This presentation is compiled by “ Drug Regulations” a  non profit organization which provides free online     resource to...
 This presentation is compiled by “ DrugRegulations” from freely available resources    like the FDA on the World wide we...
   The Generic Drug User Fee Amendments of    2012 (GDUFA) is designed to speed up the    approval process.   GDUFA requ...
   Additional resources collected will enable    ◦ The Agency to reduce a current backlog of      pending applications,  ...
   GDUFA is designed to build on the success of the    Prescription Drug User Fee Act (PDUFA).   Over the past 20 years,...
   A Drug Master File (DMF) is a submission of    information to the FDA to permit the FDA to    review this information ...
   DMFs    usually    cover    the   Chemistry,    Manufacturing and Controls (CMC) of a    component of a drug product e...
   Food Drug and Cosmetic Act (FD&C Act)   Food and Drug Administration                              Safety    Informati...
   314 New Drug Application (NDA) and    Abbreviated NDA (ANDA)    ◦ 314.50 Content and format of an      application    ...
   There is no legal or regulatory    requirement to file a DMF.   Information can be in an Application    (NDA or ANDA)...
   Permit review of information by    reviewers at FDA to support    applications submitted by one or more    applicants ...
   For a drug substance reviewed in ONDQA@   New Molecular Entity: Usually in the NDA. Even if the drug    substance is ...
   For a drug substance reviewed in OGD@   If a third party manufacturer: In a DMF - The    usual case   If NOT a third...
   Normally the CMC for a compendial    excipient (quality covered by USP or NF    monograph) is not reviewed   CMC for ...
   CMC Information is NOT reviewed for OTC drug    products “marketed without prior approval by FDA”    under the OTC mon...
   Type I: Manufacturing Site, Facilities, Operating    Procedures, and Personnel (no longer applicable)   Type II: Drug...
   Type V DMF   Must first submit a letter of intent for “pre-clearance”    by FDA to file    ◦ Clinical    ◦ Toxicology...
   “A” = Active. This means that the DMF was found acceptable for    filing, administratively, and has not been closed. ...
   Note that the Administrative Filing    review is not related to the “Initial    Completeness Assessment,” which is    ...
   Application means any of the following:    ◦ Investigational New Drug Application (IND)    ◦ New Drug Application (NDA...
   Supplement to an Application    ◦ A report of a change in an approved      Application   Amendment to an Application ...
   Holder : Submits DMF   Sponsor = CUSTOMER= AUTHORIZED PARTY (AP) :    Submits IND, References DMF   Applicant =CUSTO...
   Registration:    ◦ In many parts of the world a company ”Registers”      an application or a “dossier.”    ◦ In the US...
   Letter of Access:    ◦ In some cases a DMF holder will call the permission to      reference a DMF a “Letter of Access...
   Holder sends the DMF (No form, NO FEE, two    copies) to CDER containing :    ◦   Transmittal (cover) letter    ◦   Ad...
   Electronic Submission Gateway (ESG)–    ◦ Holder sends the DMF in Electronic Common Technical      document (eCTD) for...
   Acceptance of digital signatures the same as for    any other submission to FDA   Pre-assigned Number    ◦ A pre-assi...
   Follow Guidance for DMF’s (Link)   Guidance for Binders: (Link)   Guidance ( Drugs) : (Link)   A MaPP (Manual of Po...
   Transmittal (cover) letter, including pre-assigned number,    where applicable   Administrative information. For comp...
   DMF entered into FDA’s database (DARRTS) and    assigned a number    ◦ Status = PENDING Not available for review    ◦ ...
   Statement of Commitment:    ◦ The form for A/NDA contains a “Statement of Commitment”   No form for DMF’s    ◦ Theref...
   Notifies holder of DMF number and type.   Includes Title (Subject) and Holder of DMF.   Will appear on list posted o...
   Confidentiality of info in DMF is covered by 21 CFR    314.430(g) and is the same as other type of    submissions:   ...
   FDA will not share information with a third party    except through a FOIA request i.e. FDA will not tell    Applicant...
   Holder must follow appropriate regulations (21 CFR    314.50(d)(1) for ANDAs and NDAs and 21 CFR    312.23(a)(7) for I...
   Format: Common Technical Document (CTD)   CTD is a structured format that permits efficient    life-cycle management,...
   The DMF will be reviewed ONLY when it is referenced in    an Application or another DMF.   An LOA does two things:   ...
   LOA must contain a specific reference to a particular    item in the DMF.   Specify the item by its code name, page n...
   It is not necessary to resubmit an LOA on a    periodic basis.   However, the list of authorized parties should be   ...
   There is no requirement to submit ANY type of    application in electronic format. This is projected to    change unde...
   Not required under any regulation   Regulations require that the DMF “…contain a    complete list of each person curr...
   Should contain    ◦ List of authorized Parties    ◦ List of all changes reported since last AR    ◦ If no changes, inc...
   A DMF can be reviewed at any time when a review    is triggered by reference in an APPLICATION.   Therefore, DMF must...
