57
 
MASTER FILES
 
Guidance for Industry for the Preparation and
 
Submission of Veterinary Master Files 

1995
 
DEPARTMENT OF HEALTH AND HUMAN SERVICES 

PUBLIC HEALTH SERVICE 

FOOD AND DRUG ADMINISTRATION 

CENTER FOR VETERINARY MEDICINE 
 TABLE OF CONTENTS 

I.  INTRODUCTION 
II.  DEFINITIONS 
III.  TYPES OF MASTER FILES 
A. Veterinary Master Files (VMF's) 
B. Public Master Files (PMF's) 
IV. MASTER FILE CONTENTS 
A. Types of Veterinary Master Files 
1. Type I: Manufacturing Site, Facilities, Procedures, 
and Personnel 
2. Type II: Manufacturing Information for Finished 
Dosage Forms, Medicated Articles or Medicated 
Feeds, or Manufacturing Information for Bulk Drug 
Substances or Substance Intermediates Used in the 
Further Manufacture of Bulk Drug Substances 
a. Drug Substance Intermediates, Drug Substance, and 
Material Used in Their Preparation 
b. Drug Product 
c. Environmental Assessment 
3. Type III: Packaging Material 
4. Type IV: Excipient, Colorant, Flavor, Essence or 
Material Used in Their Preparation 
5. Type V: FDA Accepted Reference Information
 a. Sterilization Processes Validation Information 
(2)  b. Environmental Studies 
c. Animal Effectiveness, Safety, or Toxicity 
Studies 
d. List Master File 
e. Other reference information 
B. Public Master Files 
V.  SUBMISSIONS TO VETERINARY MASTER FILES 
A. Format, Assembly of Master File Documents 
B. Transmittal Letter 
1. Original Submissions 
2. Amendments 
C. Administrative Information 
1. Original Submissions 
2. Amendments 
VI.  MASTER FILE REVIEW/HOLDER OBLIGATIONS 
VII.  CONFIDENTIALITY OF INFORMATION 
VIII.  AUTHORIZATION TO REFER TO A MASTER FILE 
IX.  OWNERSHIP TRANSFER/NAME CHANGE 
X.  REORGANIZATION OF THE VETERINARY MASTER FILE 
XI.  CLOSURE OF A VETERINARY MASTER FILE 
(3)  GUIDANCE FOR INDUSTRY1
 
