CENTER FOR DRUG EVALUATION AND RESEARCH FOOD AND DRUG ADMINISTRATION DEPARTMENT OF HEALTH AND HUMAN SERVICES
GUIDELINE FOR DRUG MASTER FILES
SEPTEMBER 1989
TABLE OF CONTENTS
PAGE
I.
INTRODUCTION
1
II.
DEFINITIONS
2
III. III.
TYPE TYPES S OF OF DRU DRUG G MAS MASTE TER R FIL FILES ES
5
IV. IV.
SUBM SU BMIS ISSI SION ONS S TO TO DRU DRUG G MAS MASTE TER R FIL FILES ES
6
A. A.
B.
C.
Tran Transm smit itta tal l Lett Letter ers s
7
1.
Orig Or igin inal al Su Subm bmis issi sion ons s
7
2.
A m e n d m e nt s
8
Admi Admini nist stra rati tive ve Infor Informa mati tion on
9
1.
Orig Or igin inal al Su Subm bmis issi sion ons s
9
2.
A m e n d m e nt s
10
Drug Drug Mast Master er File File Cont Conten ents ts
11
1.
11
Type Ty pes s of Dr Drug ug Ma Mast ster er Fi File les s a.
Type I
Manufacturing Site, Facilities, Operating Procedures, and Personnel b.
Type II
Drug Substance, Drug Substance Intermediate and Material Used in Their Preparation, or Drug Product c.
14
Type IV
Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation e.
12
Type III
Packaging Material d.
11
15
Type V
FDA-Accepted Reference Information -i-
16
PAGE 2.
D.
V.
VI.. VI
VII. II.
VIll VI ll..
IX.. IX
Gene Ge nera ral l In Infor forma mati tion on an and d Su Sugge ggest stio ions ns
16
a.
Envi En viro ronm nmen enta tal l As Asse sess ssme ment nt
16
b.
S t a b i l it y
17 17
Form Fo rmat at, , Assem Assembl bly, y, an and d De Deliv liver ery y
17
AUTH AU THOR ORIZ IZAT ATIO ION NT TO O REF REFER ER TO A DRU DRUG G MASTER FILE
20
A.
Lett Le tter er of Au Auth thor oriz izat atio ion n to FM
20
B.
Copy Copy to Applica Applicant, nt, sponso sponsor r or Other Other Holder Holder
22
PROC PR OCES ESSI SING NG AND RE REVI VIEW EWIN ING G POL POLIC ICIE IES S
22
A.
Polici Policies es Relate Related d to Process Processing ing Drug Drug master master Files Files
22
B.
Drug Dr ug Ma Mast ster er Fi File le Re Revi view ew
23
HOLD HOLDE ER OBL OBLIG IGAT ATIIONS ONS
24
A.
Notice Notice Require Required d for changes changes to a Drug Drug Master Master File File
24
B.
Listin Listing g of Person Persons s Autho Authorize rized d To Refer Refer to to a Drug Drug Master File
25
C.
Annual Upd pda at e
25
D.
Appo Ap poin intm tmen ent t of an Ag Agen ent t
26
E.
Tran Tr ansf sfer er of ow owne ners rshi hip p
27
MAJO MA JOR R REO REORG RGAN ANIZ IZAT ATIO ION N OF OF A DR DRUG UG MASTER FILE
28
CLOS CLOSUR URE E OF OF A DRU DRUG G MAS MASTE TER R FIL FILE E
28
-ii-
For further information regarding the guideline please contact FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH OFFICE OF DRUG EVALUATION I (HFD-100) 5600 FISHERS LANE ROCKVILLE, MARYLAND 20857 (301) 443-4330
-iii-
GUIDELINE FOR DRUG MASTER FILES I. INTRODUCTION
A
Drug
master
File
Administration
(DMF)
(FDA)
is
that
a
submission
may
be
used
to
to
the
Food
provide
and
Drug
confidential
detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of one or more human drugs.