   Closure by Holder:    ◦ Holder submits a Closure request to DMF    ◦ Entry into database changes status to “Closed.” U...
   Reactivation of a Closed DMF   Holder submits a “Reactivation”    ◦ Should contain a complete copy of the DMF, contai...
   Types of Submissions in DARRTS:    ◦ Annual Reports    ◦ Original: Includes changes in technical information (technica...
   Amendment = A report of a change, deletion or    addition of technical or administrative information.    NOT a supplem...
   DMFs ARE NEITHER                 APPROVED                NOR    DISAPPROVED   A DMF is reviewed to determine whether ...
   A DMF is reviewed for Administrative content when    it is received.   This may take 2-3 weeks.   If the DMF is acce...
   When the reviewer receives an application that    references a DMF, the reviewer triages the DMF to    determine wheth...
 All DMFs are subject to a complete review for  technical information only when all of the following  events occur:1. The...
   The Generics Drug User Fee Act (GDUFA) section of    the Food and Drug Administration Safety and Innovation    Act” (S...
   Fee due for Type II DMFs for the API referenced by an    initial letter of authorization by an ANDA submission    on o...
   When A DMF fee is not Required    For ANDAs that are part of the backlog    For submissions not part of GDUFA (INDs,...
   Under GDUFA an important goal for the DMF holder is to get    the DMF to “Available for Reference” status so referenci...
  How fee Payment impacts filing: Fee payment status check is performed by Office of Management (OM) within several days...
   How fee Payment impacts filing:   Fee payment status check is performed by Office of    Management (OM) within severa...
   How fee Payment impacts filing:    ◦ The ANDA will not be processed further (i.e. sent to OGD     for filing review) u...
   FDA will undertake an initial CA to determine the following:   Is the DMF active?   Has the fee been paid?   Has th...
   FDA will conduct the initial CA by completing a series of    questions   listed   in   the   GDUFA   Initial    Comple...
   How the Completeness Assessment impacts filing of the ANDA:   When the OGD filing review decision on the ANDA is read...
   Fee collection is processed in FDA for GDUFA by OFM (Office    of   Financial   Management),     who    manage     the...
   FDA performs Administrative Review of submitted    DMF   If DMF is administratively complete, FDA sends the    Filing...
   CDER/OM (Office of Management) confirms User    Fee payment and sets the status for the DMF.   Once the user fee stat...
   New DMF Correspondences and Meetings    ◦ DMF Complete Response (CR) letter    ◦ DMF No Further Comments letter    ◦ D...
   The DMF CR Template has been in use since mid-    October 2012 and contains the following sections    ◦ Chemistry Defi...
   FDA will not delay issuing DMF CR letters based on    pending compliance evaluations or inspections.   Letters   will...
   The DMF letters will issue before the ANDA CR    letter for a given review cycle to comply with ANDA    CR requirement...
   Note that statements in the DMF amendment    deferring response to a future submission are not    acceptable.   DMF m...
   The Commitment letter states:   • “Once a DMF has undergone a complete review and the    ANDA referencing same is eit...
   Not to be construed as an indication of any future    status of the DMF (i.e. not equivalent to an    approval letter)...
   Issued to communicate issues discovered during    the Completeness Assessment   Comments in the letter will describe ...
   Cover letter of the amendment should indicate that    the submission is a “Response to DMF Incomplete”   Notification...
   Specific type of teleconference described in the   commitment letter   30 minute t-con for first cycle deficiency le...
   Contact    information        for      requesting            these    teleconferences is included in the DMF CR letter...
   Required by the GDUFA legislation   Comprehensive list of all Type II DMFs for APIs that have    paid    the   DMF   ...
   New requirement in the GDUFA legislation   Drug substance (Type II) DMFs must be deemed    “available for reference” ...
   ANDAs can only be filed by OGD if all DMFs for the drug    substance(s) are “available for reference”   Improve quali...
   DMF Fee is a one-time fee   Not to be confused with the facility fee related to the    drug substance manufacturing f...
   DMF Fee may be paid independent of a referencing    ANDA in order to get a completeness assessment and    be to listed...
 This presentation is compiled by “ DrugRegulations” from freely available resources    like the FDA on the World wide we...
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Drug Master Files under GDUFA

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This presentation is compiled by “ Drug Regulations” from freely available resources like the FDA on the World wide web. “Drug Regulations” is a non profit organization which provides free online resource to the Pharmaceutical Professional.
Visit http://www.drugregulations.org for latest information from the world of Pharmaceuticals.