FOR THE PREPARATION AND SUBMISSION OF 

VETERINARY MASTER FILES 

I. INTRODUCTION 
Purpose 
This document is intended to provide guidance for the preparation and 
submission of master files to the Center for Veterinary Medicine. This 
document discusses the types of master files, information needed, submission 
format, procedures governing the review of master files, and obligations of 
the master file holder. 
A master file (MF) is a voluntary submission to the Food and Drug 
Administration (FDA) that may be used to provide confidential, detailed 
information about facilities, processes, or articles used in the manufacturing, 
processing, packaging, and storing of one or more veterinary drugs. We 
generally refer to master files on file with the Center for Veterinary Medicine 
as veterinary master files (VMF's). Whereas, those on file with the Center for 
Drug 
____________________________ 
1This guidance has been prepared by the Office of New Animal Drug 
Evaluation, Division of Chemistry, Chemistry Manufacturing Controls review 
group of the Center for Veterinary Medicine (CVM), at the Food and Drug 
Administration. This guidance is an informal communication under 21 CFR 
10.90(b)(9) that represents the best judgment of CVM employees at this time. 
This statement does not bind or otherwise obligate CVM employees at this 
time. This statement does not bind or otherwise obligate CVM to the views 
expressed. For further information about this guidance, contact William  G. 
Marnane, Center for Veterinary Medicine, Office of New Animal Drug 
Evaluation, Division of Chemistry, HFV-143, 7500 Standish Place, Rockville 
MD 20855 (Phone: 301-594-0678; Fax: 301 594-2298) 
(4)  Evaluation and Research (CDER) are referred to as drug master files 
(DMF's). There are no real differences between DMF's and VMF's other than 
their filing location. The differences in designation are used only for 
document and filing purposes to avoid  confusion in possible numbering 
systems between the Centers. The information contained in a VMF or DMF 
may be used to support an investigational new animal drug application, a new 
animal drug application, an abbreviated new animal drug application, another 
VMF or DMF, an export application, or amendments or supplements to any 
of these. 
A master file is NOT a substitute for an INADA, NADA, ANADA, or Export 
Application. The master file is used to provide support information and data 
for an NADA, ANADA, INADA, Export Application, or other master files. It 
is not approved or disapproved. Rather, the submission is found acceptable or 
deficient in support of an INADA, NADA, ANADA, Export Application, or 
other master file. 
The submission of a master file is not required by law or FDA regulation. 
Master files are generally created to allow a party other than the holder of the 
master file to reference material without disclosing to that party the contents 
of the file. When an applicant references its own material, the applicant 
should reference the information contained in its own INADA, NADA, or 
ANADA directly rather than establishing a master file. 
A master file is submitted solely at the discretion of the holder. The contents 
of a master file are reviewed by the Center only in conjunction with the 
review of an INADA, NADA, ANADA, or Export Application. All 
information submitted in a master file is considered confidential in accordance 
with 21 CFR 514.11 and is reviewed only when the master file holder 
provides appropriate authorization permitting the FDA to refer to it on behalf 
of an applicant or sponsor. 
The Center for Drug Evaluation and Research (CDER) has defined five 
distinct categories of master file submissions that it will accept and maintain, 
and has designated these as Type I through Type V drug master files 
(DMP's), 21 CFR 314.420 (a)(5). The Center for Veterinary Medicine 
provided for the same five distinct categories of VMF's by referral to a 
guideline in Section 514.420 (c) of the New Animal Drugs; Proposed Rule 
(5) 
 ("NADA Rewrite") published in the FEDERAL REGISTER on December 
17, 1991. However, the NADA Rewrite has not been published as a Final 
Rule and the referenced guideline was not issued by the Center for Veterinary 
Medicine. Consequently, master files on file with the Center for Veterinary 
Medicine have not officially been designated as Type I through Type V 
Veterinary Master Files. Rather, these submissions have been accepted and 
maintained under the general category of Master Files. 
The recently published proposed rule (60 FR 34486, July 3, 1995) amends 
the human drug regulations (21 CFR 314.420) and  eliminates Type I drug 
master files for CDER. Prior to eliminating Type I master files the FDA 
evaluated the usefulness of these submission. The agency determined that its 
inspectors were not using Type I DMF's to plan inspections and that they 
could be eliminated without adversely affecting inspections of manufacturing 
facilities. FDA also determined that its review divisions do not rely on Type I 
DMF's. Although Type I DMF's are often incorporated by reference, the 
information that the agency requested to be submitted under Type I DMF's is 
not required for chemistry, manufacturing, and controls (CMC) review. 
Additionally, the basic information (e.g. name and location of facilities used 
in the manufacture of the drug substance or product) is on file as part of the 
application. Therefore, Type I DMF's could be eliminated without adversely 
affecting the CMC review. 
