Selection of the Appropriate
Package Type Terms andRecommendations forLabeling Injectable Medical
Products Packaged in
Multiple-Dose, Single-Dose,and Single-Patient-Use
Containers for Human Use
Guidance for Industry

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
Center for Devices and Radiological Health (CDRH)
Office of Combination Products
October 2018
Pharmaceutical Quality/CMC

1816211 FNL

Selection of the Appropriate Package Type Terms andRecommendations for Labeling Injectable Medical
Products Packaged in Multiple-Dose, Single-Dose,and Single-Patient-Use Containers for Human Use
Guidance for Industry
Additional copies are available from:

Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: druginfo@fda.hhs.gov
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

and/orOffice of Communication, Outreach and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
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Silver Spring, MD 20993-0002
Phone: 800-835-4709 or 240-402-8010
Email: ocod@fda.hhs.gov
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

and/orOffice of the Center Director
Center for Devices and Radiological Health
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 66, Room 5431
Silver Spring, MD 20993-0002
Email: CDRH-Guidance@fda.hhs.gov
https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/default.htm
and/orOffice of Combination Products
Office of Special Medical Programs
Office of the Commissioner
Food and Drug Administration
10903 New Hampshire Avenue, WO-32 Hub 5129

Silver Spring, MD 20993-0002(Tel) 301-796-8930 (Fax) 301-796-8619
http://www.fda.gov/CombinationProducts/default.htm

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
Center for Devices and Radiological Health (CDRH)
Office of Combination Products
October 2018
Pharmaceutical Quality/CMC

Contains Nonbinding Recommendations
TABLE OF CONTENTSI.

INTRODUCTION............................................................................................................. 1II.

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

III.

DISCUSSION .................................................................................................................... 3

Definitions ............................................................................................................................................... 3
1. Single-Dose Container. .................................................................................................................... 3
2. Multiple-Dose Container. ................................................................................................................ 3
3. Single-Patient-Use Container. ......................................................................................................... 5IV.

LABELING REQUIREMENTS AND RECOMMENDATIONS ................................ 6

A.

Change from “single-use” to “single-dose” package type term ................................................. 7

B.

All other changes to a package type term .................................................................................... 7

C.

Changes made to add a package type term to the container/carton labeling (and, in somecases, the prescribing information) when no package type is included (or listed) ................... 7D.

Any other proposed changes in package type terminology ........................................................ 8

E.

Addition of a discard statement or changes to an existing discard statement .......................... 8i

Contains Nonbinding Recommendations

Selection of the Appropriate Package Type Terms andRecommendations for Labeling Injectable Medical Products
Packaged in Multiple-Dose, Single-Dose, and Single-Patient-Use
Containers 1 for Human Use
Guidance for Industry 2This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on
this topic. It does not establish any rights for any person and is not binding on FDA or the public. You
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on thetitle page.

I.

INTRODUCTION

This guidance provides industry with the Food and Drug Administration’s (FDA’s)
recommendations on the selection of appropriate package type terms and selection of appropriate
discard statements 3 for injectable medical products for human use, packaged in multiple-dose,
single-dose, and single-patient-use containers. Specifically, this guidance provides FDA’s
revised definitions for single-dose and multiple-dose containers as well as for the new package
type term single-patient-use container. 4 These containers may be part of a drug, a biologicalproduct, or a combination product assigned to CDER, CBER, or certain combination products
assigned to CDRH. 5 Marketing applications for such products include: New Drug Applications(NDAs), Abbreviated New Drug Applications (ANDAs), Biologics License Applications(BLAs), Premarket Approval Applications (PMAs), Premarket Notifications under section
510(k) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), and requests for classification
submitted under section 513(f)(2) of the FD&C Act (De Novo request).
1

The term container in this guidance refers to all package types used for injectable medical products for human use.
This guidance does not discuss all package type terms (e.g., Pharmacy Bulk Package). Please refer to United States
Pharmacopeia (USP) General Chapter <659> Packaging and Storage Requirements for other package type terms.
2This guidance has been prepared by the Office of Pharmaceutical Quality in the Center for Drug Evaluation andResearch (CDER) in cooperation with the Center for Biologics Evaluation and Research (CBER), the Center for
Devices and Radiological Health (CDRH), and the Office of Combination Products in the Office of theCommissioner at the Food and Drug Administration.
3
This guidance is intended to provide recommendations on the selection of discard information for containers. It
does not provide information on disposal instructions. Discard information is a statement supported by appropriate
data on when to stop using an injectable medical product. Disposal information is a statement on how to safely andappropriately destroy any unused injectable medical product.
4
For the purpose of this guidance, such products are referred to as medical products. Diluents used to reconstitute or
dilute human drug and biological products are also considered to be medical products.
5
See 21 CFR 3.2. Combination products are composed of a drug, device, and/or a biological product. For
information on center assignment, see 21 CFR 3.4.

