Subpart C - Abbreviated Applications

Applications for FDA Approval to Market a New Drug

GFI Good-ANDA-Submission-Practices-Guidance-for-Industry JAN 2018

Subpart C - Abbreviated Applications

OMB: 0910-0001

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Good ANDA
Submission Practices
Guidance for Industry
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 60 days of
publication in the Federal Register of the notice announcing the availability of the draft
guidance. Submit electronic comments to https://www.regulations.gov. Submit written
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630
Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the
docket number listed in the notice of availability that publishes in the Federal Register.
For questions regarding this draft document, contact (CDER) Lisa Bercu at 240-402-6902.

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
January 2018
Generics

Good ANDA
Submission Practices
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

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
January 2018
Generics

Contains Nonbinding Recommendations
Draft — Not for Implementation

TABLE OF CONTENTS

INTRODUCTION............................................................................................................. 1

II.

BACKGROUND ............................................................................................................... 1

III.

PATENT AND EXCLUSIVITY DEFICIENCIES ........................................................ 3

Documentation and Notification of a Legal Action Filing.......................................................... 5

Resolution or Appeal of a Legal Action ....................................................................................... 6

Notice of a Paragraph IV Certification ........................................................................................ 6

New or Revised Information in the Orange Book ....................................................................... 7

Amendments to an Unapproved ANDA....................................................................................... 8

Notification of Commercial Marketing ........................................................................................ 8

IV.

LABELING DEFICIENCIES ......................................................................................... 9

Draft Container Labels and Carton Labeling ............................................................................. 9

Color Differentiation for Container Labels and Carton Labeling .......................................... 10

Labeling Format .......................................................................................................................... 10

Parenteral Drug Products ........................................................................................................... 10
1. Package Type ................................................................................................................................. 10
2. Product Strength ............................................................................................................................ 11
3. Ferrules and Cap Overseals .......................................................................................................... 11

PRODUCT QUALITY DEFICIENCIES ..................................................................... 12
A.

Drug Substance ............................................................................................................................ 12

Drug Product ................................................................................................................................ 16

In Vitro Dissolution (Biopharmaceutics) ................................................................................... 19

1. Development and Validation of an In-House Dissolution Testing Method When Dissolution
Testing Cannot Be Standardized ........................................................................................................ 20
2. Dissolution Acceptance Criteria .................................................................................................... 20
D. Facilities ........................................................................................................................................ 22
1. Identification of Manufacturing Facilities ..................................................................................... 22
2. Readiness for Inspection ................................................................................................................ 23
3. Selection of Contract Manufacturing Facilities and CGMPs ........................................................ 23
E. Commercial Manufacturing Process.......................................................................................... 24
F.

Microbiology Considerations ...................................................................................................... 25
1. In-Process Bioburden Testing and Acceptance Criteria ............................................................... 25
2. Description and Validation of Bacterial Endotoxins Test Method ................................................ 25
3. Microbiological Data To Support Extended Storage Times .......................................................... 26

VI.

BIOEQUIVALENCE DEFICIENCIES........................................................................ 27

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Bioanalytical Study Data ............................................................................................................. 27

Clinical Summary ........................................................................................................................ 27

Deviations from Product-Specific Guidances ............................................................................ 28

Information on BE and Safety Related to In Vivo BE Studies ................................................ 28

Differences in Formulations and Inactive Ingredients ............................................................. 29

Waiver Requests Under 21 CFR 314.99(b)................................................................................ 29

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Good ANDA Submission Practices
Guidance for Industry 1

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This draft guidance, when finalized, will represent 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 staff responsible
for this guidance as listed on the title page.

INTRODUCTION

This guidance is intended to assist applicants preparing to submit to FDA abbreviated new drug
applications (ANDAs). This guidance highlights common, recurring deficiencies that may lead
to a delay in the approval of an ANDA. It also makes recommendations to applicants on how to
avoid these deficiencies with the goal of minimizing the number of review cycles necessary for
approval.
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

The Generic Drug User Fee Amendments (GDUFA I) 2 was signed into law on July 9, 2012.
Based on an agreement negotiated by FDA and industry, 3 GDUFA I was designed to increase the
likelihood that American consumers have timely access to low cost, safe, effective, and highquality generic drugs and to improve the predictability of the ANDA review process. Under
GDUFA I, FDA constructed a modern generic drug program that resulted in a significant and
sustained increase in communications between FDA and industry, ANDA regulatory actions, and
ANDA approvals.

This guidance has been prepared by the Office of Generic Drugs and the Office of Pharmaceutical Quality in the
Center for Drug Evaluation and Research at the Food and Drug Administration.

Public Law 112-144.

This agreement is reflected in the Generic Drug User Fee Act Program Performance Goals and Procedures letter,
available at https://www.fda.gov/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM282505.pdf.

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Despite the advances made under GDUFA I, approximately half of all ANDAs with GDUFA
review goals required three or more review cycles to reach approval or tentative approval. 4
Multiple review cycles are highly inefficient, require significant resources from applicants and
FDA, and delay timely patient access to more affordable generic drugs.
Accordingly, after receiving public input, FDA and industry negotiated a revised agreement,
reflected in the GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal
Years 2018-2022 letter (GDUFA II Commitment Letter), 5 and GDUFA was reauthorized
(GDUFA II) 6 on August 18, 2017. GDUFA II includes important program enhancements that
are designed to improve the predictability and transparency of ANDA assessments 7 and to
minimize the number of review cycles necessary for approval. These program enhancements are
intended to foster the development of high-quality submissions, ensure the timely resolution of
filing reconsideration requests, promote the correction of deficiencies in the current review cycle,
and support the development of high-quality resubmissions.
This guidance has been developed as part of FDA’s “Drug Competition Action Plan,” which, in
coordination with the GDUFA 8 program and other FDA activities, is expected to increase
competition in the market for prescription drugs, facilitate entry of high-quality and affordable
generic drugs, and improve public health. In conjunction with this guidance, FDA is issuing a
Good ANDA Assessment Practices Manual of Policies and Procedures, which establishes good
ANDA assessment practices for the Office of Generic Drugs and the Office of Pharmaceutical
Quality to increase their operational efficiency and effectiveness. This guidance and the Manual
of Policies and Procedures are intended to build upon the success of the GDUFA program and to
help reduce the number of review cycles for an ANDA to attain approval.
This guidance describes common, recurring deficiencies identified during FDA’s substantive
assessment of an ANDA with respect to (1) patents and exclusivities, (2) labeling, (3) product
quality, and (4) bioequivalence (BE). 9 This guidance also provides recommendations to

A tentative approval is a notification from FDA that an ANDA otherwise meets the requirements for approval
under the Federal Food, Drug, and Cosmetic Act (FD&C Act) but cannot be approved until the expiration of a
period of patent and/or exclusivity protection; until the expiration of a 30-month stay of approval; or, because of a
court order in patent litigation, before a specific date. See 21 CFR 314.3(b) and 314.105(d).
5

The GDUFA II Commitment Letter is available at
https://www.fda.gov/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM525234.pdf.

Pub. Law 115-52.

Going forward, the Office of Generic Drugs and the Office of Pharmaceutical Quality will generally use the term
assessment in place of review. Assessment means the process of both evaluating and analyzing submitted data and
information to determine whether the application meets the requirements for approval and documenting that
determination.

In this guidance, GDUFA refers to the generic drug user fee program codified in the Generic Drug User Fee
Amendments of 2012 and the Generic Drug User Fee Amendments of 2017.

The deficiencies and accompanying recommendations in this guidance are organized by FDA’s review disciplines
and generally follow the same order as the electronic common technical document. Information on the electronic
common technical document format is available at

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applicants on how to avoid these deficiencies. FDA comprehensively communicates deficiencies
identified during a substantive review 10 of an ANDA in complete response letters. 11 Applicants
may address the deficiencies identified by FDA by submitting an amendment to their
application. 12
This guidance does not include a comprehensive list of all of the deficiencies identified during
ANDA assessment. In addition, it is each applicant’s responsibility to submit a high-quality,
complete application that FDA can approve in the first review cycle. FDA strongly encourages
applicants to review FDA regulations and all applicable guidances for industry 13 to understand
FDA’s current thinking on each topic.

III.

