Drug Master Files14

Drug Master Files (DMFs)This site contains lists of Drug Master Files (DMFs) as well as information concerning submission of DMFs. The list is updated quarterly, although there may be delays of up to a month. See below for information regarding the current DMF Guideline.Only an Annual Report is considered to be sufficient to prevent an Overdue Notice Letter (ONL) from being sent.A response to an Overdue Notice L1etter (ONL) to retain activity of a DMF MUST be identified as an Annual Report (with additional amendments as applicable) and contain the information listed below for an Annual Report. Responses to ONL2s that are not labeled as Annual Reports or that state that an update will be submitted in the future are NOT sufficient to keep the DMF in active status.∙Important Guidance Information3∙Download DMF Files 4QUESTIONS OR COMMENTS ABOUT DMFs∙Please address ALL comments or questions regarding DMFs to dmfquestion@.∙All inquiries MUST have an entry in the "Subject" field of the e-mail that indicates what the e-mail is about and how it relates to DMFs.∙Due to concerns about viruses and the amount of "spam" received by this account, e-mails with subject fields that are blank or contain meaningless text strings or contain only question marks will not be opened.∙If the inquiry concerns a specific DMF, the DMF number should be in the subject field of the message.∙Other inquiries unrelated to DMFs should go todruginfo@.DMF LISTSThe list of DMFs is current as of December 31, 2010, through DMF 24550. Changes to the DMF activity status, DMF type, holder name, and subject made since the last update of September 30, 2010 are included.Other lists are:1.New DMFs since the last list.2. A list of changes in DMF activity status, DMF type, holder name,and subject.The lists are available in Microsoft Excel and in ASCII(tab-delimited)5. Please note that only ACTIVE DMFs have been sorted into different types. Note that the ASCII file contains all the DMFs. There are no ASCII files for the active DMFs and the different types of active DMFs.For the Excel files, the following lists are provided as different worksheets within one Excel file6.∙All DMFs∙Active DMFs∙Active Type II DMFs∙Active Type III DMFs∙Active Type IV DMFs∙Active Type V DMFsThe following lists are still provided as separate files.∙New DMFs since the last list7∙Changes8TYPES OF DMFsThe types of DMFs are:∙Type I Manufacturing Site, Facilities, Operating Procedures, and Personnel (no longer applicable)∙Type II Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product∙Type III Packaging Material∙Type IV Excipient,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∙Type V FDA Accepted Reference InformationSTATUS OF DMFS∙“A” = Active. This means that the DMF was found acceptable for filing, administratively, and is up-to-date. The ∙“I” = Inactive∙“N” = Not an assigned number∙“P” = DMF Pending Filing ReviewThe status conveys no information about whether DMF has been reviewed for technical content.INACTIVE STATUS OF DMFsThere are three reasons for a DMF to be listed as INACTIVE:1.The DMF has been CLOSED. There are two mechanisms for closure ofa DMF.a.CLOSED BY THE HOLDER: The holder requested that the DMF beclosed (or retired, closed, inactivated, or withdrawn) bysubmission of a Closure Request . Submission of a ClosureRequest will close the DMF, which can only be returned toACTIVE status by submission of a Reactivation.b.CLOSED BY THE FDA: The holder did not respond to an OverdueNotification Letter within 90 days to update the DMF.2.OVERDUE FOR UPDATE: For DMFs submitted before December 31, 2007,a DMF is considered OVERDUE FOR UPDATE when there have been no AnnualReports submitted since that date.Note that only an Annual Report is considered to be sufficient to prevent an Overdue Notice Letter (ONL) from being sent.Note that the sta tus “INACTIVE” in the list does not distinguish among the reasons listed above.Overdue Notification Letters: DMFs must be current at the time of review. According to the regulations regarding DMFs (21 CFR314.420(c)9):“Any addition, change, or deletion of information in a drug master file (except the list required under paragraph (d) of this section) is required to be submitted in two copies and to describe by name, reference number, volume, and page number the information affected in the drug master file.”The Guideline for Drug Master Files10 (September 1989), recommends that DMF holders update their DMFs annually (see below under Annual Reports).In order to ensure that DMFs are current, FDA is in the process of sending “Overdue Notification Letters” (ONLs) to DMF holders for DMFs that are OVERDUE FOR UPDATE (see above). If a DMF holder does not respond to this letter within 90 days with the submission of an Annual Report, the DMF will be considered “CLOSED BY THE FDA.” It will then be RETIRED.Note that there is a backlog in sending out ONLs.11 DMF holders can forestall the sending of an ONL by updating their DMFs, following