The submission of a DMF is not required by law
or FDA regulation. A DMF is submitted solely at the discretion of the holder. The information contained in the DMF may be used to support an Investigational New Drug Application (IND), a New Drug Application
(NDA),
an
Abbreviated
New
Drug
Application
(ANDA),
another DMF, an Export Application, or amendments and supplements to any of these.
A
DMF
is
NOT
a
Application.
substitute
It
is
not
for
an
approved
IND, or
NDA,
ANDA,
or
disapproved.
Export
Technical
contents of a DMF are reviewed only in connection with the review of an IND, NDA, ANDA, or an Export Application
This guideline guideline does 10.90(b)).
It
approaches
to
approaches
may
not
does, meeting be
impose
mandatory mandatory
however,
offer
regulatory
followed,
requirements requirements
guidance
requirements.
on
(21
CFR
acceptable Different
but the applicant is encouraged to
1
discuss significant variations in advance with FDA reviewers to preclude spending time and effort in preparing a submission that FDA may later determine to be unacceptable.
Master
Files
guideline
is
are
provided
intended
to
for
in
provide
DMF
21
CFR
314.420.
holders
with
This
procedures
acceptable to the agency for preparing and submitting a DMF.
The
guideline discusses types of DMF's, the information needed in each type,
the
format
of
submissions
to
a
DMF,,
the
administrative
procedures governing review of DMF's, and the obligations of the DMF holder.
DMF's are generally created to allow a party other than the holder of the DMF to reference material without disclosing to that party contents
of
the
file.
When
an
applicant
references
its
own
material, the applicant should reference the information contained in its own IND, NDA, or ANDA directly rather than establishing a new DMF.
II. DEFINITIONS For the purposes of this, guideline, the following definitions apply:
1. Agency means the Food and Drug Administration. 2
drug and any other person who owns, an approved application (21 CFR 314.3 (b)).
4.
Drug
prod uct
means
a
finished
dosage
form,
for
example,
tablet, capsule, or solution, that contains a drug substance, generally,
but
not
necessarily,
in
association
with
one
or
more other ingredients (21 CFR 314.3(b)).
5.
Drug substance means an active ingredient that is intended to
furnish
pharmacological
the diagnosis,
cure,
activity
or
other
direct
mitigation, treatment,
effect
in
or prevention
of disease or to affect the structure or any function of the human
body,
but
does
not
include
intermediates
used
in
the
synthesis of such ingredient (21 CFR 314.3(b)).
6.
Export
application
section
802
of
the
means
an
Federal
application
Food,
Drug,
and
submitted Cosmetic
under Act
to
export a drug that is not approved for marketing in the United States.
3
7. Holder means a person who owns a DMF.
8. Letter of authorization means a written statement by the holder or designated agent or to
information
in
representative
the
DMF
in
permitting FDA to
support
of
another
refer
person's
submission.
9. Person
includes
association.
individual,
(Section
201(e)
partnership, of
the
Federal
corporation, Food,
and
Drug,
and
Cosmetic Act.)
10. Sponsor means initiates individual academic
a
a
person
clinical or
who
investigation.
pharmaceutical
institution,
takes
The
company,
private
organization (21 CFR 312.3(b)).
responsibility sponsor
for
may
governmental
organization,
or
and
be
an
agency, other
III. TYPES OF DRUG MASTER FILES FILES
There are five types of DMF's:
Type I
Manufacturing Site, Facilities, Operating Procedures, and Personnel
Type II
Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product
Type Ty pe II III I
Pack Pa ckag agin ing g Mat Mater eria ial l
Type IV
Excipi Exci pien ent, t, Col Color oran ant, t, Fla Flavo vor, r, Ess Essen ence ce, , or Material Used in Their Preparation
Type V
FDA-Accepted Re Reference In Information
5
Each
DMF
should
supporting
contain
data.
See
only
one
Section
type
IV.C
of
of
information
the
guideline
and for
all more
detailed descriptions of the kind of information desired in each type.
Supporting
information
and
data
in
a
DMF
can
be
cross-referenced to any other DMF (see Part V).