The Center for Veterinary Medicine concurs with these decisions. This 
information is already evaluated on site by FDA field activities, and a master 
file containing Type I information is of very limited value to either our review 
staff or the FDA field investigator. 
Accordingly, this guidance document recognizes five distinct types of 
Veterinary Master Files (Type I - V), as well as public master files and 
eliminates Type I VMF's. The Center will no longer accept new Type I 
VMF's, or correspondence updating existing Type I VMF's. The information 
in Type I VMF's currently on file could no longer be incorporated by 
reference into new applications, amendments, or supplements, and the VMFs 
would be transferred to the Federal Records Center, Suitland, MD. Further. 
comment regarding the mechanism by which this may be accomplished are 
provided below (see IV., A.,1., - Remarks). 
(6)  The veterinary industry was informed of CVM's intent to eliminate Type I 
Veterinary Master Files in a Policy Letter dated July 26, 1995. This informal 
guidance document is intended to provide further clarification of this Policy 
Letter. 
II. DEFINITIONS 
For the purposes of this guidance document, the following definitions apply: 
1. Agency - means the Food and Drug Administration. 
2. Agent or representative - means any person who is appointed by a 
VMF holder to serve as the contact for the holder. 
3. Applicant - means any person who submits an application or 
abbreviated application or an amendment or supplement to obtain 
FDA approval. 
4. Drug product - means a finished dosage form, medicated article or 
medicated feed that contains a drug substance, generally, but not 
necessarily, in association with one or more other ingredients. 
5. Drug substance - means a material which is intended to furnish 
pharmacological activity or other direct effect in the diagnosis, cure, 
mitigation, treatment, or prevention of disease or to affect the 
structure and function of the human body of man or other animals. 
The substance may be administered independently or as a component 
of a finished dosage form, medicated article or medicated feed. 
6. Export application - means an application submitted under section 
802 of the Federal Food, Drug, and Cosmetic Act to export a drug 
that is not approved for marketing in the United States. 
7. Holder - means a person who owns a VMF. 
(7)  8. Intermediate - means a pivotal, key or final intermediate whose 
process must be adequately controlled to assure the quality and purity 
of the drug substance. 
a. Pivotal intermediate - means an intermediate which may be 
prepared by more than one manufacturing process to provide 
material of suitable quality for use in the production of a drug 
substance. 
b. Key intermediate - means an intermediate in which an 
essential molecular characteristic(s) is first introduced into the 
structure and for which significant in-process controls are 
needed to ensure the purity of the drug substance. 
c. Final intermediate - means the last intermediate isolated and 
controlled during the manufacturing process; prior to the final 
step which provides the crude drug substance. 
9. Letter of authorization - means a written statement by the 
holder or designated agent or representative permitting FDA to 
refer to information in the VMF in support of another person's 
submission. 
10. Medicated Article - means a Type A Medicated Article (21 
CFR 558.3(b)(2) intended solely for use in the manufacture of 
another Type A medicated article or a Type B or Type C 
medicated feed. It consists of a new animal drug(s), with or 
without carrier (e.g., calcium carbonate, rice hulls, corn, gluten) 
with or without inactive ingredients. 
11. Medicated Feeds - means Type B Medicated Feed or Type C 
Medicated Feed. A Type B Medicated Feed (21 CFR 558.3 (b)(3) is 
intended solely for the manufacture of other medicated feeds (Type B 
or Type C). A Type C Medicated Feed (21 CFR 558.3 (b)(4) is 
intended as the complete feed for the animal or may be fed "top 
dressed" or offered "free choice". 
12. Person - includes individual, partnership, corporation, and 
association. (Section 201(e) of the Federal Food, Drug, and Cosmetic 
Act.) 
(8)  13. Sponsor - means a person who takes responsibility for and 
initiates a clinical investigation. The sponsor may be an individual 
or pharmaceutical company, governmental agency, academic 
institution, private organization, or other organization. 
III. TYPES OF MASTER FILES 
There are six types of master files recognized by the Center for Veterinary 
Medicine. These master files cover the following information and data 
categories: 
A. Veterinary Master Files (VMF's) 
Type I  Manufacturing Site, Facilities, Personnel and 
Operating Procedures. 
Type II  Manufacturing Information for finished dosage 
forms, medicated articles or medicated feeds, or 
manufacturing information for bulk drug 
substances or intermediates used in the 
further manufacture of bulk drug substance. 
Type III  Packaging Materials. 
Type IV  Excipient, Colorant, Flavor, Essence or material 
used in their preparation. 
Type V   FDA Accepted Reference Information. 
Each VMF should contain only one type of information and all 
supporting data. Supporting information and data in a VMF 
may be cross-referenced to another VMF or DMF. 
B.  Public Master Files (PMF's) 
These master files usually contain safety and efficacy data and information 
that has been generated with public funds. 
(9) 
 IV. MASTER FILE CONTENTS
 