PATENT AND EXCLUSIVITY DEFICIENCIES

The timing of ANDA approval depends on, among other things, the patent and exclusivity
protections for the reference listed drug (RLD) on which the applicant relies in seeking approval.
An applicant must provide, in its ANDA, information related to any patents listed for the RLD in
FDA’s Approved Drug Products With Therapeutic Equivalence Evaluations (the Orange
Book). 14 In particular, an ANDA applicant generally must submit to FDA one of four specified
certifications regarding the patents for the RLD under section 505(j)(2)(A)(vii) of the Federal
Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(j)(2)(A)(vii)).

https://www.fda.gov/drugs/developmentapprovalprocess/formssubmissionrequirements/electronicsubmissions/ucm1
53574.htm.
10

Prior to a substantive review, FDA communicates with ANDA applicants that deficiencies were identified during
the filing review of their submitted application either through a notification to the applicants (if fewer than 10 minor
deficiencies were identified) or in a refuse-to-receive decision. Please see FDA’s guidance for industry ANDA
Submissions — Refuse-to-Receive Standards for additional information on how FDA conveys to applicants
deficiencies identified during the filing review and for a non-exhaustive list of deficiencies that may or will lead to a
refuse-to-receive determination by FDA. We update guidances periodically. For the most recent version of a
guidance, check the FDA guidance web page at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
11

It should be noted that the Agency also issues discipline review letters, which are defined in the GDUFA II
Commitment Letter as “a letter used to convey preliminary thoughts on possible deficiencies found by a discipline
reviewer and/or review team for its portion of the pending application at the conclusion of the discipline review.” In
addition, information requests are communications “sent to an applicant during a review to request further
information or clarification that is needed or would be helpful to allow completion of the discipline review.”
GDUFA II Commitment Letter.

For information on amendment classifications and categories, please see FDA’s draft guidance for industry ANDA
Submissions — Amendments to Abbreviated New Drug Applications Under GDUFA. When final, this guidance will
represent FDA’s current thinking on this topic.

Applicants may review the Center for Drug Evaluation and Research’s Manuals of Policies and Procedures, which
are Federal directives and documentation of internal policies and procedures that are made available to the public at
https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ManualofPoliciesProc
edures/default.htm.
14

The Orange Book is available at https://www.accessdata.fda.gov/scripts/cder/ob/.

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If the Orange Book does not list a patent for the RLD that, in the opinion of the ANDA applicant
and to the best of its knowledge, claims the RLD or that claims a use of such listed drug for
which the applicant is seeking approval, 15 the ANDA applicant must certify that such patent
information has not been submitted by the new drug application (NDA) holder for listing in the
Orange Book (a paragraph I certification). 16
With respect to each patent listed in the Orange Book for the RLD, the applicant’s patent
certification must state one of the following:
•

That such patent has expired (a paragraph II certification)

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The date on which such patent will expire (a paragraph III certification)

•

That such patent is invalid, unenforceable, or will not be infringed by the manufacture,
use, or sale of the new drug for which the application is submitted (a paragraph IV
certification) 17

On or after the date on which FDA has received an ANDA for review, 18 an applicant that has
submitted a paragraph IV certification to a listed patent must provide the NDA holder and each
patent owner notice of its paragraph IV certification, including a description of the legal and
factual basis for the ANDA applicant’s assertion that the patent is invalid, unenforceable, or will
not be infringed. 19 If a patent is listed at the time an original ANDA is submitted and, in
response to a notice of a paragraph IV certification, the NDA holder or patent owner initiates a
patent infringement action against the ANDA applicant within 45 days of receiving the required
notice, approval of the ANDA generally will be stayed for 30 months from the latter of the date
of receipt of the notice by any owner of the patent or the NDA holder or such shorter or longer
time as the court might order. 20

If, in the opinion of the applicant and to the best of its knowledge, there are no patents claiming the RLD that are,
or should have been, listed in the Orange Book, the applicant must include in the ANDA a certification in the
following form:
In the opinion and to the best knowledge of (name of applicant), there are no patents that claim the listed
drug referred to in this ANDA or that claim a use of the listed drug.
21 CFR 314.94(a)(12)(ii).
16

21 CFR 314.94(a)(12)(i)(A).

Section 505(j)(2)(A)(vii) of the FD&C Act; see also 21 CFR 314.94(a)(12)(i)(A).

21 CFR 314.101(b).

Section 505(j)(2)(B) of the FD&C Act. See section III.C of this guidance for more information on notice of a
paragraph IV certification.
20

Section 505(j)(5)(B)(iii) of the FD&C Act and 21 CFR 314.107(b)(3)(i). Note that, in some circumstances, the
period of the stay may be 7½ years after the date of approval of the RLD rather than 30 months from the date of the
notice. See 21 CFR 314.107(b)(3).

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The statute provides an incentive and a reward to ANDA applicants that expose themselves to
the risk of patent litigation; the statute does so by granting a 180-day period of exclusivity vis-àvis certain other ANDA applicants to the applicant that is first to file a substantially complete
ANDA that contains, and for which the applicant lawfully maintains, a paragraph IV certification
to a listed patent for the RLD (First Applicant).
A.

Documentation and Notification of a Legal Action Filing

Applicants that file a paragraph IV patent certification 21 must subsequently amend their ANDA
to provide documentation to FDA regarding (1) their notice of certification that was sent to the
patent owner(s) and NDA holder and (2) any legal action that has been taken against the
applicant under that paragraph IV notice. 22 Specifically, applicants must amend their ANDAs to
provide documentation:
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That their notice of a paragraph IV certification was sent on a date that complies with the
time frame provided in the regulations for sending this notice

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Of the date that this notice was received by the patent owner(s) and NDA holder

This documentation must be submitted to the ANDA within 30 days after the last date on which
the notice was received by the patent owner(s) and NDA holder. 23
Applicants also must submit documentation “within 14 days of the filing of any legal action filed
within 45 days of receipt of the notice of paragraph IV certification.” 24 Any submission
indicating that legal action was initiated against the applicant should include a complete copy of
the civil action. If a legal action was not filed by either the patent owner(s) or the exclusive
patent licensee within 45 days of its or their receipt of the notice of the paragraph IV
certification, applicants should submit an amendment to their ANDA immediately after the 45day period elapses stating that no legal action was taken by the patent owner(s) and exclusive
patent licensee.
However, applicants have often not submitted to FDA written documentation in a timely fashion:
•

Of their timely sending notice of a paragraph IV certification and of the dates that the
patent owner(s) and NDA holder received notice of a paragraph IV certification

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That the patent owner(s) and/or exclusive patent licensee have filed a legal action

Paragraph IV patent certifications are described in 21 CFR 314.94(a)(12)(i)(A)(4).

21 CFR 314.95(e) and 21 CFR 314.107(f)(2).

21 CFR 314.95(e).

21 CFR 314.107(f)(2).

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That includes a statement that the patent owner(s) and exclusive patent licensee did not
file a legal action within 45 days of receipt of the notice of the paragraph IV certification

Applications that lack all required patent/legal documentation or those that do not respond in a
timely manner to a request for information may receive a complete response letter.
B.

Resolution or Appeal of a Legal Action

If an applicant submitted a paragraph IV certification, litigation is brought against that applicant,
and the court enters a decision in favor of the patent owner(s) and/or NDA holder finding the
patent valid and infringed, that applicant must notify FDA of the court’s decision within 14
days. 25
If the applicant appeals the court decision within the time permitted to appeal, the applicant
similarly must notify the Agency within 14 days. 26 If the applicant does not appeal the court’s
decision, the applicant must submit an amendment to change its paragraph IV certification to a
paragraph III certification; this amendment must certify that the patent will expire on a specific
date, or, if applicable, that the applicant is no longer seeking approval for a method of use
claimed by the patent. 27
Similarly, if the litigation results in a district court decision, a court of appeals mandate, or a
settlement order “signed and entered by the . . . district court or court of appeals” 28 that specifies
that the patent in question is invalid, unenforceable, or not infringed, the ANDA applicant must
submit to the ANDA: a copy of the court judgment, written notification of whether or not there
is an appeal within the time for appeal, and/or a copy of any order by the court terminating the
30-month or 7½-year stay of approval. If the litigation is resolved with written consent to
approval of the ANDA from the patent owner or the exclusive patent licensee, a copy of that
written consent must be submitted. 29
Timely notification that the court has issued a decision or that the court’s decision has been
appealed and, when applicable, submission of a timely amendment of the patent certification are
necessary for FDA to determine the timing of an ANDA’s approval. 30
C.

Notice of a Paragraph IV Certification

An applicant may not provide notice of a paragraph IV certification that was submitted in an
original ANDA to the patent owner(s) and NDA holder until that applicant receives a paragraph
25

21 CFR 314.107(e)(2).

Id.

21 CFR 314.94(a)(12)(viii)(A).

21 CFR 314.107(e)(1).

Id.

See 21 CFR 314.107(b)(3).

