Act of 1995 (44 U.S.C.
3501-3520).

11

See footnote 8.

12

Applicable requirements include, for example, the requirement that manufacturers not adulterate a drug product
by preparing, packing, or holding the drug product under insanitary conditions. See section 501(a)(2)(A) of the
FD&C Act.

13

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.

14

For purposes of the applicability of the conditions in this guidance document, references to a State-licensed
pharmacy or Federal facility do not include a facility that is registered as an outsourcing facility under section 503B
of the FD&C Act.

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Contains Nonbinding Recommendations
1. The drug product that is being repackaged is a prescription drug product that:
a. is approved under section 505 of the FD&C Act, or
b. is an unapproved drug product that appears on the drug shortage list in effect
under section 506E of the FD&C Act, and the repackaged drug product is
distributed during any period in which it is listed on that drug shortage list or
during the 30 days following such period.
2. The drug product is repackaged in a State-licensed pharmacy, a Federal facility, or an
outsourcing facility.
3. The drug product is repackaged by or under the direct supervision of a licensed
pharmacist.
4. If the drug product is repackaged in a State-licensed pharmacy or a Federal facility, it
is distributed 15 only after the receipt of a valid prescription for an identified,
individual patient (including a written order or notation in a patient’s chart in a health
care setting) directly from the prescribing practitioner or patient. 16 This condition
does not apply to drug products repackaged in an outsourcing facility. 17
5. Except as provided below for a single-dose vial, the drug product is repackaged,
stored, and shipped in a way that does not conflict with approved drug product
labeling. 18
For a drug product that is packaged in a single-dose vial that is repackaged into
multiple units, the drug product is repackaged in a way that does not conflict with the

15

“Distributed” means that the repackaged drug product has left the facility in which it was repackaged.

16

FDA is considering the applicability of this condition to certain non-sterile drug products repackaged by Statelicensed pharmacies for distribution to long-term care facilities, and intends to revise this guidance or issue separate
guidance to address this issue. During this interim period, FDA does not intend to apply this condition to non-sterile
drug products repackaged by State-licensed pharmacies for use in long-term care facilities.
17

Note, however, that drugs produced by outsourcing facilities remain subject to the requirements in section 503(b)
of the FD&C Act. Therefore, a prescription drug cannot be dispensed to a patient without a prescription.

18

If the approved labeling contains instructions for handling or storage of the product, the drug product is
repackaged in accordance with those instructions. Otherwise, the repackaging would be considered to be in conflict
with the approved labeling. For example, the approved labeling for propofol states that “propofol undergoes
oxidative degradation in the presence of oxygen and is therefore packaged under nitrogen to eliminate this
degradation path”, and it states, “Do not freeze.” Therefore, exposing propofol to oxygen during the repackaging
process or freezing it would be in conflict with the approved labeling. In contrast, the labeling of propofol is silent
on the type of container into which it can be packaged. Therefore, packaging it into an appropriate container would
not conflict with the approved labeling. Also note that section 502(g) of the FD&C Act states that a drug is
misbranded if it is a drug that is recognized in an official compendium and among other things it is not packaged as
prescribed therein.

5

Contains Nonbinding Recommendations
approved labeling, except for the statements designating the product as a single-dose
or single-use product and related language (e.g., discard remaining contents). 19
6. The container into which the drug product is repackaged is suitable for storage of the
drug product through its beyond-use-date (BUD). 20
7. If the labeling for the approved drug product being repackaged includes storage
and/or handling instructions (e.g., protect from light, do not freeze, keep at specified
storage temperature), the labeling for the repackaged drug product specifies the same
storage conditions.
8. The repackaged drug product is assigned a BUD 21,22 as described below, unless
literature or other scientific information suggests that a shorter BUD would be
appropriate, in which case a shorter BUD is assigned consistent with such scientific
information. The BUD timeframes in this condition begin from the time in which the
container of the original drug product to be repackaged is punctured or otherwise
opened.
a. Sterile drug products repackaged by State-licensed pharmacies or
Federal facilities:
i.

FDA-approved drug product with a specified in-use time: If the
drug product being repackaged is an FDA-approved drug product that
specifies in the labeling a time within which the opened product is to
be used (an “in-use” time), the repackaged drug product is assigned a
BUD (1) that is established in accordance with the in-use time on the
drug product being repackaged; or (2) that is the expiration date on the
drug product being repackaged, whichever is shorter. 23

19

This condition would not be satisfied if a drug product repackaged from a single-dose vial is repackaged in a way
that conflicts with other language in the approved labeling (e.g., regarding storage conditions).

20

For example, for State-licensed pharmacies and Federal facilities, information provided by the container’s
manufacturer could indicate that the container is suitable for drug products repackaged in accordance with this
condition. For outsourcing facilities, CGMP requirements address container suitability and drug stability.

21

The BUD is the date beyond which a drug product should not be used.