IV. SUBMISSIONS TO DRUG MASTER FILES
Each
DMF
submission
should
contain
a
transmittal
letter,
administrative information about the submission, and the specific information to be included in the DMF as described in this section.
The DMF must be in the English language.
Whenever a submission
contains
an
information
in
another
language,
accurate
certified
English translation must also be included.
Each page of each copy of the DMF should be dated and consecutively numbered.
An updated table of contents should be included with
each submission.
6
A.
T r a n sm i t t a l L e tt e r s
The following should be included:
1.
Original Submissions
a. Identif Identifica icatio tion n of submissio submission: n: Origina Original, l, the type of DMF as classified in Section III, and its subject. b. Identificatio Identification n of the applications, applications, if known, that the DMF is intended to support, including the name and address of each sponsor, applicant, or holder, and all relevant document numbers. c. Signatu Signature re of the the representative.
holder holder
or or
the
auth authoriz orized ed
d. Typewri Typewritte tten n name name and title title of of the signe signer. r.
7
2. Amendments
a.
Identi Iden tifi fica cati tion on of su subm bmis issi sion on: : Amen Am endm dmen ent, t, the DMF number,, type of DMF,, and the subject or the amendment.
b.
A descri rip ption of of th the pu purpose of of submission, e.g., update, revised formula, or revised process.
c.
Signat Sign atur ure e of of the the ho hold lder er or th the e representative.
d.
Type Ty pewr writ itte ten n n nam ame e a and nd ti titl tle e o of f t the he si sign gner er. .
8
aut autho hori rize zed d
B.
Adm dmi inistrative Inform rma ation Administrative information should include the following:
1.
O r ig i n a l S u b m i s s i o ns
a.
Name Na mes s and and ad addr dres esse ses s of of the the fo foll llow owin ing: g: (1)
D M F h ol d e r .
(2) (2 )
Corp Co rpor orat ate e he head adqu quar arte ters rs. .
(3) (3 )
Manu Ma nufa fact cturi uring ng/p /pro roce cess ssin ing g facil facilit ity. y.
(4) (4 )
Cont Co ntac act t for for FDA FDA corr corres espo pond nden ence ce. .
(5)
A g e n t (s ) i f a n y
b.
The The s spe peci cifi fic c r res espo pons nsib ibil ilit itie ies s o of f e eac ach h person listed in any of the categories in Section IV.B.1.a.
c.
St a t e m e n t o f c o m mi t m e n t . A signed statement by the holder certifying that the DMF is current and that the DMF holder will comply with the statements made in it.
9
2.
Am e n d m e n t s
a.
Na m e o f D M F h o l d er .
b.
DM F n u m be r .
c.
Name Na me an and d add addre ress ss fo for r cor corre resp spon onde denc nce. e.
d.
Affect Affe cted ed se sect ctio ion n DMF.
e.
The n The nam ame e a and nd ad addr dres ess s o of f e eac ach h p per erso son n w who hose se IND, NDA, ANDA, DMF, or Export Application relies on the subject of the amendment for support.
f.
The Th e num numbe ber r of of eac each h IND IND, , NDA NDA, , AND ANDA, A, DM DMF, F, an and d Export Application that relies on the subject of the amendment for support, if known.
g.
Partic Part icul ular ar it item ems s wit withi hin n the the IN IND, D, ND NDA, A, AN ANDA DA, , DMF, and Export Application that are affected, if known.
and and/o /or r
10
pag page e
num numbe bers rs of th the e
C.
D r u g M a s te r F i l e C on t e n t s
1.
Ty p e s o f D r u g M a st e r r i l es
a. Type I:
Manu Ma nufa fact ctur urin ing g
Site Si te, , Fa Faci cili liti ties es, , Op Oper erat atin ing g
Procedures, and Personnel
A Type I DMF is recommended f or a person outside of the
United
States
to
assist
FDA
in
conducting
on-
site inspections of their manufacturing facilities. The
DMF
should
describe
the
manufacturing
site,
equipment capabilities, and operational layout.