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IV acknowledgement letter from FDA. 31 Similarly, if an applicant submits an amendment to its
ANDA that includes a paragraph IV certification and FDA has not yet informed the applicant
that the ANDA was received for review, that applicant must wait to provide notice of its
paragraph IV certification to the patent owner(s) and NDA holder until after the applicant has
received a formal acknowledgement letter from FDA that the ANDA was received for review. 32
The applicant must send notice of the paragraph IV certification contained in the amendment on
or after the date it receives acknowledgement from FDA that the ANDA was received for
review; this notice must be sent no later than 20 days after the date of acknowledgement from
FDA. 33 If FDA has notified the applicant that it has received the ANDA and the ANDA
applicant makes a subsequent amendment that requires a paragraph IV certification (see section
III.E of this guidance), the notice must be sent at the same time that the amendment is
submitted. 34
Notice of a paragraph IV certification that was submitted in an original ANDA or in an
amendment before FDA has received the ANDA for review is invalid. 35
D.

New or Revised Information in the Orange Book

If a new patent is listed for the RLD after an applicant submits an ANDA or information related
to a patent listed for the RLD is revised 36 after an applicant submits an ANDA, that applicant
must address these changes to the patent listing for the RLD by submitting an appropriate patent
certification or statement for each patent. 37 However, applicants have either:
•

Provided “serial submissions” of amendments with paragraph IV certifications and sent
multiple notices of paragraph IV certifications in anticipation of a newly issued patent
being listed in the Orange Book, which is not permissible under FDA’s regulations 38 or

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Failed to submit an appropriate patent certification or statement for each newly listed
patent or revised patent information

21 CFR 314.95(b)(2). An ANDA acknowledgement letter is the letter that FDA sends when it has determined that
the ANDA can be received for review.

21 CFR 314.95(b)(1) and 21 CFR 314.95(d)(2).

Id.

21 CFR 314.95(d)(1). Similarly, if the ANDA applicant submits a supplement to an approved ANDA and that
supplement requires a paragraph IV certification, its notice must be sent at the same time that the supplement is
submitted to FDA. Id.
35

21 CFR 314.95(d)(2).

For example, if a new use code is added to the Orange Book for a currently listed patent for the RLD, the
applicant must provide an updated paragraph IV certification or statement to FDA to address the newly listed use
code.
37

21 CFR 314.94(a)(12)(i) and 21 CFR 314.94(a)(12)(iii).

81 FR 69610 (Oct. 6, 2016).

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An applicant must not submit a paragraph IV certification to the ANDA for a newly listed patent
“earlier than the first working day after the day the patent is published in [the Orange Book].” 39
FDA recommends that applicants monitor the Orange Book and address newly listed patents and
revised patents in a timely manner to avoid unnecessary delays to ANDA approval.
In addition, ANDA applicants have failed to address new exclusivities for the RLD, which may
result in a delay in FDA’s approval of an application. FDA recommends that applicants monitor
the Orange Book and address exclusivities in a timely manner to avoid unnecessary delays to
ANDA approval.
E.

Amendments to an Unapproved ANDA

An amendment to an unapproved ANDA must contain either:
•

“an appropriate patent certification or statement” or “a recertification for a previously
submitted paragraph IV certification” if approval is sought for (1) a new indication or
other condition of use, (2) a new strength, (3) an other-than-minor change in product
formulation, or (4) a change to the physical form or crystalline structure of the active
ingredient or

•

A verification statement that states that the amendment does not contain one of the those
four types of changes 40

Applicants, however, have failed to provide either:
•

An appropriate patent certification or statement (or recertification) or

•

The required verification statement in their amendment to an unapproved ANDA when
that amendment did not contain one of the four types of changes described above

To address this requirement, FDA recommends that applicants provide an appropriate patent
certification or statement (or recertification) or, if applicable, include a verification statement
(stating, e.g., “This amendment does not contain one of the proposed changes under 21 CFR
314.96(d)(1)”) in the cover letter of their amendment to an unapproved ANDA.
F.

Notification of Commercial Marketing

The 180-day exclusivity period commences upon any First Applicant’s commercial marketing of
its drug product (including the commercial marketing by the First Applicant of the RLD or an
authorized generic). 41 Under either scenario, a First Applicant must submit correspondence to its
39

21 CFR 314.94(a)(12)(viii)(C)(1)(ii).

21 CFR 314.96(d).

Section 505(j)(5)(B)(iv)(II)(aa) of the FD&C Act and 21 CFR 314.3.

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ANDA notifying FDA “within 30 days of the date of its first commercial marketing of its drug
product or the reference listed drug.” 42 If a First Applicant commences marketing of its
approved drug product (or the RLD or an authorized generic) and does not notify FDA within
this time frame, “the date of first commercial marketing will be deemed [by FDA] to be the date
of the drug product’s approval.” 43
To address this requirement and avoid losing the benefit of part of the 180-day exclusivity
period, FDA recommends that applicants submit the required notification of commercial
marketing to FDA within the 30-day time frame.

IV.

LABELING DEFICIENCIES
A.

Draft Container Labels and Carton Labeling

Generally, an ANDA’s labeling must be the same as its RLD’s labeling. 44 There are, however,
limited exceptions, including an exception for differences caused by the ANDA and RLD being
produced or distributed by different manufacturers. 45 These differences between the ANDA’s
labeling and the RLD’s labeling may include differences (e.g., in the expiration date or in the
formulation) that were made to comply with current FDA labeling guidelines or other guidance
documents. 46 FDA reviews ANDA container labels and carton labeling to make certain that
differences from the RLD’s labeling do not raise safety concerns. 47 During this review, FDA
considers formatting factors such as the font size, style, and color of the required text; the
labeling’s identification of different product strengths; and other methods used to ensure that the
required information is presented with adequate prominence. 48 Applicants sometimes submit
draft container labels and carton labeling that do not accurately represent the formatting factors
that will be used with the final printed labels and labeling, which makes it challenging for FDA
to confirm that the final printed labels and labeling will be adequate.
To ensure that container labels and carton labeling are adequately evaluated for potential
deficiencies, FDA recommends that the draft version of container labels and carton labeling
“reflect the content as well as an accurate representation of the layout, text size and style, color,
and other formatting factors that will be used with the [final printed labeling].” 49 In addition, as
explained in the FDA guidance for industry Acceptability of Draft Labeling to Support ANDA
42

21 CFR 314.107(c)(2).

Id.

Section 505(j)(2)(A)(v) of the FD&C Act and 21 CFR 314.94(a)(8)(iv).

Id.

21 CFR 314.94(a)(8)(iv).

FDA guidance for industry Acceptability of Draft Labeling to Support ANDA Approval, at 3.

Id.

Contains Nonbinding Recommendations
Draft — Not for Implementation

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Approval, applicants that “receive approval based on draft labeling are responsible for ensuring
the content of the [final printed labeling] is identical to the approved labeling.” 50 Failure to
receive this approval may render the product misbranded and an unapproved new drug. 51
B.

Color Differentiation for Container Labels and Carton Labeling

Factors such as the color and format of container labels and carton labeling can help differentiate
multiple strengths within the same product line as well as multiple products within a company’s
product line, thereby reducing the likelihood of medication errors. Applicants, however, have
submitted container labels and carton labeling for products that lack an adequate differentiation
between various strengths and from other drug products.
FDA recommends that applicants ensure that the color and/or format of container labels and
carton labeling is adequately differentiated from other pending and approved products in their
product line. As noted in FDA’s draft guidance for industry Safety Considerations for Container
Labels and Carton Labeling Design to Minimize Medication Errors, when applying color,
applicants “should ensure that the text highlighted by the color has adequate color contrast
against the background color.” 52 In addition, “[c]olor differentiation is most effective when the
color used has no association with a particular feature and there is no pattern in the application of
the color scheme.” 53
C.

Labeling Format

FDA requests that labeling be submitted in Microsoft Word, structured product labeling, and
text-based portable document format (PDF) files. 54 Labeling submitted in PDF format should be
text based and not scanned to enable the use of search and compare functions. Applicants should
also ensure consistency in the content between their different formats (i.e., in their Microsoft
Word, structured product labeling, and text-based PDF files). If the text of the labeling differs in
any of the three requested formats, applicants may be asked to resubmit their labeling for review.
D.

Parenteral Drug Products

Package Type

Labeling indicating the package type (i.e., single-dose, multiple-dose, or single-patient-use) for
ANDAs of parenteral drug products must be the same as the labeling indicating the RLD’s
50

Id.

FDA draft guidance for industry Safety Considerations for Container Labels and Carton Labeling Design to
Minimize Medication Errors, at 8. When final, this guidance will represent FDA’s current thinking on this topic.
53

Id.

FDA draft guidance for industry ANDA Submissions — Content and Format of Abbreviated New Drug
Applications. When final, this guidance will represent FDA’s current thinking on this topic.