22

FDA does not intend to take action against an outsourcing facility for assigning a BUD to be used as an expiration
date in lieu of conducting stability studies required under 21 CFR part 211 for its repackaged drug products if the
outsourcing facility assigns a BUD consistent with this condition.

23

For example, if an approved drug product that includes a 3-day in-use time and an expiration date of January 15,
2017, on the label is repackaged on January 1, 2017, the applicable BUD for the repackaged drug product would be
January 4, 2017, because the labeled in-use time of 3 days is shorter than the time until the labeled expiration date of
the drug product (14 days). If the drug product is repackaged on January 14, 2017, the applicable BUD for the
repackaged drug product would be January 15, 2017, because the time until the labeled expiration date of the
approved drug product is 1 day, which is shorter than the labeled 3-day in-use time.

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Contains Nonbinding Recommendations
ii.

FDA-approved drug product without an in-use time or
unapproved drug product: If the drug product being repackaged is
an FDA-approved drug product whose labeling does not specify an inuse time, or if it is an unapproved drug product on the FDA drug
shortage list (which does not have an in-use time reviewed by FDA as
part of the drug approval process), the repackaged drug product is
assigned a BUD (1) that is established in accordance with the proposed
revision to USP Chapter <797> published in the Pharmacopeial Forum
(PF) 41(6) [Nov.–Dec. 2015] on November 2, 2015, 24 or (2) that is the
expiration date on the drug product being repackaged, whichever is
shorter.

b. Sterile drug products repackaged by outsourcing facilities:
The outsourcing facility assigns a BUD as described in the guidance,
Current Good Manufacturing Practice — Interim Guidance for
Human Drug Compounding Outsourcing Facilities Under Section
503B of the FD&C Act. 25
c. Non-sterile drug products repackaged by State-licensed pharmacies,
Federal facilities, or outsourcing facilities: 26
i.

FDA-approved drug product with a specified in-use time: If the
drug product being repackaged is an FDA-approved drug product that
specifies in the labeling an “in-use” time, the repackaged drug product
is assigned a BUD (1) that is established in accordance with the in-use
time on the drug product being repackaged; or (2) that is the expiration
date on the drug product being repackaged, whichever is shorter.

ii.

FDA-approved drug product without an in-use time or
unapproved drug product: 27

24

Once USP has considered the public comments that it received and finalizes the revised Chapter <797>, FDA
intends to evaluate whether condition 8 should refer to the updated chapter or BUDs that are different than those
included in final Chapter <797>. Although USP Chapter <797> addresses compounded sterile preparations, many
of the same principles for conditions and practices to assure sterility and stability of compounded drug products,
such as the requirement to maintain a sterile environment, engage in appropriate sterile processing techniques, and
assign the appropriate BUD to the product, also apply to repackaged sterile drug products to help assure their quality
is not compromised during and after the repackaging operation.

25

The longer BUDs set forth for outsourcing facilities reflect that conditions maintained to comply with CGMP
requirements provide greater assurance of the quality of manufacturing operations and the products that are
produced at the facility, and that outsourcing facilities are subject to FDA inspections on a risk-based schedule.

26

In lieu of the BUDs set forth in this condition, outsourcing facilities may establish BUDs for non-sterile drug
products that they repackage based on stability studies conducted in accordance with 21 CFR Part 211.

27

The BUDs in this condition are based on the BUDs applicable to non-sterile compounded preparations in USP
Chapter <795>.

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Contains Nonbinding Recommendations

• For nonaqueous formulations, the BUD does not exceed six
months or the expiration date of the drug product being
repackaged, whichever is shorter.
• For water-containing oral formulations, the BUD does not exceed
14 days or the expiration date of the drug product being
repackaged, whichever is shorter.
• For water-containing topical/dermal and mucosal liquid and
semisolid formulations, the BUD does not exceed 30 days or the
expiration date of the drug product being repackaged, whichever is
shorter.
9. The drug product is repackaged in accordance with the following 28:
a. If the drug product is repackaged in a State-licensed pharmacy or a Federal
facility:
i. If it is a non-sterile drug product, it is repackaged in accordance with
USP Chapter <795>, except the BUD is as specified in condition 8; or
ii. If it is sterile drug product, it is repackaged in accordance with USP
Chapter <797>, except the BUD is as specified in condition 8.
b. If the drug product is repackaged in an outsourcing facility, repackaging is
conducted in accordance with CGMP requirements. 29
10. The drug product that is being repackaged does not appear on a list of drug products
that have been withdrawn or removed from the market because they have been found
to be unsafe or ineffective. For purposes of this provision, repackagers should refer
to the list of drug products in 21 CFR 216.24, developed for use with sections 503A
and 503B of the FD&C Act.
11. The drug product is not sold or transferred by an entity other than the entity that
repackaged such drug product. For purposes of this condition, a sale or transfer does
not include administration of a repackaged drug product in a health care setting.
12. The repackaged drug product is distributed only in States in which the facility
repackaging the drug product meets all applicable State requirements.

28

The intention is that the BUDs are set in accordance with condition 8.

