drug master file

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Drug Master File :

Drug Master File Prepared By: Trupti k. Kanani M. Pharm, Q.A., Sem-II 1 Guided By: Dr. Rina Gokani M.Pharm, Ph.D S. J. Thakkar Pharmacy College-Rajkot.


Contents: 1. Introduction to DMFs 2. Drug master file process 3. Drug master file format 4. Drug Master File contents 4.1 Submission of DMF 4.2 Authorization to refer to a drug master file 4.2.1 Format for Letter of authorization to review DMF 4.3. Processing and reviewing policies 4.4. Changes in DMFs 4.5. Closure of a drug master file 4.6. Retiring DMFs 5.Electronic Filing of DMFs and CTD 6. Changes in DMF system: 7.Application 8. Difference in European DMFS compare to us DMFs 9. European DMFs 10. Difference in European DMFS compare to US DMFs 11. Case study 12. References 13.Study questions 2

1.Introduction :

1.Introduction A Drug Master File (DMF) is a set of documents that provides detailed information concerning facility protocols and procedures used in the manufacturing, packaging and storing of pharmaceuticals. A Drug Master File (DMF) is a submission to the FDA of information, usually concerning the Chemistry, Manufacturing and Controls (CMC) of a component of a drug product, to permit the FDA to review this information. Drug product information or other non-CMC information may be filed in a DMF . Generally DMFs have two parts: (1) Applicant’s part : which contain non-confidential information that the license-holder needs to assess for the marketing. (2)Restricted part: which contains confidential information about the manufacturing procedure that only needs to be disclosed to the authorities. 3

Who Must File a DMF? :

Who Must File a DMF? NOBODY There is no legal or regulatory requirement to file a DMF. A DMF may be filed to provide Chemistry, Manufacturing and Controls (CMC) information that the FDA reviews. It is only for Maintain confidentiality of proprietary information (e.g., Manufacturing procedure, key ingredients, etc.) for the holder 4

2. Drug master file process :

2. Drug master file process Two copies of the Drug Master File with one signed original of the covering letter and other necessary documents are send to the FDA’s Central Drug Evaluation and Research (CDRL). [1] The Drug Master File staff will audit the non-technical information for completeness and adequacy for submission. If the key elements are missing, the staff will contact the proposed holder to try to obtain the necessary documents in order to file the DMF. Once the DMFs are determined to be acceptable for filing, the document room staff assigns a DMF number and a letter is sent to the contact person listed in the DMF. All DMF submitted in CTD format is accepted by any authorities. 5

Steps for filing the DMF::

Steps for filing the DMF: Set the document margins at 3/4 inch for the left (at least) and 1/2 inch for the right. Print the transmittal page, administrative information and DMF information on standard letter-size paper. If a larger sheet of paper is required for a diagram or schematic, fold the sheet and attach it to a letter-sized page in a manner that will allow for the page to be opened and refolded. At a maximum, each volume of a DMF should be no more than 2 inches thick . Number multiple volumes for one submission according to the total number of volumes (if more than one). (For example, 1 of 3, 2 of 3, etc.) Sign all documents requiring signature (only if you are the DMF holder or authorized representative). Copy and collate the document; FDA requires you submit both. Punch documents with a standard hole-punch. Cover each original and copy of each volume with a document jacket. Prepare the submission for shipping and mail to: Drug Master File Staff Food and Drug Administration 5901-B Ammendale Rd. Beltsville, MD 20705-1266 6

3. Drug master file format :

3. Drug master file format The DMF must meet the format requirements. [2] The DMF is submitted as Original and Duplicate jackets, collated, assembled, paginated, and jacketed, using covers obtained from the government printing office and are specifically provided for the DMFs. Multiple volumes are numbered, and the paper must be standard paper size. The DMF must be submitted in two copies, one with a blue cover and one with a red cover. The jacket covers are purchased from the government printing office. 7 Figure : DMFs Jacket

Binders for drug master file:

Binders for drug master file Material should have a surface smooth enough to allow printing with a complete bonding of ink to the surface after drying - Should be free from streaks, blisters, scratches and mottling - Binder weight MUST be .023-.025 gauge - Ink colour MUST be BLACK - Binders include – FDA Form 3316 - Red - DRUG MASTER FILE ARCHIVAL BINDER FDA Form 3316a - Blue - DRUG MASTER FILE BINDER PAPER BINDERS Front (flat size) - 267 x 292mm (10-1/2 x 11-1/2") Back (flat size) - 267 x 305mm (10-1/2 x 12") (size includes 13mm (1/2") lip at top [3] For maroon coloured binder ink should be white and for other binder ink used to print on it must be black. 8