A. Types of Veterinary Master Files 
1.	   Type I:  Manufacturing Site, Facilities, Operating 
Procedures, and Personnel 
[As discussed in the Introduction to this guidance 
document, the Center is eliminating the need to submit 
and maintain a Type I Veterinary Master File. The 
Center currently has a number of these submissions on 
file and is only providing a description of this type of 
master file to aid holders of these master files in their 
determination that these are recognized by the Center as 
Type 1 master files and will no longer be accepted or 
maintained.] 
Manufacturing Site and Facilities - This information consists of 
a diagram of the general layout of the site and buildings and 
includes the various sections of all operations. A diagram of 
the major production and processing areas is usually outlined 
and a list of the makes and models of major pieces of 
equipment are described in terms of application and location. 
Equipment that is specific for the operations performed at the 
facility is also normally provided. This list includes 
manufacturing and laboratory equipment. 
Operating Procedures - Information, such as, general validation 
information, as well as, other general operating procedures are 
normally contained in this type of file. Sufficient information is 
normally provided in the master file to cover the significant 
operating areas. 
Personnel - This information includes the major corporate 
organizational elements, such as, key manufacturing, quality 
control and quality assurance positions. A detailed flowchart 
illustrating the specific line of command is normally provided. 
Key personnel are identified with their role and qualifications 
in the specific operations designated in the file. 
(10)  Remarks: 
While some of CVM's master files contain only Type I 
information and may be easily eliminated, we do have many 
that contain additional information. This additional information 
includes: sterilization processes validation information, 
environmental assessment information, actual manufacturing 
information for finished dosage forms, medicated articles and 
medicated feeds, manufacturing information for bulk drug 
substances and intermediates, etc.. These types of information 
are important for our chemistry/manufacturing/control (CMC) 
evaluation and must remain available for our review and 
comment (see below). 
If a VMF holder believes that their master file, which contains 
some Type I information should be categorized as a specific 
type of VMF other than a Type I VMF, the VMF holder should 
submit a request to the Center for Veterinary Medicine, Office 
of New Animal Drug Evaluation, Division of Chemistry, HFV
140, 7500 Standish Place, Rockville MD. 20855. This request 
should be submitted by the responsible official or designated 
U.S. agent, should briefly identify the subject of the VMF, and 
should propose the VMF Type (e.g., Type II, III, IV, or V) to 
which the VMF, or components of, should be recategorized. 
CVM would consider transferring an entire VMF containing 
Type I information to another type only if the VMF contains 
substantive information other than information concerning 
manufacturing site, facilities, operating procedures, and 
personnel. 
CVM recognizes that some master files currently on file 
contain information concerning sterilization process validation 
and other information relevant to the review, evaluation, and 
assurance of sterility of sterile products. For sterile items that 
are not the subject of an INADA, NADA, ANADA, and that 
are sold to a second party (e.g., rubber closures that are 
sterilized by the manufacturer and sold to a second party), 
CVM would consider transferring product-specific and general 
(11) 
 information concerning sterilization process validation to the 
type VMF (e.g., II through IV) under which manufacturing 
information for the specific item is filed. Contract 
manufacturers of sterile finished drug products, contract 
sterilization firms (e.g., ethylene oxide, gamma radiation), and 
manufacturers of sterile finished drug products that are the 
subject of a drug product application could request a transfer to 
a Type V VMF of nonproduct-specific information and 
procedures that are submitted to support a claim of sterility. 
Where applicable, the content and format of such transferred 
information should follow FDA's guidance entitled, "Guidance 
for Industry for the Submission of Documentation for 
Sterilization Process Validation in  Applications for Human and 
Veterinary Drug Products". The mechanism for requesting a 
transfer would be the same as the mechanism for recategorizing 
VMF's, as described above. 
Likewise, manufacturing information for medicated articles, 
medicated feeds, finished dosage forms, bulk drug substance, 
and intermediates should be retained in Type II VMF's. In 
many cases, the master files on file with CVM contain the 
appropriate information. These master files simply need to be 
appropriately designated as Type II VMF's containing specific 
manufacturing information for finished dosage forms 
medicated articles or medicated feeds, or manufacturing 
information for bulk drug substances or intermediates used in 
the further manufacture of bulk drug substance. 
2.  Type II: 	 Manufacturing Information for finished dosage forms, 
medicated articles or medicated feeds, or manufacturing 
information for bulk drug substances or intermediates 
used in the further manufacture of bulk drug substance. 
A Type II VMF should, in general, be limited to a single drug 
intermediate, drug substance, finished dosage form, medicated article, 
medicated feed or type of material used in their preparation. 
(12)  a. Drug Substance Intermediates, Drug Substances, and 
