CVM GFI #227 Chemistry, Manufacturing, and Controls (CMC) Technical Section Filing Strategies

Administrative draft guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

#227
Chemistry, Manufacturing, and Controls
(CMC) Technical Section Filing
Strategies
Guidance for Industry
Draft Guidance
This guidance document is being distributed for comment purposes only.
This version of the guidance replaces the version made available September 2015 entitled “Two-
Phased Chemistry, Manufacturing and Controls Technical Sections.” 	This revision provides
recommendations for submission of the individual components of the CMC technical section: a
drug substance component, a drug product component, and a sterile process validation component
for sterile drug products. This revision also includes additional strategies for sponsors to obtain
CVM input on certain types of information prior to submission of the CMC technical section.
Submit comments on this draft guidance by the dated provided in the Federal Register notice
announcing the availability of the draft guidance.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 docket number FDA-2014-D-1492.
For further information regarding this document, contact Heather Longstaff, Center for
Veterinary Medicine, Food and Drug Administration, 7500 Standish Place, Rockville MD
20855, 240-402-0651, email: heather.longstaff@fda.hhs.gov.
Additional copies of this draft guidance document may be requested from the Policy and
Regulations Staff, Center for Veterinary Medicine, Food and Drug Administration, 7500
Standish Place, Rockville MD 20855, and may be viewed on the Internet at
https://www.fda.gov/animal-veterinary, https://www.fda.gov/regulatory-information/search-fda-
guidance-documents, or http://www.regulations.gov.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Veterinary Medicine (CVM)
September 2024

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Table of Contents
I. 	Introduction ....................................................................................................................... 1
II. 	Background ....................................................................................................................... 1
III. 	Content of the Components of the CMC Technical Section ......................................... 2
A. Drug Substance Component ...................................................................................... 2
B. Drug Product Component .......................................................................................... 2
C. Facility Sterile Process Validation Component ........................................................ 2
IV. 	Requesting CVM Input Prior to Submission of the CMC Technical Section ............. 3
A. Meeting Requests ........................................................................................................ 3
B. Protocols and Supporting Data ................................................................................. 3
V. 	Filing Strategies for the CMC Technical Section........................................................... 3
A. (A)NADA or (J)INAD File Submission with Complete CMC Technical Section . 4
B. (J)INAD File Submission with CMC Technical Section Components ................... 5
VI. 	Submission of the CMC Technical Section..................................................................... 6
A. Complete CMC Technical Section ............................................................................ 6
B. CMC Technical Section by Component.................................................................... 6
VII. 	Review Outcomes for the CMC Technical Section ........................................................ 7
A. Information is Found Acceptable .............................................................................. 7
B. Information is Found Incomplete .............................................................................. 8
VIII. 	Review Clock ..................................................................................................................... 8
A. (J)INAD File Phased-Review Process ......................................................................... 8
B. (A)NADA Process ......................................................................................................... 8

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Chemistry, Manufacturing, and Controls (CMC) Technical Section
Filing Strategies
Draft Guidance for Industry
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.
I. 	Introduction
This guidance provides recommendations to sponsors submitting chemistry, manufacturing, and
controls (CMC) data submissions. There are several mechanisms to receive input from the
Center for Veterinary Medicine (CVM) prior to submission of the CMC technical section, as
well as various approaches to submitting the CMC technical section itself. For review
efficiency, CVM prefers that full CMC information be provided in a single technical section
submission. However, there may be instances when submission of the individual components of
the technical section (drug product, drug substance, and facility sterile process validation (SPV)
information for sterile drug products) could reduce the overall time to complete a technical
section, and therefore drug approval. This guidance describes the options for soliciting early
input from CVM and the process for submission of components of the CMC technical section.
This guidance does not provide recommendations on the specific CMC information that should
be submitted to comply with 21 CFR 514.1(b)(4) and (5). A sponsor should consider all relevant
FDA guidance documents for recommendations on the information that should be submitted to
support drug 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
A complete New Animal Drug Application (NADA) or Abbreviated New Animal Drug
Application (ANADA) must include the CMC information identified in 21 CFR 514.1(b)(4) and
(5). To facilitate the approval of NADAs or ANADAs, CVM accepts major data submissions for
individual sections of an NADA or ANADA (technical sections) under the Investigational New