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  • The company liberty management group provides drug master filing services. refer to http://www.fdahelp.us/drug-master-files.html
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Drug Master Files under GDUFA

  1. 1. This presentation is compiled by “ Drug Regulations” a non profit organization which provides free online resource to the Pharmaceutical Professional. Visit http://www.drugregulations.org for latest information from the world of Pharmaceuticals. 2/25/2013 1
  2. 2.  This presentation is compiled by “ DrugRegulations” from freely available resources like the FDA on the World wide web.  “Drug Regulations” is a non profit organization which provides free onlineresource to the Pharmaceutical Professional. Visit http://www.drugregulations.org for latest information from the world of Pharmaceuticals. Drug Regulations : Online Resource for Latest Information 2/25/2013 2
  3. 3.  The Generic Drug User Fee Amendments of 2012 (GDUFA) is designed to speed up the approval process. GDUFA requires industry to pay user fees for reviewing generic drug applications and inspecting facilities Drug Regulations : Online Resource for Latest Information 2/25/2013 3
  4. 4.  Additional resources collected will enable ◦ The Agency to reduce a current backlog of pending applications, ◦ Cut the average time required to review generic drug applications and ◦ Increase risk-based inspections. Drug Regulations : Online Resource for Latest Information 2/25/2013 4
  5. 5.  GDUFA is designed to build on the success of the Prescription Drug User Fee Act (PDUFA). Over the past 20 years, PDUFA has ensured a more predictable, consistent, and streamlined premarket program for industry. PDUFA helped speed access to new, safe and effective prescription drugs. GDUFA will also enhance global supply chain safety by requiring that generic drug facilities and sites around the world self-identify. Drug Regulations : Online Resource for Latest Information 2/25/2013 5
  6. 6.  A Drug Master File (DMF) is a submission of information to the FDA to permit the FDA to review this information in support of a third party’s submission without revealing the information to the third party. Drug Regulations : Online Resource for Latest Information 2/25/2013 6
  7. 7.  DMFs usually cover the Chemistry, Manufacturing and Controls (CMC) of a component of a drug product e.g. drug substance, excipient, packaging material. Drug product information or non-CMC information may be filed in a DMF. Drug Regulations : Online Resource for Latest Information 2/25/2013 7
  8. 8.  Food Drug and Cosmetic Act (FD&C Act) Food and Drug Administration Safety Information Act (FDASIA) The Generic Drug User Fee Act (GDUFA) Prescription Drug User Fee Act (PDUFA) Drug Regulations : Online Resource for Latest Information 2/25/2013 8
  9. 9.  314 New Drug Application (NDA) and Abbreviated NDA (ANDA) ◦ 314.50 Content and format of an application ◦ 314.70 Changes to an Approved Application ◦ 314.420 Drug Master Files Drug Regulations : Online Resource for Latest Information 2/25/2013 9
  10. 10.  There is no legal or regulatory requirement to file a DMF. Information can be in an Application (NDA or ANDA) OR a DMF. Maintain confidentiality of proprietary information (e.g., Manufacturing procedure) for the holder Drug Regulations : Online Resource for Latest Information 2/25/2013 10
  11. 11.  Permit review of information by reviewers at FDA to support applications submitted by one or more applicants Drug Regulations : Online Resource for Latest Information 2/25/2013 11
  12. 12.  For a drug substance reviewed in ONDQA@ New Molecular Entity: Usually in the NDA. Even if the drug substance is manufactured by a third party, FDA prefers the CMC info be in the NDA. However, a DMF can be used in this case. Not recommended “Old” molecular entity e.g., previously approved drug in a new dosage form. If a third party manufacturer, usually in a DMF @ Office of New Drug Quality Assessment Drug Regulations : Online Resource for Latest Information 2/25/2013 12
  13. 13.  For a drug substance reviewed in OGD@ If a third party manufacturer: In a DMF - The usual case If NOT a third party manufacturer (i.e., drug substance is manufactured by the same company as the applicant) CMC info can be in ANDA Drug Regulations : Online Resource for Latest Information 2/25/2013 13
  14. 14.  Normally the CMC for a compendial excipient (quality covered by USP or NF monograph) is not reviewed CMC for many packaging materials (See MaPP 5015.5 CMC Reviews of Type III DMFs for packaging Materials) (Link) Drug Regulations : Online Resource for Latest Information 2/25/2013 14
  15. 15.  CMC Information is NOT reviewed for OTC drug products “marketed without prior approval by FDA” under the OTC monograph system. e.g. aspirin CMC information IS reviewed for non- prescription drug products (OTC) drug products which are marketed after approval of A/NDAs e.g. OTC Tagamet. CMC for drug substance reviewed - usually in DMF. Drug Regulations : Online Resource for Latest Information 2/25/2013 15
  16. 16.  Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel (no longer applicable) 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 Drug Regulations : Online Resource for Latest Information 2/25/2013 16
  17. 17.  Type V DMF Must first submit a letter of intent for “pre-clearance” by FDA to file ◦ Clinical ◦ Toxicology May be filed without submission of letter of intent ◦ Sterile processing facilities ◦ Biotech manufacturing facilities Information about these facilities can, like any other type of information, be submitted directly in an NDA or ANDA Drug Regulations : Online Resource for Latest Information 2/25/2013 17