Material Used in Their Preparation 
o Summarize all significant steps in the manufacture and 
control of the drug intermediates or substance. Detailed 
guidance on what should be included in a Type II VMF for 
drug substances and intermediates may be found in the 
following guidelines: 
Guideline for Submitting Support Documentation in 
Drug  Applications for the Manufacture of Drug 
Substances, Center for Drugs and Biologics, February, 
1987 
Center for Veterinary Medicine Stability Guidelines 
In part, this information includes: 
o Description, including physical and chemical characteristics 
and stability. 
Names - Provide the chemical names and the generic and 
proprietary names, synonyms, chemical abstracts service 
registry number, and code number. 
Structural formula - Provide the chemical structure 
(including stereochemistry), molecular formula, and 
molecular weight. 
Physical and chemical characteristics - Describe 
physicochemical characteristics including, where 
applicable, such information as physical description, 
solid-state form, solubility profile, melting point, pH, 
specific rotation, and refractive index. 
Elucidation of structure - Supply physical and chemical 
data collected to elucidate and confirm the chemical 
structure of the drug substance. 
(13) 
 Stability - Describe fully the studies on the stability of 
the new animal drug substance and include the results. 
Reference to stability information from prior studies or 
the literature may be used, as appropriate, to meet some 
or all of these requirements.  Also, stability-indicating 
analytical methods information should also be included. 
o Manufacturer(s) - Provide the name and address of each 
facility, excluding the applicant, that participates in 
manufacturing the drug  substance (e.g., performs the 
synthesis, isolation, purification, micronization, testing, 
packaging, or labeling). Describe the  operation(s) that each 
will perform. 
o Method(s) of Manufacture and Packaging - Provide a full 
description of the materials and method(s) used in the 
synthesis, isolation, and purification of the drug substance. 
This description should include a list of starting materials, 
reagents, solvents, and auxiliary materials with specifications 
or a statement of the quality of  each. The description should 
include a diagrammatic flow chart of the synthesis and a 
detailed description of each step. Any alternate methods or 
variations in the synthesis should be included with an 
explanation of the circumstances under which they would be 
used. 
Process controls  - Provide a full description of the control 
checks performed at various stages of the manufacture, 
processing, and packaging of the drug substance. The 
description should include the specifications and tests for 
pivotal and key/critical intermediates. The description should 
include the impurity profile for the drug substance. 
Container-closure system - Provide appropriate information 
about the characteristics of, and the test methods used for the 
container, closure, or other component parts to assure their 
suitability for shipment and storage of the drug substance. 
(14) 
 If the drug substance is prepared by fermentation or by extraction 
from natural sources (plant or animal), provide a full description of 
the process. 
o Specifications and Analytical Methods for Drug Substance -
Provide a full description of the acceptance specifications and test 
methods used to assure the identity, strength, quality, and purity of 
the drug substance. The methods and standards of acceptance should 
be sufficiently detailed to permit duplication and validation by FDA 
laboratories. Adequate documentation should be submitted to support 
the precision, accuracy, specificity, and sensitivity of the  methodology 
and the integrity of the reference standard. 
Where test methods and specifications are included in an official 
compendium or other public standard, the standard used should be 
cited. 
b. Drug Product 
Manufacturing procedures and controls for finished dosage forms, 
medicated articles or medicated feeds should ordinarily be submitted 
in an INADA, NADA, ANADA, or export application. If this 
information cannot be submitted in an INADA, NADA, ANADA or 
export application, it should be submitted in a Type II VMF. When a 
Type II VMF is submitted for a drug product, the applicant/holder 
should follow the following guidance: 
Animal Drug Manufacturing Guidelines, 1994 (Revised) 
Center for Veterinary Medicine Drug Stability Guidelines 
Code of Federal Regulations (21 CFR 514.1(4)&(5)) 
c. Environmental Assessment 
An environmental assessment (EA) according to 21 CFR 25.31a which 
addresses the manufacture at each drug substance and  drug 
product manufacturing site should be submitted, when applicable. 
(15) 
 3.  TYPE III: Packaging Material 
Each packaging material should be identified by the intended use, 
components, composition, and controls for its release. The names of the 
suppliers or fabricators of the components used in preparing the  packaging 
material and the acceptance specifications should also be  given. Data 
supporting the acceptability of the packaging material for  its intended use 
should also be submitted. 
4. TYPE IV: Excipient, Colorant, Flavor, Essence or material used in 
their reparation 
Each additive should be identified and characterized by its method of 
manufacture, release specifications, and testing methods. 
Toxicological data, where necessary, should be included under this type of 
VMF, if not otherwise available by cross-reference to another document. 
Usually, the official compendia for excipients and FDA regulations f or 
color additives (21 CFR Parts 70 through 82), direct food additives (21 CFR 
