1. COMPARITIVE STUDY OF US DMF V/S EDMFs
Parameters US DMF EDMF
Definition A Drug Master File (DMF) is a 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 human drugs.
European Drug Master File (EDMF) allows
valuable confidential intellectual property or
'know-how' of the manufacturer of the active
substance (ASM) to be protected, while at the
same time allowing the Applicant or Marketing
Authorization (MA) holder to take full
responsibility for the medicinal product and the
quality and quality control of the active
substance. National Competent Authorities/EMA
thus have access to the complete information
that is necessary for an evaluation of the
suitability of the use of the active substance in
the medicinal product.
Types I – Manufacturing information(now
withdrawn)
II – Drug substance, intermediates
chemistry manufacturing and control
III – Packaging
IV – Excipients
V – Other Information
a) Certificate of Suitability to the
monographs of the European
Pharmacopoeias (CEP)
b) Active Substance Master File(ASMF)
Scope 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.
CEP:
 The evaluation of the suitability of the
monograph for the control of the
chemical purity and microbiological
quality of their substance
 The evaluation of the reduction of a risk
of TSE
 The evaluation of the suitability of the
monograph for the control of herbal
drugs and herbal drug preparations.
ASMF:
 New active substances.
 Existing active substances not included in
the European Pharmacopoeia (Ph. Eur.)
or the pharmacopoeia of an EU Member
State.
 Pharmacopeial active substances
included in the Ph. Eur. or in the
pharmacopoeia of an EU Member State.
 The ASMF procedure cannot be used for
biological active substances

2. COMPARITIVE STUDY OF US DMF V/S EDMFs
Authority US FDA CEP: European Directorate for Quality of
Medicines and Healthcare
ASMF: European Medical Agencies
Reviewing
committee
Office of business and informatics(OBI)
within CDER
CEP: DCEP within EDQM
ASMF: Various working bodies.
Format of
submission
and
specifications
a) Paper format: size of paper used is
8 ½ inches ×12 inches.
Binders used:
Blue binder( Form 3316)
Red Binder (Form 3316a)
From 5th
May, 2018 onwards, all
Master Files are to be submitted
in eCTD format only.
b) eCTD format: Format in
accordance with ICH guideline
M4Q: Quality
CEP:
a) Paper format: From June 2016 onwards,
paper format has become obsolete and
all submissions are to be made
electronically.
b) eCTD format: Format in accordance with
ICH guideline M4Q: Quality and EDQM
guidelines for electronic submissions.
c) NeeS
d) PDF: Module 1 to Module 3 each single
PDF files bookmarked according to
relevant subsections in each.
ASMF: In eCTD
ASMF is to be submitted in separate two parts
viz. Applicant’s part (AP) and Restricted part(RP)

3. COMPARITIVE STUDY OF US DMF V/S EDMFs
Content  Module 1  Module 1 of CEP
 Module 1 of ASMF(Both AP and RP)
 Module 2:
 QOS
 Module 2 of CEP
 QOS
 Experts’ report
 Module 2 of ASMF
 QOS( Separate copies for AP and
RP)
1.2
•Cover letter
•GDUFA fee cover sheet
•Statement of commitment
1.3:
Administrative
information
•1.3.1.1: Change of address or corporate
name
•1.3.1.2: Change of contact of US agent
•1.3.3: Debarment certificate
1.4:
References
•1.4.1:LOA
•1.4.2:Statement of right of reference
•1.4.3:List of authorised persons to
incorporate by reference
1.5:Applicati
on status
•1.5.3:Reactivation request
•1.5.5:Withdrawal of unapproved
NDA/BLA/ ANDA
1.6:
Meetings
•1.6.1: Meetings request
•1.6.2:Meetings background material
•1.6.3:Communication regarding meetings
1.11:Informati
on
amendment
•1.11.1:Quality
•1.11.2:Non clinical
•1.11.3: Clinical
•1.11.4:Multiple module
1.12:Other
communication
•1.12.4:Request for comments or
advice
•1.12.14:Environmental assessment
1.13: Annual
Report
•1.13.5:Summary of Manufacturing
changes
1.14:
Labeling
•1.14.1.1: Draft labeling for container.
1
•Cover Letter
2
•EDQM Application form including signed
declarations as relevant
3
•Information about experts, CV as relevant
4
•Responses
5
•Additional data and revisions
1.0
•LOA
1.1
•Contents
1.2
•Application for ASMF
1.3
•Labelling and packaging
1.4
•Experts' infortmation
1.5
•Specific requirements for different types of applications
1.6
•Environmental assessment
1.7
•cGMP certificates
1.8
•Details of compliance with screening outcomes
1.9
•Individual patient data
1.10
•Foreign regulatory status
1.11
•Bioequivalence trial information
1.12
•Paediatric development report
1.13
•Risk management plan

