Drug Master FilesGlobal Perspectives

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Drug Submissions: US, Canada, EUTYPES OF DRUG SUBMISSIONS: US, Canada, EU

USA New Drug Application (NDA), for new drugsAccelerated New Drug Application (ANDA)-for genericsBiologic License Application (BLA), for biologic

Canada New Drug Submission (NDS)―for both drugs and biologic products

EU Marketing Authorization Application (MAA)―via the Centralized Procedure for eligible products. For other products, via the decentralized, mutual recognition or national authorization are applicable.

Role of DMFs

Supporting documents for the registration / approval of drug products

In the Chemistry, Manufacturing and Controls (CMC) sections of the drug submission, the DMF documents the drugs identity, purity, strength and quality.

Protect Proprietary and Confidential Information

DMFs Globally

Highly Regulated Markets (Drug Master Files used to support approval process)United States:

Canada: Australia

JapanEurope: China is developing its own DMF system

Nearly Regulated Markets (Technical Package / Registration Dossier)Brazil

Russia South Africa

Less Regulated Markets (No Drug Master Files used in registration process)India and many others

Drug Master Files: USA

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.There is no legal or regulatory requirement to file a DMF.

A DMF may be filed to provide CMC information that the FDA reviews instead of including this information in the Application (IND, NDA, ANDA).

A DMF is neither approved nor disapproved by the FDA. It is provided for in 21 CFR 314.420 (Code of Federal Regulations)

The US DMF System“Closed”

DMF – US: Important Facts

DMFs are Confidential (Closed)DMF Stakeholders

DMF Holder: Company or Person who submits the DMFApplicant: Company or person who references the DMF in an application or another DMF

Information contained in a DMF may be used to :Support an Investigational New Drug Application (IND))

Support a New Drug Application(NDA)Support an Abbreviated New Drug Application (ANDA)

Support another DMF Support an Export Application

Support amendments and supplements to any of these.

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How the US DMF System Works

Filing the DMFHolder sends two copies of the DMF to FDA

DMF is reviewed for administrative purposes only by Central Document Room staffDMF entered into database, assigned a number and acknowledgment letter sent to holder

A DMF is neither approved or disapprovedAccessing the DMF: Letter of Authorization (LOA)

The DMF will be reviewed only when it is referenced in an Application or another DMFThe Holder must submit a two copies of the LOA to the DMF, plus a copy to the Applicant

The Applicant submits a copy of the LOA in their ApplicationThe LOA is the only mechanism to trigger a review of the DMF by the FDA

DMF Review ProcedureThe DMF is reviewed only if referenced by an Applicant or another DMF

If the reviewer finds deficiencies in the DMF, the deficiencies are detailed in a letter to the HolderThe Applicant will be notified that deficiencies exist, but the nature of the deficiencies are not communicated to the

Applicant

US DMFs - Types

Type I: Manufacturing Site, Facilities, Operating Procedures, and PersonnelNo longer accepted by the FDA (as of January 2000)

Type II – Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product

Type III – PackagingType IV – Excipients, Colorant, Flavor, Essence, or Material Used in Their Preparation

Type V – FDA Accepted Reference InformationUsed for sterile manufacturing plants and contract facilities for biotech products

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US DMF’s – Statistics

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Considerado o status de Inativo para os DMFs sem atividade pelos últimos 3 anos, ou sob exigência do detentor do DMF. Todos os dados são para 4T 2011

Description DMF Type No of DMFsManufacturing site, facilities, operating procedures, and personnel I 1,826

Drug substance, drug substance intermediate, and materials used in the preparation, or Drug Product II 15,230

Packaging Material III 4,511

Excipient, Color, Flavor, Essence or material used in their preparation IV 1,749

FDA Accepted reference information V 355

Blanks Blanks 1,969

GRAND TOTAL 25,640

US DMFs – Type II

Active / Inactive US Type II DMFs -- 2011Active US Type II DMFs -- 2011

Global DMF Trends

Not Yet Harmonized: US FDA: 2 copies of each Type II DMF u sing CTD format, but not in CTD module form. FDA format combines Modules 2 & 3 as there is no Applicant vs Restricted

part. FDA moving towards eCTD applications

EU: has separate portions for Modules 2 & 3 (Applicant / Restricted), but some countries in EU have different requirementsEU wants electronic format but there are several formats; some countries still require paper

Overhead: DMFs often run in excess of 1,000 pages. Storage and care of them can be a major burden.