the procedure below under “Retaining the Activity of a DMF.”Retirement of DMFsA DMF can be RETIRED ONLY if it has been CLOSED.. A RETIRED DMF is unavailable for review.Retaining the Activity of a DMFA DMF holder that wants to retain the activity of a DMF that is listed as Inactive and that has not been CLOSED should submit an Annual Report (two copies). This process should also be used to respond to an ONL.12The cover letter should specify that it is an “Annual Report.”GUIDANCESGuideline for Drug Master Files13 The version posted on the web is the current version. Note that the address for submitting DMF documentation to the FDA in the Guidance has been superseded by the Beltsville address below. Please address question regarding the DMF Guideline to dmfquestion@.Note: FDA regulations require that all submissions to INDs and NDAs that are in a foreign language have “complete and accurate translations.” The same is true for DMFs. A “certified” translation is not required.MORE INFORMATION ABOUT DMFsSee slides from DIA Webinar, 2007/Revised 20081914All links to FDA Web sites in the slides 13, 16 are outdated.Slide 24: Desk copies not accepted.Slide 27: Administrative changes may be submitted along with an Annual Report ONLY if they are clearly identified in the coverletter.Slide 30: The title of the DMF which will appear on the list of DMFs will be “MATERIAL manufacture in LOCATION OF COM PANY A for COMPANYB.” The name of Company A will not appear on the list (see discussionbelow under HOLDER NAMES15The recommendations in the DMF Guidance are, in general, still applicable. However the information below provides additional information or clarification of the recommendations in theGuidance. This information provided below falls into three categories:Category 1: Recommendations which are no longer applicable due to changes in regulations or guidances.Category 2: Additional clarification of recommendations in the Guidance. Category 3: New information for aspects of DMF filing that was not in effect when the Guidance was written.Address for Filing Original DMFs and Subsequent DMF Documents (Category 3)Food and Drug AdministrationCenter for Drug Evaluation and ResearchCentral Document Room5901-B Ammendale RoadBeltsville MD 20705-1266Pre-assignment of DMF Numbers (Category 3)Requests for preassigned DMF numbers will be granted ONLY for electronic DMFs.Format and Content of the Chemistry, Manufacturing, and Controls Section of an Application (Category 1)The “Guideline for the Format and Content of the Chemistry, Manufacturing, and Controls Section of an Application” cited in the DMF Guidance has been withdrawn. DMFs may be submitted following the format recommended in the "Guidance for Industry M4Q: The CTD - Quality16".DMFs that cover multiple items e.g. Type III DMFs for components of container-closure systems or Type IV DMFs for flavors, can be submitted in CTD format. The technical information can be in Module 3, following the outline in the Drug Substance Section. The different sections within 3.2.S. can be populated as appropriate. Each product e.g. different flavors, would have a different name e.g. 3.2.S.[Flavor 1], 3.2.S.[Flavor 2]. Information that is common to different products e.g. analytical procedures can be accessed by reference (or links in the case of an electronic DMF) from the relevant section for that product e.g.3.2.4.2 [Flavor 1].DMF holders submitting DMFs for Sterile Manufacturing can consult the Manual of Policies and Procedures 5040.1: Product Quality Microbiology Information in the Common Technical Document - Quality (CTD-Q)17Products manufactured at separate facilities do not need to be filed as separate sections unless the manufacturing processes are different.Module 1 should contain the following informationSection 1.2: Cover Letter and Statement of CommitmentSection 1.3: Administrative Information1.3.1 Contact/sponsor/Applicant information1.3.1.1 Change of address or corporate nameCan be used to supply addresses of DMF holder and manufacturing and testing facilities1.3.1.2 Change in contact/agentCan be used to supply the name and address of contact persons and/or agents, including Agent Appointment Letter.1.4.1 - Letter of Authorization (LOA)Submission by the owner of information, giving authorization for the information to be used by another. An Agent Appointment Letter is NOT an LOA and should not be called “Letter of Authorization” and should not be submitted in Section 1.4.11.4.2 - Statement of Right of ReferenceSubmission by recipient of a Letter of Authorization with a copy of the LOA and statement of right of reference.1.4.3 - List of authorized persons to incorporate by referenceThis list should be submitted in DMF annual reports.The language in the following sentence in the DMF Guidance, Section VII.B.1, has given rise to some confusion on the part of DMF holders.