Contains Nonbinding Recommendations
Draft — Not for Implementation

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package type. For example, if the RLD is appropriately labeled and packaged in a single-dose
vial, the ANDA should also be labeled and packaged in a single-dose vial.
Applicants have proposed package types for parenteral drug products that differ from those
approved for the RLD (e.g., an applicant proposed a single-dose vial when the RLD is packaged
in a multi-dose vial), which resulted in a deficiency.
2.

Product Strength

A parenteral drug product’s strength is critically important information that should be clearly
displayed and correctly expressed on the container label to avoid dosing errors, among other
reasons. Overdoses have occurred with small-volume parenterals because of end-user failure to
determine the total amount of the drug product in the container. As described in FDA’s draft
guidance for industry Safety Considerations for Container Labels and Carton Labeling Design to
Minimize Medication Errors,
[i]n most cases, the user noticed the concentration (e.g., 10 [milligrams] (mg)/[milliliter]
(mL)) but failed to see the net quantity (e.g., 10 mL), which often appears in a different
location on the container label. This confusion has led to administration of the entire
contents of the container, when only a portion of the total volume was needed. 56
To avoid confusion, “the strength per total volume should be the primary and prominent
expression on the principal display panel of the label, followed in close proximity by strength per
milliliter enclosed by parentheses.” 57 The following format is acceptable: 58
500 mg/10 mL
(50 mg/mL)

Ferrules and Cap Overseals

The ferrules and cap overseals of injectable drug products should clearly and concisely convey
cautionary statements that will help prevent imminent, life-threatening situations. 59 In particular,
FDA recommends that the text on ferrules and cap overseals either “be limited to important
safety messages critical for the prevention of imminent, life-threatening situations” or remain
blank. 60 An example of an acceptable cautionary statement is “Warning-Paralyzing Agent.”
55

Section 505(j)(2)(A)(v) of the FD&C Act and 21 CFR 314.94(a)(8)(iv).

FDA draft guidance for industry Safety Considerations for Container Labels and Carton Labeling Design to
Minimize Medication Errors, at 11.
57

Id.

FDA draft guidance for industry Safety Considerations for Container Labels and Carton Labeling Design to
Minimize Medication Errors. See also U.S. Pharmacopeia (USP) General Chapter <7>.
60

FDA draft guidance for industry Safety Considerations for Container Labels and Carton Labeling Design to
Minimize Medication Errors, at 17.

Contains Nonbinding Recommendations
Draft — Not for Implementation

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Applicants should refer to the FDA draft guidance for industry Safety Considerations for
Container Labels and Carton Labeling Design to Minimize Medication Errors for further
information.
Applicants have submitted proposed labeling for ANDAs covering drug products with integrated
ferrules and cap overseals that does not convey safety information critical for the prevention of
imminent, life-threatening situations. In other instances, applicants have proposed labeling
containing information on ferrules and cap overseals that is not recommended for certain drug
products (e.g., some ferrules and cap overseals of injectable drug products have displayed lot
numbers, logos, or product names). Applicants should consider the appropriateness of including
or excluding such information for drug products with integrated ferrules or cap overseals because
this inclusion or exclusion may impact the approvability of a particular application.
In addition, FDA recommends that applicants state in Module 3.2.P.7 of their ANDA submission
whether text appears on the ferrule and cap overseal and, if so, what the text is. Applicants
should also indicate the color of the ferrule and cap overseal to ensure that the color black, which
is to be used only with potassium chloride injectable products, is not used for other drug
products.

PRODUCT QUALITY DEFICIENCIES
A.

Drug Substance

Applicants are required to submit data and information in their ANDAs about the drug
substance(s) in their proposed drug products. 61 To satisfy this requirement, FDA regulations
permit applicants either to provide this information directly in their ANDA or to reference a drug
master file (DMF) in their ANDA. 62 Specifically, in their ANDA, applicants may choose to
either (1) include all sections of Module 3.2.S.2 or (2) reference a DMF, which should contain
the same information that would have been provided by the applicant in Module 3.2.S.2.
The recommendations in this section apply both to applicants that include all sections of Module
3.2.S.2 in their ANDAs and to DMF holders that submit DMFs to FDA.
The DMF holder is required to notify each person authorized to reference the DMF of any
additions, changes, or deletions to any information contained in the DMF. 63 Changes made to a
DMF referenced in an ANDA that may impact the safety, efficacy, quality, or substitutability of
the drug product (e.g., new facilities added by the DMF holder that need to be addressed by the
applicant in an amendment to the ANDA) may be considered unsolicited amendments to the

21 CFR 314.94(a)(5).

21 CFR 314.420(b).

21 CFR 314.420(c).

Contains Nonbinding Recommendations
Draft — Not for Implementation

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ANDA and therefore may extend existing GDUFA review goals or create new review goals. 64 It
is important for applicants to be aware of when amendments will be submitted to the DMF
because these amendments may affect the adequacy of the DMF to support approval of the
ANDA.

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In Module 3.2.S.2, DMF holders 65 should include information on the control of materials used in
the manufacture of the drug substance and provide a justification for the starting material
selection for the process. Often, the designated starting material is a late-stage intermediate, and
DMF holders fail to include:

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Active Pharmaceutical Ingredient Starting Material

•

The route of synthesis to the proposed starting material to support the starting material
specification (i.e., the impurity control)

•

A discussion on the fate and purge of the potential impurities arising from the starting
material manufacturing process

•

The carry-over studies of reagents/solvents into the final active pharmaceutical ingredient
(API)

•

A demonstration of the suitability of analytical methods used to detect impurities in the
starting material

Without this information, FDA cannot assess the starting material selection and its impact on
both the manufacturing process and the final drug substance quality.
FDA recommends that DMF holders provide sufficient information, in Module 3.2.S.2, on their
API starting material, including the information specified in the bulleted list in this section. For
recommendations on the justification and selection of starting materials, DMF holders should
review the International Council for Harmonisation of Technical Requirements for
Pharmaceuticals for Human Use (ICH) guidances for industry Q11 Development and
Manufacture of Drug Substances and Q11 Development and Manufacture of Drug Substances
Questions and Answers. 66
2.

API Manufacturing Process

FDA draft guidance for industry ANDA Submissions — Amendments to Abbreviated New Drug Applications
Under GDUFA.

As noted above, the recommendations in section V.A of this guidance also apply to applicants that include all
sections of Module 3.2.S.2 in their application but do not reference a DMF.
66

ICH guidances for industry can be found on the FDA Drugs guidance web page
at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

Contains Nonbinding Recommendations
Draft — Not for Implementation

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DMF holders should fully describe, in their DMF, their API manufacturing process, but they
have commonly failed to include the following information as part of a complete description of
the API manufacturing process:
•
•
•
•
•
•
•
•

A detailed synthetic scheme
The molar ratios of starting materials/reagents
The reaction conditions (e.g., time and temperatures)
A flow chart of the manufacturing process
The batch size for each step (i.e., input/output of materials)
The batch blending or mixing operations
The recovered solvents, reprocessing, and reworking
Documentation of the consistent manufacture of the claimed polymorphic form

FDA recommends that DMF holders provide complete information in Module 3.2.S.2.2 on their
API manufacturing process, including the information in the bulleted list above. DMF holders
should include a flow chart for every stage, and if the API is synthetic or semisynthetic, they
should provide a complete synthetic scheme from the appropriately supported starting
materials. 67
3.

Impurities
a.

API characterization information

DMF holders should include characterization information for the API, including information on
all potential impurities. In some cases, however, DMF holders have failed to provide
information on the identification and purge of impurities (i.e., process impurities and
degradants), including those with mutagenic potential. 68
DMF holders should include a discussion of impurities in Modules 3.2.S.2 and 3.2.S.3. For
information on the limits for potentially genotoxic impurities, FDA recommends that DMF
holders refer to the ICH guidance for industry M7 Assessment and Control of DNA Reactive
(Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk (ICH M7).
Applicants should carefully assess and consider all of the control options outlined in ICH M7.
b.

Safety assessment of mutagenic potential for actual and potential
impurities

The impurity profile of a proposed generic drug should not pose a greater mutagenic risk than the
RLD. DMF holders should provide an assessment of the actual and potential mutagenic
67

FDA guidance for industry Completeness Assessments for Type II API DMFs Under GDUFA, at 11, and ICH
guidances for industry Q11 Development and Manufacture of Drug Substances and Q11 Development and
Manufacture of Drug Substances Questions and Answers.
68

See the ICH guidance for industry M7 Assessment and Control of DNA Reactive (Mutagenic) Impurities in
Pharmaceuticals to Limit Potential Carcinogenic Risk.

