Allowable Excess Volume and 
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 Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
June 2015 
Pharmaceutical Quality/CMC 
 
   
Allowable Excess Volume and 
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 Research 
Food and Drug Administration 
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Silver Spring, MD 20993  
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druginfo@fda.hhs.gov  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
and/or 
 
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 Food and Drug Administration 
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Phone: 800-835-4709 or 240-402-7800 
Email: ocod@fda.hhs.gov 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/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) 
 
June 2015 
Pharmaceutical Quality/CMC 
  Contains Nonbinding Recommendations 
 
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 
  Contains Nonbinding Recommendations 
 
1
1  Allowable Excess Volume and Labeled Vial  Fill Size in Injectable 
2  Drug and Biological Products   
2
3  Guidance for Industry  
4   
5   
6  This guidance represents 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 use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
9  To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the 
10  title page.   
11   
12   
13   
14   
15  I.  INTRODUCTION  
16   
17  This guidance provides the pharmaceutical industry with the Center for Drug Evaluation and 
18  Researchs (CDERs) and the Center for Biologics Evaluation and Researchs (CBERs) 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 
22  recommendations pertaining to allowable excess volume in injectable vials and describes when 
23  justification is needed for a proposed excess volume in these injectable drug3 products.  This 
24  guidance also discusses the importance of appropriate fill volumes for injectable drug products 
25  and recommends that labeled vial fill sizes be appropriate for the intended use and dosing of the 
26  drug product.   
27   
28  This guidance addresses withdrawable volume and labeled vial fill size for injectable drug 
29  products that are packaged in vials and ampules, including products that require reconstitution.  
30  It does not address injectable drug products in other packaging types (e.g., prefilled syringe 
31  package systems and intravenous infusion bags) or noninjectable products, because there may be 
32  unique considerations for these packaging configurations.  The recommendations in this 
33  guidance apply to new drug applications (NDAs), abbreviated new drug applications (ANDAs), 
34  biologics license applications (BLAs), as well as supplements or other changes to these 
35  applications for new packaging or other changes that may affect the fill volume.   
36   
37  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
38  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
39  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
                                                 
1 The term vial used 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 
Research in collaboration with the Center for Biologics Evaluation and Research at the Food and Drug 
Administration.  
3 The term drug used throughout this guidance refers to drugs, including biological drug products. 
  1  Contains Nonbinding Recommendations 
 
40  the word should in Agency guidances means that something is suggested or recommended, but 
41  not required.  
42   
43  II.  BACKGROUND 
44   
45  Injectable vial misuse, including unsafe handling and injection techniques, has led to vial 
46  contamination and an increased risk of bloodborne illness transmission between patients.4,5 
47  Inappropriate excess volume and labeled vial fill sizes are two factors that may contribute to 
48  unsafe handling and injection practices by consumers and health care providers.  FDA has been 
49  concerned about these issues and is publishing this guidance to clarify its regulatory 
50  requirements and recommendations. 
51   
52  III.  OVERVIEW    
53   
54  A.  Allowable Excess Volume 
55   
56  The United States Pharmacopeia (USP) General Chapter <1> Injections provides that each 
57  container of an injectable product is filled with a volume that slightly exceeds the content 
58  indicated in the labeling.6  The excess volumes are meant to be sufficient to permit withdrawal 
59  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 
61  contents on the label is considered to express the minimum quantity of contents and further 
62  requires that variation above the stated measure must comply with the excess volumes set 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 
66  labeled volumes.  Allowable excess volume may also be referred to as overfill, but should not 
67  be confused with overage, which is addressed in a separate guidance.7  Generally, an applicant 
68  should not declare the amount of overfill on the container label.  
69   
                                                 
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 Disease, 14:137-151.   
5 Centers for Disease 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 (http://www.cdc.gov/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 set forth therein, including the standards set forth in General Chapter <1>, unless expressly excepted in 
that drug product monograph.  See Federal Food, Drug, and Cosmetic Act, sections 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 proposed moving the text discussing the container content 
from USP General Chapter <1> Injections to USP General Chapter <697> Container Content for Injections. These 
proposed changes are being considered for USP 38. 
7 Overage is an amount of a drug substance in excess of the label claim. The use of an overage to compensate for 
degradation during manufacture or a products shelf life, or to extend the shelf life is generally discouraged.  The use 
of an overage is discussed in section 2.2.2 of the International Conference on Harmonisation (ICH), Guidance for 
Industry, Q8(R2) Pharmaceutical Development. 
  2  Contains Nonbinding Recommendations 
 