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Contains Nonbinding Recommendations
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

Unsafe injection practices, including the use of needles or syringes for more than one patient or
the improper use of medication vials for more than one patient, threaten patient safety and haveresulted in multiple blood borne bacterial and viral infection outbreaks. Bacterial and viral
infections have been transmitted to patients when single-dose containers were used improperly,
the contents became contaminated and these contents were then administered to multiple
patients. Failure to follow standard precautions and aseptic techniques has also been associatedwith several outbreaks of infections involving multiple-dose vials. Examples of such incidents
with single-dose and multiple-dose vials are:•From 1998 through 2008, patient to patient transmission of blood borne pathogens due tounsafe injection practices resulted in 33 outbreaks of viral hepatitis in nonhospital healthcare settings in the United States. 6•

According to the Centers for Disease Control and Prevention (CDC), at least 26 incidents
involving the improper use of single-dose medications in outpatient settings haveoccurred over a five year period resulting in the potential exposure of more than 95,000
patients to infectious diseases. 7•

In 2002, 71 cases of hepatitis C virus (HCV) infection and 31 cases of hepatitis B virus
infection were attributed to unsafe needle/syringe practices in an Oklahoma pain clinic. 8•

In 2008, an investigation of an HCV outbreak in Nevada revealed that reuse of syringes
in multiple patients and use of single-use medication vials for multiple patients were thelikely mechanisms by which HCV infections were transmitted. 9

It is evident from the examples described above that single-dose containers, which are intended
for use for a single patient, have been used for more than one patient in the past, and that thispractice has contributed to many of these bacterial and viral infection outbreaks. Additionally,
there is a concern that existing package type terms do not adequately convey that some
6

Thompson, ND, et al. 2009, Nonhospital Health Care-Associated Hepatitis B and C Virus Transmission: UnitedStates, 1998-2008. Ann Int Med; 150:33-39.
7
CDC: Injection Safety, 2012, CDC’s position-protect patients against preventable harm from improper use of
single-dose/single-use vials. Atlanta, GA: US Department of Health and Human Services. Available at:
http://www.cdc.gov/injectionsafety/cdcposition-singleusevial.html.
8
Comstock RD, et al. 2004, A Large Nosocomial Outbreak of Hepatitis C and Hepatitis B Among Patients
Receiving Pain Remediation Treatments. ICHE; 25:576-583.
9
CDC: 2007, Acute hepatitis C virus infections attributed to unsafe injection practices at an endoscopy clinicNevada. MMWR 2008; 57:513-7. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5719a2.htm.

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Contains Nonbinding Recommendations
containers (e.g., insulin pens) that provide multiple doses are intended for use for only a single
patient. 10
III.

DISCUSSION

As part of its review of medical products, FDA clears or approves package type terms anddiscard statements as part of the labeling of injectable medical products. FDA believes thatconsistent use of correct package type terms and discard statements for injectable medical
products for human use will promote their proper use and provide a foundation for educational
efforts to reduce the transmission of blood borne pathogens. The following sections describe theappropriate package type terms for multiple-dose, single-dose, and single-patient-use containersthat may be part of injectable drug and biological products for human use, CDER-led, CBER-led,or certain CDRH-led combination products for injection, and diluents used to reconstitute or
dilute human drug and biological products.
Definitions
The package type terms “single-dose” container and “multiple-dose” container have been in use
for a long time. To provide clarity on the intended use of these terms, the definitions are being
revised as follows:
1.
Single-Dose Container: A single-dose container is a container of a sterile
medication 11 for parenteral administration (injection or infusion) that is not
required to meet the antimicrobial effectiveness testing requirements. A singledose container is designed for use with a single patient as a single injection/
infusion. When space permits, a single-dose container is labeled as such andshould include on the label appropriate discard statements. Examples of singledose containers are vials, ampules, and prefilled syringes.
2.
Multiple-Dose Container: 12 A multiple-dose container is a container of asterile medication 13 for parenteral administration (injection or infusion) that has
met antimicrobial effectiveness testing requirements, or is excluded from suchtesting requirements by FDA regulation. 14 A multiple-dose container is intended
10