Contains Nonbinding Recommendations
Draft — Not for Implementation

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impurities resulting from synthesis or degradation of the drug substance and discuss the
corresponding control strategy as outlined in ICH M7. The bulleted list below describes (1)
information DMF holders have commonly failed to include about their evaluation of actual and
potential genotoxic impurities, and when appropriate, (2) FDA’s recommendations on
conducting these evaluations:
•

An assessment of potential and actual impurities with a risk assessment and a follow-up
evaluation of mutagenicity at the time of the DMF submission. For impurities that
require an evaluation of the mutagenic potential, a hazard assessment should initially
include conducting either (1) literature and database searches on the carcinogenicity and
bacterial mutagenicity potential or (2) Quantitative Structure-Activity Relationship
((Q)SAR) and Structure Activity Relationship studies. Failure to include a full
evaluation of potential mutagenic risk at the time of the DMF submission can disrupt the
review process and prevent the timely review of the ANDA.

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•

Appropriate spike/purge or purging factor studies performed in a manner representative
of the commercial process, with a corresponding validated and fit-for-purpose analytical
method to support Options 3-4 described in ICH M7. 69

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•

A (Q)SAR evaluation that includes both an expert-based and a statistical-based model for
bacterial mutagenicity prediction. (Applicants have supplied a single model or used
models without submitting sufficient information on their validation.) Applicants should
submit full study reports for in silico predictions. 70

• An appropriately conducted in vitro bacterial reverse mutation assay to address a positive
prediction by a (Q)SAR analysis. For these assays, applicants should (1) test neat
impurities; (2) test concentrations up to 5,000 micrograms/plate, unless limited by
precipitation or cytotoxicity; and (3) adequately document that an impurity is unstable or
difficult to synthesize and provide a scientific justification of their due diligence to
synthesize the impurity. 71

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Specifications for Isolated Intermediates

DMF holders should justify their specification for isolated intermediates so that FDA reviewers
can understand why the DMF holder set that specification. The justification should focus on
69

As described in ICH M7: (1) under Option 3, the DMF holder controls potentially genotoxic impurities upstream
at higher than the threshold of toxicological concern with spike/purge data to less than 30% of that threshold and (2)
under Option 4, the DMF holder does not use a control based on high chemical reactivity, solubility, and proven
process-purging capability.
70

For additional information, see Amberg, A, L Beilke, and J Bercu, et al., 2016, Principles and Procedures for
Implementation of ICH M7 Recommended (Q)SAR Analyses, Regul Toxicol Pharmacol, 77:13–24; Barber, C, A
Amberg, and L Custer, et al., 2015, Establishing Best Practise in the Application of Expert Review of Mutagenicity
Under ICH M7, Regul Toxicol Pharmacol, 73:367–377.
71

ICH M7; ICH guidance for industry S2(R1) Genotoxicity Testing and Data Interpretation for Pharmaceuticals
Intended for Human Use; and OECD Guidelines for Testing of Chemicals, Section 4: Health Effects, available at
http://www.oecd-ilibrary.org/environment/test-no-471-bacterial-reverse-mutation-test_9789264071247-en.

Contains Nonbinding Recommendations
Draft — Not for Implementation

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how the impurity specifications for the intermediates were chosen, particularly if that was the
only point in the process where a particular impurity was controlled. If the DMF holder did not
isolate an intermediate, it should explain why that was a reasonable choice. FDA also
recommends that DMF holders review the FDA guidance for industry Completeness Assessments
for Type II API DMFs Under GDUFA, which makes recommendations about the information on
intermediates that should be included in a DMF.

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Tests for Critical Quality Attributes (CQAs) should be included in the drug substance
specifications, but DMF holders have failed to demonstrate a clear rationale that includes CQAs
when establishing drug substance specifications. DMF holders should follow the ICH limits or
justify their proposed limits for the existing tests (i.e., the limits for impurities, including the
residual solvents).

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CQAs describe product characteristics that are chosen to demonstrate that any given drug
product is of sufficient quality to ensure that drug product’s safety and effectiveness. Failure to
establish appropriate CQAs of the proposed generic drug product (including meaningful ranges
or limits) may lead to a determination that the ANDA cannot be approved.

Tests for Certain Critical Quality Attributes

FDA recommends that DMF holders set appropriate limits based on ICH guidances for
industry 72 and include a complete justification and the necessary information for qualification of
the limits when they exceed ICH recommendations, as explained in the FDA guidance for
industry ANDAs: Impurities in Drug Substances.
B.

Drug Product

Establishing Critical Quality Attributes

FDA recommends that applicants evaluate their drug products using (1) the general and dosage
form-specific recommendations for the relevant characteristics and testing described in the ICH
guidance for industry Q6A Specifications: Test Procedures and Acceptance Criteria for New
Drug Substances and New Drug Products: Chemical Substances and (2) the recommendations
on quality target product profiles and CQAs in the ICH guidance for industry Q8(R2)
Pharmaceutical Development. In their ANDAs, applicants should include information
developed from their use of these two ICH guidances for industry to support their selection of
and rationale for CQAs.
2.

Impurities: Identification, Control, and Qualification
a.

Identifying and controlling impurities

ICH guidances for industry Q3A Impurities in New Drug Substances, Q3C Impurities: Residual Solvents, Q3D
Elemental Impurities, and ICH M7.

Contains Nonbinding Recommendations
Draft — Not for Implementation

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Applicants’ identification and control of impurities are important aspects in ensuring the safety
of the drug product. When applicants have used inadequate protocols for generating and
identifying impurities and have failed to provide an appropriate rationale for their acceptance
criteria for impurities, FDA has refused to approve their ANDAs.

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Generic drug formulations are expected to have the same safety profile as the RLD. 74 Applicants
may qualify drug substance degradants or drug product impurities either by using a comparative
impurity analysis with the RLD 75 or by submitting a safety justification for these impurities if
they exceed the relevant qualification thresholds. 76 A safety justification for impurities that
exceeds the relevant qualification thresholds should include an assessment of both genetic
toxicology and general toxicity (14- to 90-day) in a single species. Below is information that
applicants should include in their application but have commonly failed to include:

To develop acceptance criteria for impurities in generic drug products, FDA recommends that
applicants refer to the FDA guidance for industry ANDAs: Impurities in Drug Products; the
FDA draft guidance for industry Elemental Impurities in Drug Products; 73 the ICH guidances for
industry Q3B(R2) Impurities in New Drug Products, Q3C Impurities: Residual Solvents, Q3D
Elemental Impurities; and ICH M7.
b.

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Safety qualification of impurities in drug substances or drug products that
exceed relevant qualification thresholds

•

Applicants should provide general toxicity information to qualify their impurity.
Applicants have submitted (Q)SAR evaluations to predict general toxicity, but their in
silico predictions have not been validated for the endpoints of a general toxicity study.
To address this, applicants should submit either safety information such as a repeat-dose
general toxicology study or published literature to characterize the safety of the impurity
for the intended route of administration.

•

When providing a justification that an impurity is a metabolite, applicants should provide
qualitative and quantitative information to support this justification. Applicants have
submitted qualitative information that an impurity is a metabolite but failed to provide
quantitative data to demonstrate the relevant systemic exposure to the proposed impurity
level. Applicants should provide quantitative information (e.g., plasma levels of the
metabolite in animals and humans at the maximum daily dose or the exposure levels in
animals that equals or exceeds the proposed clinical exposure levels) to demonstrate that
the systemic exposure is at such a level to qualify the proposed level of the impurity.

When final, this guidance will represent FDA’s current thinking on this topic.

21 CFR 314.3(a).

FDA guidances for industry ANDAs: Impurities in Drug Substances and ANDAs: Impurities in Drug Products.

ICH guidances for industry Q3A Impurities in New Drug Substances and Q3B(R2) Impurities in New Drug
Products.

Contains Nonbinding Recommendations
Draft — Not for Implementation

•

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Applicants should provide full articles of the publications that are cited in their
justification to facilitate a complete review of their ANDA.

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Applicants should submit nonclinical information to Module 4 of their submission. Applicants
that submit a justification for the safety of their impurities should also include references and
hyperlinks between related topics in the quality module (Module 3) and the nonclinical safety
module (Module 4).

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Unless otherwise specified in 21 CFR 314.94(a)(9)(ii), applicants must identify and characterize
the inactive ingredients in their proposed drug product and provide information demonstrating
that these inactive ingredients do not affect the safety or efficacy of that product. The quantity of
an inactive ingredient in a given formulation should be based on a prior determination by FDA of
the safety of that inactive ingredient in an FDA-approved product. However, applicants have
sought approval for formulations that contain amounts of inactive ingredients at levels higher
than the maximums listed in the Agency’s Inactive Ingredient Database (IID) 77 without
providing a justification for exceeding those maximum levels.

