FDA 发布 MAPP 5019.2，确立注射剂与生物制品适宜净装量评估程序
MAPP 5019.2 Assessment of the Appropriate Net Container Content for Injectable Drug and Biological Products
FDA 药品质量办公室发布 MAPP 5019.2，确立对瓶装注射剂与生物制品净装量适宜性的评估与记录程序，该文件于 2022 年 6 月 6 日生效。适用范围包括新药申请、依据 PHS 法案 351(a) 的生物制品许可申请及拟新增规格的补充申请，涵盖单剂量瓶与多剂量瓶。
文件列出 FDA 评估注射剂与生物制品净装量适宜性的内部流程，涉及单剂量瓶残留与多剂量瓶超出 30 mL 等考量。
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MANUAL OF POLICIES AND PROCEDURES
CENTER FOR DRUG EVALUATION AND RESEARCH MAPP 5019.2
POLICY AND PROCEDURES
OFFICE OF PHARMACEUTICAL QUALITY
Assessment of the Appropriate Net Container Content for Injectable Drug and
Biological Products
Table of Contents
PURPOSE ..............................................................................1
BACKGROUND ...................................................................2
POLICY .................................................................................3
RESPONSIBILITIES ...........................................................4
PROCEDURES .....................................................................5
REFERENCES......................................................................7
EFFECTIVE DATE ..............................................................7
CHANGE CONTROL TABLE............................................7
PURPOSE
This MAPP establishes procedures for the assessment and documentation of the net
container content(s) 1 for injectable drug products filled into vials 2 including drug
products that require constitution/reconstitution submitted in new drug applications
(NDAs), biologics license applications (BLAs) seeking licensure under 351(a) of the
Public Health Service Act (PHS Act), and supplements to these applications that propose
new strengths. This MAPP applies to drug 3 products in single-dose and multiple-dose
vials including drug products approved for dosing regimens with fixed doses and drug
products approved for dosing regimens with doses based on body weight or body surface
area. 4 This MAPP also establishes what information regarding the net container
1
In this MAPP, “net container content” is synonymous with “labeled vial fill size” as described in the FDA
guidance for industry Allowable Excess Volume and Labeled Vial Fill Size in Injectable Drug and
Biological Products (June 2015), and refers to net quantity of contents as described in 21 CFR 201.51. The
net container content shall appear as a distinct item on the label (21 CFR 201.51(d)). For injectable drug
products that are marketed as: 1) liquids – the net container content will be expressed as a measure of
volume (e.g., milliliter (mL)); 2) solids – the net container content will be expressed as a measure of weight
(e.g., milligram (mg)) (see 21 CFR 201.51(a)).
2
The term “vial” used throughout this MAPP refers to both vial and ampule package types.
3
The term “drug” used throughout this MAPP refers to drugs, including biological drug products that are in
scope of the MAPP.
4
For the definition of multiple-dose (i.e., multi-dose) and single-dose, see FDA guidance for industry
Selection of the Appropriate Package Type Terms and Recommendations for Labeling Injectable Medical
Products Packaged in Multiple-Dose, Single-Dose, and Single-Patient-Use Containers for Human Use
(October 2018), and the United States Pharmacopeia (USP) General Chapter <659> Packaging and Storage
Requirements, Injection Packaging Systems.
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MANUAL OF POLICIES AND PROCEDURES
CENTER FOR DRUG EVALUATION AND RESEARCH MAPP 5019.2
content(s) for injectable drug products filled into vials should be communicated to
sponsors 5 during product development.
The policies and practices established by this document are intended to standardize the
Office of Pharmaceutical Quality (OPQ) assessment of information contained in the
electronic Common Technical Document (eCTD) section 3.2.P.2., Pharmaceutical
Development.
The principles outlined in this MAPP may also apply to different injection packaging
types (e.g., prefilled syringe package systems and intravenous infusion bags) and
abbreviated new drug applications (ANDAs) in which a suitability petition for a different
drug product strength has been approved. 6
BACKGROUND
This MAPP conveys information related to OPQ’s implementation of the final guidance
for industry Allowable Excess Volume and Labeled Vial Fill Size in Injectable Drug and
Biological Products (June 2015). The guidance provides recommendations to industry on
two topics: 1) allowable excess volumes during manufacturing of injectable drug
products filled into vials, and 2) appropriate drug product net container content sizes (i.e.,
labeled vial fill sizes) for injectable drug products.
As a companion to this MAPP, MAPP 5019.1 Allowable Excess Volume/Content in
Injectable Drug and Biological Products provides information on excess content of
injectable drug products filled into vials. This MAPP outlines considerations for FDA
staff reviewing relevant applications and supplements to ensure sponsors develop the
appropriate drug product net container content(s). The proper net container content is
important for proper dosing of the patient, to minimize medication errors, to avoid drug
product contamination, and to limit drug product waste.
Misuse of injectable drug products filled into vials and other packaging types, including
unsafe handling and injection techniques, has led to drug product contamination and an
increased risk of bloodborne illness transmission between patients. A factor that can
contribute to unsafe handling and injection practices by patients and health care providers
is inappropriate net container content sizes resulting in:
• An excess of drug product that could be used as a partial dose or pooled to
produce a second dose; and/or
5
In this MAPP, “sponsors” include applicants who are pursuing approval of an application or a new
package size postapproval.
