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Guidance for Industry 
 
Two-Phased Chemistry, Manufacturing,  and Controls (CMC) 
Technical Sections 
 
Submit comments on this guidance at any time.  Submit  electronic comments on the guidance to 
http://www.regulations.gov.   Submit written comments to the Division  of Dockets Management 
(HFA-305), Food and Drug Administration,  5630 Fishers Lane, Room 1061, Rockville,  MD 
20852.  All comments should be identified  with the Docket No. FDA-2014-D-1492. 
 
For further information  regarding this document, contact Heather Longstaff, Center for 
Veterinary Medicine (HFV-145), Food and Drug Administration,  7500 Standish Place, 
Rockville,  MD 20855, 240-402-0651,  e-mail: heather.longstaff@fda.hhs.gov. 
 
Additional  copies of this guidance document may be requested from the Policy and Regulations 
Staff (HFV-6), Center for Veterinary Medicine, Food and Drug Administration,  7519 Standish 
Place, Rockville,  MD 20855, and may be viewed on the Internet at either 
http://www.fda.gov/AnimalVeterinary/default.htm  or http://www.regulations.gov. 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Veterinary Medicine 
September 2015 
  Contains Nonbinding  Recommendations 
Table of Contents 
 
 
I.  INTRODUCTION ...................................................................................................... 3 
II.  WHAT IS A TWO-PHASED CMC TECHNICAL SECTION .................................. 3 
III.  PROCESS FOR THE TWO-PHASED CMC TECHNICAL SECTION ................... 4 
A.  Recommended Communications..................................................................... 4 
B.  How to Submit Two-Phased Submissions in eSubmitter ................................ 4 
IV.  FIRST PHASED SUBMISSION ................................................................................ 4 
A.  What to Include............................................................................................... 5 
B.  How Information from First Phase Relates to Second Phase ......................... 5 
C.  Review Outcomes ............................................................................................ 5 
D.  Review Clock................................................................................................... 6 
V.  SECOND PHASED SUBMISSION............................................................................ 6 
A.  What to Include............................................................................................... 6 
B.  Review Outcomes ............................................................................................ 6 
C.  Review Clock................................................................................................... 7 
   
2  Contains Nonbinding  Recommendations 
Guidance for Industry 
 
Two-Phased Chemistry, Manufacturing,  and Controls (CMC) 
Technical Sections 
 
This guidance represents 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.   For review efficiency, the Center for Veterinary Medicine 
(CVM) prefers that CMC information  be submitted in a single technical section.  However, there 
may be instances when a two-phased technical submission  process is more beneficial to improve 
the overall time to drug approval.  Sponsors may submit the phased CMC technical section as a 
single technical section or a two-phased technical section.  This guidance describes the use of the 
two-phased technical section submission  process. 
 
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. 
 
FDAs guidance documents, including  this guidance, do not establish legally  enforceable 
responsibilities.   Instead, guidances describe the Agencys 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 guidance means that something is suggested or 
recommended, but not required. 
 
II.  WHAT IS A TWO-PHASED CMC TECHNICAL SECTION 
 
A complete New Animal Drug Application  (NADA) or Abbreviated New Animal Drug 
Application  (ANADA) must include information  identified  in 21 CFR  514.1(b)(4) and (5).  In 
order to facilitate the approval of NADAs or ANADAs, CVM now accepts major data 
submissions  for individual  sections of an NADA or ANADA (technical sections) under the 
Investigational  New Animal Drug (INAD) or Generic Investigational  New Animal Drug 
(JINAD) file.  The CMC technical section is considered one of the major data submissions.1 
 
                                              
1 For details of the administrative (A)NADA process, refer to GFI #132: The Administrative New Animal Drug 
Application Process. 
3  Contains Nonbinding  Recommendations 
Traditionally,  sponsors submit complete CMC information  in one submission,  under either the 
(J)INAD or the (A)NADA process.  Some CMC information,  as described below, may be 
available for review prior to submitting  a single traditional  CMC technical section. In such 
instances and with CVMs concurrence, sponsors may submit the CMC data using a two-phased 
submission  process. 
 
The two-phased process allows the submission  of two separate CMC submissions,  each with its 
own review clock, and each including  complete appropriate CMC information  that is available 
for review at the time of submission.   The two submissions  may both be submitted to the 
(J)INAD, or the first submission  may be submitted to the (J)INAD and the second to the 
(A)NADA after transition  of the (J)INAD to the (A)NADA. 
 
III.  PROCESS FOR THE TWO-PHASED CMC TECHNICAL SECTION 
 
A.  Recommended Communications 
 
CVM recommends that sponsors contact the Division  of Manufacturing Technologies 
(HFV-140) prior to using the two-phased submission  process in order to obtain 
concurrence of the sponsor's approach to submitting  the CMC technical section(s).  A 
sponsor may also contact CVM regarding the first phase, to discuss or seek clarification 
on any deficiencies prior to submitting  the second phase. 
 
B.  How to Submit Two-Phased Submissions in eSubmitter 
 
Sponsors may submit two-phased submissions  in paper or preferably through 
eSubmitter.2  If sponsors elect to use eSubmitter, all of the questions in the CMC 
template must be answered in both phases.  When submitting  the first phase, 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 second phase, any questions that were addressed in the first phase may be answered 
with a reference to the first phased submission. 
 
IV.  FIRST PHASED SUBMISSION 
 
CVM has identified  several components of the CMC technical section that sponsors may 
complete early in the development process and therefore are available to submit to CVM in the 
first phase of the two-phased submission  process.  For example, a second-party or master file 
holder often prepares a master file containing  CMC information  for the drug substance, which 
may be available for review prior to the submission  of a referencing data submission.   If a 
sponsor references the master file in the first phase, the master file holder may have time to 
address any deficiencies and CVM may schedule cGMP inspections without significantly 
impacting  the overall time to approval for the (A)NADA. 
 