Inactive Ingredients
a.

Justification by reference to the Inactive Ingredient Database

FDA recommends that applicants (1) refer to the IID to determine the previously approved level
of an inactive ingredient in a given drug product and not exceed that level or (2) submit
controlled correspondence to the Agency requesting information on whether the use of a
particular inactive ingredient is acceptable in an ANDA if it is higher than the maximum listed
in the IID. 78 Applicants should provide an adequate justification to the Agency regarding the
safety of that inactive ingredient if the amount exceeds the maximum level indicated in the IID
for the proposed route of administration (see subsection (b) immediately below).
b.

Justification of the safety of inactive ingredients in generic drug products
that exceed the maximum level in the IID

A generic drug formulation should include inactive ingredients that have a well-defined safety
profile for the proposed context of use (i.e., dose, route of administration, duration of use, and
patient population) and maintain a similar safety profile as the RLD. Applicants, however,
should provide a safety justification for inactive ingredients that exceed FDA-approved levels for
the route of administration. Below is information that applicants should include in a safety
justification for inactive ingredients that exceed FDA-approved levels:
•

Applicants should provide a justification to demonstrate that an inactive ingredient is safe
for the proposed context of use (i.e., dose, route of administration, duration of use, and

FDA’s IID is available at https://www.accessdata.fda.gov/scripts/cder/iig/index.cfm.

See FDA’s draft guidance for industry Controlled Correspondence Related to Generic Drug Development. When
final, this guidance will represent FDA’s current thinking on this topic.

Contains Nonbinding Recommendations
Draft — Not for Implementation

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patient population). Applicants have submitted justifications that fail to address contextspecific information that is necessary to evaluate the safety of a proposed dose, route of
administration, or duration of use for an inactive ingredient in a specific patient
population. Additionally, applicants have proposed inactive ingredients without a wellestablished safety profile, which has led to FDA’s refusal to approve the ANDA. Generic
drug formulations do not undergo clinical safety studies during ANDA development, so
inactive ingredients without an established safety profile should not be included in a
generic drug formulation.

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•

Applicants should provide a complete account of the composition of complex mixtures of
inactive ingredients (e.g., flavors and fragrances) — including the mixtures’ individual
components and quantities — in either the ANDA or by referencing a DMF. Applicants
should identify each component of a complex mixture, including its synonyms, the
Chemical Abstracts Service Number, and any applicable citations to the Code of Federal
Regulations that are relevant to its proposed use. In addition, applicants should include
safety information for each component, including a history of the component’s prior use
and safety profile (i.e., the component’s general safety and genetic toxicity).

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•

Applicants should provide a justification supporting the safety of a proposed inactive
ingredient grade when relying on the established safety information from a similar grade
of inactive ingredient. 79 The grades of an inactive ingredient may have different
manufacturing processes, impurity profiles, and chemical or physical characteristics.
Because these factors may result in different safety profiles for each grade of inactive
ingredient, FDA needs sufficient details to identify the proposed inactive ingredient grade
and to determine whether similarities or differences between grades may affect safety.

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Validating Analytical Methods

Analytical methods that applicants use for the characterization or analysis of drug products
should be validated by the applicant to determine if these methods are suitable for such use.
However, applicants have failed to appropriately validate their analytical methods, which has led
to incorrect results and incorrect conclusions about the drug product quality because the
analytical methods were not specific, accurate, or precise. This failure has contributed to FDA’s
refusal to approve the ANDAs.
FDA recommends that applicants (1) refer to the ICH guidance for industry Q2(R1) Validation of
Analytical Procedures: Text and Methodology to identify the appropriate validation of the
analytical methods used in their drug product analysis and (2) provide method validation reports
in their application.
C.

In Vitro Dissolution (Biopharmaceutics)

FDA guidance for industry Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients.

Contains Nonbinding Recommendations
Draft — Not for Implementation

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Development and Validation of an In-House Dissolution Testing Method When
Dissolution Testing Cannot Be Standardized

It is critical that applicants submit a complete method development and validation report when
an in-house dissolution testing method is used. Below is information that should be included in
the dissolution method development and validation report but applicants have commonly
omitted:
•

Solubility data for the drug substance over the physiologic pH range

•

A detailed description of both the dissolution test being proposed for the evaluation of the
product and the developmental parameters used to select the proposed dissolution method

•

Data (with appropriate statistics) to support the discriminating ability of the selected
dissolution method related to the critical material attributes and critical process
parameters

•

Complete dissolution data (i.e., individual (n=12), mean, range, and percent relative
standard deviation at each time point and mean profiles) and detailed information for all
strengths of the test product and the reference product (e.g., the batch/lot number,
manufacturing date, manufacturing site, testing date, and batch size) in Module 2.7.1

•

Supportive validation data for the dissolution method (e.g., method robustness and
method transfer) and analytical method (e.g., specificity, precision, accuracy, linearity,
and stability)

FDA recommends that applicants include a summary of the in vitro dissolution development in
Module 3.2.P.2.2.3 with a cross-reference to studies in Module 5, as appropriate. A justification
for the dissolution specification should be included in Module 3.2.P.5.6. FDA also recommends
that applicants refer to the U.S. Pharmacopeia (USP) General Chapter <1092> and certain FDA
guidances for industry 80 that provide general guidelines on the development and validation of
dissolution procedures.
2.

Dissolution Acceptance Criteria

The specification for solid oral dosage forms normally includes a test to measure the in vitro
release of a drug substance from the drug product. Applicants should provide a justification for
the in vitro release specification (i.e., the dissolution method and acceptance criteria) that is
reflective of the dissolution data from the representative batch that underwent in vivo BE testing

See FDA guidance for industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms and FDA
draft guidance for industry Dissolution Testing and Specification Criteria for Immediate-Release Solid Oral Dosage
Forms Containing Biopharmaceutics Classification System Class 1 and 3 Drugs. When final, the draft guidance
will represent FDA’s current thinking on this topic.

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(bio-batch) and supported by exhibit and registration batches that were included for stability. 81
Below is information that should be included in the selection of dissolution acceptance criteria:
Immediate-release solid oral dosage forms:
•

A single-point acceptance criterion where Q=80% 82 dissolution occurs

•

The setting of the dissolution acceptance criterion, which is drug product specific and
based on USP Level 2 testing (n=12) (understanding that Level 2 testing and Level
3 83 testing may be needed)

•

Support for a wider (i.e., more permissive) dissolution specification with an approved
in vitro/in vivo correlation model, a physiologically based absorption and
pharmacokinetic model, or a clinically relevant justification

Modified-release solid oral dosage forms:
•

Acceptance criteria time points that cover the early, middle, and late stages of the
release profile

•

Dissolution acceptance criteria ranges that are based on (1) a mean target value ±10%
at any given time point and (2) >80% for the last specification time point

•

A two-stage testing approach for delayed-release dosage forms

Applicants should provide a justification for the in vitro release specification in Module
3.2.P.5.6. Applicants should also refer to certain FDA guidances for industry 84 and ICH
guidance for industry85 that provide general guidelines for dissolution specification settings. In
addition, the applicant’s dissolution specification should not only confirm adequate formulation
and process control but also ensure consistent in vivo performance to the bio-batch.
81

FDA guidance for industry ANDAs: Stability Testing of Drug Substances and Products.

USP General Chapter <711> defines the quantity, Q, as “the amount of dissolved active ingredient specified in the
individual monograph, expressed as a percentage of the labeled content of the dosage unit.”
83

USP General Chapter <711>.

See FDA guidances for industry Extended Release Oral Dosage Forms: Development, Evaluation, and
Application of In Vitro/In Vivo Correlations and Dissolution Testing of Immediate Release Solid Oral Dosage
Forms.

ICH guidance for industry Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug
Substances and New Drug Products: Chemical Substances.