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Animal Drug (INAD) or Generic Investigational New Animal Drug (JINAD) file. The CMC
technical section is considered one of the major data submissions.1
Submissions are made using eSubmitter2 and this guidance includes some information about
what selections to make or information to include in the eSubmitter templates, depending on the
submission strategy chosen.
III. 	Content of the Components of the CMC Technical Section
The content provided to address each of the components of the CMC technical section will be the
same regardless of filing strategy.
A. Drug Substance Component
Drug substance information may be provided directly or as a reference to a Type II
master file.3 For sterile drug substances, we recommend providing the sterile process
validation information in a Type V master file.
B. Drug Product Component
The drug product component includes all information necessary to assess the CMC of the
drug product. There are additional questions in the eSubmitter template about how the
drug product manufacturer ensures the quality of the drug substance, including questions
about the properties of the drug substance, the specifications to which the drug product
manufacturer holds the drug substance, and the methods used by the drug product
manufacturer to perform those tests. For sterile drug products, there are also product-
specific sterile process validation questions in the eSubmitter template about topics such
as filtration, container-closure integrity, preservative effectiveness, pyrogen or endotoxin
testing, sterility testing, and bioburden testing.
C. Facility Sterile Process Validation Component
Facility sterile process validation information may be provided directly or as a reference
to a Type V master file. This component will include information that supports sterile
processing at the facility, such as process simulations (media fills), component
preparation, closure preparation, closure-related thermal qualification of the cycle,
closure-related microbial efficacy of the cycle, container preparation, microbial
monitoring of the environment, steam in place, moist steam sterilization of equipment,
equipment-related thermal qualification of the cycle, equipment-related microbial
efficacy of the cycle, and single use disposable (SUD) equipment. There will be
1 For details of the administrative (A)NADA process, refer to GFI #132, “Administrative Applications and the
Phased Review Process,” (May 2018).
2 eSubmitter can be found at: http://www.fda.gov/ForIndustry/FDAeSubmitter/default.htm.
3 CVM accepts references to both Veterinary Master Files and Drug Master Files. For a description of the content of
different types of master files, see GFI #57, “Preparation and Submission of Veterinary Master Files,” (January
1995).

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additional questions about the drug product manufacturing process to provide a linkage
between the overall validation done at the facility and how the drug product fits into that
validation.
IV. 	Requesting CVM Input Prior to Submission of the CMC Technical Section
Discussions with CVM about the strategy to generate content, particularly for complex or new
approaches, prior to the submission of a CMC technical section may result in fewer incomplete
comments on that information during CVM’s review of the CMC technical section. The
following are some of the mechanisms that can be used to solicit input from CVM.
A. Meeting Requests
Meetings with CVM may be requested to discuss specific questions related to the CMC
technical section submission.4,5 Following the meeting, CVM will provide a
Memorandum of Conference summarizing the discussion and documenting the responses
to any specific questions posed by the sponsor. For input provided by CVM in response
to a meeting request, the meeting submission number should be referenced in the CMC
technical section.
B. Protocols and Supporting Data
Protocols may be submitted to gain formal concurrence from CVM on the design of a
variety of studies, including method validations, stability studies, and approaches to
sterile process validation.6 Protocol submissions should not include supporting data, but
where data are necessary for assessment of the protocol, supporting data may be
submitted in an H submission7 prior to submission of the protocol. Any protocol
submissions should be referenced in the CMC technical section.
V. 	Filing Strategies for the CMC Technical Section
The CMC technical section may be submitted in an application or to an investigational file. If
submitted to an investigational file, there are multiple filing strategies available. Sponsors
submitting their CMC technical section as part of a non-administrative (A)NADA-A-0000
should submit a complete CMC technical section. When using the (J)INAD file phased-review
process, sponsors may submit either a complete CMC technical section or the individual
components of the CMC technical section. Figure 1 illustrates the various filing strategies
available for the CMC technical section and includes how a response to an incomplete letter, if
required, should generally be submitted. A sponsor may also submit CMC information in a
4 For information on meetings, see CVM Program Policy and Procedures (P&P) Manual 1243.3024 Scheduling and
Holding Meetings with Outside Parties (September 2023).
5 See CVM P&P Manual 1243.2200 Submission and Review of Early Information (EI) to Presubmission
Conferences and Protocol Review (September 2023).
6 For information on protocols, see CVM P&P Manual 1243.4060 Review of Protocols (April 2021).
7 For information on “H” submissions, see CVM P&P Manual 1243.4092 H Submissions Preceding Meetings and
Protocols (November 2023).