  18. 18.  “A” = Active. This means that the DMF was found acceptable for filing, administratively, and has not been closed. “C” = Complete. This means that the DMF has undergone a successful Completeness Assessment “I” = Inactive. This means a DMF that has been closed, either by the holder or by the FDA. “P” = DMF Pending Administrative Filing review “N” = Not an assigned number. This can occur for a number of reasons, e.g., the holder withdrew the DMF during the administrative review or the DMF was transferred to another Center. Drug Regulations : Online Resource for Latest Information 2/25/2013 18
  19. 19.  Note that the Administrative Filing review is not related to the “Initial Completeness Assessment,” which is performed for Type II DMFs submitted to support ANDAs ONLY Drug Regulations : Online Resource for Latest Information 2/25/2013 19
  20. 20.  Application means any of the following: ◦ Investigational New Drug Application (IND) ◦ New Drug Application (NDA) ◦ Abbreviated New Drug Application (ANDA) ◦ Biological License Application (BLA) ◦ New Animal Drug Application (NADA) ◦ Abbreviated New Animal Drug Application (ANADA) Drug Regulations : Online Resource for Latest Information 2/25/2013 20
  21. 21.  Supplement to an Application ◦ A report of a change in an approved Application Amendment to an Application ◦ Additional information to a pending Application or Supplement Amendment to a DMF ◦ Additional information to an existing DMF Drug Regulations : Online Resource for Latest Information 2/25/2013 21
  22. 22.  Holder : Submits DMF Sponsor = CUSTOMER= AUTHORIZED PARTY (AP) : Submits IND, References DMF Applicant =CUSTOMER=AP : Submits NDA, ANDA, BLA, NADA, ANADA, References DMF Quality or Quality Microbiology Reviewer: Reviews DMF, Reviews Quality and Quality Microbiology parts of Application Regulatory Project Manager: Communicates with the HOLDER and the APPLICANT/SPONSOR Drug Regulations : Online Resource for Latest Information 2/25/2013 22
  23. 23.  Registration: ◦ In many parts of the world a company ”Registers” an application or a “dossier.” ◦ In the US, only manufacturing sites are “registered” in the Drug Registration and Listing System (DRLS). Active Pharmaceutical Ingredient (API): ◦ This term is defined in ICH Q7. An API is the same as a “drug substance.” ◦ API does not appear anywhere in the CFR. Drug Regulations : Online Resource for Latest Information 2/25/2013 23
  24. 24.  Letter of Access: ◦ In some cases a DMF holder will call the permission to reference a DMF a “Letter of Access.” (Phrase used in Europe). ◦ In the US, this is called a “Letter of Authorization (LOA). An LOA does not permit anyone except FDA to “Access” i.e. “read” the DMF Transmittal Letter = Cover Letter Annual Report = Annual update Drug Regulations : Online Resource for Latest Information 2/25/2013 24
  25. 25.  Holder sends the DMF (No form, NO FEE, two copies) to CDER containing : ◦ Transmittal (cover) letter ◦ Administrative information ◦ Technical information ◦ The “Subject” (title) of the DMF, which will appear on the Web site, can use whatever name the holder wishes e.g.. A code name rather than a chemical or established name Two copies of all subsequent submissions (Amendments, Annual Reports, Letters of Authorization) are also sent to CDER. Drug Regulations : Online Resource for Latest Information 2/25/2013 25
  26. 26.  Electronic Submission Gateway (ESG)– ◦ Holder sends the DMF in Electronic Common Technical document (eCTD) format through the ESG ◦ ( Link to the gateway) ◦ Choose "CDER" as the Center and "eCTD" as the submission type“ Physical Media (CD-ROM, DVD or USB drive) ◦ Holder sends the DMF on physical medium in eCTD format to CDER ◦ See the Transmitting Specifications website when transmitting via physical media (CDDVD) ◦ ( Link) Drug Regulations : Online Resource for Latest Information 2/25/2013 26
  27. 27.  Acceptance of digital signatures the same as for any other submission to FDA Pre-assigned Number ◦ A pre-assigned number is required for an EDMF. May also be obtained for paper DMF. ◦ See “Requesting a Pre-Assigned Application number ◦ ( Link) Drug Regulations : Online Resource for Latest Information 2/25/2013 27
  28. 28.  Follow Guidance for DMF’s (Link) Guidance for Binders: (Link) Guidance ( Drugs) : (Link) A MaPP (Manual of Policies and Procedures) contains instructions for FDA personnel on performing administrative and review functions (Link) Drug Regulations : Online Resource for Latest Information 2/25/2013 28
  29. 29.  Transmittal (cover) letter, including pre-assigned number, where applicable Administrative information. For complete list of information to include see DMF Web site . Make sure to include ◦ Telephone number, fax number and e-mail address for the responsible individual (contact person) ◦ A Statement of Commitment (Recommended in the DMF Guideline : “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.”) List of Referenced applications e.g. DMF for intermediates Technical information Drug Regulations : Online Resource for Latest Information 2/25/2013 29
  30. 30.  DMF entered into FDA’s database (DARRTS) and assigned a number ◦ Status = PENDING Not available for review ◦ Reviewed for administrative purposes ONLY by the Office of Business Informatics (OBI) staff. If incomplete, OBI sends a request for additional information. If administratively complete, OBI sends an acknowledgement letter Status = ACTIVE Available for review Usual processing time is 2-3 weeks Drug Regulations : Online Resource for Latest Information 2/25/2013 30