A
Type
I
DMF
is
normally
not
needed
to
describe
domestic facilities, except in special cases, such as when a person is not registered and not routinely inspected.
The description of the site should include acreage, actual site address, and a map showing its location with
respect
to
the
nearest
city.
An
aerial
photograph and a diagram of the site may be helpful.
11
A diagram of major production and processing areas in helpful for understanding the operational layout. Major
equipment
should
be
capabilities,
application,
model
not
would
described and
normally
in
location. be
terms Make
needed
of and
unless
equipment is new or unique.
A
diagram
elements,
of
with
major key
corporate
manufacturing,
organizational quality
control,
and quality assurance positions highlighted, at both the
manufacturing
site
and
corporate
headquarters,
is also helpful.
b.
Type II
Drug Substance. Drug Substance Intermediate, and Material Used in Their Preparation. or Drug Product
A
Type
II
DMF
single
drug
product,
or
should,
in
general,
intermediate, type
of
drug
material
be
limited
substance, used
in
to
a
drug their
preparation.
(1) Drug Substance Substance Intermed Intermediates, iates, Drug Drug Substances, Substances, and and Material Used in Their Preparation
12
Summarize and
all
controls
Detailed
significant of
the
guidance
Type II DMF
steps
drug
on
the
manufacturing
intermediate
what
for drug
in
should
be
substances
or
substance.
included
in
a
and intermediates
may be found in the following guidelines:
Guideline in
Drug
for
Submitting
Applications
Supporting
for
the
Documentation
Manufacture
of
Drug
Substances.
Guideline
for
Chemistry,
the
Format
Manufacturing,
and
and
Content
Controls
of
the
Section of
an Application.
(2) Drug Product
Manufacturing
procedures
dosage
should
IND,
forms
NDA,
ANDA,
information ANDA, or
cannot
controls
ordinarily Export be
When
drug product, guidance
the
be
submitted
submitted
in
13
the
an
If IND,
in
an
this NDA,
is submitted for a
applicant/sponsor in
finished
it should be submitted
a Type II DMF
provided
for
Application.
Export Application,
in a DMF.
the
or
and
should follow
following guidelines:
Guideline
for
the
Format
chemistry,
Manufacturing,
and
Content
and Controls
of
the
Section of
an Application.
Guideline
for
Submitting
Documentation
for
the
Manufacture of and Controls for Drug Products
Guideline for Submitting Samples and Analytical Data for Methods Validation
c. Type III: Packaging Material
Each packaging material should be identified by the intended
use,
for
release.
its
components, The
composition,
names
of
the
and
controls
suppliers
or
fabricators of the components used in preparing the packaging material and the acceptance specifications should
also
be
acceptability
of
given. the
packaging
intended use should also in
the
"Guideline
for
Data
supporting material
be submitted as
Submitting
for
the its
outlined
Documentation
for
Packaging for Human Drugs and B Biologics."
Toxicological
data
on
these
materials
would
included under this type of DMF, if not otherwise
be
available by cross-reference to another document.
d Type IV :
Exci Ex cipi pien ent, t, Co Colo lora rant nt, , Fl Flav avor or,. ,. Es Esse senc nce, e, or Material Used in Their Preparation
Each additive should be identified and characterized by
its
method
of
manufacture,
release
specifications, and testing methods.
Toxicological included
data
under
on
this
these
type
of
materials
DMF,
if
not
would
be
otherwise
available by cross-reference to another document.
Usually, the official compendia and FDA regulations for
color
direct 173),
additives
food
(21
additives
indirect
food
CFR (21
Parts CFR
additives
70
Parts (21
through 170
CFR
82),
through
Parts
174
through 178), and food substances (21 CFR Parts 181 through
186)
tests,
specifications,
suggested
for
may
a
be
Type
used
as
and II
preparing a Type IV DMF.