Who Must File a DMF?NOBODY

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There is no legal or regulatory requirement to file a DMF. A DMF may be filed to provide CMC information that the FDA reviews.

The information contained in DMF may be used to support an IND / NDA /ANDA ,another DMF,an export application or amendments and supplements of any of these.

Remember that,DMF is NOT a substitute for IND / NDA / ANDA or export application.Technical contents of a DMF are reviewed only in connection with the review of IND /NDA /ANDA or an export application.

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II. Some basic terminologies HOLDER: The person /company who submits DMF.

AGENT : The person / company who represents a DMF HOLDER. (Also called Representative.)

APPLICANT / CUSTOMER / AUTHORISED PARTY (AP ) :The person / company who references the DMF.

APPLICATION:Investigational New Drug Application (IND), New Drug Application (NDA), Abbreviated New Drug Application (ANDA)

SUPPLEMENT TO AN ANDA / NDA: A report of change in an approved ANDA / NDA.

AMENDMENT TO AN APPLICATION: Additional information to… an existing IND, a pending ANDA / NDA a pending ANDA / NDA supplement.

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III. Types of DMFS with their contents

Type I : plant information

Points included:

Manufacturing site Equipment capabilities Operational layout Actual site address A map showing its location with respect to the nearest city Corporate headquarters

As per Jan. 12, 2000 FR notice : Elimination of Type I DMFs done by July 10, 2000.

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TYPE II DMF

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CONTENTS:(1)Drug Substance Intermediates, Drug Substances, and Material Used in Their Preparation.

It Summarizes all significant steps in the manufacturing and controls of the drug intermediate or substance.

Detailed guidance on what should be included in a Type II DMF for drug substances and intermediates may be found in the following guidelines:

1.Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances.

2.Guideline for the Format and Content of the Chemistry, Manufacturing, and Controls Section of an Application.

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(2) Drug Product (finished dosage forms)

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Manufacturing procedures and controls for finished dosage forms

shouldordinarily be

submitted in an IND, NDA, ANDA, or

Export Application.

If can not be submitted to above

documents

It should be submitted in a DMF/ 45

For a drug product, the applicant/sponsor should follow the guidance provided in the following guidelines:

1.Guideline for the Format and Content of the Chemistry, Manufacturing, and Controls Section of an Application.

2.Guideline for Submitting Documentation for the Manufacture of and Controls for Drug Products.

3.Guideline for Submitting Samples and Analytical Data for Methods Validation.

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GENERAL POINTS INCLUDED IN TYPE II DMF

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Manufacturing Section

Quality Controls

Validations Stability data

Impurities Packaging & Labeling

Inputs Intermediates & In-process

Finished Drug Substance

Raw materials

Packaging materials

(1) (2) (3) (4) (5) (6)

a. b. c.

a.1 a.2

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Type III: Packaging Material Contents:-Packaging material intended for which use. Its components and composition.Names of the suppliers or fabricators of the components used in

preparing the packaging material.Acceptance specifications.Toxicological data on these materials.

FOLLOW THE GUIDELINE: "Guideline for Submitting Documentation for Packaging for Human Drugs and Biologics."

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BUT REMEMBER THAT, Responsibility for compatibility and safety of

packaging components in finished drug product is the responsibility of the AUTHORISED PARTY(AP).

It is not the responsibility of DMF HOLDER.

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Type IV  Excipients CMC for a compendial excipient is usually not

reviewed and therefore a DMF is not necessary.

Exceptions: New route of administration or total dosing that may affect safety and efficacy. E.G..RESPITOSE, lactose for dry powder inhalation products.

CMC requirements for a novel excipient should be submitted same as type II DMF.

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Type V DMF FDA discourages the use of Type V DMFs for miscellaneous

information, duplicate information, or information that should be included in one of the other types of DMFs.