  31. 31.  Statement of Commitment: ◦ The form for A/NDA contains a “Statement of Commitment” No form for DMF’s ◦ Therefore the DMF Guideline recommends that the DMF contain: “ 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.” Drug Regulations : Online Resource for Latest Information 2/25/2013 31
  32. 32.  Notifies holder of DMF number and type. Includes Title (Subject) and Holder of DMF. Will appear on list posted on web site Reminder of obligations of holder ◦ Submit all changes as amendments ◦ Notify FDA of change in holder name or address ◦ Notify FDA of change in agent/representative ◦ Notify authorized parties of changes ◦ SUBMIT ANNUAL REPORT (ANNUAL UPDATE ) ◦ Submit Letter of Authorization (LOA) for each item referenced for each customer Drug Regulations : Online Resource for Latest Information 2/25/2013 32
  33. 33.  Confidentiality of info in DMF is covered by 21 CFR 314.430(g) and is the same as other type of submissions: “The following data and information in an application or abbreviated application are not available for public disclosure … (1) Manufacturing methods or processes, including quality control procedures.” This relates to information available upon submission of a Freedom of Information Act (FOIA) request Drug Regulations : Online Resource for Latest Information 2/25/2013 33
  34. 34.  FDA will not share information with a third party except through a FOIA request i.e. FDA will not tell Applicant anything about what is in the DMF. 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.” Drug Regulations : Online Resource for Latest Information 2/25/2013 34
  35. 35.  Holder must follow appropriate regulations (21 CFR 314.50(d)(1) for ANDAs and NDAs and 21 CFR 312.23(a)(7) for INDs Recommend that holder follow appropriate Guidances Facilities information (former Type I) not necessary Address of facility is sufficient. Additional requirements under GDUFA. Recommend include statement of compliance with Current Good Manufacturing Practices (CGMPs) Drug Regulations : Online Resource for Latest Information 2/25/2013 35
  36. 36.  Format: Common Technical Document (CTD) CTD is a structured format that permits efficient life-cycle management, which is important for DMFs and for electronic submissions ( Link ) Drug Substance: ( Link) ICH Guidelines: ( Link) ( Link ) Drug Regulations : Online Resource for Latest Information 2/25/2013 36
  37. 37.  The DMF will be reviewed ONLY when it is referenced in an Application or another DMF. An LOA does two things: ◦ Grants FDA authorization to review the DMF ◦ Grants the Authorized Party the right to incorporate the information in the DMF by reference. The holder MUST submit an LOA (2 copies for paper) to the DMF THEN send a copy to the APPLICANT APPLICANT submits copy of LOA in their Application. ONLY mechanism to trigger complete technical review of the DMF Drug Regulations : Online Resource for Latest Information 2/25/2013 37
  38. 38.  LOA must contain a specific reference to a particular item in the DMF. Specify the item by its code name, page number and, most importantly, DATE OF THE SUBMISSION as it appears on the cover letter of that submission (not an internal document date) Volume number not useful When the Authorized Party (AP) changes its name, the DMF holder should issue a new LOA and send a copy to new AP. When holder changes name the DMF holder should issue a new LOA and send a copy to all APs. Drug Regulations : Online Resource for Latest Information 2/25/2013 38
  39. 39.  It is not necessary to resubmit an LOA on a periodic basis. However, the list of authorized parties should be submitted in the Annual Report Withdrawal of Authorization: If a DMF holder withdraws authorization for a customer to reference the DMF this should be submitted as a “Withdrawal of Authorization” document. Drug Regulations : Online Resource for Latest Information 2/25/2013 39
  40. 40.  There is no requirement to submit ANY type of application in electronic format. This is projected to change under FDASIA two years after final guidance issued. However ALL electronic applications MUST follow the Electronic Common Technical Document (ECTD), unless a waiver is granted. No waivers granted for DMFs How to submit: ( Link) Can convert paper DMF to EDMF but once electronic, cannot submit paper, even for LOA. Drug Regulations : Online Resource for Latest Information 2/25/2013 40
  41. 41.  Not required under any regulation Regulations require that the DMF “…contain a complete list of each person currently authorized to incorporate by reference any information in the file…” See 21 CFR 314.420(d). Recommended in Guidance to permit DMF holders to fulfil this requirement on an annual basis, rather than submitting a new list whenever a new Authorized Party is added. Drug Regulations : Online Resource for Latest Information 2/25/2013 41
  42. 42.  Should contain ◦ List of authorized Parties ◦ List of all changes reported since last AR ◦ If no changes, include a statement to that effect The list of “authorized parties” is a list of the customers. It is NOT a list of individuals who work for the holder or their agent who are authorized to ADD material to the DMF. All changes in technical or administrative information (including updates to stability data) MUST be reported as amendments when they occur. See 21 CFR 314.420(c). . Drug Regulations : Online Resource for Latest Information 2/25/2013 42