Parts 170 through 173), indirect food additives (21 CFR Parts 174 through 
178), and food substances (21 CFR Parts 181 through 186) may be used as 
sources for release tests, specifications, and  safety. The guidance documents 
suggested for the preparation of a Type II VMF may be helpful for preparing 
a Type IV VMF. The VMF should include any other supporting information 
and data that are not available by cross reference to another document. 
5. TYPE V: FDA Accepted Reference Information 
This type of master file should include reference information that is not 
covered by Type II through Type IV VMF's. Some examples of these types of 
information may include: 
a. Sterilization Processes Validation Information - Contract 
manufacturers of sterile finished drug products, contract 
sterilization  firms (e.g., ethylene oxide, gamma radiation), and 
manufacurers of  sterile finished drug products that are the 
subject of a drug product application could provide their 
nonproduct-specific information and 
(16)  procedures that are submitted to support a claim of sterility in this 
type of master file. Where applicable, the content and format of such 
information should follow FDA's guidance entitled, "Guidance for 
Industry for the Submission of Documentation for Sterilization 
Process Validation in Applications for Human and Veterinary Drug 
Products". 
b. Environmental Studies - Environmental information that is  not 
appropriate for submission in a Type II through Type IV VMF may 
be provided in this type of master file. 
c. Animal Effectiveness, Safety, Residue and Metabolism, or Toxicity 
Studies - Generally this information is contained in an INADA or 
NADA for a specific product under investigation. In instances where 
the information and data may be applicable to numerous submissions 
it may be advantageous to maintain the information in this type of 
master file. 
d. List Master File - The reference list of feed mills for the 
manufacture of medicated feeds may be provided in this type of 
master file. 
e. Other Reference Information - The Center discourages the use of 
Type V VMF's for miscellaneous information, duplicate information, 
or information that should be included in one of the other types of 
VMF's. If any holder wishes to submit information and supporting 
data in a Type V VMF that is not covered by a Types II through IV 
VMF, a holder should first submit a letter of intent to the Center for 
Veterinary Medicine, Division of Chemistry, HFV-140, 7500 
Standish Place, Rockville, Maryland 20855. The Center will then 
contact the holder to discuss the proposed submission. 
B.  Public Master Files (PMF'S): 
These files usually contain safety and efficacy information and data that has 
been generated with public funds. This information is available to the public 
without the concern for trade secret and confidentiality associated with other 
types of master files. Public master files do not usually contain manufacturing 
information. The existence of a public master file is made known through a 
notice of availability in the Federal Register. 
(17)  V. SUBMISSIONS TO VETERINARY MASTER FILES 
A. Format, Assembly of Master File Documents 
The information in a master file may be used to support multiple 
applications (INADA's, NADA's, ANADA's, another VMF or DMF, 
an export application, or amendments or supplements to any of 
these). 
Each veterinary master file submission should contain a transmittal 
letter, administrative information about the submission, and the 
specific information to be included in the VMF. 
The master file should be written in the English language. Whenever 
a submission contains information in another language, an accurate 
certified English translation should also be included. 
Each page of each copy of the VMF should be consecutively 
numbered. An updated table of contents should be included with each 
submission. 
An original and duplicate are to be submitted for all VMF submissions. 
Veterinary Master File holders and their agents/representatives 
should retain a complete reference copy that is identical to, and 
maintained in the same chronological order as, their submission to 
FDA. 
The original and duplicate copies must be collated, fully assembled, 
and individually jacketed. Each volume of a VMF should, in general, 
be no more than 2 inches thick. For multivolume submissions, each 
volume should be numbered. For example, for a 3-volume 
submission, the volumes would be numbered 1 of 3, 2 of 3, 3 of 3. 
Additionally, U.S. standard paper size (8 1/2 by 11 inches) is 
preferred. Paper length should not be less than 10 inches nor more 
than 12 inches. However, it may occasionally be necessary to use 
individual pages larger than standard paper size to present a floor 
plan (for a facility manufacturing sterile drug products), synthesis 
diagram, etc. Those pages should be folded and mounted to 
(18)  allow the page to be opened for review without disassembling the 
jacket and refolded without damage when the volume is shelved. The 
Center's system for filing VMF's provides for assembly on the left 
side of the page. The left margin should be  at least three-fourths of an 
inch to assure that text is not obscured in the fastened area. The right 
margin should be at least one-half of an inch. The submitter should 
punch holes 8 1/2 inches apart in each page. 
Veterinary Master File submissions and correspondence should be 
addressed to: 
Document Control Unit 
HFV-199 
Food and Drug Administration 
Center for Veterinary Medicine 
Metro Park North 2 - Room N 403 
7500 Standish Place 
Rockville, MD 20855 
Delivery charges to the above address must be prepaid. 
The submission of an original master file will be acknowledged by 
letter with the designation of a document number, VMF-XXXX. 