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TO SUBMIT THE DATA WHICH IS NOT COVERED IN

TYPE I TO IV DMF(CLINICAL / TOXICITY DATA)

A holder

must first submit

a letter of intent

to the drug master file staff

FDA will then contact the holder to discuss the

proposed submission. / 45

IV. SUBMISSIONS OF DRUG MASTER FILES How the System Works ?

Holder sends the DMF (NO FEE two copies) to Central Document Room Center for Drug Evaluation and Research 5901-B Ammendale Road Beltsville, MD 20705-1266

Containing: 1 – Transmittal (cover) letter 2 – Administrative information 3 – Technical information

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Follow the Guideline at www.fda.gov/cder/guidance/dmf.htmBinders recommended http://www.fda.gov/cder/ddms/binders.htm

NEW ADDRESS

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1 – Transmittal (cover) letterOriginal Submissions and Amendments

Identification of submission. (Original /supportive to original DMF / Amendment)

Type of DMF and subject (update, revised formula, or revised process)

The name and address of each sponsor, applicant, or holder, and all relevant document numbers.

Signature of the holder or the authorized representative.

Typewritten name and title of the signer 25 / 45

2 – Administrative information Original Submissions:

a. Names and addresses of the following:(1) DMF holder.(2) Corporate headquarters.(3) Manufacturing/processing facility.(4) Contact for FDA correspondence.(5) Agent(s), if any.

b. The specific responsibilities of each person listed in any of the categories in Section a.

c. Statement of commitment.

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.

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2 – Administrative information

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Amendments a. Name of DMF holder.

b. DMF number.

c. Name and address for correspondence.

d. Affected section and/or page numbers of the DMF.

e. The name and address of each person whose IND, NDA, ANDA, DMF, or Export Application relies on the subject of the amendment for support.

f. The number of each IND, NDA, ANDA, DMF, and Export Application that relies on the subject of the amendment for support, if known.

g. Particular items within the IND, NDA, ANDA, DMF, and Export Application that are affected, if known. / 45

DMF reviewed for administrative purposes ONLY by Central Document Room (CDR) staff.

DMF entered into DMF DATABASE, assigned a number, and a letter sent to the HOLDER.

If no response from FDA side,…DMF HOLDER can put a query on the e-mail: dmfquestion@cder.fda.gov

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Letter sent by FDA to DMF HOLDER consists of …

• Number given to DMF in database and Type.

• Reminder of obligations (responsibilities) of holder :– Submit all changes as amendments.– Notify FDA of change in holder name or address.– Notify FDA of change in agent/representative.– SUBMIT ANNUAL UPDATE (Annual Report).– Submit Letter of Authorization (LOA) for each item

referenced.29 / 45

Letter of Authorization (LOA)The DMF will be reviewed ONLY when it is referenced in an Application or another DMF.

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DMF HOLDERUS FDA Send a letter to remind holder obligations

Send 2 copies of LOA to the FDA

1 copy of LOA to the APPLICANT

The applicant submits THIS copy of LOA in their Application.

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IMPORTANCE OF LOA

Sending LOA is the only mechanism which triggers the review procedure of DMF.

A letter of authorization permits the FDA to reference the DMF.

If the holder cross references its own DMF, the holder should supply following information in a LOA.

-DMF number -Specific product(s) covered by the DMF -Section numbers and/or page numbers to be referenced

In Europe, the permission to reference a DMF is called a Letter of Access.3

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Review of the DMF

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REVIEWER

When reviewer receives an application (IND/NDA/ANDA) that

references a DMF

Requests the DMF fromthe CDR (central document room)

but Delivery of DMF can take a couple of days.

This review procedure of DMF is in Contrast with APPLICATION,

where document is deliveredautomatically to reviewer.

Next slide/ 45

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After getting DMF,the Reviewer starts the review

procedure

If Reviewer found any deficiency in the content

of DMF,

The DETAILED DEFICIENCIESare communicated to the holder.

The APPLICANT is also notified but, the nature of the deficiencies is not communicated to the applicant.

If no deficiencies, no letter, applicant not notified.

HOLDER should submit the REQUESTED INFORMATION to the

DMF in response to the agency's deficiency letter along with transmittal

letter having subject matter.