4. COMPARITIVE STUDY OF US DMF V/S EDMFs
 Module 3: Format is common and in accordance with ICH M4Q guidelines.
 For ASMF:
1. AP includes 3.1, 3.2 S.2.1, 3.2 S.2.2. 3.2 S.3, 3.2 S.4, 3.2 S.5 , 3.2 S.6, 3.2 S.7
2. RP includes 3.1, 3.2 S.2.3, 3.2 S.2.4, 3.2 S.2.5, 3.2 S.3, 3.2 S.4, 3.2 S.5 , 3.2 S.6,
3.2 S.7
3.1:Tableof
contents
3.2S:Bodyofdata
(drugsubstance
3.2 S.1: General information
3.2 S.1.1: Nomenclature
3.2 S.1.2: Structure
3.2 S1.1.3: General properties
3.2 S.2: Manufacture
3.2 S.2.1:Name, address and other
information about manufacturer
3.2 S.2.2: Description of manufacturing
process, identification of critical steps
3.2 S.2.3:Control of materials
3.2 S.2.4: Control of critical steps and
intermediates
3.2 S.2.5: Process validation
3.2 S.2.6: Manufacturing process
development
3.2 S.3: Characterisation
3.2 S.3.1: Elucidation of structure
3.2 S.3.2: Impurities
3.2 S.4: Control of drug
substance
3.2 S.4.1:Specifications
3.2 S.4.2: Analytical procedures
3.2 S.4.3: Validation of analytical
procedures
3.2 S.4.4: Batch analyses
3.2 S.4.5: Justification
3.2 S.5: Reference
standards
3.2 S.6: Container
closure system
3.2 S.7: Stability data
3.2 S.7.1: Stability summary
3.2 S.7.2: Post approval stability
commitment
3.2 S.7.3: Stability data
3.2R:Regional
information
3.2A:Appendices

5. COMPARITIVE STUDY OF US DMF V/S EDMFs
Submission
and review
process
 A US DMF is neither reviewed nor
approved by the FDA.
 Review process is initiated only when
an application (NDA/ANDA/BLA)
references the given DMF.
 The DMF review takes place in 2
stages viz.
a) Administrative review(2-3
weeks)
 CEP:
DMF holder
requests pre
assigned DMF
number from FDA
DMF entered into
DARRTS, assigned a
number,
communicated to
holder
Status =
PENDING(Not
available for
review)
DMF holder logs on
to OFM user fee
system, generates
cover sheet, pays
fees
Holder submits
DMF document
along with LOA
Administrative
Review
If incomplete, FDA
sends appropriate
request (IR/CR)
If complete: FDA
sends
Acknowledgement
letter
Status= ACTIVE(
Available for
review)
CDER confirms fee
payment status
If fee paid: Status=
MET
Proceed to
Complete
assessement/
Technical Review
SUBMIT
APPLICATION
FORM
EDQM ISSUES
RECEIPT
INVOICE
PAY
APPLICATION
FEES
FEE
RECEIVED
RECEIPT VALIDATION
(ADMINISTRATIVE
AND TECHNICAL
IS CEP
DEFICIENT?
CEP
BLOCKED
EVALUATION
1
IS CEP COMPLETE?
CEP
GRANTED
REQUEST
ADDITIONAL
INFORMATION
APPLICANT
RESPONDS
EVALUATION
2
IS CEP
SATISFACTORY?
CEP
BLOCKED
CEP
GRANTED
NO
NO
YES
YES
NO
YES