“A DMF is required to contain a complete list of persons authorized to incorporate information in the DMF by reference [21 CFR314.420(d)].”It does NOT mean a list of individuals within the DMF holder’s c ompany who are authorized to submit information to the DMF.The language in the CFR is more explicit:“The drug master file is required to contain a complete listof each person currently authorized to incorporate by reference any information in the file, identifying by name, reference number, volume, and page number the information that each person isauthorized to incorporate.”TYPES OF DMFsType I DMFs (Category 1)Type I DMFs are no longer accepted per a Final Rule published January 12, 2000 (65 FR 177618). See Type V DMFs below.Holders of Type II, III, and IV DMFs should not place information regarding facilities, personnel or general operating procedures in these DMFs. Only the addresses of the DMF holder and manufacturing site and contact personnel should be submitted. See Administrative Information in a DMF.Type II DMFs (Category 1)For Type II DMFs filed in CTD-Q format, Module 2 is expected.Drug SubstanceType II DMFs for drug substances may be submitted in the formatfor "Drug substance" in the "Guidance for Industry M4Q: TheCTD - Quality19".(Category 3) Drug Substance:See the current Guideline for Submitting SupportingDocumentation in Drug Applications for the Manufacture of DrugSubstances20.Drug Product:Type II DMFs for drug products may be submitted in the formatfor "Drug product" in the "Guidance for Industry M4Q: The CTD- Quality21".(Category 3) Drug Product.See the Guideline For Submitting Supporting Documentation InDrug Applications For The Manufacture Of Drug Products.22Separate DMFs should be submitted for drug substances and drugproducts.Type III DMFs (Category 1)The applicable Guidance for Type III DMFs is the “Guidance for Industry: Container Closure Systems for Packaging Human Drugs andBiologics: Chemistry, Manufacturing, and ControlsDocumentation”23 and Questions and Answers24. (Category 3)A new Manual of Policies and Procedures covering reviewer responsibilities for review of Type III DMFs has been implemented. MAPP 5015.5 CMC Reviews of Type III DMFs for Packaging Materials 25Type V DMFs (Category 3)The following types of DMFs may be filed as Type V DMFs without requesting prior clearance from FDA.∙Manufacturing Site, Facilities, Operating Procedures, and Personnel for sterile manufacturing plants. See Guidance forIndustry for the Submission Documentation for SterilizationProcess Validation in Applications for Human and Veterinary Drug Products26.∙Contract Facilities for the manufacture of biotech products. See Draft Guidance for Industry: Submitting Type V Drug Master Files to the Center for Biologics Evaluation and Research 27For other submissions as Type V DMFs the holder must request permission from FDA before filing a Type V DMF. (21 CFR 314.420(a)28(5)). Prospective Type V DMF holders may send their request to dmfquestion@, explaining the necessity for filing the information in a Type V DMF.Administrative Information in a DMF (Category 3)The only elements of the administrative information that should be in a DMF are:∙The name and address of the holder∙The name and address of manufacturing facility∙For the contact person:o Nameo Mailing Addresso Telephone numbero Fax numbero E-mail address∙The name and address of the agent (if applicable)∙For the contact person at the agent (if applicable):o Nameo Mailing Addresso Telephone numbero Fax numbero E-mail addressThe appointment of an Agent is optional. See discussion below under “Agents”Submission of Amendments, Annual Reports, and Letters of Authorization (Category 3)To facilitate processing of documents that are submitted to an existing DMF, please list the Submission Type and the Category/Subcategory of the document in bold type in the header on the transmittal letter. More than one Submission Type/Category/Subcategory can be used but all must be listed.If updated stability data is submitted at the same time as an Annual Report, the heading of the Cover Letter should state:Annual ReportQuality/StabilityPlease use the following as a guide. Note that only Amendments have Categories/Subcategories.Please use the following as a guide. Note that only Amendments have Categories/Subcategories.Submission Types∙Annual Report∙Letter of Authorization∙Closure Request∙Reactivation (Used only when a DMF has been Closed29.)