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Differences between Applicationsand DMFs

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Applications DMFs1. COMES UNDER REGULATORY

STATUS.MUST BE FILED BY APPLICANT.

1.NOT COME UNDER REGULATORY STATUS.IT IS NOT MANDATORY TO FILE A DMF.

2. EACH APPLICATION AND ITS SUPPLEMENT ARE ENTERED INTO A COMMON DATABASE.

2. DMFs ARE ENTERED IN TO DATABASE AS PER THEIR TYPES.

(SEPARATE DATABASE FOR EACH TYPE OF DMF)

3.SUBMITTED TO A PARTICULAR REVIEW DIVISION.

3.SUBMITTED TO CDR.

4. ASSIGNMENT TO A REVIEWER AND EACH SUBMISSION HAS A DUE DATE.

4.NO ASSIGNMENT TO A REVIEWER, NO DUE DATE.

5.REVIEW PROCEDURE QUITE DIFFERENT THAN DMF.

5.DMFs ARE REVIEWED ONLY WHEN REFERENCED BY APPLICATION OR ANOTHER DMF

6.IF THE ANNIVERSARY DATE FOR ANNUAL UPDATE IS MISSED FDA

WILL NOT SEND A REMINDER.

6.IF THE ANNIVERSARY DATE FOR ANNUAL UPDATE IS MISSED FDA

SENDS A REMINDER./ 45

Annual Update of DMFThe holder should provide an annual report on the

anniversary date of the original submission.

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 can cause delays in FDA review of a pending IND, NDA, ANDA or any amendment or supplement to such application; and FDA can initiate procedures for closure of the DMF.

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Retiring DMFsIf a DMF has no activity (amendment orannual report) in three years FDA will initiateretirement procedure.

Note: LOA is not counted for activity.

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DMF Retirement Procedure

FDA sends overdue notice letter (ONL) to holder and/or agent using most recent address.

If no response in 90 days, one copy of DMF is sent to Federal Records Center (FRC) and the other is destroyed.

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Summary The DMF system presents challenges for both the industry and the FDA.

Some of the changes have made the system smoother (hopefully for both industry and FDA).

Problems can be minimized:– With full understanding of their responsibilities andadherence to Guidances on the part of holders andapplicants.– With adherence to policies and procedures on the part ofreviewers.

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THIS WAS ALL ABOUT WHAT USFDA SAYS

ABOUT DMF.

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NOW,…What European Drug Master File Procedure for Active Substances says about the DMF…

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CONTENT OF DRUG MASTER FILE

APPLICANT’S PART OF DMF ASM RESTRICTED PART OF DMF2 PARTS

OPEN PART CLOSED PART

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APPLICANT’S PART OF DMF OPEN PART

( AVAILABLE TO APPLICANT)

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ACTIVE SUBSTANCE MANUFACTURER

SUPPLIES INFORMATION TO THE APPLICANT

THIS INFORMATION INCLUDES:-outline of the manufacturing method-impurities originating from the manufacturing method, isolation procedure and degradation

-information on the toxicity of specific impurities/ 45

The applicant’s part of a DMF is provided by the ASM to the applicant directly and becomes part of the application for marketing authorization.

The applicant’s part of the DMF is still a confidential document which cannot be submitted to third parties without the written agreement of the ASM.

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ASM Restricted Part of DMF

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CLOSED PART( NOT AVAILABLE TO THE APPLICANT)

IT INCLUDES:Detailed information about…Individual steps of the manufacturing method such as reaction conditions, temperature,

Validation and evaluation data for certain critical steps of the manufacturing method,etc.

Such information is supplied to the authorities only./ 45

MODEL QUESTIONS1. What are DMFs? Describe various types of DMFs.2. Write a short note on type II DMFs.3. Give details about latter of authorization. 4. What are the differences between DMFs and

APPLICATIONS?5. What are the open and closed part of DMF as per

European guidelines?6. Describe the submission, review and retiring of DMF.

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REFERENCES• www.fda.gov/cder/guidance/dmf.html• www.emea.eu.int/htms/vet• http://www.fda.gov/cder/Offices/ONDQA/prese

ntations/shaw.pdf

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