6
For ANDAs, unless a suitability petition for a different drug product strength has been approved, an
ANDA is required to select from the approved product strengths of the reference listed drug (RLD). See 21
CFR 314.94. When reviewing a suitability petition in accordance with MAPP 5240.5 Rev. 3 ANDA
Suitability Petitions (September 2023), a labeled net container content change request for a parenteral drug
product will include considerations set forth in this MAPP.
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MANUAL OF POLICIES AND PROCEDURES
CENTER FOR DRUG EVALUATION AND RESEARCH MAPP 5019.2
• The need to use multiple vials to dose a single patient, which can lead to an
increased risk of contamination due to inappropriate aseptic technique when
combining material from different vials.
There are unique considerations for drug products dosed by body weight or body surface
area. Marketing only one single-dose drug product net container content to cover all
possible doses may necessitate the need to use multiple vials for some patients and may
result in medication errors. In addition, there can be a significant amount of leftover drug
product after administration. Leftover drug after administration may encourage pooling
of the remaining contents to make additional doses. This, in turn, may lead to adverse
events because the practice of puncturing single-dose vials multiple times and pooling
preservative-free drug product may lead to contamination of the pooled drug product,
particularly if unsafe handling techniques are used. For example, if the patient dose
ranges from 225 mg to 510 mg and the vial net container content is 100 mg, multiple 100
mg vials would need to be pooled for administration and a significant amount of leftover
drug product could remain in the last vial depending on the patient dose. In this example,
for the lowest 225 mg dose, a practitioner would need to pool the contents of three 100
mg vials, and after withdrawal of the 225 mg dose, the unused drug product remaining in
the third vial would be approximately 75 mg. This substantial amount of unused drug
product encourages pooling of leftover contents to be used as additional doses.
POLICY
• The Office of Product Quality Assessment (OPQA) I or OPQA II or OPQA III
quality assessor 7 will inform an investigational new drug (IND) sponsor as early
as possible in the product development process that the proposed drug product net
container content(s) should be appropriate for the intended use and dosing.
• OPQ will request a justification from the sponsor for the drug product net
container content(s), if not provided, no later than the end of phase 2 to ensure the
sponsor has sufficient time to generate adequate stability data in the event a
change in the drug product net container content is needed to support the
submission of the NDA or BLA.
• If needed, OPQ may consult the Office of New Drugs (OND) to provide input to
the quality assessor related to drug product net container content(s) based on
available clinical information derived from clinical trial data, published literature,
or other sources of clinical data.
• If needed, OPQ may consult the Office of Surveillance and Epidemiology
(OSE)/Division of Medication Error Prevention and Analysis (DMEPA) to
7
In this document, we use the term assessment instead of the term review. Assessment means the process
of both evaluating and analyzing submitted data and information to determine whether the application or
supplement meets the requirements for approval and documenting that determination.
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provide recommendations related to proposed drug product net container
content(s) from a medication error perspective.
RESPONSIBILITIES
OPQA I, OPQA II, OPQA III, 8 or OPMA 9 Quality Assessor
For INDs, NDAs, BLAs, and their supplements, determines the appropriateness of the net
container content(s) for an injectable drug product.
OND Clinical Reviewer
When requested:
• Verifies the expected dosing range.
• Assesses clinical risk for overdosing (e.g., increased toxicity) or underdosing
(e.g., reduced efficacy) because of the drug product net container content(s). This
may include an assessment of clinical information from dose-finding clinical
trials and consideration of exposure-response and dose-response relationships for
safety and efficacy.
OSE/DMEPA 1 or DMEPA 2 Safety Evaluator
When consulted:
• Provides recommendations related to proposed drug product net container
content(s). Their recommendations may specifically address whether the drug
product net container content(s) proposed in the application or supplement is
appropriate from a medication error perspective.
8
In the event that there is a supplemental change for new net container content(s) for an approved NDA,
the OPQA I or OPQA II quality assessor should confirm that adequate justification is provided in the
supplement.
9
Microbiological information submitted in an NDA or BLA to support the labeled in-use period should be
evaluated by the quality assessor in Office of Pharmaceutical Manufacturing Assessment (OPMA).
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PROCEDURES
1. The OPQA I, OPQA II, or OPQA III quality assessor will:
a. Communicate to the sponsor as early as possible during development that the drug
product net container content(s) should be appropriate for the intended use and
dosing of the drug product.
b. For dosing based on body weight or body surface area in multiple containers of
varying net container contents, request a justification from the sponsor for the
proposed drug product net container content(s) no later than the end of phase 2, if
not provided. The justification should include whether the development of a
single- or multiple-dose vial is needed to cover the typical adult dose range in a
manner that minimizes dosing errors and limits the amount of leftover drug
product in the vial after administration.
c. For a fixed dose drug product in a single-dose container, request a justification
from the sponsor for the proposed drug product net container content(s) if there is
significant 10 drug product left in the single-dose vial following withdrawal of a
fixed dose, or more than one vial is required for administration of a dose. If such a
justification is needed, the request should be communicated to the sponsor no later
than the end of phase 2.
d. For a drug product provided in a multiple-dose container, request a justification
from the sponsor for the proposed drug product net container content(s) no later
than the end of phase 2. The justification should consider the dose of the drug
product, the net content in excess of 30 mL, 11 the number of times the stopper
could be punctured and still maintain its integrity, and the amount of drug product
that could reasonably be used in 28 days. 12
10
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 significant.