DMF
sources safety. may
be
for
release
Guidelines helpful
for
The DMF should include any
other supporting information and data that are not available by cross-reference to another document 15
e. Type V :
FDA
F D A - A cc e p t e d R ef e r e n c e In f o r m a t i o n
discourages
miscellaneous
the
use
of
information,
Type
V
duplicate
DMF's
for
information,
or information that should be included in one of the other
types
of
DMF's.
If
any
holder
wishes
to
submit information and supporting data in a DMF that is not covered by Types I through IV, a holder must first submit a letter of intent to the Drug Master File
Staff
section).
(for FDA
address,
will
then
see
D.5.a.
contact
the
of
this
holder
to
discuss the proposed submission.
2. General Information and Suggestions
a. Environmental Assessment
Type II, Type III, and Type IV DMF's should contain a commitment by the firm that its facilities will be operated
in
environmental
compliance laws.
If
a
with
completed
applicable environmental
assessment is needed, see 21 CFR Part 25.
16
b . S t a b i li t y
Stability other
study
design,
information
applicable, Submitting
as
data,
should
outlined
Documentation
interpretation,
be in
for
submitted,
the the
and when
"Guideline
Stability
of
for Human
Drugs and Biologics."
D. Format, Assembly, and Delivery
1. An original original and duplicate duplicate are to be submitted submitted for all all DMF submissions.
Drug Master File holders and their agents/representatives should retain a complete reference copy that is identical to,
and
maintained
in
the
their submissions to FDA.
17
same
chronological
order
as,
2.
The orig original inal and dupl duplica icate te copie copies s must must be coll collate ated, d, fully fully assembled, and individually jacketed.
Each volume of a
DMF should, in general, be no more than
2 inches thick. volume.
For multivolume submissions, number each
For example, for a 3-volume submission, volumes
would be numbered 1 of 3, 2 of 3, and 3 of 3.
3.
U.S.
standa standard rd
pape paper r
size size
(8-1 (8-1/2 /2
by by
11
inches inches) )
is
preferred. Paper length should not be less than 10 inches nor more than 12 inches. However, it may occasionally be necessary paper
to
size
to
use
individual
present
a
pages
floor
larger
plan,
than
standard
synthesis
diagram,
batch formula, or manufacturing instructions.
Those pages
should
be
page
opened
for
folded review
and
mounted
without
to
allow
disassembling
the the
to
jacket
refolded without damage when the volume is shelved. Figures 1 and 2.
18
be and See
Fold
Fold 11”
8-1/2”
7-3/4”
16-1/4”
Figure 1
11”
7- 3 /4”
7- 3 /4”
15-1/2”
Figure 2
4.
The The age agenc ncy' y's s sys syste tem m for for fili fi ling ng DM DMF' F's s pro provi vide des s for 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. See the page measurements shown in Figure 3.
11” 1-3/4”
8- 1 /2”
3 /8”
Figure 3
19
5.
D e li v e r y t o F D A a.
Drug Dr ug
Mast Ma ster er
File Fi le
sub submi miss ssio ions ns
and and
corr co rres espo pond nden ence ce
should be addressed as follows:
Drug Master File Staff Food and Drug Administration 12420 Parklawn Drive, Room 2-14 Rockville, Maryland 20852 b. Deli De live very ry prepaid.
V.
char ch arge ges s
t to o
t the he
abov ab ove e
a add ddre ress ss
must mu st
be
AUTHORIZATION TO REFER TO A DRUG MASTER FILE
A.
Lette tter of of Au Authorizatio tion to to FD FDA
Before
FDA
can
review
DMF
information
in
support
of
an
application, the DMF holder must submit in duplicate to the DMF a letter of authorization permitting FDA to reference the DMF. holder
If the holder cross-references its own DMF, the
should
supply
in
a
letter
of
authorization
the
information designated by items 3, 5, 6, 7, and 8 of this section.
The
holder
does
not
need
to
letter with its letter of authorization.
20
send
a
transmittal
The letter of authorization should include the following:
1.
T h e d a te .
2.
N a m e o f D M F h o l d er
3.
D M F n u mb e r
4.
Name
o of f
p pe erson(s (s) )
incorporate
information
a au uthori riz zed
t to o
in
by
the
DMF
reference. 5.