∙Amendment: The types of information should be specified as follows:∙Category: QualitySubcategory under Quality Category with corresponding CTD Sections.Changes to a Subsection e.g. changes in S.2.3 Control ofMaterials not specifically listed below should be reported as the next level up e.g. should be reported as Manufacture Information S.2.o New item: Additional item e.g. flavor added to a multi-item DMFo Controls Information (specifications) S.4o Dissolution Data (Usually applies to drug product only) P.5o Facility Information (changes in manufacturing and or testing sites) S.2.1o Formulation Information (Usually applies to drug product only) P.1 and related sectionso Lot Release (batch analysis) S.4.4o Manufacture Information S.2o Microbiology Informationo New Strength (Usually applies to drug product only) P.1 and related sectionso Quality (Not covered by other subcategories)o Packaging Information (Applies to packaging of the material that is the subject of the DMF e.g. plastic bags for packaginga bulk drug substance in a Type II DMF) S.6 and P.7o Stability Information S.7 and P.8o Response to Information Requesto Response to Deficiency Letter∙Category: AdministrativeSubcategory under Administrative CategoryA response to an Overdue Notice Letter (ONL) to retain activity of a DMF MUST be identified as an Annual Report (with additional amendments as applicable) and contain the information listed below for an Annual Report. Responses to ONL s that are not labeled as Annual Reports or that state that an update will be submitted in the future are NOT sufficient to keep the DMF in active status.FDA does not send acknowledgment letters for any submission after the original DMF.Amendments or Annual Reports that cover multiple DMFs MUST have a copy submitted for each DMF.ELECTRONIC DMFs (Category 3)There is no requirement to file DMFs in electronic format. Paper DMFs will continue to be accepted. If this policy changes there will be advance notification.See Electronic Common Technical Document (eCTD)30Requesting a Pre-Assigned Application number. 31 All electronic submissions must have a pre-assigned number in order to populate in the US Regional.xml.If a DMF available in paper is being converted to electronic format, it is not necessary to request a pre-assigned number.See also Guidance for Industry: Providing Regulatory Submissions in Electronic Format — Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications32. To make sure you have the most recent versions of the specifications referenced in this guidance please check Electronic Common Technical Document (eCTD).33 Companies are encouraged to submit their DMFs in electronic form, including updating current paper DMFs. Note that all applications to CDER, including DMFs, that are submitted in electronic format MUST be in ECTD format, unless a waiver is granted34. Waivers are not granted for DMFs.All Letters of Authorization for electronic DMFs should specify that the DMF has been submitted in electronic format.Companies may convert an existing DMF in paper format to electronic format (ECTD only). In such cases DMF holders are advised to resubmit the entire DMF in CTD format as an amendment. If there are any changes in the technical content of the DMF as a result of the reformatting, e.g. addition of new information, the cover letter for the new electronic submission should specify what areas of technical information have been changed. Once the DMF holder has made an electronic submission every subsequent submission must be in electronic format (ECTD only).The ECTD format provides the backbone for the submission and a guide as to where to place information. It is not necessary to submit all Modules nor is it necessary to submit all sections within a Module. However, Module 1 is required for all eCTD submissions, as it contains the necessary administrative information to identify the DMF.Electronic signatures are accepted for electronic DMFs.LETTERS OF AUTHORIZATION (Category 2)All Letters of Authorization (LOAs) must be submitted in two copies to the DMF. A copy of the LOA must then be sent by the DMF holder to the Authorized Party (company or individual authorized to incorporate the DMF by reference). Failure to submit the LOA to the DMF may result in a delay in review of the DMF. LOAs should specify the name of the specific item being referenced and the date of the submission of information about that item. The LOA should not be called a “Letter of Access.”An LOA is required even if the DMF holder is the same company as the authorized party.AGENTS (Category 2)There is no regulatory requirement for an agent for any DMF, foreign or domestic. An agent for DMF purposes is not the same as an agent for the purposes of the Drug Listing and Registration System. (DRLS)35. Holders should not include the name of the agent for Registration purposes in the DMF. A lso note that in the US, the process of “Registration” applies ONLY to “registering” an establishment with the FDA.All “Agent Appointment Letters” for DMFs MUST be sent by the holder. FDA recommends that such letters include the phrase “appoint AGENT NAME as the agent for DMF” rather than “authorize AGENT NAME to act as the agent for DMF,” since the latter can be confused with a “Letter of Authorization.”An “Agent Appointment Letter” may be included in an original DMF.If possible, the word “Agent” should be used for the legal entity (whether a company or an individual) who is authorized to act on behalf of the DMF holder. The word “Representative” should be used for an individual who is employed by the Agent or Holder as the contact point for FDA.If a company acting as an Agent