B.  Transmittal Letter 
1. Original Submission 
The transmittal letter should contain the following: 
Identification of submission: Original, the type of VMF (II-V), 
and its subject. 
Identification of the applications, if known, that the VMF is 
intended to support, including the name and address of each 
sponsor, and relevant document numbers. 
Signature of the holder or the authorized representative. 
(19) 
 Typewritten  name and title of the signer. 
2.  Amendments 
The transmittal letter should contain the following: 
Identification of submission: Amendment, the VMF number, 
Type of VMF, and the subject of the amendment. 
A description of the purpose of the submission (e.g., update, 
revised formula, revised process, etc.). 
Signature of the holder or the authorized representative. 
Typewritten name and title of the signer. 
C.  Administrative Information 
Administrative information should include the following: 
1.  Original Submissions: Administrative information for original 
submissions (Type II-V) should include the following names and 
addresses: 
o VMF holder 
o Corporate headquarters 
o Manufacturing/processing facility 
o Contact for FDA correspondence 
o Agents, if any 
o Statement of commitment - A signed statement by  the holder 
certifying that the VMF is current and that the VMF holder will 
comply with the statements made in it. 
2. Amendments: Administrative information for amendments (Type 
II-V) should include the following: 
o VMF holder 
o VMF number 
o Contact for FDA correspondence 
(20)   o Affected section and/or page numbers of the VMF 
o The name and address of each person whose INADA, 
NADA, ANADA, VMF or DMF, or Export application relies 
on the subject amendment. 
VI. MASTER FILE REVIEW/HOLDER OBLIGATIONS 
The contents of a master file (VMF or DMF) will be reviewed by the Center 
only when the master file holder provides appropriate authorization permitting 
the FDA to refer to it on behalf of the sponsor. Authorization must be in the 
form of a letter, a copy of which should be available in the application 
(INADA, NADA, ANADA, Export Application, or amendments and 
supplements to any of these). 
Before making significant changes in processes covered in the master file 
(VMF or DMF), the master file holder must notify each sponsor. The sponsor 
is required by regulation to supplement or amend the affected application(s). 
A Veterinary Master File will only be reviewed in conjunction with an 
application (INADA, NADA, ANADA, Export Application, or amendments 
and supplements to these applications). Previously, the Center routinely 
reviewed submissions (original and amendments to VMF's) that were not 
necessarily linked to a specific application, but for which authorization for 
FDA review were provided. In some instances, these master files were never 
referenced in support of a pending application. The Center has concluded that 
the routine review and evaluation of Veterinary Master Files not specifically 
referenced in applications may be a waste of resources. Therefore, the routine 
evaluation of updates and amendments to Veterinary Master Files will be 
discontinued. This change in the Center's review process only serves to 
emphasize that the affected applicants must be notified of significant changes 
in a Veterinary Master File that require the submission of an amendment or 
supplemental application. At that time, the Center (with appropriate 
authorization) will refer to the Veterinary Master File and evaluate the change 
in process, etc., and the impact of these changes on the affected application. 
(21) 
 Acceptance of a master file is granted only upon the satisfactory  review of the 
file contents. During the course of the review of a master file, should the 
information be considered deficient, the holder will be notified by the 
Center.Communications relevant to the contents of the master file are made 
by the Center directly with the responsible holder of the master file. At the 
same time, the Center will notify the person who relies on the information in a 
deficient DMF or VMF that additional information is needed in the 
supporting master file, and that separate communication detailing the 
deficiencies has been sent to the master file holder. While the general subject 
of the deficiencies may be identified, the details of the master file deficiencies 
are disclosed only to the master file holder. When the holder submits the 
requested information to the master file in response to the Center's deficiency 
letter, the holder should also send a copy of the accompanying transmittal 
letter to the affected persons relying on the master file. The transmittal letter 
will provide notice that the deficiencies have been addressed. 
The master file should be routinely updated on an annual basis to assure that 
operations are current and information correct. A current list of authorized 
users of the file should be maintained. 
VII. CONFIDENTIALITY OF INFORMATION 
All information contained in a master file (DMF or VMF) is considered 
confidential. Further, it is Center policy not to make known the existence of 
specific master files. Rather, it is the responsibility of a sponsor to make sure 
that a master file (DMF or VMF) is available and request authorization for 
FDA referral. 
VIII. AUTHORIZATION TO REFER TO A MASTER FILE 
Letter of Authorization 
Before FDA can review VMF or DMF information in support of an 
application, the  holder must submit in duplicate to the master file  a letter of 
authorization permitting FDA to reference the master file. 
(22) 
 The letter of authorization should include the following: 
o Date of letter 
o Name of Veterinary Master File holder 
o VMF or DMF number 
o Name of persons authorized to incorporate 