6. COMPARITIVE STUDY OF US DMF V/S EDMFs
b) Technical review/ Complete
assessment review(For Type II
DMF only)
 Once the administrative review of the
DMF is complete, further review is
conducted.
 Basis for CA:
1. GDUFA fee payment
2. DMF status(Active or no)
3. Review occurring after November 30,
2007.
4. Complete technical data required for
review.
 Process:
GENERATE CA
WORK QUEUE
INITIATE CA
FORM
HAS DMF BEEN
REVIEWED?
DMF IS
COMPLETE AS
PER POLICY;
COMPLETE
REVIEW ON
DARRTS
GENERATE
DARRTS
REVIEW FOR
FEE PAID AND
COMPLETE
DMF
FORM ASSIGNED TO
REVIEWER FOR FULL
CA
REVIEWER
COMPLETES
CA FORM
IS DMF
COMPLETE?
FILE CA IN
DARRTS AS
INCOMPLETE,
SEND
INCOMPLETE
LETTER TO
HOLDER
DMF
HOLDER’S
RESPONSE
FILE CA
REVIEW IN
DARRTS AS
COMPLETE
DMF AVAILABLE FOR
REFERENCE
GDUFA FEE
PAID
DMF PM TASK
DMF REVIEWER TASK
DMF HOLDER TASK
CDER TASK
YES
YES NO
NO
 The EDQM Certification Division is
responsible for the organization of the
inspections and their follow-up,
including the implementation of any
subsequent action regarding the
related CEPs and communication with
the concerned authorities.
Every year, a programme of
inspections is elaborated based on
prioritization, in accordance with the
EU recommendations. This programme
is adopted by the Steering Committee
for the Procedure for ‘Certification of
Suitability to the Monographs of the
European Pharmacopoeia'
 Only 3% of CEPs are granted after the
first round of evaluation
 ASMF:
 A multitude of review procedures is
applicable to ASMF which includes:
1. Centralised Procedure:
Acceptance in all 27 EU
member nations
2. Decentralized : For drugs
that have not received
authorization in an EU nation
3. Mutual recognition: For
drugs that have
authorization in at least one
EU nation.
 Identical ASMFs are often submitted as
part of new marketing authorization or
variation applications through any of
the authorization routes in Europe.
This may result in the same ASMF
being authorized by different
competent authorities
 To avoid this, a Working Group on
ASMF has been established under
HMA.

7. COMPARITIVE STUDY OF US DMF V/S EDMFs
 FDA correspondence letters for DMF:
1. Complete Response (CR): Details
all identified Chemical,
Microbiological, and Facility
deficiencies.
2. Incomplete letter: Deficiencies
observed during CA.
3. No further comments: Issued at
approval of the ANDA, not when
the DMF is first deemed
adequate.
4. GDUFA incomplete comments:
Detail description of all the
reasons why DMF failed CA.
5. Deficiency letter: If the
information in the DMF cannot
support approval of the
application that references it FDA
sends a Deficiency Letter (DEF).
PROCESS:
TIMELINES FOR APPROVAL:
REQUEST FOR
CAP/DCP NUMBER
REQUEST FOR
ASMF REF
NUMBER
SUBMIT NO MORE
THAN 2 WEEKS
BEFORE INTENDED
ASMF SUBMISSION
WITHIN 10 DAYS REF
NUMBER ISSUED
SUBMIT ASMF FORM,
LOA AND COMPLETE
ASMF TO ALL
COMPETENT
AUTHORITIES
MRP
VALIDATION-
14 DAYS
DAY 0: START
PROCEDURE
DAY 50: CMS
COMMENTS
DAY 60 :
APPLICANT'S
RESPONSE
DAY 75: CMS
COMMENTS
DAY 85:
FINAL CMS
POSITION
DAY 90:
PREPARATION
OF AR,
CLOSURE OF
PROCEDURE
DAY 210:
NATIONAL
REGISTRATION
DCP
VALIDATION
: 14 DAYS
ASSESSMENT
1
DAY 0: START
PROCEDURE
DAY 70:
PRELIMNARY
AR
DAY 100: CMS
COMMENTS
DAY 106:
APPLICANTS
RESPONSE
DAY 120:
CONSENSUS/CLOSUR
E
ASSESSMENT 2
DAY 150:
RMS+CMS
COMMENTS
DAY 160:
APPLICANTS
RESPONSE
DAY 180:
CONSENSUS/
CLOSURE
DAY 210:
REGISTRATION
CAP
DAY 1: START
PROCEDURE
DAY 80:
PRELIMNARY
AR
DAY 121:
SUBMISSION
RESPONSES
DAY 157:
JOINT AR
DAY 180:
CHMP
DISCUSSION
DAY 181-210:
PREPARATION
OF FINAL
PRODUCT
INFORMATION
DAY 210:
CHMP
OPINION

