US DMF Preparation and submission

DEFINITION

A drug master file (DMF) is a confidential

detailed document contains the

chemistry, manufacturing and controls of

a Active Pharmaceutical Ingredient (API).

REGULATORY REQUIREMENT

• The submission of a DMF is not required by law or FDA regulation.

21 CFR

314.420 (a)

• DMF is a submission of information to the FDA by holder to support an

Investigational New Drug Application (IND) or an New Drug Application

(NDA) or an Abbreviated New Drug Application (ANDA).

• A Drug Master File (DMF) is a submission to the U.S. 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 human drugs.

TYPES OF DMFS

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 III•Packaging Material

TYPE IV•Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation

TYPE V•FDA Accepted Reference Information

Type I DMF

No longer accepted per a Final Rule published January 12, 2000.

Type I Manufacturing Site, Facilities, Operating Procedures, and Personnel (no longer applicable)

A Type I DMF is recommended for 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.

TYPE II DMF

Type II Drug Substance, Drug Substance (DS) Intermediate, and Material Used in Their Preparation, or Drug Product (DP)

DS : Summarize all significant steps in the manufacturing and

controls of the drug intermediate or substance.

DP : Manufacturing procedures and controls for finished

dosage forms should ordinarily be submitted in an IND, NDA,

ANDA, or Export Application. If this information cannot be

submitted in an IND, NDA, ANDA, or Export Application, it

should be submitted in a DMF.

TYPE III DMFS

Type III Packaging Material

Each packaging material should be identified by the intended

use, components, composition, and controls for its release.

Toxicological data on these materials would be included under

this type of DMF, if not otherwise available by cross reference

to another document.

TYPE IV DMFS

Type IV Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation

Each additive should be identified and characterized by its

method of manufacture, release specifications, and testing

methods.

Toxicological data on these materials would be included under

this type of DMF.

Usually, the official compendia and FDA regulations (21 CFR)

may be used as sources for release tests, specifications, and

safety.

TYPE V DMFS

Type V FDA Accepted Reference Information

If any holder wishes to submit information and supporting data

in a DMF that is not covered by Types I through IV.

As specified in 21CFR 314.420(a)(5), DMF holders wishing to

submit a Type V DMF must obtain clearance from the FDA.

FDA discourages the use of Type V DMF's for miscellaneous

information, duplicate information, or information that should

be included in one of the other types of DMF's.

DRUG MASTER FILE (TYPE II) SPECIFICATIONS

For drug substances (API) and intermediates DMF will falls

under Type II DMF submission.

DMFs for drug substances shall be submitted in the format

"Guidance for Industry M4Q: The CTD - Quality".

U.S. standard paper size (Letter : 8½" × 11") is preferred.

The left margin should be at least 0.75" (~2 cm)

The right margin should be at least 0.5" (~1.25cm)

All submissions should be paginated within the submission.

All submissions should be made in English only.

21 CFR.1(a)(1) states:“If any part of the application is in a foreign language, an accurate and complete English translation shall be appended to such part.”

CONTENT OF DMF

The CTD is organized into five modules, those are:

Module 1 : References regional information such as forms, cover

letter, labeling, and investigational brochures

(region specific)

Module 2 : Quality Overall Summary

Module 3 : Quality

Module 4 : Non-clinical information

Module 5 : Clinical information

common for all regions

CONTENT OF DMF

ICH-CTD TRIANGLEModule 1, 2 & 3 are applicable for Drug

substances (APIs) and Intermediates.

MODULE-1 CONTENTS

Module 1 Administrative & Prescribed Information

Contain the following information:

Cover Letter

Administrative Information

• Addresses of DMF holder and manufacturing and testing

facilities

• Responsible & Contact persons

Statement of Commitment

US Agent appointment letter

Declaration on Debarment [Section 306(k)(1)]

Environmental certification

Specimen product label

MODULE-2 CONTENTS

Module 2 Quality Overall Summary (QOS)

The Quality Overall Summary (QOS) is a summary that follows

the scope and the outline of the Body of Data in Module 3.

The QOS should include sufficient information from each

section to provide the Quality reviewer with an overview of

Module 3.

This QOS normally should not exceed 40 pages of text,

excluding tables and figures.

US DMF QOS should be submit in Question Based Review (QbR)

format.