In March 2009, in response to reports of improper use of insulin pens in hospitals, FDA issued a Safety Alert for
health care professionals reminding them that insulin pens are meant for use on a single patient only and are not to beshared between patients. Available at:https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInfor
mationforHeathcareProfessionals/ucm133352.htm.
11
The term sterile medication applies to both active drug products and diluents.
12
The term multi-dose may be used instead of multiple-dose.
13
See footnote 11.
14
Antimicrobial effectiveness testing determines whether the product prevents microbial growth if contamination of
the container occurs during patient use conditions. Some injectable chemical formulations may possess sufficient
inherent antimicrobial effectiveness characteristics without the addition of a preservative, while other products relyon the addition of a preservative to meet this requirement. However, certain specially designed packaging anddelivery systems or certain radiopharmaceuticals with short expiration dates permit the use of preservative-free injectable3

Contains Nonbinding Recommendations
to contain more than one dose of the drug product. When space permits, amultiple-dose container is labeled as such. Multiple-dose containers are generally
expected to contain 30 mL or less of medication. 15 The beyond-use date 16 for an
opened or entered (e.g., needle-punctured) multiple-dose container is 28 days,
unless otherwise specified by the manufacturer on the label. 17, 18 An example of amultiple-dose container is a vial.
In the vast majority of cases, the package type terms “single-dose” and “multiple-dose” areproperly used. However, in some unique situations, a package contains multiple doses of a
medical product that is intended to be for use in a single patient. The medical product in thispackage type may not contain a preservative or be able to pass antimicrobial effectiveness if
tested, yet this package type contains multiple doses for use in a single patient. An example ofthis package type is a drug intended for intrathecal administration that is packaged in a patientcontrolled analgesia cartridge. Because the package type is designed to administer multiple
doses, the package type term “single-dose” is not appropriate. However, the package type term
“multiple-dose” is also inappropriate because the package contents are not able to meet
antimicrobial effectiveness testing requirements.
In other cases, the medical products in this package type do contain a preservative and are
expected to pass antimicrobial effectiveness if tested, yet the intent is that the package is to be
restricted to use by a single patient. In this scenario, referring to the package type as “multipledose” does not adequately convey the intent to restrict the use to a single patient. An example
of such a product is an insulin pen that contains multiple doses of insulin for individual patientuse.
In the past, the term “single-use” container has been used by FDA to describe a package typethat contained multiple doses but was intended to be used in a single patient. Unfortunately, theterm “single-use” was also inappropriately used as if it were interchangeable with the term“single-dose” which was not the Agency’s original intent. To address this confusion regarding
the terminology, the Agency is retiring the term “single-use” and a new package type term“single-patient-use” container, has been created to address the need for describing a package that
contains multiple doses of an injectable medical product that is intended to be used in a single
patient.

products for multiple patient uses. While most multiple dose biological products require a preservative, 21 CFR
610.15 provides for a few exceptions.
15
United States Pharmacopeia-National Formulary (USP-NF-) <659> PACKAGING AND STORAGE
REQUIREMENTS, Injection Packaging.
16
Beyond-use date (BUD) is the date or time beyond which a product should not be used. See USP-NF <7>
LABELING, Expiration Date and Beyond-Use Date.
17
See
https://www.jointcommission.org/standards_information/jcfaqdetails.aspx?StandardsFaqId=1091&ProgramId=46.
18
Vaccines in multiple-dose vials should be used and disposed of according to their FDA approved product labeling.
Unless a multiple-dose vial is labeled otherwise, vaccines supplied in multiple-dose vials may be used up to the dateof expiry of the product. See also http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6002a1.htm.