Spec Sp ecif ific ic pr prod oduc uct( t(s) s) co cove vere red d b by y t the he DM DMF. F.
6.
Submission d da ate(s) o of f 5 5, , a abo bov ve.
7.
Sect Se ctio ion n num numbe bers rs an and/ d/or or pa page ge nu numb mber ers s to to be be referenced.
8.
Stat St atem emen ent t current
of of
and
com commi mitm tmen ent t that
the
tha that t DMF
the the DM DMF F holder
is is
will
comply with the statements made in it. 9.
Sign Si gnat atur ure e of of aut autho hori rizi zing ng of offi fici cial al. .
10. 10 .
Type Ty ped d
nam name e
and and
tit title le
of
authorizing reference to the DMF.
21
offi of fici cial al
B.
Copy Co py to Ap Appl plic ican ant, t, Sp Spon onso sor, r, or Ot Othe her r Hol Holde der r
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
specific information contained in the DMF.
reference
the
The applicant,
sponsor, or other holder referencing a DMF is required to include a copy of the DMF holder's letter of authorization in the application.
VI.. VI A.
PROC PR OCES ESSI SING NG AN AND D RE REVI VIEW EWIN ING G POLI POLICI CIES ES
Poli Po lici cies es Re Rela late ted d to to Proc Proces essi sing ng Dr Drug ug Ma Mast ster er Fi File les s
1.
Publ Pu blic ic ava avail ilab abil ilit ity y of th the e info inform rmat atio ion n and and data data in in a DMF
is
determined
under
21
CFR
Part
20,
21
CFR
314.420(e), and 21 CFR 314.430.
2.
An original DMF submission will be examined on receipt to determine
whether
it
meets
minimum
requirements
for
format and content. if the submission is administratively acceptable, FDA will acknowledge its receipt and assign it a DMF number.
22
If
the
submission
is
administratively
incomplete
or
inadequate, it will be returned to the submitter with a letter of explanation from the
Drug Master File Staff,
and it will not be assigned a DMF number.
B.
Drug Master File Review
A DMF IS NEVER APPROVED OR DISAPPROVED. The IND
agency will sponsor,
review information in a DMF only when an
an
applicant
for
an
NDA,
ANDA,
or
Export
Application, or another DMF holder incorporates material in the
DMF
by
reference.
As
noted,
the
incorporation
by
reference must be accompanied by a copy of the DMF holder's letter of authorization.
If
FDA
reviewers
find
deficiencies
in
the
information
provided in a DMF, a letter describing the deficiencies is sent to the DMF holder. the
At the same time, FDA will notify
person who relies on the information in the deficient
DMF that additional information is needed in the supporting DMF.
The general subject of the deficiency is identified,
but details of the deficiency are disclosed only to the
DMF
holder.
information
to
When the
deficiency letter,
the
the DMF
holder in
holder 23
submits
response should
to also
the the
requested agency's
send a copy of
the accompanying transmittal letter to the affected persons relying on the DMF and to the FDA reviewing division that identified
the
deficiencies.
The
transmittal
letter
will
provide notice that the deficiencies have been addressed.
VII.
HOLDER OBLIGATIONS
Any change or addition, including a change in authorization related to
specific
customers,
should
be
submitted
in
duplicate
and
adequately cross-referenced to previous submission(s). The reference should
include
the
date(s),
volume(s),
section(s),
and/or
page
number(s) affected.
A.
Noti No tice ce Re Requ quir ired ed fo for r Cha Chang nges es to a Dru Drug g Mas Maste ter r Fil File e
A holder must notify each affected applicant or sponsor who has
referenced its DMF of any pertinent change in the DMF
(21 CFR 314.420(c)). Notice should be provided well before making
the change in order to permit the sponsor/applicant
to supplement or amend any affected application(s) needed.
24
B.
Listi Listing ng of Pe Pers rson ons s Aut Autho hori rize zed d To To Ref Refer er to a Dru Drug g Mas Master ter Fi File le 1.