MODULE-2 CONTENTS

About Question Based Review (QbR)

The Office of Generic Drugs (OGD) is developing a question-based review (QbR) for its Chemistry, Manufacturing, andControls (CMC) evaluation that is focused on critical qualityattributes.

QbR-QOS is designed with the expectation that the drugsubstance application (DMF, NDA, ANDA) is organized in theCTD format.

The QbR, a general framework for the CMC assessment ofANDAs, incorporates the most important scientific andregulatory review questions that focus on critical attributesessential for ensuring generic drug product quality.

MODULE-2 CONTENTS

Benefits of QbR

Improve submission quality of Drug Master Files.

Decrease number of review cycles

Encourage process understanding and control strategies and proposed API specifications.

Shift from data/regulation driven to knowledge driven review

MODULE-2 CONTENTS

QbR - Questions

MODULE-2 CONTENTS

QbR - Questions

MODULE-2 CONTENTS

QbR - Questions

MODULE-2 CONTENTS

Response to QbR Questions:

Information provided in response to the

QbR-QOS should be consistent with the

information provided in Module 3.

If a question is not relevant, the

question can be answered “Not

applicable”, followed by a brief

justification.

MODULE-3 CONTENTS

MODULE 3 : QUALITY

3.1. TABLE OF CONTENTS OF MODULE 3

3.2. BODY OF DATA

3.2.S DRUG SUBSTANCE (NAME, MANUFACTURER)

3.2.S.1 General Information

3.2.S.1.1 Nomenclature

3.2.S.1.2 Structure

3.2.S.1.3 General Properties

3.2.S.2 Manufacture

3.2.S.2.1 Manufacturer(s)

3.2.S.2.2 Description of Manufacturing Process and Process Controls

3.2.S.2.3 Control of Materials

3.2.S.2.4 Controls of Critical Steps and Intermediates

3.2.S.2.5 Process Validation and/or Evaluation

3.2.S.2.6 Manufacturing Process Development

3.2.S.3 Characterisation

3.2.S.3.1 Elucidation of Structure and other Characteristics

3.2.S.3.2 Impurities

MODULE-3 CONTENTS

3.2.S.4 Control of Drug Substance

3.2.S.4.1 Specification

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 of Specification

3.2.S.5 Reference Standards or Materials

3.2.S.6 Container Closure System

3.2.S.7 Stability

3.2.S.7.1 Stability Summary and Conclusions

3.2.S.7.2 Post-approval Stability Protocol and Stability Commitment

3.2.S.7.3 Stability Data

Relevant information shall be presented in relevant sections as prescribed in ICH M4QCTD guideline and should comply with GDUFA (Generic Drug User Fee Amendment)initial complete assessment checklist.

http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/CTD/M4_R1_Quality/M4Q__R1_.pdf

SUBMISSION(S)

Drug Master File Submissions:

Original Submissions

Initial/first time submission is known as Original submission.

Amendments

Change in the content of original submission i.e. specifications, validations, etc.

For each submission covering letter should be prepared tofacilitate processing of documents, list the Submission type inbold type in the header on the cover letter.

SUBMISSION(S)

All submissions should be done through electronic submissions gateway in

e-CTD format.

The DMF should be compiled in E-CTD format as per the US FDA guidance.

The documents scanned/converted should be legible and searchable.

E-CTD Guidance:

http://www.fda.gov/drugs/developmentapprovalprocess/formssubmissionreq

uirements/electronicsubmissions/ucm153574.htm

SUBMISSION(S)

The electronic-Common Technical Document submission is composed of

the following:

Directory structure

The directory structure (module titles) is a structure of directories and files.

XML eCTD instance

The instance is in the submission sequence number directory. The

intention is to have links from the leaf elements of the instance to the files

in the eCTD submission as opposed to creating a single XML document that

contains the entire eCTD submission.

Content files

CTD Module data files i.e. DMF section files.

SUBMISSION(S)

Content file hierarchy is as follows:

SUBMISSION(S)

SUBMISSION(S)

The completed /complied e-CTD xml is as follows:Directory structure

Content files

SUBMISSION(S)

SUBMISSION(S)

AMENDMENT:

When a change is made to one part of a DMF the entire DMF does not

need to be resubmitted.

