Labeled Vial Fill Size in Injectable Drug and Biological
Products
Guidance for Industry
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Rearch (CDER)
Center for Biologics Evaluation and Rearch (CBER)
June 2015
Pharmaceutical Quality/CMC
Labeled Vial Fill Size in Injectable Drug and Biological
Products
Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Rearch
Food and Drug Administration
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Silver Spring, MD 20993
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
druginfo@v
refudv/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
and/or
Office of Communication, Outreach and Development
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Food and Drug Administration
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Phone: 800-835-4709 or 240-402-7800
Email: ocod@v
v/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Rearch (CDER)
Center for Biologics Evaluation and Rearch (CBER)
June 2015
Pharmaceutical Quality/CMC
TABLE OF CONTENTS
I.INTRODUCTION (1)
II.BACKGROUND (2)
III.OVERVIEW (2)
A.Allowable Excess Volume (2)
B.Labeled Vial Fill Size (3)
IV.DISCUSSION AND RECOMMENDATIONS (3)
Allowable Excess Volume and Labeled Vial1 Fill Size in Injectable 1
Drug and Biological Products
2
Guidance for Industry2
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cubita4
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This guidance reprents the current thinking of the Food and Drug Administration (FDA or Agency) on 7
this topic. It does not establish any rights for any person and is not binding on FDA or the public. You 8
can u an alternative approach if it satisfies the requirements of the applicable statutes and regulati
ons. 9
To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the 10
title page.
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I. INTRODUCTION
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This guidance provides the pharmaceutical industry with the Center for Drug Evaluation and
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Rearch’s (CDER’s) and the Center for Biologics Evaluation and Rearch’s (CBER’s) current 19
thinking on allowable excess volume and labeled vial fill size in injectable drug and biological 20
products. It replaces the draft of the same name that was published on March 14, 2014 (79 FR 21
14517). Specifically, the guidance clarifies the FDA regulatory requirements and
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recommendations pertaining to allowable excess volume in injectable vials and describes when 23
justification is needed for a propod excess volume in the injectable drug3 products. This
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guidance also discuss the importance of appropriate fill volumes for injectable drug products 25
and recommends that labeled vial fill sizes be appropriate for the intended u and dosing of the 26
drug product.
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This guidance address withdrawable volume and labeled vial fill size for injectable drug
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products that are packaged in vials and ampules, including products that require reconstitution.打电话给我的英文
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It does not address injectable drug products in other packaging types (e.g., prefilled syringe
package systems and intravenous infusion bags) or noninjectable products, becau there may be
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unique considerations for the packaging configurations. The recommendations in this
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guidance apply to new drug applications (NDAs), abbreviated new drug applications (ANDAs), 34
biologics licen applications (BLAs), as well as supplements or other changes to the
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applications for new packaging or other changes that may affect the fill volume.
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In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
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Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only 39
as recommendations, unless specific regulatory or statutory requirements are cited. The u ofever since
1 The term vial ud throughout this guidance refers to both vial and ampule package types.
2 This guidance has been prepared by the Office of Pharmaceutical Quality in the Center for Drug Evaluation and
Rearch in collaboration with the Center for Biologics Evaluation and Rearch at the Food and Drug
Administration.
3 The term drug ud throughout this guidance refers to drugs, including biological drug products.
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the word should in Agency guidances means that something is suggested or recommended, but 41
not required.
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II. BACKGROUND
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Injectable vial misu, including unsafe handling and injection techniques, has led to vial
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contamination and an incread risk of bloodborne illness transmission between patients.4,5
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Inappropriate excess volume and labeled vial fill sizes are two factors that may contribute to
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dead giveaway
unsafe handling and injection practices by consumers and health care providers. FDA has been 49
concerned about the issues and is publishing this guidance to clarify its regulatory
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requirements and recommendations.
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III. OVERVIEW
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A. Allowable Excess Volume
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The United States Pharmacopeia (USP) General Chapter <1> Injections provides that each
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container of an injectable product is filled with a volume that slightly exceeds the content
indicated in the labeling.6 The excess volumes are meant to be sufficient to permit withdrawal
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and administration of the labeled volumes. FDA regulations at 21 CFR 201.51(g) provide that 60
for drugs in ampules or vials that are intended for injection, the declaration of net quantity of
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contents on the label is considered to express the minimum quantity of contents and further
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requires that variation above the stated measure must comply with the excess volumes t forth 63
in USP. USP General Chapter <1151> Pharmaceutical Dosage Forms provides excess volume 64
recommendations for mobile and viscous liquids in a range of fill volumes, noting that the excess 65
volumes recommended are usually sufficient to permit withdrawal and administration of the
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labeled volumes. Allowable excess volume may also be referred to as “overfill,” but should not 67
be confud with “overage,” which is addresd in a parate guidance.7 Generally, an applicant 68
should not declare the amount of overfill on the container label.
