Dr. Raghuveer Pharma Consultants

1
DRPC

• Dr. Raghuveer Pharma Consultants

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Summary of Presentation

• Introduction on DMF
• US Procedures
• EU procedures

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DRUG MASTER FILES- INTRODUCTION 1

• DEFINITION-
• A Drug Master File (DMF) is a submission to
  the Regulatory Agencies of information, usually
  concerning the
• Chemistry, Manufacturing and Controls (CMC) of
  a drug product or a component of a drug product,
  to permit the Agency to review this information
  in support of a third partys submission.

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DRUG MASTER FILES- INTRODUCTION 2

• Regulatory agencies and DMF
• US- FDA - Originally Five types were accepted
• I Plant Information
• II Drug substance, drug product, intermediates
  and material used in their manufacture
• III Packaging
• IV Excipients
• V Other Usually clinical, toxicity data
• Currently only Four types are handled
• (Numbering retained to avoid confusion)
• EU - EMEA accepts EDMF- Currently named as
• 
  ASMF (Active Substance Master File)
• No procedure for Packaging
  /Excipients

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DRUG MASTER FILES- INTRODUCTION 3

• Terminology
• DMF Holder - The person or company who submits
  a DMF
• 2. AGENT - The person/company who
  represents a DMF HOLDER
• Agents for DMFs
  Not required, although recommended to
• facilitate
  communication for foreign company
• 3. APPLICANT
• -The person/company
  who references the DMF
• 4. DMF can be submitted in support of
• a. Investigational New Drug Application (IND),
• New Drug Application (NDA),
• Abbreviated New Drug Application (ANDA)
• Supplement or Amendment to a NDA /ANDA(A report
  of a change in an approved NDA /ANDA

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DRUG MASTER FILES- INTRODUCTION 4

• For a Common understanding,
• We will use the terminology as DMF and
  
• proceed US Type II DMF for Drug
  Substance
• - Equivalent to EU ASMF / EDMF

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DRUG MASTER FILES- INTRODUCTION

• Requirements for a DMF
• There is no legal or regulatory
  requirement to file a DMF
• A DMF may be filed to provide CMC
  information that the FDA
• reviews. Example novel excipient
• Normally the CMC for a compendial
  excipient is not reviewed
• Many drug substance for OTCs (not NDA)
  not reviewed
• However if a drug substances used in
  non-NDA OTC products
• are also used in NDA OTC products. DMFs
  for these are reviewed.
• A DMF may be submitted for information
  that is normally
• reviewed as part of the CMC review.
• Reasons for a DMF
• Maintain confidentiality of proprietary
  information
• (e.g., Manufacturing procedure) for
  the holder
• Permit review of information referenced
  by a number of
• applicants

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DRUG MASTER FILES- US Address

• Address (US)
• 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
• E-mail dmfquestion_at_cder.fda.gov

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DRUG MASTER FILES- How it works

• Contents
• Transmittal (cover) letter
• Administrative information
• Technical information
• Process
• DMF reviewed for administrative purposes
  ONLY, entered into
• - DMF database, assigned a number and
  acknowledgement letter sent

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DRUG MASTER FILES- US Review Procedure

• When the reviewer receives an application that
  references a DMF, the reviewer requests the DMF
  from the CDR.
• If there are deficiencies the detailed
  deficiencies are communicated to the holder
• The APPLICANT is notified that deficiencies
  exist, by an IR or AE or NA letter. The nature of
  the deficiencies is not communicated to the
  applicant.
• If no deficiencies, no letter, applicant not
  notified.
• (IR Information Request, AE Approvable,
  NA Not Approvable)

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DRUG MASTER FILES- US Obligations of Holder
Applicant

• 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) -
  Letter of Access in EU
• for each item referenced for each
  customer
• Notify authorized parties of changes
• APPLICANT
• The holder MUST submit an LOA (2 copies)
  to the DMF
• and send a copy to the APPLICANT
• The applicant submits copy of LOA in
  their Application.
• LOA to contain a
• Specific reference to a particular item
  in the DMF, by its code
• name, page number and most importantly
  DATE OF THE
• SUBMISSION on the cover letter

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DRUG MASTER FILES- US 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 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 is received in 90 days, one copy
  of DMF is sent to Federal Records Center (FRC)
  and the other are destroyed.
• Response Close DMF or submit annual update to
  keep it open.