  43. 43.  A DMF can be reviewed at any time when a review is triggered by reference in an APPLICATION. Therefore, DMF must be up-to-date at the time of review. If changes have been made but not reported to DMF, reviewer can waste valuable time (on the APPLICANT’s clock) reviewing obsolete information. Drug Regulations : Online Resource for Latest Information 2/25/2013 43
  44. 44.  Closure by Holder: ◦ Holder submits a Closure request to DMF ◦ Entry into database changes status to “Closed.” Unavailable for review. Closure by FDA ◦ If a DMF has not had an Annual Report in three years, FDA issues an ◦ Overdue Notice Letter (ONL).After ONL issued, holder can retain activity of DMF ONLY by submitting an Annual Report. ◦ If no response to ONL in time period specified in ONL (90 days), FDA can change the status to “Closed.” Unavailable for review Drug Regulations : Online Resource for Latest Information 2/25/2013 44
  45. 45.  Reactivation of a Closed DMF Holder submits a “Reactivation” ◦ Should contain a complete copy of the DMF, containing any revisions since the last submission. ◦ Contact DMF Question for a request for an exception to the recommendation to resubmit the entire DMF. Entry of a Reactivation into DARRTS changes status to “Active” and the DMF is available for review. Status of DMF shows up on DMF Web site list Drug Regulations : Online Resource for Latest Information 2/25/2013 45
  46. 46.  Types of Submissions in DARRTS: ◦ Annual Reports ◦ Original: Includes changes in technical information (technical amendments) ◦ General: Includes changes in administrative information (administrative amendments) ◦ Letters of Authorization (LOAs) General and Original Submission Types have a number of Categories/Subcategories (CSCs). List of CSCs at DMF Web site. Header of Cover Letter (Transmittal Letter) should identify all Submission Types and CSCs included in the Submission. Templates for different types of letters at DMF Web site. Multiple Submissions, Categories and Subcategories may be submitted at the same time as long as they are specified in the header to the Cover Letter. Drug Regulations : Online Resource for Latest Information 2/25/2013 46
  47. 47.  Amendment = A report of a change, deletion or addition of technical or administrative information. NOT a supplement (Supplements apply only to approved applications) All amendments should be paginated within the submission. Pages that replace an already-numbered page from a previous submission should also contain the page number in the current submission Drug Regulations : Online Resource for Latest Information 2/25/2013 47
  48. 48.  DMFs ARE NEITHER APPROVED NOR DISAPPROVED A DMF is reviewed to determine whether it is adequate to support the particular Application that references it. Drug Regulations : Online Resource for Latest Information 2/25/2013 48
  49. 49.  A DMF is reviewed for Administrative content when it is received. This may take 2-3 weeks. If the DMF is acceptable from an administrative point of view an Acknowledgement Letter will be issued, notifying the holder of the DMF number. If it is not acceptable from an administrative point of view, the holder will be notified of what deficiencies need to be corrected. Drug Regulations : Online Resource for Latest Information 2/25/2013 49
  50. 50.  When the reviewer receives an application that references a DMF, the reviewer triages the DMF to determine whether it requires review. If information has been reviewed previously and found acceptable and there has been no new information, the DMF does not need to be reviewed. See MAPP 5015.4: Chemistry Reviews of DMFs for Drug Substances/Intermediates (DSI) (Link) Drug Regulations : Online Resource for Latest Information 2/25/2013 50
  51. 51.  All DMFs are subject to a complete review for technical information only when all of the following events occur:1. The DMF holder submits a Letter of Authorization (LOA) in two copies (if a paper submission) to the DMF. This LOA should contain the DMF number2. The holder sends a copy of the LOA to the authorized party (customer).3. The customer submits an application to the FDA that contains a copy of the LOA. Drug Regulations : Online Resource for Latest Information 2/25/2013 51
  52. 52.  The Generics Drug User Fee Act (GDUFA) section of the Food and Drug Administration Safety and Innovation Act” (S.3187 )includes ◦ provisions for fees for DMF, ◦ an initial completeness assessment , ◦ communications with DMF holders, and ◦ electronic submission of DMFs. GDUFA applies only to Type II DMFs for drug substances (Active Pharmaceutical Ingredients (APIs)) used to support Abbreviated New Drug Applications (ANDAs). It does not apply to any other type of DMF or to Type II DMFs used to support NDA or INDs. Drug Regulations : Online Resource for Latest Information 2/25/2013 52
  53. 53.  Fee 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: ◦ Original ANDA ◦ An amendment to an ANDA ◦ A Prior Approval Supplement (PAS) ◦ An amendment to a PAS Drug Regulations : Online Resource for Latest Information 2/25/2013 53
  54. 54.  When A DMF fee is not Required For ANDAs that are part of the backlog For submissions not part of GDUFA (INDs, NDAs, Changes Being Effected (CBE) 0 or 30 supplements) For any non-Type II DMF (Type IV DMF for an excipient) For any Type II DMF that is not referenced as the API ◦ DMFs for API intermediates ◦ DMFs for drug product manufacturing intermediates DMFs for Drug Products For submissions reporting a change to the DMF that had established a relationship to the ANDA before GDUFA Issuing an updated Letter of Authorization that does not establish a new relationship to the ANDA submission Drug Regulations : Online Resource for Latest Information 2/25/2013 54