70  FDA becomes concerned when the excess volume in a vial is greater or less than the USP 
71  recommended amount without appropriate justification. Such excesses and deficiencies may 
72  result in medication errors and may lead to misuse of leftover drug product or pooling of vials to 
73  obtain a single dose.   
74   
75  B.  Labeled Vial Fill Size  
76   
77  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 
79  be used.  For example, single-dose vials are designed for use in a single patient as a single 
80  injection/infusion.  However, even when appropriately labeled, single-dose vials that contain 
81  significantly8 more drug than is required for a single dose may result in the misuse of the leftover 
82  drug product.  Similarly, the need to combine several single-dose vials for a single patient dose 
83  may lead to medication errors and microbial contamination.   
84   
85  According to USP General Chapter <1>, multiple-dose vials have a maximum container volume 
86  sufficient to permit the withdrawal of not more than a total of 30 mL, unless otherwise specified 
87  in the USP drug product monograph.9,10  Setting a maximum volume in multiple-dose vials will 
88  minimize vial septum punctures, which will reduce the risk of compromising vial integrity and 
89  the potential for vial contamination.   
90   
91  IV.  DISCUSSION AND RECOMMENDATIONS 
92   
93  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 
95  applicant to comply with the excess volume recommendations prescribed by the USP.  
96  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 case 
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 
101  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 second dose, or would encourage pooling for a 
second dose, would be considered excessive.  
9 USP has proposed moving the text discussing the maximum container volume for multiple-dose vials from USP 
General Chapter <1> Injections to USP General Chapter <659> Packaging and Storage Requirements.  These 
proposed changes are being considered for USP 38. 
10 For products without a USP monograph, multiple-dose 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 case, because FDAs 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 dosed based 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 dose. 
This consideration may be used to justify a slight deviation from the recommended overfill. 
  3  Contains Nonbinding Recommendations 
 
102  described in USP General Chapter <1> under Packaging, Determination of Volume of Injection 
103  in Containers, or other appropriately justified methods.  A variety of approaches may be 
104  considered acceptable for sample collection, for example: 
105    
106    For BLAs:  Lot release testing and/or collection from batches representative of the 
107  commercial process, using appropriate sampling and methods.  
108   
109    For NDAs and ANDAs:  One or more batches representative of the commercial 
110  process as part of the product development studies using appropriate sampling 
111  and methods. 
112   
113  The applicant should provide data related to proposed excess volume in the following sections of 
114  the application:13 
115   
116    The excess volume included in a drug product should be described in the common 
117  technical document (CTD) section 3.2.P.1, Description and Composition of the 
118  Drug Product. 
119   
120    The studies and justification (i.e., extractable volume testing, viscosity studies, fill 
121  volume variability) should be described in CTD section 3.2.P.2.2.1, Formulation 
122  Development and/or 3.2.P.2.3, Manufacturing Process Development. 
123   
124  FDA recommends that a drug products vial fill size should be appropriate for the labeled use 
125  and dosing of the product.14   FDA may request justification when there are questions about the 
126  appropriateness of the proposed labeled vial fill sizes in an application.  When deciding what is 
127  appropriate, applicants should consider the following: 
128   
129    Single-dose vials should not contain a significant15 volume beyond what would be 
130  considered a usual or maximum dose for the expected use of the drug product. 
131   
132    Consumers and/or health care providers should not be routinely required to use 
133  more than one vial to administer a typical single dose of the drug product. 
134   
135    Multiple-dose vials should contain no more than 30 mL of drug product except 
136  under specific circumstances.16   
137   
138  For all application types, the applicant should communicate with FDA early in the drug 
139  development process about the vial fill size and unique excess volume concerns.  For example, 
                                                 
13 Guidance for Industry, M4: The CTD  Quality Questions and Answers/Location Issues 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm073285.pdf. 
14 An ANDA that references a currently approved reference listed drug (RLD) is generally expected to have the 
same labeled vial fill size as the RLD.  In the event of a suitability petition permitting a change in vial fill size, the 
basic principles of this guidance would be applied to the petitioned ANDA. 
15 See footnote 8 for information on significant volumes.   
16 Exceeding the 30mL multiple-dose vial limit may be justified if the usual dose of the drug product packaged in a 
multiple-dose vial is large, making the 30 mL limit impractical.   
  4  Contains Nonbinding Recommendations 
 
140  applicants should consider such communications during the end of phase II meetings or other 
141  communications for investigational new drug applications (INDs). 
142   
143  We recommend communicating with FDA as outlined in existing recommendations related to 
144  communication with applicants, including the Guidance for Review Staff and Industry Good 
145  Review Management Principles and Practices for PDUFA Products.17 
                                                 
17 See 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM079748.pdf. 
We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA 
Drugs guidance Web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm and the CBER Web 
page. 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
  5