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Facilities

Identification of Manufacturing Facilities

Applicants should provide information on their manufacturing facilities both in their Form FDA
356h and in the appropriate module within the application. However, applicants have not
consistently provided (1) complete manufacturing facility information in their Form FDA 356h
and (2) manufacturing facility information in the correct modules within their application, both
of which have made this information not readily accessible to Agency reviewers and led to
FDA’s refusal to approve the ANDAs.
For “original (initial) applications . . . CMC supplements, and resubmissions to these submission
types,” applicants should include “complete information on the locations of all manufacturing,
packaging, and control sites for both [the] drug substance and [the] drug product” in Form FDA
356h (i.e., the facility information that is listed in Modules 3.2.S.2 and 3.2.P.3.1). 86 Form FDA
356h should include information on: 87
•

All drug product (in process material and final) manufacturing and testing sites —
including the stability testing, primary packaging, and labeling sites — that are proposed
to be involved in the commercial manufacture of the drug product 88

•

All intermediate (i.e., performing operations governed by the ICH guidance for industry
Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients) and
final drug substance manufacturing and testing sites, including the sterilization and
micronization sites, that are proposed to be involved in the commercial manufacture of
the drug substance

•

For combination products, 89 all manufacturing sites 90 for the non-lead constituent part of
the combination product, including any separate sites responsible for design activities,
that are proposed to be involved in the commercial manufacture of the finished product

•

All current good manufacturing practice (CGMP) storage and warehousing facilities
involved in the manufacture of the drug product

Instructions for Filling out Form 356h – Application to Market a New or Abbreviated New Drug or Biologic for
Human Use, available at https://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/default.htm.
87

See 21 CFR 314.50.

FDA does not recommend listing facilities (1) that have not performed any functions or (2) for which a
technology transfer of data has not occurred.

See 21 CFR 3.2(e).

See 21 CFR 4.

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Applicants do not need to list “bioequivalence testing sites, excipient testing sites, and
container/closure manufacturing and testing establishments” on their Form FDA 356h. 91
Module 3.2.S.2 should include all manufacturing facilities that are listed on Form FDA 356h as
well as all research and development manufacturing and testing sites that generated data to
support the application in accordance with 21 CFR 314.50(d)(1)(ii)(b). Applicants should list all
laboratories that perform testing, including drug substance characterization and method
comparisons, and functions integral to the control strategy. This module should also include any
testing sites that generate stability testing or release data to support the application as well as the
testing sites for the planned commercial testing.
2.

Readiness for Inspection

All manufacturing facilities should be ready for inspection at the time of the ANDA submission,
and applicants should indicate whether each site is ready for inspection on their Form FDA 356h.
In the past, applicants have specified on Form FDA 356h that a manufacturing facility was ready
for inspection, but once FDA was ready to commence inspection, the manufacturing facility
indicated it was not ready for this inspection, which has led to FDA’s refusal to approve the
ANDAs.
If there are extenuating circumstances that prevent a facility from being ready for inspection,
applicants should indicate this on Form FDA 356h. FDA considers it a good business practice
for applicants to regularly communicate with manufacturing facilities, including contract
manufacturing facilities, about changes in their inspection status to prevent any problems that
may delay approval of their application.
3.

Selection of Contract Manufacturing Facilities and CGMPs

Applicants should consider several factors in selecting suitable contract manufacturing facilities,
including their manufacturing capability for the product and compliance with CGMPs. In the
application, applicants should certify that contract manufacturing facilities are compliant with
CGMPs. 92 FDA has observed that applicants have certified that contract manufacturing facilities
are CGMP compliant, but upon assessment or inspection, FDA determined that they were not
compliant at the time of the ANDA submission, which caused the ANDA to not be approved.
FDA recommends that applicants and contract manufacturing facilities clearly define the CGMPrelated roles and manufacturing operations and activities of each of the parties in a quality
agreement. 93 A quality agreement should clearly describe the materials or services to be
91

Instructions for Filling out Form 356h – Application to Market a New or Abbreviated New Drug or Biologic for
Human Use.
92

Section 505(j)(4) of the FD&C Act states that FDA shall approve an ANDA unless “the methods used in, or the
facilities and controls used for, the manufacture, processing, and packing of the drug are inadequate to assure and
preserve its identity, strength, quality, and purity.” See also FDA’s draft guidance for industry ANDA Submissions
— Content and Format of Abbreviated New Drug Applications.

FDA guidance for industry Contract Manufacturing Arrangements for Drugs: Quality Agreements.

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provided, quality specifications, and communication mechanisms between the applicant and the
contract manufacturing facility.
E.

Commercial Manufacturing Process

Applicants should provide — in Modules 3.2.P.2, 3.2.P.3, and 3.2.R — both details of the
commercial manufacturing process and information to support the use of that particular process.
These details and information help FDA determine whether applicants are ready to commercially
manufacture a drug product. However, applicants often provide inconsistent, inaccurate, or
incomplete information in these modules, leading to refusals to approve. Below is information
that should be included in these modules:
•

Applicants should provide, in Module 3.2.P.2, a justification for their process selection
that relies on established scientific principles to identify potential risks to their
manufacturing process. This justification should include batch data (from the exhibit
and/or development batches) that demonstrate that any risks to the manufacturing process
are adequately mitigated. Applicants should also include a discussion of their risk
mitigation approaches and explain any differences between the exhibit and commercial
batches regarding their manufacturing processes and in-process controls.

•

Applicants should demonstrate that their proposed control strategy will ensure that the
quality of the intermediate critical material attributes will remain unchanged across the
exhibit and commercial batches. Applicants should clearly identify and justify, in
Module 3.2.P.3.4, the in-process controls utilized in the exhibit and commercial batch
manufacturing processes.

•

The commercial batch formula identified in Module 3.2.P.3.2 should (1) reflect the unit
dose composition identified in Module 3.2.P.1 and (2) clearly identify and justify any
overage and overfill used. Applicants should provide a table comparing the quantity and
the quality standard of each ingredient, including any solvents removed during the
process, used in the exhibit and commercial batches. 94

•

Applicants should demonstrate a readiness for the commercial scale manufacture of the
drug product by providing the set points and ranges of the commercial scale process
parameters in the commercial equipment. Applicants should also clearly identify and
justify, in Module 3.2.P.3, any differences in the equipment used for the exhibit and
commercial batches, as well as provide process parameters that are (1) scaled-up using
established principles, (2) supported by process development data, and (3) specified (i.e.,
“To Be Determined” should not be used) and not open-ended (e.g., no more than 200
revolutions per minute).

Please note that FDA may request the manufacture of a new batch if there are inappropriate overages, overfills, or
composition differences in the exhibit and commercial batches.

Contains Nonbinding Recommendations
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•

Applicants should use a table, in Module 3.2.P.3.3, to submit the hold times and hold
conditions of the intermediates and bulk drug products used in the commercial process.

•

Executed batch records provided in Module 3.2.R should clearly specify the batch usage
(e.g., development and stability) for each submitted executed batch record. In particular,
the batch used for BE testing should be noted along with the BE study identifier.
F.

Microbiology Considerations

In-Process Bioburden Testing and Acceptance Criteria

An ANDA for an aseptically processed generic drug product should contain in-process
acceptance criteria for the total number of microorganisms associated with the unfiltered bulk
drug solution prior to its sterilization (bioburden) because the “bioburden can contribute
impurities (e.g., endotoxin) to, and lead to degradation of, the drug product.” 95 Applicants have
commonly submitted ANDAs for drug products without providing bioburden testing and inprocess bioburden acceptance criteria for the bulk drug solution prior to any filtration, which has
led to FDA’s refusal to approve the ANDAs.
As described in the guidances for industry For the Submission of Documentation for Sterilization
Process Validation in Applications for Human and Veterinary Drug Products and Sterile Drug
Products Produced by Aseptic Processing — Current Good Manufacturing Practice, FDA
recommends that applicants both establish a prefiltration bioburden acceptance criteria and
design manufacturing process controls to minimize the bioburden in the bulk drug solution prior
to sterilization.
2.

Description and Validation of Bacterial Endotoxins Test Method

An application for a parenteral generic drug product with a product endotoxin specification
should contain both a description and validation of the bacterial endotoxins test method used.
However, applicants have submitted ANDAs for parenteral generic drug products with a product
endotoxin specification that have not described the bacterial endotoxins test method used,
including the sample preparation and routine test dilution. Without this test method description,
the Agency has been unable to determine whether the bacterial endotoxins method was
adequately validated, which has led to FDA’s refusal to approve the ANDAs. For the bacterial
endotoxins method validation, applicants have not always accounted for the additional dilution
that resulted from sample pooling in maximum valid dilution (MVD) calculations, which has
again led to FDA’s refusal to approve the ANDAs.

FDA guidance for industry Sterile Drug Products Produced by Aseptic Processing — Current Good
Manufacturing Practice, at 36.

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Applications for parenteral generic drug products with a product endotoxin specification should
contain a description and validation of the endotoxins test method used, 96 including any test
sample pooling and dilution performed routinely for method validation. In validating the chosen
test method, applicants should understand that FDA generally accepts sample pooling for
small-volume parenterals (those with volumes of 100 mL or less) as long as the
MVD is adjusted to a proportional, lower value because of the potential for
diluting a unit containing harmful levels of endotoxins with other units containing
lower, less harmful, levels of endotoxins. This “adjusted MVD” is obtained by
dividing the MVD computed for an individual sample by the total number of
samples to be pooled . . . . If this reduction in MVD results in an inability to
overcome product-related assay interference because of an insufficient dilution,
then the samples should be tested individually. 97
3.