  55. 55.  Under GDUFA an important goal for the DMF holder is to get the DMF to “Available for Reference” status so referencing ANDAs can be filed Only ANDA submissions which reference DMFs for APIs that are “Available for Reference” can be received and filed by FDA Under GDUFA, an “Available for Reference” DMF must meet two requirements: ◦ The DMF fee must be paid ◦ The DMF must pass the Completeness Assessment Payment of the DMF fee is the trigger that automatically places the DMF in queue for the Completeness Assessment Drug Regulations : Online Resource for Latest Information 2/25/2013 55
  56. 56.  How fee Payment impacts filing: Fee payment status check is performed by Office of Management (OM) within several days of the ANDA being submitted to FDA ANDA sponsor will receive a notification from OM (Office of Management) that the DMF fee is due and ask that you pay within a 20- calendar day grace period. Note that FDA does not care who pays the fee…ANDA sponsor or DMF holder is ok. After 20 days, if 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. When all fees are paid (including the DMF fee) the ANDA is placed in queue at OGD for the comprehensive filing review and the DMF is automatically placed in queue for the Completeness Assessment. Drug Regulations : Online Resource for Latest Information 2/25/2013 56
  57. 57.  How fee Payment impacts filing: Fee payment status check is performed by Office of Management (OM) within several days of the ANDA being submitted to FDA ANDA sponsor will receive a notification from OM (Office of Management) that the DMF fee is due and ask that you pay within a 20- calendar day grace period. Fees can be paid by ANDA sponsor or DMF holder After 20 days, if the DMF fee is still NOT paid, the ANDA submission will be Refuse to Receive due to User Fee obligation not satisfied. Drug Regulations : Online Resource for Latest Information 2/25/2013 57
  58. 58.  How fee Payment impacts filing: ◦ 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. ◦ When all fees are paid (including the DMF fee) the ANDA is placed in queue at OGD for the comprehensive filing review and the DMF is automatically placed in queue for the Completeness Assessment. Drug Regulations : Online Resource for Latest Information 2/25/2013 58
  59. 59.  FDA will undertake an initial CA to determine the following: Is the DMF active? Has the fee been paid? Has the DMF been previously reviewed? Does the DMF pertain to a single drug substance? Does the DMF contain certain administrative information? Does the DMF contain all the information necessary to enable a scientific review? Is the DMF written in the English language? Drug Regulations : Online Resource for Latest Information 2/25/2013 59
  60. 60.  FDA will conduct the initial CA by completing a series of questions listed in the GDUFA Initial Completeness Assessment Checklist for Type II API DMFs. ( Link ) This guidance provides additional detail on the kinds of information FDA will confirm when performing an initial CA on a DMF. Drug Regulations : Online Resource for Latest Information 2/25/2013 60
  61. 61.  How the Completeness Assessment impacts filing of the ANDA: When the OGD filing review decision on the ANDA is ready to be made the DMF must be Available for Reference (i.e. the DMF must have passed the Completeness Assessment) If the DMF is not Available for Reference, the ANDA will be Refuse to Receive by OGD for technical reasons and only a 75% refund of the ANDA submission fee can be granted. OGD can not guarantee that the Completeness Assessment of the DMF will be finished during the filing window of the ANDA. To reduce the risk of losing 25% ANDA submission fee due to DMF issues Recommended to pay the DMF fee at least 3-months prior to ANDA submission (allow even more time for expedited ANDAs) Drug Regulations : Online Resource for Latest Information 2/25/2013 61
  62. 62.  Fee collection is processed in FDA for GDUFA by OFM (Office of Financial Management), who manage the payment infrastructure and OM (Office of Management) who manage and track the user fee obligations. Two common cases for fee payment: ◦ Paying DMF fees for DMFs which are not yet filed with FDA ◦ Paying DMF fees for DMFs which are already filed with FDA Amount of the DMF fee for GDUFA year one is $21,340. Drug Regulations : Online Resource for Latest Information 2/25/2013 62
  63. 63.  FDA performs Administrative Review of submitted DMF If DMF is administratively complete, FDA sends the Filing Acknowledgement to holder and DMF is Active. If DMF is not administratively complete, FDA sends a letter to firm identifying issues. DMF is not Active until issues are resolved. Drug Regulations : Online Resource for Latest Information 2/25/2013 63
  64. 64.  CDER/OM (Office of Management) confirms User Fee payment and sets the status for the DMF. Once the user fee status is “Met” OGD can perform the completeness assessment. Drug Regulations : Online Resource for Latest Information 2/25/2013 64
  65. 65.  New DMF Correspondences and Meetings ◦ DMF Complete Response (CR) letter ◦ DMF No Further Comments letter ◦ DMF Incomplete Letter ◦ 10-day teleconferences ◦ List of “Available for Reference” DMFs posted on FDA website Drug Regulations : Online Resource for Latest Information 2/25/2013 65
  66. 66.  The DMF CR Template has been in use since mid- October 2012 and contains the following sections ◦ Chemistry Deficiencies (if applicable) ◦ Microbiology Deficiencies (if applicable) ◦ Facilities information (if available)  Standard language approved by the Office of Compliance  No further questions if facilities acceptable  Inspections/evaluations pending 2/25/2013 66