A DMF DMF is re requ quir ired ed to to cont contai ain n a com compl plet ete e list list of of pers person ons s authorized
to
incorporate
information
reference [21 CFR 314.420(d)].
in
the
DMF
by
The holder should update
the list in the annual update. The updated list should contain the holder's name, DMF number, and the date of the update. The update should identify by name (or code) the
information
that
each
person
is
authorized
to
incorporate and give the location of that information by date, volume, and page number.
2.
Any An y per perso son n who whose se autho authori riza zati tion on ha has s bee been n wit withd hdra rawn wn du duri ring ng the previous year should be identified under a suitable caption.
3.
If th the e list list is is unc uncha hang nged ed on the the ann anniv iver ersa sary ry dat data, a, the the DMF holder should also submit a statement that the list is current.
C.
A n n u a l U pd a t e The
holder
anniversary
should date
should contain
of
provide the
an
original
the required
25
annual
report
submission.
list as
on
This
the
report
described in B.1., and
should also identify all changes and additional information incorporated into
the DMF since the previous annual report
on the subject matter of the DMF. If the subject matter of the
DMF
is
unchanged,
the
DMF
holder
should
provide
a
statement that the subject matter of the DMF is current.
Failure to update or to assure FDA annually that previously submitted material and lists in the DMF remain current can cause
delays
in
FDA
review
of
a
pending
IND,
NDA,
ANDA,
Export Application, or any amendment or supplement to such application; and FDA can initiate procedures for closure of the DMF (see Section IX).
D.
Appointment of of an an Ag Agent
When
an
agent
is
appointed,
the
holder
should
submit
a
signed letter of appointment to the DMF giving the agent's name,
address,
and/or appoint
and
scope
scientific). an
agent
or
of
Domestic
responsibility DMF
holders
representative,
(administrative do
although
holders are encouraged to engage a U.S. agent.
26
not
need
foreign
to DMF
E.
T r an s f e r o f O w n e r s hi p To transfer ownership of a DMF to another party, the holder should so notify FDA and authorized persons in writing. letter should include the following:
1.
N a m e o f t r a n s f e r ee
2.
A d d r e s s o f t r a n s fe r e e
3.
Name o of f r res esp ponsible o of fficia ial l o of f transferee
4.
Effective d da ate o of f t tr r a n sf e r
5.
Sign Si gnat atur ure e of th the e tra trans nsfe ferr rrin ing g off offic icia ial l
6.
Typewritten name a an nd t ti itle o of f t th he transferring official.
27
The
The new holder should submit a letter of acceptance of the transfer and an update of the information contained in the DMF,
where
ownership
appropriate. (e.g.,
plant
Any
change
location
and
relating methods)
to
the
should
new be
included.
VIll VI ll.. MA MAJO JOR R REOR REORGA GANI NIZA ZATI TION ON OF OF A DRUG MASTER FILE A holder who plans a major reorganization of a DMF is encouraged to submit a detailed plan of the proposed changes and request its review by the Drug Master File Staff. The staff should be given sufficient time to comment and provide suggestions before a major reorganization is undertaken.
IX.
CLO CLOSU SURE RE OF A DRU DRUG G MAS MASTE TER R FIL FILE E
A holder who wishes to close a DMF should submit a request to the Drug
Master
File
Staff
stating
the
reason
for
the
closure.
See
Section IV.D.5.a for the address.
The request should include a statement that the holder's obligations as detailed in Section VII have been fulfilled.
28
The Agency may close a DMF that does not contain an annual update of persons authorized to incorporate information in the DMF by reference and a list of changes made since the previous annual report. The holder will be notified of FDA's intent to close the DMF.
Many of the guidelines referred to in the text and a current list of available guidelines may be obtained from the following:
Legislative, Professional, and Consumer Affairs Branch (RFD-365) Center for Drug Evaluation and Research Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857
Copies of the Code of Federal Regulations (CFR) may be purchased from the following:
Superintendent of Documents U.S. Government Printing office Washington, D.C. 20402
29