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Contains Nonbinding Recommendations
3.
Single-Patient-Use Container: A single-patient-use container is acontainer of a sterile medication 19 for parenteral administration (injection or
infusion) that is intended to be used multiple times for a single patient. Whenspace permits, a single-patient-use container is labeled as such and should include
on the label appropriate discard statements. Examples of single-patient-use
containers are patient controlled analgesia cartridges and certain pens forinjection.
For multiple-dose and single-patient-use containers, the antimicrobial effectiveness testing
results, if performed, will be used to support the labeled beyond-use date or discard statements.
The following diagram illustrates how the appropriate package type term for an
injectable medical product can be determined:* Use of the term “single-dose” container does not imply the entire contents of the container constitute a single dose.
In some instances, a single-dose container may contain more drug than is required for a single dose or multiple vials
may be needed to obtain a single dose. For example, for a medical drug product that is dosed based on body weight,
or due to the required overfill in vials and ampules, there may be excess amount constituting more than one dose in
the container, which should be discarded. Please refer to FDA’s guidance for industry on Allowable Excess Volume
and Labeled Vial Fill Size in Injectable Drug and Biological Products. 20 Furthermore, although dosed over an
extended time period, infusion containers (large or small volume) are considered single-dose containers because
they are designed for use with a single patient as a single infusion.

19

See footnote 11.
This guidance is available on the Internet athttps://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm under Guidances(Drugs).
20

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Contains Nonbinding RecommendationsIV.

LABELING REQUIREMENTS AND RECOMMENDATIONSApplicants should determine the proper package type term (“single-dose,” “multiple-dose,” or“single-patient-use”) for injectable medical products for human use and use only the correctterm for the package type throughout the labeling. FDA recommends that the appropriate
package type term appear on all components of the labeling of injectable medical products forhuman use so the user will be able to easily identify the package type. This includes thecontainer label and carton labeling, prescribing information, and where applicable, labelingintended for the patient. 21
The package type term “single-dose” is required to appear on the container labels of single-dose
injectable medical products that have a United States Pharmacopeia (USP) monograph, whenspace permits (FD&C Act section 502(g) (21 U.S.C. 352(g)). 22 When space does not permit the“single-dose” term to appear on such products’ container labels, then according to 21 CFR
201.10(i)(2), it must appear on the carton or other outer container or wrapper, if space permits,or in the prescribing information. In FDA’s experience, there has always been sufficient space
to include this information on the carton labeling.
When space permits, the appropriate package type term should appear on the container label ofmultiple-dose and single-patient-use injectable medical products, as well as single-dose
injectable medical products that do not have a USP monograph. If there is insufficient space toinclude this information on the container label, the package type term should appear on the
carton labeling where it will be easily visible.
When appropriate, the prescribing information for single-patient-use and single-dose
injectable medical products should include a discard statement. 23 The discard statement
should also be included on the container label and carton labeling, when space permits. For
example, single-dose container labeling should typically include the statement “Discard
unused portion.”
Multiple-dose containers do not normally have a discard statement because the beyond-use dateis assumed to be 28 days for an opened or entered (e.g., needle-punctured) multiple-dosecontainer, unless otherwise indicated. 24 If the beyond-use date is other than 28 days for a
product in a multiple-dose container, an appropriate discard statement (supported byappropriate data) should be included on the container label, carton labeling, and in the21

Examples of sections within the prescribing information for drug products where the package type term may
appear include, but are not limited to: DOSAGE AND ADMINISTRATION, DOSAGE FORMS AND
STRENGTHS, DESCRIPTION, and HOW SUPPLIED/STORAGE AND HANDLING (21 CFR 201.56 and201.57).
22
21 U.S.C. section 352(g); The following statement “A single-dose container shall be labeled as such….” appears in
United States Pharmacopeia-National Formulary (USP-NF), <7> Labeling, and a similar phrase “…a single-dosecontainer is labeled as such….” appears in <659> Packaging and Storage Requirements.
23
This statement should be placed in the DOSAGE AND ADMINISTRATION, Preparation Instructions section of
the prescribing information and, when applicable, in patient labeling such as the INSTRUCTIONS FOR USE. (21CFR 201.56, and 201.57).
24
See footnotes 17, 18.