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(J)INAD file using the phased-review process and may address any deficiencies that may be
issued in an incomplete letter after review of the technical section by submitting the response as
part of the (A)NADA-A-0000.
Figure 1. Filing Strategies for the CMC information, including a response in the event of
incomplete comments on the initial submission. A response to an (A)NADA is called a
reactivation and a response to a (J)INAD file submission is called a resubmission.
A. (A)NADA or (J)INAD File Submission with Complete CMC Technical Section
Traditionally, sponsors submit complete CMC information in one submission, under
either the (J)INAD file or the (A)NADA. This submission includes the drug product
information, drug substance information, and facility sterile process validation
information, if applicable for the drug product. Sponsors receive one CVM response to
the submission, either a technical section complete letter for a (J)INAD file, an approval
letter for an (A)NADA, or an incomplete letter. For incomplete letters, a
reactivation/resubmission is submitted that includes the responses to all incomplete items.

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B. (J)INAD File Submission with CMC Technical Section Components
Another filing option for the CMC technical section is to separate the complete CMC
technical section into individual components that are submitted in parallel to one another.
The recommended ways to split the CMC technical section are described in the sections
below.
1. 	CMC Technical Section by Individual Component: Parallel Process for Drug
Substance, Drug Product, and Facility Sterile Process Validation
Components
When using the (J)INAD file phased-review process, the CMC technical section
submission can be divided into three components: drug substance, drug product, and
facility sterile process validation (if applicable for the drug product). Each
component can be submitted separately and will have an independent review clock
based on the date of submission of that individual component. Drug substance, drug
product, and facility sterile process validation components may be submitted in
parallel to each other (i.e., it is not necessary to wait for one component to be
reviewed or found complete before submitting another component); however, CVM
will cross-reference new information received in each CMC individual component in
the context of the other CMC individual components to ensure all information is
complete and consistent. Therefore, CVM recommends that the drug substance
component be submitted prior to or concurrent with the drug product component.
Information in the drug substance component is likely to impact the review of the
drug product component (e.g., information related to impurities), so submission of the
drug product component prior to submission of the drug substance component could
result in an increased number of review cycles.
Once the CMC technical section has been submitted for an individual component,
each subsequent submission for that component (i.e., a response to incomplete
comments) should be sequential and only submitted following receipt of the letter
from the previous submission. Responses to incomplete comments from multiple
components should not be combined into a single submission.
2. 	CMC Technical Section by Individual Component: Sequential Process for
Drug Product Component
Generally, the drug product component will be one complete submission. Depending
on the drug product information a sponsor has ready for review, in certain
circumstances it may be beneficial to divide the drug product information between
two sequential submissions. For the drug product component only, there is an option
to submit the information either in one complete component or in two sequential
submissions, drug product Phase I and II, as depicted in Figure 1. The only routine
situation where sponsors may submit the drug product component in two phases is for
Type A medicated articles, where information specific to the Type A medicated
article is submitted in Phase I and other information, such as the Type B and Type C

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medicated feed studies or a medicated feed assay method transfer study, is submitted
in Phase II. Submission of a Phase I drug product component for drug products other
than Type A medicated articles without prior CVM concurrence is not acceptable and
CVM may refuse to review the submission.8,9 Any incomplete comments sent for the
information in Phase I should be addressed in Phase II, along with the remaining
information to complete the drug product component.
VI. 	Submission of the CMC Technical Section
A. Complete CMC Technical Section
When submitting a complete CMC technical section, select “Complete CMC Technical
Section” for the submission type in eSubmitter. In situations where the sponsor is
referencing another (J)INAD file, (A)NADA, or CDER product in lieu of submitting
complete CMC information, the “Complete CMC Technical Section” option should still
be selected in eSubmitter. The authorization to the referenced application or file can be
uploaded there, along with the appropriate authorizations for any master files.
B. CMC Technical Section by Component
1. 	Drug Substance Component
To submit the drug substance component, select the submission type “Drug
Substance.” All questions in the drug substance CMC eSubmitter templates should
be answered at the time of submission. The template will allow either submission of
full information for the manufacture of the drug substance or a reference to a Type II
master file.
In situations where the drug product includes multiple drug substances, separate drug
substance components should be submitted for each individual drug substance. These
submissions for different drug substances will be evaluated parallel to each other, as
well as to the other components submitted. In order to expeditiously reach a technical
section complete, and therefore approval, CVM recommends submitting the CMC
technical section with a single supplier for each drug substance and adding additional
drug substance suppliers post-approval through supplemental applications.10
8 As stated in the Animal Drug User Fee Amendments of 2023 Performance Goals Letter (at p. 3), “[w]ithin 60 days
of receipt, FDA will refuse to review an INAD submission which is determined to be insufficient on its face or
otherwise of unacceptable quality upon initial inspection using criteria and procedures similar to those found in 21
CFR 514.110.” Submitting a Phase I drug product component for drug products other than Type A medicated
articles without CVM’s prior concurrence may render it so inadequate that we determine that the submission is not
reviewable (see 21 CFR 514.110(b)(4)).
9 For additional information on “refuse to review” (RTR), see CVM P&P Manual 1243.2050 Refuse to File and
Refuse to Review (May 2023).
10 See GFI #83, “Chemistry, Manufacturing, and Controls Changes to an Approved NADA or ANADA,” (May
2007).