changes its name, FDA recommends that the DMF holder issue a new Agent Appointment Letter.A different agent can be appointed for different DMFs submitted by the same holder.HOLDER NAMES (Category 2)When the company that owns a DMF (DMF holder) changes its name, whether through sale of the company or simply a change in the company’s name, the DMF holder must notify FDA. See Section VII.E. in the Guideline for DMFs for further recommendations on the procedure for transferring ownership. A change in the name of a company for registration purposes under DRLS36 will not change the DMF holder name.A DMF holder is expected to retain a complete reference copy that is identical to, and maintained in the same chronological order as, their submissions to FDA (See Section IV.D.1 in the Guideline forDMFs). Therefore the old owner of the DMF is expected to transfer that copy to the new owner of the DMF.In general FDA expects the manufacturer to be the holder. If a manufacturer (Company A) of a MATERIAL wishes to have the DMF submitted by another company (Company B) and Company B wishes to act as the holder, the DMF should include statements from both companies that Company B takes full responsibility for all the information in the DMF and for all the processes and testing performed by the manufacturer. The title of the DMF which will appear on the list of DMFs will be “MAT ERIAL manufactured in LOCATION OF COMPANY A for COMPANY B.”ANNUAL REPORTS (Category 2)According to the DMF Guideline, Annual Reports are NOT to be used to report changes in the DMF. However, as described above, an Annual Report can be submitted at the same time as other information.The Annual Report should contain:1. An administrative page containing:∙Holder name∙Manufacturing Site name if different from Holder∙U.S. Agent company name (if applicable)∙Name of contact person for each of the above∙Mailing address, phone number, fax and email address of responsible individual(s)AND 2. One of the following∙Date(s) of the amendment(s) reporting changes since the last Annual Report or the original DMF filing date, whichever is most recent.Or∙ A statement that no amendments have been submitted since the last Annual Report or the original DMF filing date, whichever is most recent.AND 3. One of the following:∙ A complete list of all parties authorized to make reference to the DMF, identifying by name, reference number, volume, date, and page number the information that each person is authorized toincorporateOr∙ A statement that no changes have been made to the list of Authorized Parties since the last Annual Report or the original DMF filing date, whichever is most recent.Or∙ A statement that there are no Authorized Parties.AND 4. List of all parties whose authorization has been withdrawnNote that the DMF Guidance uses the terms “Annual Update” and “Annual Report” interchangeably. All submissions of Annual Reports should be labeled “Annual Report.”The term “Annual Update” should not be used.BIOLOGICS MASTER FILES (Category 3)Master Files submitted in support of products regulated by the Center for Biologics Evaluation and Research (CBER) should be submitted asBB-MFs37. See the CBER web site38 for the products regulated by CBER. BINDERS (Category 2)See ”FDA IND, NDA, ANDA, or Drug Master File Binders39The “binders” are actually covers. These may be ordered from theU.S. Government Printing Office (GPO)Washington, DC 20404-0001(202) 512-1800In addition these can be ordered online at∙stocknumber=017-012-00394-040∙stocknumber=017-012-00395-841One copy of the DMF should use the blue cover and one should use the red cover.Fasteners must be obtained separately. Use 2 Piece Prong Fasteners, 8 1/2" Center to Center, 3 1/2" Capacity. Binders should be used for all subsequent submissions to FDA that are more than 10 pages.FEES (Category 3)There are no fees or charges for filing a DMF or any subsequent documents.FORMS (Category 2)Certain forms are required for submission of NDAs and INDs. However there are no forms required or available for DMFs, except for the forms discussed above under Binders42.CONFIDENTIALITY OF DMFs (Category 2)The public availability of the contents of DMFs is covered in 21 CFR 314.430(e). All requests for information about DMFs beyond that provided in the tables above must be made through the CDER Freedom of Information Web site.43FILING DMFs AND PATENT EXPIRATION AND EXCLUSIVITY ISSUES (Category 2)DMFs may be filed at any time. The Patent Expiration date and the Exclusivity Expiration dates listed in the Orange Book44 have no impact on DMF filing. The submission of Abbreviated New Drug Applications (ANDAs) that reference DMFs are /subject to the regulations regarding filing of ANDAs.-Drug Master Files - All∙DMF zip file (ZIP - 2760KB)45--Drug Master Files - Excel ∙New - Excel (XLS - 94KB)46∙Changes - Excel (XLS - 230KB)47∙All - Excel (XLS - 8644KB)48--Drug Master Files - Text ∙New - Text (TXT - 42KB)49∙Changes - Text (TXT - 76KB)50∙All - Text (TXT - 2495KB)51-。