Conti…… Paper Binders for review of DMFs include – FDA Form 2626a - Red - NDA CHEMISTRY BINDER FDA Form 2626b - Yellow - NDA PHARMACOLOGY BINDER FDA Form 2626c - Orange – NDA PHARMACOKINETIC BINDER FDA Form 2626d - White – NDA MICROBIOLOGY BINDER FDA Form 2626e - Tan – NDA CLINICAL DATA BINDER FDA Form 2626f - Green – NDA STATISTICS BINDER FDA Form 2626h - Maroon – NDA FIELD SUBMISSION CHEMISTRY BINDER COVER FORM [3] 9

4. Drug Master File contents: :

4 . Drug Master File contents: Types of drug master file : 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 Manufacturing section Quality controls Inputs (raw/packaging Materials) Intermediates and in-process Finished drug substance Validations Stability data Impurities Packaging and labelling Type III : Packaging Material Type IV : Excipient, Colorant, Flavour, Essence, or Material Used in Their Preparation Type V : FDA-Accepted Reference Information 10

4.1 Submission of DMF: :

4.1 Submission of DMF: A. Transmittal Letters The following should be included: 1. Original Submissions a. Identification of submission: Original, the type of DMF as classification and its subject. b. Identification of the 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. Signature of the holder or the authorized representative. d. Typewritten name and title of the signer. 2. Amendments a. Identification of submission: Amendment, the DMF number, type of DMF, and the subject of the amendment. b. A description of the purpose of submission, e.g., update, revised formula, or revised process. c. Signature of the holder or the authorized representative. d. Typewritten name and title of the signer. 11


Conti…… B. Administrative Information Administrative information should include the following: 1. 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. 2. 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. 12


4.2 AUTHORIZATION TO REFER TO A DRUG MASTER FILE Letter of Authorization to 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. The holder does not need to send a transmittal letter with its letter of authorization. The letter of authorization should include the following: The date. Name of DMF holder. DMF number. Name of person(s) authorized to incorporate information in the DMF by reference. Specific product(s) covered by the DMF. Submission date(s) of above. Section numbers and/or page numbers to be referenced. Statement of commitment that the DMF is current and that the DMF holder will comply with the statements made in it. Signature of authorizing official. Typed name and title of official authorizing reference to the DMF. 13

4.2.1 Format for Letter of authorization to review DMF::

4.2.1 Format for Letter of authorization to review DMF: Food and Drug Administration Center for Drug Evaluation and Research Re: DMF ###XXX, Type II Hair tonic Dear sir/ madam, By copy of this letter, DRUG HOLDER ’XYZ’ is authorizing APPLICANT ABC to incorporate by reference into their NDA/ANDA our DMF ###XXX, date, section, pages 105-115. We hereby authorize your office to review the aforementioned specific information in DMF ###XXX in considering the application filed by APPLICANT ABC. The component/material furnished will be manufactured in accordance with DMF ###XXX and in compliance with CGMPS. This DMF holder status that DMF###XXX is current and will comply with all statements made within it. Sincerely, XYZ 14

The DMF will be reviewed only when it is referenced in an application or another DMF. :

The DMF will be reviewed only when it is referenced in an application or another DMF. USFDA send a letter to remind dmf holder holder obligations SEND 2 copies of LOA to the FDA one copy of LOA to the applicant The applicant submits this copy of LOA in their application. 15

4.3. Processing and reviewing policies :

4.3. Processing and reviewing policies Policies Related to Processing Drug Master Files 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. 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. If FDA reviewers find deficiencies in the information provided in a DMF, a letter describing the deficiencies is sent to the DMF holder. At the same time, FDA will notify the 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. When the holder submits the requested information to the DMF in response to the agency's deficiency letter, the holder should also 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. 16

4.4 Changes in DMFs: :

4.4 Changes in DMFs: Notice Required for Changes to a Drug Master File A holder must notify each affected applicant or sponsor who has referenced its DMF of any pertinent change in the DMF. Notice should be provided well before making the change in order to permit the sponsor/applicant to supplement or amend any affected application(s) as needed. B. Annual Update The holder should provide an annual report on the anniversary date of the original submission. A ll changes and additional information incorporated into the DMF since the previous annual report on the subject matter of the DMF should be provided. 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. C. Appointment of an 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 scope of responsibility (administrative and/or scientific). Domestic DMF holders do not need to appoint an agent or representative, although foreign DMF holders are encouraged to engage an agent. D. Transfer of Ownership To transfer ownership of a DMF to another party, the holder should so notify FDA and authorized persons in writing. The new holder should submit a letter of acceptance of the transfer and an update of the information contained in the DMF, where appropriate. Any change relating to the new ownership (e.g., plant location and methods) should be included. 17

4.5 Closure of a DMFs [4,5] :

4.5 Closure of a DMFs [4,5] A holder who wishes to close a DMF should submit a request to the Drug Master File Staff stating the reason for the closure. or 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. Any changes will be send to FDA. 18

4.6 Retiring DMFs :

4.6 Retiring DMFs If a DMF has had no activity (amendment or annual report) in three years FDA will initiate retirement procedure Note: LOA does not count for activity 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 destroyed. 19

5.Electronic Filing of DMFs and CTD :