8. COMPARITIVE STUDY OF US DMF V/S EDMFs
Amendments
and post
approval
submission
 The DMF holder can submit the
following amendments:
1. Annual reports: Contains
administrative changes such as:
a) List of authorized parties
b) List of all changes reported since
last AR
c) If no changes, a statement to that
effect.
2. Original submissions: Changes in
technical information
3. Letter of Authorizations:
a) New LOA submitted when either
AP or DMF holder undergo a
name change
b) It is not necessary to reissue LOAs
if there have been no changes in
the holder, authorized party,
subject of the DMF or item
referenced.
c) If there has been a name change,
it is not necessary to submit a
Withdrawal of Authorization
Letter for the holder or
authorized party’s previous name.
 Any addition, change, or deletion of
information in a DMF is required to be
submitted to the DMF. In addition
the DMF holder must notify each
person authorized to reference the
DMF (authorized party) (21 CFR
314.420(c)) There are no reporting
categories for DMFs. All changes
must be reported as amendments.
The DMF holder should notify each
authorized party of the nature of the
changes, providing as much detail as
is consistent with the confidentiality
agreement between the DMF holder
and the authorized party, so that the
authorized party can determine how
to report the changes in their
approved NDA or ANDA.
 CEP:
o Amendments are of two types:
Revisions and Renewal.
o Types of changes classified as
Revision:
1) Annual notification
2) Immediate notification
3) Major notification
4) Minor notification
o Documentation to be submitted
for revisions:
1) For module 1, the following
information is required:
 A cover letter.
 A completed application form (specific for
revisions) describing the kind of revision and
listing all the changes applied for.
 A description of each change, together with
a justification and supporting information as
necessary.
 The differences between the approved and
proposed text of module 3 must be presented
as a comparative table.
2) For module 3, the following
information is required:
 Each complete updated section which is
affected by the change(s) being made.
 Any changes to the text should be
highlighted.
o The Certificate of suitability is
valid for five years from the date
when the original certificate was
granted. Regardless of any
revisions treated in the
meantime, the holder of a
Certificate of suitability shall ask
for its renewal six months prior
to expiry date by providing an
update of the Certification
dossier.
 ASMF:
o ASMF holders shall not modify
the contents of their ASMF (e.g.
manufacturing process or
specifications) without informing
each Applicant/MA holder and
each National Competent

9. COMPARITIVE STUDY OF US DMF V/S EDMFs
 Amendments differ from supplements
in the way that supplements are
required to be submitted for
approved applications only.
 Types of supplements include:
1. Prior approval supplement
2. Changes being affected in 30 days
3. Changes being affected
Authority/EMA. This obligation
remains valid until the Letter of
Access has been withdrawn by
the ASMF holder.
o Any change to the ASMF should
be reported by every MA holder
to the relevant National
Competent Authority/EMA by
means of an appropriate variation
procedure (Type IA, IB, and II). A
Submission Letter should be
provided.
o In cases where the contents of
the ASMF cannot be changed for
a certain period of time because
of other procedural provisions
(i.e. mainly because of on-going
MRP procedures), the ASMF
holder should still provide the
aforementioned data to the MA
holder and National Competent
Authorities/EMA making
reference to this reason and
requesting a later date of
implementation.
o At the occasion of the 5-year
renewal of a medicinal product,
MA holders are required to
declare that the quality of the
product, in respect of the
methods of preparation and
control, has been regularly
updated by variation procedure
to take account of technical and
scientific progress, and that the
product conforms with current
CHMP/CVMP quality guidelines.
They will also declare that no
changes have been made to the
product particulars other than
those approved by the
Competent Authority/EMA.