11
Per USP General Chapter <659> Packaging and Storage Requirements, Injection Packaging Systems,
multiple-dose vials have a maximum container volume sufficient to permit the withdrawal of not more than
a total of 30 mL, unless otherwise specified in an applicable USP drug product monograph. Exceeding the
30 mL multiple dose vial limit may be justified if the recommended dose of the drug product packaged in a
multiple dose vial is large, making the 30 mL limit impractical.
12
The beyond-use date for an opened or entered (e.g., needle-punctured) multiple-dose container is 28
days, unless otherwise specified by the manufacturer on the label. See
https://www.jointcommission.org/standards/standard-faqs/nursing-care-center/medication-management-
mm/000001529/
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e. Consult with the OND clinical reviewer and the OSE/DMEPA safety evaluator to
identify potential safety or efficacy concerns with the proposed drug product net
container content(s), if deemed necessary.
f. Communicate to the sponsor any identified issues with the proposed net container
content(s).
g. Coordinate with the relevant review disciplines and, in the absence of adequate
justification, issue an information request letter or complete response letter to the
sponsor for the identified net container content issue(s). Options for proposed
changes include adjustment of the drug product net container content by changing
the fill volume, changing the concentration of the active ingredient in the
formulation, or adding additional options for net container content(s) as
appropriate.
h. Summarize drug product net container content issues and document this
information in the appropriate product quality assessment template.
2. For multiple-dose vials, the OPQA I, OPQA II, OPQA III, or OPMA quality
assessor will:
a. Evaluate for appropriateness when the net content of drug product is greater than
30 mL.
b. Confirm that appropriate chemical and microbiological information has been
submitted to support the labeled in-use period. If no in-use period is specified in
the labeling, the data should support an in-use period of 28 days after first entry.
c. Ensure that adequate justification is provided for the proposed drug product net
container content(s). It should include the proposed dosing range of the drug
product, the number of times a stopper can be punctured and still maintain its
integrity, and the amount of drug product that can reasonably be used in 28 days.
3. For drug products administered as a fixed dose, the OPQA I, OPQA II, or
OPQA III quality assessor will:
Confirm that the amount of drug product in a single-dose vial contains only a single
dose by requesting a justification from the sponsor for the proposed drug product net
container content(s) when:
• There is significant drug product left in the vial following withdrawal of a
fixed dose from a single-dose vial.
• More than one vial is required for administration of the dose.
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4. For dosing based on body weight or body surface area, the OPQA I, OPQA II,
or OPQA III quality assessor will:
a. Evaluate the proposed net container content(s) and justification to ensure that
dosing flexibility is provided across the intended U.S. patient population in the
application or supplement to avoid excessive pooling of multiple vials and to
minimize leftover drug product in the vial.
b. Consult the OND clinical reviewer, if necessary, to confirm whether the sponsor’s
dosing range analysis is appropriate.
REFERENCES
1. FDA draft guidance for review staff and industry Good Review Management
Principles and Practices for New Drug Applications and Biologics License
Applications (September 2018, Rev. 1)
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio
n/Guidances/UCM079748.pdf
2. Guidance for industry M2 eCTD: Electronic Common Technical Document
Specification (April 2003); section 3.2.P.2., Pharmaceutical Development
3. FDA guidance for industry Allowable Excess Volume and Labeled Vial Fill Size
in Injectable Drug and Biological Products (June 2015)
4. FDA guidance for industry Selection of the Appropriate Package Type Terms and
Recommendations for Labeling Injectable Medical Products Packaged in
Multiple-Dose, Single-Dose, and Single-Patient-Use Containers for Human Use
(October 2018)
5. United States Pharmacopeia (USP) General Chapter <659> Packaging and
Storage Requirements, Injection Packaging Systems
6. MAPP 5019.1 Allowable Excess Volume/Content in Inj-ctable Drug and
Biological Products (January 28, 2022)
7. MAPP 5240.5 Rev. 3 ANDA Suitability Petitions (September 29, 2023)
EFFECTIVE DATE
This MAPP is effective on June 6, 2022.
CHANGE CONTROL TABLE
Effective Revision Revisions
Date Number
6/6/2022 N/A Initial version
N/A N/A 12/5/2024 Administrative changes posted to reflect changes to
OPQ’s suboffices’ names consistent with the 2024 OPQ
reorganization
Originating Office: Office of Pharmaceutical Quality
Effective Date: 6/6/2022 Page 7 of 7
来源：FDA Pharmaceutical Quality Documents · fda.gov