Microbiological Data To Support Extended Storage Times

If the proposed generic drug product is sterile, then the extended post-constitution and/or postdilution storage times in the draft labeling should be supported by microbiological data. This
data should demonstrate that the drug product does not support microbial growth from
inadvertent contamination over the storage periods/conditions described in the labeling.
FDA recommends that applications contain a summary of the microbiological study, including
the challenge organisms and challenge titers, the product sample concentrations and storage
conditions, the diluents tested, and a summary of the study results. In addition, applicants should
refer to FDA’s Question-based Review (QbR) for Sterility Assurance of Terminally Sterilized
Products: Quality Overall Summary Outline, 98 Question-based Review (QbR) for Sterility
Assurance of Terminally Sterilized Products: Frequently Asked Questions, 99 and Questionbased Review (QbR) for Sterility Assurance of Aseptically Processed Products: Quality Overall
Summary Outline. 100

FDA guidances for industry Pyrogen and Endotoxins Testing: Questions and Answers, at 4, and For the
Submission of Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug
Products, at 8.

FDA guidance for industry Pyrogen and Endotoxins Testing: Questions and Answers, at 4.

This document is available at
https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/Appro
valApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM276168.pdf.
99

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VI.

BIOEQUIVALENCE DEFICIENCIES
A.

Bioanalytical Study Data

It is critical for applicants to submit complete bioanalytical study reports and to validate
bioanalytical methods used in their BE studies. Below is information that should be included in
an application’s bioanalytical study report:
•
•
•
•

Complete dilution integrity data, stock stability data, and recovery data
Analytical raw data from the study runs (accepted and rejected) of all subjects
Serially selected chromatograms for 20% of the study subjects
Bioanalytical standard operating procedures used in the application

FDA recommends that applicants submit complete bioanalytical reports and review the FDA
draft guidance for industry Bioanalytical Method Validation 101 to help ensure that applicants
provide the bioanalytical method validation data needed for FDA’s review of the ANDA.
Providing complete bioanalytical study reports and bioanalytical methodology validation data
will help ensure that FDA has the information required to determine whether the method used
was suitable and reliable.
B.

Clinical Summary

Applicants should submit clinical summary data from in vivo BE studies that are critical to
FDA’s determination of BE. To help applicants summarize this data,
FDA has developed model summary tables . . . . The[se] tables provide a format
for applicants to summarize various aspects of the BE submission such as the
design and outcome of in vivo and in vitro BE studies as well as the results of in
vitro dissolution testing. 102
Applicants can find these model tables on the FDA ANDA Forms and Submission Requirements
website. 103
Applicants, however, have submitted summary tables that are neither filled out completely nor
prepared properly. For example, applicants have failed to list, in formulation tables, all of the
strengths of the products for which they are seeking approval. Applicants have also submitted
101

When final, this guidance will represent FDA’s current thinking on this topic.

102

FDA draft guidance for industry ANDA Submissions — Content and Format of Abbreviated New Drug
Applications, at 10-11.
103

These tables are available at
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplicat
ions/AbbreviatedNewDrugApplicationANDAGenerics/ucm120955.htm. Applicants should periodically refer to that
website because the Agency may update the existing tables or add new tables to address both additional study types
and waiver requests.

Contains Nonbinding Recommendations
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summary tables to FDA in a scanned document rather than in a text-based PDF file and
Microsoft Word document. These actions have led to FDA’s refusal to approve the ANDAs.
FDA recommends that applicants provide accurate and complete information in their model
summary tables. Applicants should submit summary tables for all studies conducted, whether
they were passing or failing studies, 104 in a text-based PDF file and Microsoft Word
document. 105
C.

Deviations from Product-Specific Guidances

Applicants that deviate from a relevant product-specific guidance 106 should provide a detailed
justification for this deviation, as well as data to support this deviation, in their original ANDA
submission. Below is information that should be included, as applicable:
•

A detailed justification for and data (such as their inclusion/exclusion criteria or
demographic information) to support why their use of a particular study population does
not affect their BE determination

•

A detailed explanation of how any deviation in their primary endpoint from the productspecific guidance is as sensitive as the product-specific guidance’s endpoint for detecting
differences between the RLD and the generic product

•

A detailed justification, in their protocol and Statistical Analysis Plan, for why their
proposed prespecified statistical method is different from the product-specific guidance’s
recommendation
D.

Information on BE and Safety Related to In Vivo BE Studies

In original ANDA submissions, applicants should include all of the BE and safety information
related to the conduct of in vivo BE studies that is listed in the FDA draft guidance for industry
ANDA Submissions — Content and Format of Abbreviated New Drug Applications. However,
applicants have not always included in their original ANDAs the information that is necessary
for FDA to fully evaluate the BE of the test product in a timely manner, resulting in FDA’s
refusal to approve the ANDAs. Below is information that applicants should provide:
•

104

To ensure the welfare of human subjects involved in comparative clinical BE studies,
applicants should provide, with dates, their protocol, Institutional Review Board approval
forms, and consent forms. If their protocol was amended after the study was initiated,
applicants should highlight the changes, compare the original protocol with the amended

FDA guidance for industry Submission of Summary Bioequivalence Data for ANDAs.

105

FDA draft guidance for industry ANDA Submissions — Content and Format of Abbreviated New Drug
Applications, at 11.

106

FDA regularly publishes product-specific guidances that describe the Agency’s current thinking and expectations
on how to develop generic drug products that are therapeutically equivalent to the RLD.

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protocol, and provide an explanation for why the change did not affect the safety or
efficacy of the study product.
•

For subjects with serious adverse events, who died, or became pregnant, applicants
should provide a written narrative that provides complete follow-up details on the
condition of the subjects so that the Agency can complete a comprehensive review of
safety reports for the generic drug product. In particular, if a pregnancy follow-up is not
complete at the time of the original ANDA submission, applicants should provide
updates (such as whether the pregnancy resulted in a live birth) as soon as the
information becomes available.
E.

Differences in Formulations and Inactive Ingredients

For drug products for parenteral use, applicants should provide a clear justification and
documentation for any differences permissible under FDA regulations between the formulation
of the proposed generic drug product and the formulation of the RLD. 107 In addition, if
applicants used inactive ingredients or amounts of inactive ingredients in their placebo test
formulation used for BE testing that were different than the inactive ingredients or amounts of
inactive ingredients in the proposed generic drug product formulation, they should provide a
rationale and documentation in their original ANDA submission that explains why these
differences did not affect their demonstration of BE of the proposed generic drug product to the
RLD. Applicants, however, have commonly failed to provide necessary justifications and
documentation for these differences, which has led to FDA’s refusal to approve the ANDAs.
F.

Waiver Requests Under 21 CFR 314.99(b)

Applicants have submitted ANDAs for formulations for products for ophthalmic or otic use that
are not qualitatively and quantitatively (Q1/Q2) the same as the approved RLD’s formulation but
for which Q1/Q2 sameness is required under FDA’s regulations. 108 When an applicant has
sought approval for a formulation that is Q1/Q2 the same as the formulation previously marketed
by the innovator, FDA has determined that, in appropriate circumstances, under 21 CFR
314.99(b), it may waive the requirement in the regulation that the inactive ingredients approved
in the drug product under an ANDA be the same as those in the current formulation of the RLD
if the statutory requirement regarding safety of inactive ingredients has been met.
FDA recommends that ANDA applicants:

107

See, e.g., 21 CFR 314.94(a)(9)(iii).

108

21 CFR 314.94(a)(9)(iii) and 21 CFR 314.94(a)(9)(iv). Generally, a generic drug product is considered
qualitatively and quantitatively the same as the RLD if the concentration or amount of each inactive ingredient in the
test product differs by no more than +/- 5% of the concentration or amount for the same ingredient in the RLD.

Contains Nonbinding Recommendations
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•

Determine whether they are seeking approval of a drug product where Q1/Q2 sameness
to the RLD is required but the proposed generic product duplicates a previously approved
(and not current) formulation of the RLD 109

•

Consider submitting a request for waiver of the above-identified regulatory requirements
under 21 CFR 314.99(b)

FDA will determine whether to grant a waiver under 21 CFR 314.99(b) during its substantive
review of the ANDA.

109

21 CFR 314.127(a)(8).

File Type	application/pdf
File Title	Good ANDA Submission Practices Guidance for Industry
Subject	Good ANDA Submission Practices Guidance for Industry
Author	FDA/CDER/"Bercu, Lisa"
File Modified	2018-01-03
File Created	2017-12-29