10. COMPARITIVE STUDY OF US DMF V/S EDMFs
Withdrawal
procedures or
inactivation
1) Inactivation of DMF:
 If a DMF has had no activity
(amendment or annual report) in
three years FDA will initiate
retirement procedure
 FDA sends overdue notice to holder
and/or agent using most recent
address. Highlights the importance of
keeping holder/agent name and
address up-to-date.
 If no response in 90 days, one copy of
DMF is sent to Federal Records Center
(FRC) and the other is destroyed.
2) Reactivation of Inactive DMF:
 An Inactive DMF can be returned to
ACTIVE status only by submission of a
REACTIVATION, which should contain
a complete resubmission of the DMF,
updated to meet current
Guidances. The cover letter must
specify that the submission is a
"REACTIVATION." Alternatively the
DMF holder can submit a new DMF.
3) Closure of DMF:
 A holder who wishes to close a DMF
should submit a request to the Drug
Master File Staff stating the reason
for the closure
 The request should include a
statement that the holder's
obligations have been fulfilled.
 CEP:
 Following actions may be taken on CEP by
EDQM:
a) Suspension: Temporary withdrawal
of granted CEP which may occur due
to the following reasons:
1) GMP noncompliance on
inspection
2) Request by holder.
A suspension is limited to a period of
2 years. Failure to meet the
conditions to lift a suspension leads
to the withdrawal of the CEP if no
justified extension to the suspension
has been requested by the CEP
holder and accepted by the EDQM.
b) Withdrawal: Definitive cancellation
CEP which may occur due to the
following reasons:
1) GMP noncompliance on
inspection.
2) After a CEP suspension, when
the company is not able to fulfil
the requirements of the
Certification procedure with
regards to the updating of the
CEP dossier and compliance with
GMP (e.g. repeated GMP non-
compliance even if the
inspections are not consecutive).
3) CEP ceases to exist
4) Refusal of company to be
inspected
5) Withdrawal by holder.
c) Closure: Cancellation of an ongoing
CEP application which can occur due
to:
1) GMP noncompliance
2) Refusal of a company for
inspection
 ASMF:
o Where the active substance is no
longer supplied to the MA holder
or the corresponding ASMF is
replaced by a Ph. Eur. Certificate
of Suitability (CEP), the ASMF
holder should provide a
Withdrawal of Access Letter to
the NCA/EMA.

11. COMPARITIVE STUDY OF US DMF V/S EDMFs
Confidentiality • Confidentiality of info in DMF is covered
by 21 CFR 314.430(g) and is the same as other
type of submissions
• DMF holder and their customers can
reach their own agreements about
information sharing
• There are no “Open” and “Closed” part of
a DMF in the US, as there are in Europe. All
parts are considered “closed.”
 CEP:
• There are no “Open” and “Closed”
part of a CEP. All parts are considered
“closed.”
 ASMF:
o There are separate open and
closed parts (AP AND RP).
Acceptability
in nations:
 FDA is restricted to the USA only.
 However, seeking FDA approval first gives
drug companies with significant financial
resources the advantage of being able to
launch and market their products to the
largest drug consumer in the world, with
about 50 percent of the worldwide
market share, sooner versus later.
Additionally, drug companies can expect
more consistent reimbursement, better
intellectual property protection, and less
foreign competition with this approach.
 CEP:
o CEPs are recognized by the
signatory parties of the
Convention on the Elaboration of
a European Pharmacopoeia, i.e.
all member states and the
European Union. They are also
recognized by other countries,
e.g. Canada, Australia, New
Zealand, Tunisia and Morocco.
 ASMF:
o Accepted across all EU members
depending on the route of
application.
Fees :  The DMF fee under GDUFA is due for Type
II DMFs for the API referenced by an initial
letter of authorization by an ANDA
submission on or after October 1, 2012
 Required upon the first reference on or
after October 1, 2012
 Paid only once during the DMF lifecycle
 Is triggered when the DMF reference is
included in the following ANDA
submissions:
1) Original ANDA
2) An amendment to an ANDA
3) A Prior Approval Supplement (PAS)
4) An amendment to a PAS
 If after 20 days of receiving Fee status by
OM, the DMF fee is still NOT paid, the
ANDA submission will be Refuse to
Receive due to User Fee obligation not
satisfied. The ANDA will not be processed
further (i.e. sent to OGD for filing review)
until the DMF payment is received. This
will delay both the filing of the ANDA and
the processing of the DMF for
Completeness Assessment.
 CEP:
o Simple chemical certificate:
5000 €
o Certificate for chemical purity
and sterility + TSE: 9000 €
o Renewal 1500 €
 ASMF:
o Depends on route of application.

12. COMPARITIVE STUDY OF US DMF V/S EDMFs
 DMF fee is not required for :
1) For ANDAs that are part of the
backlog
2) For submissions not part of GDUFA
(INDs, NDAs, Changes Being Effected
(CBE) 0 or 30 supplements)
3) For any non-Type II DMF (Type IV
DMF for an excipient)
4) For any Type II DMF that is not
referenced as the API
a) DMFs for API intermediates
b) DMFs for drug product manufacturing
intermediates
c) DMFs for Drug Products
5) For submissions reporting a change to
the DMF that had established a
relationship to the ANDA before
GDUFA
6) Issuing an updated Letter of
Authorization that does not establish
a new relationship to the ANDA
submission
 The GDUFA fee for FY 2017 is $ 51,140.
Validity : Valid unless inactivated or withdrawn. Both CEP and ASMF are valid for 5 years
initially and require renewals periodically.