                                              
2 eSubmitter can be located at: http://www.fda.gov/ForIndustry/FDAeSubmitter/default.htm 
 
4  Contains Nonbinding  Recommendations 
A.  What to Include 
 
The following  items may be appropriate for inclusion  in the first phased submission: 
  all master file references, e.g., Type II for drug substances and Type V for sterile 
process validation  information, 
  drug substance CMC information,   
  analytical methods and validations,  and 
  other items as discussed and agreed upon with CVM. 
 
CVM recommends a reference to one drug or veterinary master file (DMF or VMF) for 
each active pharmaceutical ingredient  (API).  CVM may not accept multiple  master file 
references for an API in the first phase and, therefore, may refuse to file or review.3  A 
sponsor can submit multiple  references in a technical section; however CVM usually 
discourages this practice since it decreases the likelihood  of a single cycle review. 
 
Each component submitted in the first phase should be complete; however, if a sponsor 
would like to use an alternate strategy this should be discussed with CVM prior to 
submission  of the first phase.  With respect to analytical controls, each individual 
analytical method and its corresponding  validation  package is considered to be a 
complete component, such that any or all of the methods may be submitted for review in 
the first phase (e.g., the assay method/validation  could be submitted in the first phase and 
the impurity  method/validation  could be submitted in the second phase, or both 
methods/validations  could be submitted together in either the first or second phase). 
 
B.  How Information from First Phase Relates to Second Phase 
 
Upon review of the second phase, CVM assesses information received in the first phase 
in the context of the information  in the second phase.  This may result in comments on 
information  previously  found acceptable based on new or additional  information 
provided in the second phase. For example, an impurity  method/validation  provided in 
the first phase may be re-evaluated during the second phase to ensure that the validation 
data support the proposed finished product specification for impurities  that is provided in 
the second submission. 
 
C.  Review Outcomes 
 
The sponsor receives a technical section incomplete letter following  review of the first 
phased submission.   There are two possible versions of the letter.  The information  in the 
first phased submission  may be found acceptable, in which case a letter will be issued 
indicating  that the submitted information  is acceptable but the technical section remains 
incomplete.  If the information  in the first phased submission  is found incomplete, the 
incomplete letter will contain CVMs comments.  A sponsor should address any 
                                              
3 21 CFR  514.110 Reasons for refusing to file applications, see also, ADUFA III/AGDUFA II goals letters. 
5  Contains Nonbinding  Recommendations 
deficiency comments from the first phased submission  in the second phased submission, 
along with any remaining information  to complete the CMC technical section. 
 
D.  Review Clock 
 
The review clock for a first phased submission  is 180 days for an INAD, and 270 days for 
a JINAD.4 
 
V.  SECOND PHASED SUBMISSION 
 
The second phased submission  should not be submitted to the (J)INAD or the (A)NADA 
until the sponsor receives correspondence from CVM regarding the first phased 
submission. 
 
A.  What to Include 
 
The second phased submission  includes the remainder of the information  necessary for a 
complete technical section that was not included in the first phased submission.   If the 
second phased submission  is missing information  required for a complete technical 
section, CVM may refuse to file it in the (J)INAD or refuse to review the (A)NADA.5 
 
Any responses to incomplete comments from the first phased submission  are also 
included in this phase.  All master files should also be referenced, regardless of whether 
master file references were provided in the first phased submission. 
 
If the sponsor chooses to transition from the investigational  phase to the application 
phase (file an (A)NADA) at the time of submission  of the second phase, the technical 
section incomplete  letter from the first phase should be included in the submission. 
 
B.  Review Outcomes 
 
There are two possible outcomes following  review of the second phased submission.   The 
information  in the second phased submission  may be found acceptable, and a letter is 
issued indicating  that the information  is acceptable.  If the second phase is part of a 
(J)INAD, the letter will  indicate that and the technical section is complete. If the second 
phase is part of the (A)NADA, an approval letter will be issued when all of the sections 
are found complete.  If the information  in the second phased submission  is incomplete, 
CVM will issue an incomplete letter.  Sponsors should then submit responses to CVM 
comments as part of the reactivation to the second phased submission.   As per the 
                                              
4 See ADUFA III/AGDUFA II goals letters, 
http://www.fda.gov/downloads/ForIndustry/UserFees/AnimalDrugUserFeeActADUFA/UCM343226.pdf, 
http://www.fda.gov/downloads/ForIndustry/UserFees/AnimalGenericDrugUserFeeActAGDUFA/UCM343235.pdf 
5 21 CFR  514.110 Reasons for refusing to file applications, see also, ADUFA III/AGDUFA II goals letters. 
6  Contains Nonbinding  Recommendations 
AGDUFA II/ADUFA III goals letter, this reactivation may be eligible  for an abbreviated 
review clock at the discretion of CVM. 6 
 
C.  Review Clock 
 
The review clock for a second phased submission  is 180 days for an INAD, and 270 days 
for a JINAD.7 
 
                                              
6 The ADUFA III goals letter stipulates that in order for INAD submissions/NADAs to be eligible for shorter 
reactivation times for the phased submissions, they must be submitted through the eSubmitter tool. 
7 See ADUFA III/AGDUFA II goals letters, 
http://www.fda.gov/downloads/ForIndustry/UserFees/AnimalDrugUserFeeActADUFA/UCM343226.pdf, 
http://www.fda.gov/downloads/ForIndustry/UserFees/AnimalGenericDrugUserFeeActAGDUFA/UCM343235.pdf 
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