information in the MF by reference. 

o Specific products covered by the master file 
o Sections, volumes and page numbers to be 

referenced 

o Statement of commitment that the master file is 

current and that the holder will abide with the 

statements made in it. 

o Signature of the authorizing official/agent 
o Typed name and title of the official authorizing 

reference to the file. 

The holder should also send a copy of the letter of authorization to the 
affected applicant, sponsor or other holder who is authorized to incorporate 
by reference the specific information contained in the master file. 
IX. OWNERSHIP TRANSFER/NAME CHANGE 
To transfer ownership of a VMF to another party, the holder should notify the 
Center for Veterinary Medicine and authorized persons in writing. 
The letter should include the following information: 
o Name of Holder/Transferee 
o Address of Holder/Transferee 
o Name of responsible official of the transferee 
o Effective date of transfer 
o Signature of the responsible transferring official 
o Typewritten name and title of the transferring official 
(23) 
 The new holder should submit a letter of acceptance indicating the acceptance 
of the document and all existing responsibilities. The holder should provide 
an update of the information in the file, where appropriate, as soon as 
possible to indicate if any changes (e.g., plant location and methods) have or 
will take place. 
X. REORGANIZATION OF THE VETERINARY MASTER FILE 
A holder who plans a major reorganization of a VMF is encouraged to submit 
a detailed plan of the proposed changes and request its review and evaluation 
by the Division of Chemistry. All authorized users should  also be notified 
when any changes are made in any operation that may affect the applicants 
products. 
XI. CLOSURE OF A VETERINARY MASTER FILE 
A holder who wishes to close a master file should submit a request to the 
Center citing the reason for the closure. The letter should include a statement 
that the holder's obligations have been fulfilled and all users have been 
notified. 
The Center may close a VMF that does not contain an annual update and a 
list of changes made since the previous annual update. The holder will be 
notified of FDA's intent to close the VMF. 
(24)