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Contains Nonbinding Recommendationsprescribing information. Examples of statements that might appear on multiple-dose containers
include:• “Discard within XX hours after opening or after assembly” or• “After first use, refrigerate or keep at a temperature not greater than XX for XX days.”
The Agency recommends that applicants make the necessary labeling changes to follow theserecommendations within two years of the publication of this guidance. All submissions (annual
reports and supplements) should clearly identify the change(s) being made. In addition, a
supplement submission to follow the recommendations in the guidance should be identified as“Labeling Changes to Follow the Package Type Term Guidance.” For approved applications,changes made to labeling to follow the recommendations in this guidance should be submitted to
the FDA as described below: 25
A. Change from “single-use” to “single-dose” package type term
For a drug product that was designed and otherwise labeled for use with a single patient as asingle injection/infusion, a change from the package type term “single-use” to “single-dose”
to accurately reflect the package type should be submitted in an annual report. See 21 CFR
314.70(d)(2)(x); 21 CFR 314.94(a)(8)(iv) and 21 CFR 601.12(f)(3)(i)(A). 26
B. All other changes to a package type term
ALL other changes to a package type term, including a change from the package type term“single-use” to “single-patient-use,” as well as a change from “multiple-dose” to “singlepatient-use” should be submitted as a “Prior Approval Supplement” (PAS) for NDAs and BLAs
only. See 21 CFR 314.70(b)(2)(v)(A); and 21 CFR 601.12(f)(1).
After FDA approval of a PAS for an NDA, the holders of any ANDAs that relied upon the
NDA as the reference listed drug (RLD) are required to submit conforming labeling revisions.
See 21 CFR 314.94(a)(8)(iv) and 21 CFR 314.150(b)(10). FDA is specifically requesting thatthese conforming ANDA labeling revisions be submitted in a “Changes Being Effected” (CBE0) supplement. See 21 CFR 314.70(c)(6)(iii)(E). If approval of the NDA for the RLD has
been withdrawn, the corresponding ANDA holders should submit a PAS to propose changes toa package type term.
C. Changes made to add a package type term to the container/carton labeling (and,in some cases, the prescribing information) when no package type is included (orlisted)25This information is specific for NDAs, ANDAs, and BLAs. For information on other cleared or approved
medical products regulated by CBER or CDRH, contact the appropriate Center.
26
This discussion of potential regulatory pathways for submission assumes that the change in package type termfrom “single-use” to “single-dose” is the only change being made to the labeling. Other changes may require
submission of a supplement.

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Contains Nonbinding Recommendations
1. If the prescribing information already includes the appropriate assigned package
type but the container/carton labeling lacks the designation for some reason otherthan lack of space, NDA, BLA, and ANDA holders may submit the addition of the
package type term to the container/carton labeling in an annual report under 21 CFR
314.70(d)(2)(x), and 21 CFR 601.12(f)(3)(i)(A), as long as the package type term
being added to the container/carton labeling is the same correct term that has
already been included in the approved prescribing information. The sameprocedure applies if the container/carton labeling includes the appropriate assigned
package type but the prescribing information lacks the designation.
2. If neither the container/carton labeling nor the prescribing information has apackage type term listed, NDA and BLA holders should submit a PAS to add theappropriate term to the container/carton labeling and prescribing information, see 21
CFR 314.70(b)(2)(v)(A) and 21 CFR 601.12(f)(1). After FDA approval of the PAS
for the NDA RLD, corresponding ANDA holders are required to submit conforming
labeling revisions. See 21 CFR 314.94(a)(8)(iv) and 21 CFR 314.150(b)(10). FDA
is specifically requesting that these conforming ANDA labeling revisions be
submitted in a CBE-0 supplement. See 21 CFR 314.70(c)(6)(iii)(E). If approval of
the NDA for the RLD has been withdrawn, the corresponding ANDA holders should
submit a PAS to propose a package type term.
D. Any other proposed changes in package type terminology
For any other proposed changes regarding package type terms, please contact the Agency. 27
E. Addition of a discard statement or changes to an existing discard statement
1. Discard unused portion
The addition of or change to the phrase “Discard unused portion” in the labelingof a single-dose container should be submitted in an annual report. See 21 CFR
314.70(d)(2)(x); 21 CFR 314.94(a)(8)(iv) and 21 CFR 601.12(f)(3)(i)(A). 28
2. Any other proposed change in a discard statement
For any other proposed change regarding a discard statement, please contact the
Agency. 29

27

See footnote 25.
See footnote 25.
29
When the submission is for an NDA or BLA, contact the specific drug product’s review division with questions.
When the submission is for an ANDA, submit questions as a General Correspondence to the application.
28

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