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4 Perz J, Thompson N, Schaefer M, Patel P, 2010, US Outbreak Investigations Highlight the Need for Safe Injection
Practices and Basic Infection Control, Clinics in Liver Dia, 14:137-151.
5 Centers for Dia Control and Prevention, Injection Safety, Safe Injection Practices to Prevent Transmission of
Infections to Patients, 2007 Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings (v/injectionsafety/IP07_standardPrecaution.html).
6 For a drug product for which there is an official USP drug product monograph, the product must comply with the
standards t forth therein, including the standards t forth in General Chapter <1>, unless expressly excepted in that drug product monograph. See Federal Food, Drug, and Cosmetic Act, ctions 501(b) (21 U.S.C. 351(b)) and 502(g) (21 U.S.C. 352(g)); USP 37-NF 32, General Notices and Requirements 2.10. Official Text. Thus, for an
injectable drug product for which a USP monograph exists and incorporates General Chapter <1>, the provision regarding inclusion of a slight volume exceeding the labeled volume is a mandatory requirement; for injectable
products without a USP monograph that incorporates General Chapter <1>, compliance with the slight excess
volume provision is strongly recommended. USP has propod moving the text discussing the container content from USP General Chapter <1> Injections to USP General Chapter <697> Container Content for Injections. The propod changes are being considered for USP 38.
7Overage is an amount of a drug substance in excess of the label claim. The u of an overage to compensate for degradation during manufacture or a product’s shelf life, or to extend the shelf life is generally discouraged. The u of an overage is discusd in ction 2.2.2 of the International Conference on Harmonisation (ICH), Guidance for Industry, Q8(R2) Pharmaceutical Development.
FDA becomes concerned when the excess volume in a vial is greater or less than the USP
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recommended amount without appropriate justification. Such excess and deficiencies may
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result in medication errors and may lead to misu of leftover drug product or pooling of vials to obtain a single do.
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B.Labeled Vial Fill Size
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While dosing flexibility is necessary with injectable drug products, applicants should determine 78
the appropriate vial fill sizes during product development, considering how the vials are likely to be ud. For example, single-do vials are designed for u in a single patient as a single
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injection/infusion. However, even when appropriately labeled, single-do vials that contain
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significantly8 more drug than is required for a single do may result in the misu of the leftover 82
drug product. Similarly, the need to combine veral single-do vials for a single patient do 83
may lead to medication errors and microbial contamination.
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According to USP General Chapter <1>, multiple-do vials have a maximum container volume 86
sufficient to permit the withdrawal of not more than a total of 30 mL, unless otherwi specified in the USP drug product monograph.9,10 Setting a maximum volume in multiple-do vials will 87
minimize vial ptum punctures, which will reduce the risk of compromising vial integrity and
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the potential for vial contamination.
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IV. DISCUSSION AND RECOMMENDATIONS
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With respect to allowable excess volume, the applicant of drugs in ampules or vials intended for 94
injection must follow the requirements in 21 CFR 201.51(g). The regulation requires an
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applicant to comply with the excess volume recommendations prescribed by the USP.
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Therefore, for drugs in ampules and vials intended for injection, the applicant must comply with 97
the excess volume recommendations that appear in USP General Chapter <1151>.11 In the ca 98
of drug products requiring reconstitution, the product should be designed to meet the label claim 99
and acceptable overfill, and allow for correct dosing. Deviations from the recommendations in 100
USP General Chapter <1151> with regard to excess volume should be justified.12 FDA
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recommends providing the justification by obtaining extractable content testing data, which is
8 While it is not possible to specify a quantitative volume of remaining drug product that would generally be
considered significant, volumes remaining that could provide a cond do, or would encourage pooling for a
cond do, would be considered excessive.
9 USP has propod moving the text discussing the maximum container volume for multiple-do vials from USP
General Chapter <1> Injections to USP General Chapter <659> Packaging and Storage Requirements. The
propod changes are being considered for USP 38.
10 For products without a USP monograph, multiple-do vials must have a maximum fill volume sufficient to
permit the withdrawal of not more than 30 mL, unless justified in the application.
11 Typically, USP General Chapters titled with numbers above <1000> are considered to be recommendations and
not requirements, unless the chapter is cited in a product-specific monograph or another General Chapter titled with
a number below <1000>. However, in this ca, becau FDA’s regulations specifically require adherence to the
USP recommendations on this topic, the recommendations in USP General Chapter <1151> are considered to be
requirements.
12 For example, for a drug product requiring reconstitution that is dod bad on body weight, it is important for the
final concentration to be a whole number that allows for easy calculation and withdrawal of the appropriate do.
This consideration may be ud to justify a slight deviation from the recommended overfill.