5.Electronic Filing of DMFs and CTD CTD (Common Technical Document) format not required for paper DMFs, although acceptable. Required for electronic DMFs Electronic DMFs are accepted http://www.fda.gov/cder/regulatory/ersr/ectd.htm DMFs originally submitted in paper can be resubmitted as electronic DMFs. Entire DMF must be resubmitted. Once a DMF has been submitted in electronic form NO paper documents (including LOAs) to be submitted. 20

6. Changes in DMF system::

6. Changes in DMF system: There have been some changes in the DMF system to help make it work better. Changes in the DMF system and procedure: Creation of Review Cover Form Elimination of Type I DMFs Creation of DMF list on website Unchanged: Review only when referenced in application DMFs are neither approved nor disapproved The holder must notify customer of changes 21


7.Application: The DMF can be referenced by drug manufacturers in support of their NDAs, ANDAs and clinical trial applications. Maintain confidentiality of proprietary information (e.g., Manufacturing procedure) for the holder. Permit review of information by reviewers in the Center for Drug Evaluation and Research (CDER) to support applications submitted by one or more applicants. 22

8. Difference between application and DMFs [6] :

8. Difference between application and DMFs [6] Applications DMFs Comes under regulatory status. Must be filed by applicant. Not come regulatory . it is not compulsory to file a DMF. Each application and its supplement are entered into a common database. DMFs are entered in to database as per their types. (separate database for each type of DMFs). Submitted to a particular review division. Submitted to FDA -CDER. Assignment to a reviewer and watch submission had a due date. No assignment to a reviewer, no due date. Review procedure quite different then DMF. DMFs are review only when referenced by application or another DMF. If the anniversary date for annual update is missed FDA sends a reminder. If the anniversary date for annual update is missed FDA will not send a reminder. 23

9. European DMFs:

9. European DMFs The DMF contains information which includes valuable know-how which should be kept confidential and submitted to the authorities only. Therefore, it should be divided into 2parts – an applicant’s part and an ASM Restricted Part. The applicant’s part of a DMF is provided by the ASM ( A ctive S ubstance Manufacturer)to the applicant directly and becomes part of the application for marketing authorization. Both the applicant’s part and the ASM Restricted Part of the DMF are submitted to the authorities. a) Applicant’s part of a DMF – opening part The applicant must be supplied by the ASM with sufficient information to be able to take responsibility for an evaluation of the suitability of the active substance specification to control the quality of the substance. This normally includes a brief outline of the manufacturing method, information on potential impurities originating from the manufacturing method, from the isolation procedure (natural products) or from degradation and, where applicable, information on the toxicity of specific impurities. b) ASM Restricted Part of DMF – closing part Deta iled information on the individual steps of the manufacturing method such as reaction conditions, temperature, validation and evaluation data for certain critical steps of the manufacturing method, etc. and on quality control during manufacture may contain valuable know-how. Such information may therefore be supplied to the authorities only. [7] 24

10. Difference in European DMFS compare to US DMFs:

10. Difference in European DMFS compare to US DMFs About DMF filing in EU (called EDMF), it is different to DMF filing in FDA. Whenever DMF is filed by person or firm is checked by FDA and if it is containing all necessary documents, FDA accept DMF file and give a DMF number. It is the identification of DMF for applicant who want to review that DMF. BUT EU Authority (EMEA) does not give DMF number. If the API is in Eu. Pharmacopoeia, EMEA can accept EDMF filing and issue a “Certificate of Suitability” for it. If the API is not in Eu. P. EMEA would not accept DMF filing alone. – Paclitaxel is not in Eu. P yet. So if you apply for Marketing Authorization in EU countries, you need to reach agreement with the API supplier to provide you the entire DMF file (which is technological confidential property of the API factory). So you can including its content into your Marketing Authorization application dossier to submit to EU authority (either your country’s Authority or EU Authority). 25

11. Case study [8] :

11. Case study [8] Here is example for PCM tablets : 26


12.References: Guideline for Drug Master Files, Center for Drug Evaluation and Research, Food and Drug Administration, Department of Health and Human Services, Office of Drug Evaluation I (HFD-100), 5600 Fishers Lane, Rockville, Maryland 20857, September 1989. 2. dmfquestion@cder.fda.gov 3.http://www.fda.gov/drugs/developmentapprovalprocess/formssubmissionrequirements/drugmasterfilesdmfs/ucm073080.htm 4. http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ManualofPoliciesProcedures/ucm04.pdf 5. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072877.pdf 6.http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm122886.htm 7. http://www.erigone.com/Vet%20folder/3aq7aen.pdf 8. http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/form/dmff_fmmf-eng.php 27

13. Study questions: :

13. Study questions: What is DMFs ? Describe various types of it? Write difference between application and DMFs. Describe opening and closing part of European DMFs? Give details about letter of authorization. Describe the submission, review and retiring of DMF. Short note on DMFs. 28

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