For DMFs in CTD format, the entire changed “Document” (Section)

should be submitted e.g. a change in the material used in the

synthesis should be included in a resubmission of Section S.2.3.

No pages are ever physically replaced in a DMF.

The DMF holder should notify customers of the nature of the changes,

providing as much detail as is consistent (21 CFR 314.420 ).

UPDATES TO DMF

DMF are to update by annually, the

updates shall be reported as

“Annual Report”, and the annual

report date will be from on the

anniversary date of the original

submission.

UPDATES TO DMF

Annual report should contain:

Administrative Information as presented in DMF

List of amendments with Date(s) reporting changes since the

last Annual Report or the original DMF filing date

A list of Letter of Authorizations issued.

List of all parties whose authorization has been withdrawn

Other information i.e. the changes reportable through annual

report like stability data, current specifications etc.

If the DMF is unchanged, a statement is also acceptable that the

DMF is current.

UPDATES TO DMF

Failure to submit an Annual report to

the DMF in past three years, FDA will

send “Overdue Notification Letters”

(ONLs) to DMF holder.

If a DMF holder does not respond to

this letter within 90 days with the

submission of an Annual Report, the

DMF may be closed by the FDA.

DMF REVIEW AT FDA

A DMF is reviewed to determine whether it

is adequate to support the particular

NDA/ANDA Application that references.

DMF review will be in two stages,

1. Initial Completeness Assessment (CA)

CA shall be carried out against a comprehensive check list

of DMF. This list contains necessary information required for

a complete DMF.

2. Scientific Assessment (SA)

“Complete” DMF contains all of the necessary information

for a full scientific review. SA shall be carried out in

conjunction with referenced application of NDA/ANDA.

DMF REVIEW AT FDA - CA

Initially the DMF will undergone for initial complete

assessment (CA).

If the DMF is incomplete as per the DMF check list, the initial

CA findings and comments will be compiled in an Incomplete

Letter and sent to DMF holder.

If the DMF is found complete, FDA will post the DMF number

on a publicly available list on FDA’s Web site.

Two things must happen for the DMF to be considered

“available for reference”

1. DMF Fee must be paid (fee will be change by year)

2. DMF must pass a “completeness assessment”

DMF REVIEW AT FDA - CA

DAARTS:

Document Archiving, Reporting, and Regulatory Tracking System

DLPS:

Division of Labeling and Program Support

CDER:

Center for Drug evaluation and research

OCOMM:

Office Of Communications

DMF REVIEW AT FDA - CA

DAARTS:Document Archiving, Reporting, and Regulatory Tracking SystemDLPS:Division of Labeling and Program SupportCDER:Center for Drug evaluation and researchOCOMM:Office Of Communications

DMF REVIEW AT FDA - SA

The complete DMF will be reviewed ONLY when it is referenced

in an Application or another DMF.

The DMF is reviewed using same regulatory and scientific

criteria as review of application.

Reference must be accompanied by a copy of the DMF holder's

letter of authorization (LOA).

LOAs should specify the name of the specific item being

referenced and the date of the submission.

DMF REVIEW AT FDA - SA

The DMF holder submits a Letter of Authorization (LOA) to the

agency and one copy to the authorized customer.

The customer submits an application to the FDA that contains

a copy of the LOA.

Failure to submit the LOA to the DMF may result in a delay in

review of the DMF/Application of drug product.

During review, If more information is needed to complete the

review communicated to the holder as Information Request (IR)

or a Complete Response (CR) letter.

Holder shall respond to CR, Deficiency or Information request

Letter and submits as Amendment.

DMF REVIEW AT FDA - SA

Holder notifies applicant that the DMF has been amended.

The amendment to the DMF must be a Complete Response to

DMF letter from FDA. Cannot be a notification that the DMF or

sections thereof WILL be amended.

If the information in the DMF cannot support approval of the

application that references it FDA sends a Deficiency Letter

(DEF) or Complete Response (CR) Letter.

If no information needed for DMF, No letter to DMF holder

except for “No Further Comments” letter specific for Type II

DMFs under GDUFA.

DMFs ARE NEITHER APPROVEDNOR DISAPPROVED

NO CONFUSION as stated 21 CFR 314.420 (a) Adrug master file is a submission of information tothe FDA to support an IND/NDA/ANDAApplication only.

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