29

See the guidance, Current Good Manufacturing Practice — Interim Guidance for Human Drug Compounding
Outsourcing Facilities Under Section 503B of the FD&C Act.

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Contains Nonbinding Recommendations
13. If the drug product is repackaged by an outsourcing facility:
a. The label on the immediate container (primary packaging, e.g., the syringe) of
the repackaged product includes the following:
i. The statement “This drug product was repackaged by [name of
outsourcing facility]”
ii. The address and phone number of the outsourcing facility that
repackaged the drug product
iii. The established name of the original drug product that was repackaged
iv. The lot or batch number of the repackaged drug product
v. The dosage form and strength of the repackaged drug product
vi. A statement of either the quantity or volume of the repackaged drug
product, whichever is appropriate
vii. The date the drug product was repackaged
viii. The BUD as the expiry date for the repackaged drug product
ix. Storage and handling instructions for the repackaged drug product
x. The National Drug Code (NDC) number of the repackaged drug
product, if available 30
xi. The statement “Not for resale,” and, if the drug product is distributed
by an outsourcing facility other than pursuant to a prescription for an
individual identified patient, the statement “Office Use Only”, and
xii. If included on the label of the drug product from which the drug
product is being repackaged, a list of the active and inactive
ingredients, unless such information is included on the label for the
container from which the individual units are removed, as described
below in 11.b.i.
b. The label on the container from which the individual units are removed for
administration (secondary packaging, e.g., the bag, box, or other package in
which the repackaged products are distributed) includes:
i. The active and inactive ingredients, if the immediate drug product
label is too small to include this information
ii. Directions for use, including, as appropriate, dosage and
administration
iii. The following information to facilitate adverse event
reporting: www.fda.gov/medwatch and 1-800-FDA-1088.
c. The drug product is included on a report submitted to FDA each June and
December identifying the drug products repackaged by the outsourcing
facility during the previous 6-month period, and providing the active
ingredient(s); source of the active ingredient(s); NDC number of the source
ingredient(s), if available; strength of the active ingredient(s) per unit; the
dosage form and route of administration; the package description; the number
30

The NDC number of the original approved drug product should not be placed on the repackaged drug product.

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Contains Nonbinding Recommendations
of individual units produced; and the NDC number of the repackaged drug
product, if assigned. 31
d. The outsourcing facility reports serious adverse events to FDA that are
associated with its repackaged drug products. 32
B. Establishment Registration and Drug Listing
Under section 510(b)(1) of the FD&C Act, between October 1 and December 31 of each year,
every person who owns or operates any establishment in any State engaged in the manufacture,
preparation, propagation, compounding, or processing of a drug or drugs is required to register
with FDA, and under section 510(j) of the FD&C Act, every person who registers with FDA
under section 510(b) must list its drugs with the Agency. A drug is misbranded under section
502(o) of the FD&C Act if it was manufactured, prepared, propagated, compounded, or
processed in an establishment that is not registered under section 510, or if it was not included on
a list required by section 510(j). Pharmacies that repackage drug products may qualify for an
exemption from registration and thus also not be required to list their drugs with FDA.
Specifically, under section 510(g)(1), the registration and listing requirements of section 510 do
not apply to:
pharmacies which maintain establishments in conformance with any applicable local laws
regulating the practice of pharmacy and medicine and which are regularly engaged in
dispensing prescription drugs or devices, upon prescriptions of practitioners licensed to
administer such drugs or devices to patients under the care of such practitioners in the
course of their professional practice, and which do not manufacture, prepare, propagate,
compound, or process drugs or devices for sale other than in the regular course of their
business of dispensing or selling drugs or devices at retail.
With respect to entities that do not qualify for the exemptions from registration under section 510
of the FD&C Act, 33 FDA does not intend to take action for violations of section 502(o) of the

31

FDA has issued a guidance for industry, Electronic Drug Product Reporting for Human Drug Compounding
Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act. This guidance describes
how outsourcing facilities submit drug product reports to FDA. Although that guidance addresses reporting of
compounded drug products, outsourcing facilities should follow the same procedure to electronically report the drug
products they repackaged.

32

FDA has issued a guidance for industry, Adverse Event Reporting for Outsourcing Facilities Under Section 503B
of the Federal Food, Drug, and Cosmetic Act, which describes how outsourcing facilities submit adverse event
reports to FDA and the content and format of the reports that they are required to submit. Although that guidance
addresses reporting of adverse events associated with compounded drug products, outsourcing facilities should
follow the procedure described in that guidance to electronically report adverse events associated with the drug
products they repackaged.
33

See also, 21 CFR 207.10.

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Contains Nonbinding Recommendations
FD&C Act for failure to register and list drugs under section 510 for drugs that are repackaged in
accordance with this guidance. 34

34

FDA has developed this policy because outsourcing facilities that repackage drug products in accordance with this
guidance are registered with FDA under section 503B of the FD&C Act and report repackaged drug products to
FDA in accordance with condition 13.c.

11