  67. 67.  FDA will not delay issuing DMF CR letters based on pending compliance evaluations or inspections. Letters will reflect the compliance status of facilities at the time the letter issues Deficiencies from any related consults are included under the discipline that requested the consult 2/25/2013 67
  68. 68.  The DMF letters will issue before the ANDA CR letter for a given review cycle to comply with ANDA CR requirements. DMF CR letters will be referred to in the ANDA CR letter along with instructions to the applicant not to respond until the DMF holder has indicated that they have submitted a complete response to the DMF CR letter. Drug Regulations : Online Resource for Latest Information 2/25/2013 68
  69. 69.  Note that statements in the DMF amendment deferring response to a future submission are not acceptable. DMF must notify the ANDA sponsor when they submit their response Drug Regulations : Online Resource for Latest Information 2/25/2013 69
  70. 70.  The Commitment letter states: • “Once a DMF has undergone a complete review and the ANDA referencing same is either approved or tentatively approved – at such time there being no further outstanding deficiencies to the DMF – FDA will issue the DMF holder a letter to indicate that the DMF does not have any further open matters as part of the review associated with the referencing ANDA.” Issued at approval of the ANDA, not when the DMF is first deemed adequate Drug Regulations : Online Resource for Latest Information 2/25/2013 70
  71. 71.  Not to be construed as an indication of any future status of the DMF (i.e. not equivalent to an approval letter) Applies only in the context of the referencing ANDA and not any other ANDA which may be referencing it Separate letters issued to the DMF holder for each referencing ANDA Drug Regulations : Online Resource for Latest Information 2/25/2013 71
  72. 72.  Issued to communicate issues discovered during the Completeness Assessment Comments in the letter will describe any issues and the additional information that is needed to address the issues DMF holders need to respond with an amendment as quickly as possible to avoid adversely impacting the filing of an ANDA Drug Regulations : Online Resource for Latest Information 2/25/2013 72
  73. 73.  Cover letter of the amendment should indicate that the submission is a “Response to DMF Incomplete” Notification instructions in the fax coversheet need to be followed to avoid delays in updating the Completeness Assessment Drug Regulations : Online Resource for Latest Information 2/25/2013 73
  74. 74.  Specific type of teleconference described in the commitment letter 30 minute t-con for first cycle deficiency letters limited to the contents of the letter To qualify, a written request must be received by FDA within 10 days of receiving the letter Drug Regulations : Online Resource for Latest Information 2/25/2013 74
  75. 75.  Contact information for requesting these teleconferences is included in the DMF CR letter Meeting timeframe is at the discretion of OGD and availability of involved parties There are limits of one teleconference per DMF holder per month Drug Regulations : Online Resource for Latest Information 2/25/2013 75
  76. 76.  Required by the GDUFA legislation Comprehensive list of all Type II DMFs for APIs that have paid the DMF fee and passed a Completeness Assessment Updated list is posted on the FDA website on a weekly basis Once the DMF is on the list it remains on the list unless fee payment is withdrawn or the DMF has a status other than “active” Drug Regulations : Online Resource for Latest Information 2/25/2013 76
  77. 77.  New requirement in the GDUFA legislation Drug substance (Type II) DMFs must be deemed “available for reference” by the HHS Secretary to be referenced by an ANDA Two things must happen for the DMF to be considered “available for reference” ◦ 1 DMF Fee must be paid ◦ 2. DMF must pass a “completeness assessment” Drug Regulations : Online Resource for Latest Information 2/25/2013 77
  78. 78.  ANDAs can only be filed by OGD if all DMFs for the drug substance(s) are “available for reference” Improve quality of the submission Improve the efficiency of the scientific review A “complete” DMF is not necessarily adequate to support approval of an ANDA. Drug Regulations : Online Resource for Latest Information 2/25/2013 78
  79. 79.  DMF Fee is a one-time fee Not to be confused with the facility fee related to the drug substance manufacturing facility Payment of the DMF fee triggers the Completeness Assessment process in OGD DMF Fee is required when the referencing ANDA is submitted Drug Regulations : Online Resource for Latest Information 2/25/2013 79
  80. 80.  DMF Fee may be paid independent of a referencing ANDA in order to get a completeness assessment and be to listed on the FDA’s “Available for Reference” webpage. DMF Fee may be paid at the strategic timing according to the referencing ANDA submission ◦ Requires proactive communication with ANDA applicant ◦ Risks of delaying the ANDA filling if DMF fee has not been paid Drug Regulations : Online Resource for Latest Information 2/25/2013 80
  81. 81.  This presentation is compiled by “ DrugRegulations” from freely available resources like the FDA on the World wide web.  “Drug Regulations” is a non profit organization which provides free onlineresource to the Pharmaceutical Professional. Visit http://www.drugregulations.org for latest information from the world of Pharmaceuticals. Drug Regulations : Online Resource for Latest Information 2/25/2013 81

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