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DRUG MASTER FILES- Electronic Filing of DMFs and
CTD-Q

• Regulatory agencies and DMF
• CTD-Q not required for paper DMFs, although
  acceptable
• Electronic DMFs may be filed as part of a pilot
  program
• http//www.fda.gov/cder/regulatory/ersr/eCTD.htm
  
• Changes in DMF System -
• Over the past decade, there have been some
  changes in the DMF system to help make it work
  better.

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DRUG MASTER FILES- EU Procedures

• The Scenario Procedure is by and large the same
• DMF Handled by 2 agencies
• 1.European Medicine Evaluation agency (EMEA)
• 7,WestferryCircus,CanaryWharf,LondonE144HB,Un
  itedKingdomwww.emea.eu.int/
• ASMF - for Drug substance in support of a
  Marketing
• eDMF - Drug product Authorisation
  Application
• Certification of Medicinal Product for export
• 2.European Directorate for Quality Medicines
  (EDQM)
• 7 allée Kastner, CS 30026, F - 67081
  Strasbourg, FRANCE.
• E-mail cep_at_edqm.eu
• Certificate of Suitability (CEP) - for Drug
  Substance

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DRUG MASTER FILES- EU Procedures(Contd.)

• ASMF - for Drug substance/eDMF - Drug product
• Details are to be given in 2 parts
• Applicants Part (AP) or OPEN PART
• Restricted Part (RP) or CLOSED PART
• (AP is also Confidential data- Not to be
  disclosed by the applicant without written
  permission of the DMF Holder)
• ASMF to contain
• A Covering Letter
• Letter of Access
• Quality Overall Summary (QOS) Separate summary
• 
  - for the AP and the RP.
• Detailed Scientific Information as per 3.2.S
  Section of CTD .
• A written assurance that there is a formal
  agreement between the
• ASM and the Applicant

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DRUG MASTER FILES- Summary

• Structure / Formats used
• EU procedure recommends the use of appropriate
  CTD structure (Module -3)
• US procedure does not mandate the use of CTD
  structure, given a different list in the
  Guideline document,but accepts both.
• Electronic submission
• EDQM accepts Electronic submission
• EMEA has not given specific detail
• USFDA has not given specific detail
• (Though both EMEA USFDA have mentioned as
  accepting them)
• Changing of the system by the Agencies in line
  with CTD and CTD is expected

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DRUG MASTER FILES- EU Procedures(Contd.)

• Similarly
• eDMF - Drug product to contain
• A Covering Letter
• Letter of Access
• Quality Overall Summary (QOS)
• Detailed Scientific Information as per 3.2.P
  Section of CTD .
• Submission
• ASMF
• One copy of the complete ASMF, comprising the 2
  parts (applicant's part and ASM's restricted
  part) should be sent by the ASM directly to each
  of the competent authorities concerned.
• A copy of the applicant's part should be supplied
  in advance by the ASM to the applicant. This
  applicant's part should be included in the
  application for marketing authorisation.
• EDMF
• One copy of the complete EDMF,directly to each of
  the competent authorities concerned.
• Details Provided by ASM MFR to be included

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DRUG MASTER FILES- EU Procedures(Contd.)

• EDQM-
• Certificate of Suitability (CEP) - for Drug
  Substance
• Has a validity of 5 years
• CEP is Accepted equivalent to ASMF in any of the
• Marketing Authorisation Application (MAA)
  reviews
• In cases where the CEP contains too little
  information (e.g.
• stability) the Competent Authorities/EMEA may
  decide that
• additional information should be provided in
  the dossier.
• In such case the MAA to refer both to an ASMF
  and a CEP.
• CEP Application to contain
• - Cover Letter
• - Application Form (form ECEP/03) and Fee Form
• - A single copy of a dossier, and
• - A single copy of the Quality Overall Summary
  (QOS)
• EDQM Assesses the CEP application, Communicate
  for Querries if any and issues a Certificate of
  Suitability CEP

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DRUG MASTER FILES- Summary

• DRPC can
• Provide services in organizing an application for
  all the above
• Structure the documents in line with CTD so that
  you are ready for the changes to come in future

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DRUG MASTER FILES

• Thank you for your time and patience

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