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2. 	Drug Product Component
The drug product component will generally be submitted as a complete drug product
component. If the drug product component is being submitted in its entirety, select
“Complete Drug Product” for the submission type in eSubmitter and answer all
questions in the template.
If a sequential two-phased drug product approach is being used, CVM’s expectation
is that all questions in the drug product CMC eSubmitter template will be answered in
one of the two phases. Within eSubmitter, the templates will allow you to submit
without answering all questions, but if all questions are not answered by the time of
the Phase II submission, CVM may refuse to review.
• 	If submitting the Phase I drug product submission, select “Drug Product Phase
I” as the purpose of submission. Any questions in the eSubmitter templates
that ask for information that will be submitted in the second phase may be
answered with “To be submitted in Phase II.”
• 	When submitting the Phase II drug product submission, select “Drug Product
Phase II” for the purpose of submission. Any questions that were fully
addressed in Phase I may be answered with a reference to the first phased
submission.
3. 	Facility Sterile Process Validation Component
To enter the facility sterile process validation (SPV) component, select the
submission type “SPV.” All questions in the SPV eSubmitter template should be
answered at the time of submission. The template will allow either submission of full
SPV information for the facility, or a reference to a Type V master file. Sponsors will
also provide information identifying how the manufacturing process for the drug
product falls within the processes used for SPV.
VII. 	Review Outcomes for the CMC Technical Section
The information provided in each CMC technical section component will be found acceptable or
incomplete. There are a variety of outcomes and considerations depending on the filing strategy
used.
A. Information is Found Acceptable
If the component is found acceptable, the type of letter sent will be determined by the
overall status of the CMC technical section. For a complete CMC technical section
submitted to a (J)INAD file, a technical section complete letter will be sent. For CMC
technical sections submitted as components, prior to the last submission where all
components have been found acceptable, components with acceptable information will
result in a letter that indicates the information is acceptable, but the technical section
remains incomplete. Once all components have been found complete, CVM will issue a

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technical section complete letter under the component submission with the latest due
date. Note that for CMC technical sections submitted by component, information that
has been found acceptable in one component may be reassessed in the context of
information submitted in another component. As an example of this, a detailed
evaluation of the synthetic route of the drug substance under the drug substance
component could impact the assessment of the drug product impurity specifications, even
if those specifications have previously been found acceptable during review of the drug
product component.
For CMC information submitted as part of a non-administrative (A)NADA, the Division
of Manufacturing Technologies will convey that the CMC information is acceptable to
the Target Animal Division (TAD). The TAD will send the appropriate letter to the
sponsor based on the status of all content in the submission.
B. Information is Found Incomplete
If the information is found incomplete, an incomplete letter will be sent. For CMC
technical section components, other than a drug product component Phase I, or a
complete CMC technical section, the initial submission should be referenced in the
response. If the information was submitted in a CMC technical section drug product
component Phase I, the incomplete comments should be addressed in the Phase II
submission. Responses to incomplete comments for all CMC technical section
submissions other than drug product component Phase I are eligible for shortened review
time (SRT) when appropriate.11 For all submissions, the incomplete letter will include
CVM’s comments.
VIII. 	Review Clock12
A. (J)INAD File Phased-Review Process
The review time for phased CMC technical section submissions under the (J)INAD file
phased-review process, which includes both complete CMC technical sections and CMC
technical section components, is 180 days. For resubmissions offered SRT, the review
time is 60 days.
B. (A)NADA Process
ANADA submissions have a 240-day review clock and reactivations offered SRT have a
120-day review clock. NADA submissions have a 180-day review clock and
reactivations offered SRT have a 135-day review clock.
11 See CVM P&P Manual 1243.3060 Implementing Shortened Review Times for New Animal Drug Application
(NADA) Reactivations and Investigational New Animal Drug (INAD) file Resubmisson using eSubmitter (March
2022) and CVM P&P Manual 1243.3070 Implementing Shortened Review Times for Abbreviated New Animal
Drug Applications (ANADA) Reactivations and Generic Investigational New Animal Drug (JINAD) Resubmission
(March 2022).
12 The review times noted are as of the 2023 reauthorization of ADUFA V/AGDUFA IV.