drug master file drug master file drug master file or dmf is a document prepared by a pharmaceutical manufacturer and submitted solely at its discretion to the appropriate regulatory authority in the intended drug market. there is no regulatory requirement to file a dmf. however, the document provides the regulatory authority with confidential, detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of one or more human drugs. typically, a drug master file is filed when two or more firms work in partnership on developing or manufacturing a drug product. the dmf filing allows a firm to protect its intellectual property from its partner while complying with regulatory requirements for disclosure of processing details. description drug master file (dmf) is a document containing complete information on an active pharmaceutical ingredient (api) or finished drug dosage form. an active substance master file (asmf) is the currently recognised term in europe, formerly known as european drug master file (edmf) or a us-drug master file (us-dmf) in the united states. the dmf contains factual and complete information on a drug product's chemistry, manufacture, stability, purity, impurity profile, packaging, and the cgmp status of any human drug product. a drug master file comprises two parts: the applicant's part (usa: open part), which contains all the information that the license-holder needs to assess the quality and submit a license or amendment application; and the restricted part (usa: closed part), which contains confidential information about the manufacturing procedure only disclosed to the authorities. dmfs in the united states in the united states, dmfs are submitted to the food and drug administration (fda). the main objective of the dmf is to support regulatory requirements and to prove the quality, safety and efficacy of the medicinal product for obtaining an investigational new drug application (ind), a new drug application (nda),as an abbreviated new drug application (anda), another dmf, or an export application. in united states there are 5 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 type iii packaging material type iv excipient, colorant, flavor, essence, or material used in their preparation type v fda accepted reference information dmfs in europe the content and the format for drug master file used in united states differs from that used in european countries to obtain market authorization (ma). the main objective of the edmf is to support regulatory requirements of a medicinal product to prove its quality, safety and efficacy. this helps to obtain a marketing authorisation grant. dmf lists important note the current list contains dmfs received by march 31, 2012. however the submitted date is listed for each dmf. the list of dmfs is current as of march 31, 2012, through dmf 25923. changes to the dmf activity status, dmf type, holder name, and subject made since the last update of january 11, 2012 are included. the list is available in microsoft excel and in ascii (tab-delimited). the current lists are posted (1q2012) as well as the lists from the last quarter (4q2011) to permit users to compare lists for updates and changes. types of dmfs the 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 information status of dmfs “a” = active. this means that the dmf was found acceptable for filing, administratively, and is up-to-date. “i” = inactive “n” = not an assigned number “p” = dmf pending filing review the status conveys no information about whether dmf has been reviewed for technical content. inactive status of dmfs there are three reasons to list a dmf as inactive: the holder requested that the dmf be closed (or retired, closed, inactivated, or withdrawn) by submitting a closure request. the fda closed the dmf because the holder did not respond to an overdue notification letter within 90 days by updating the dmf. the dmf was overdue for update. the fda considers dmfs submitted before march 31 overdue for update when the company has submitted no annual reports since that date. the fda considers only an annual report sufficient to prevent them sending an overdue notice letter (onl). the status inactive in the list does not distinguish among the reasons listed above. dmfs must be current at the time of review. according to fda regulations regarding dmfs (21 cfr 314.420(c)): “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 files (september 1989), recommends that dmf holders update their dmfs annually (see below under annual reports). to ensure dmfs are current, the fda sends 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 by submitting an annual report, the fda considers the dmf closed by the fda, and retired. note that the fda has a backlog sending out onls. dmf holders can forestall the sending of an onl by updating their dmfs, following the procedure below under retaining the activity of a dmf. retiring dmfs a dmf can be retired only if it is closed. a retired dmf is unavailable for review. retaining dmf activity a dmf holder that wants to retain the activity of a dmf listed as inactive and not closed must submit an annual report (two copies). this is also the process used to respond to an onl. the cover letter must specify that it is an annual report. reactivating a closed dmf a company can return a closed dmf to active status only by submitting a reactivation. the reactivation must contain a complete re-submission of the dmf, updated to meet current guidance. guidance for drug master files, the version posted on the web is the current version. the address for submitting dmf documentation to the fda in the guidance is dmfquestion@cder.fda.gov. fda regulations require that all foreign language submissions to inds and ndas have complete, accurate translations. the same is true for dmfs. the fda does not require a certified translation. more information about dmfs dmf guidance recommendations, in general, still apply. however, the information below provides additional information or clarification in three categories: category 1: recommendations no longer applicable due to changes in regulations or guidances category 2: additional clarification of recommendations in the guidance category 3: new information for dmf filing aspects not in effect when the company wrote the guidance mailing address for filing original dmfs and all subsequent dmf documents (category 3): food and drug administration center for drug evaluation and research central document room 5901-b amendale road beltsville md 20705-1266 companies send two paper copies of all submissions to an existing paper dmf to the address above. the fda does not accept submissions via e-mail or cds. companies may submitted two-sided copies of dmfs. dmf reviews (category 3) when the fda receives a dmf, they review it for administrative content. this may take 2–3 weeks. if the dmf is acceptable from an administrative point of view, the fda issues an acknowledgement letter, which notifies the holder of the dmf number. if the fda finds the dmf not acceptable from an administrative view, they notify the holder of the deficiencies they must correct. the fda reviews the dmf for technical information only after the following events occur: the dmf holder submits a letter of authorization (loa) in two copies to the fda. this loa must contain the dmf number. the holder sends a copy of the loa to the authorized party (customer). the customer submits an application to the fda that contains a copy of the loa. pre-assignment of dmf numbers (category 3) the fda grants requests for preassigned dmf numbers for electronic or paper dmfs. (see requesting a pre-assigned application number.) format and content of the application's chemistry, manufacturing, and controls section (category 1) companies submit dmfs following the format recommended in the guidance for industry m4q: the ctd - quality. conversion to common technical document companies may convert an existing dmf in non-ctd format to ctd format. in such cases, the fda advises dmf holders to submit an amendment that contains all applicable ctd-specified sections to the material in the dmf. each section must be complete and current. for drug substances and excipients, companies must submit all sections of 3.2.s in module 3. for drug products, companies must submit all sections of 3.2.p in module 3. if the reformatting causes changes in the dmfs technical content—e.g., adds new information—the cover letter for the new submission must describe these changes. dmfs in ctd format must follow ctd guidance, e.g., be paginated within each section. this supersedes dmf guidance. for conversion of a paper dmf to electronic ctd format, see electronic dmf. 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. technical information can be in module 3, following the outline in the drug substance section. sections within 3.2.s. can be populated as appropriate. each product, such as different flavors, must have a different name—e.g. 3.2.s., 3.2.s.. information 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 . dmf holders who submit 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). companies don't have to file separate sections for the same product manufactured at separate facilities unless the manufacturing processes are different. module 1 must contain the following information section 1.2: cover letter and statement of commitment section 1.3: administrative information 1.3.1 contact/sponsor/applicant information 1.3.1.1 change of address or corporate name can be used to supply addresses of dmf holder and manufacturing and testing facilities 1.3.1.2 change in contact/agent can 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 1.4.1 1.4.2 - statement of right of reference submission by recipient of a letter of authorization with a copy of the loa and statement of right of reference. submitted in a dmf only when another dmf is referenced. 1.4.3 - list of authorized persons to incorporate by reference this list should be submitted in dmf annual reports. section 1.12.14 environmental analysis: see environmental assessment the language in the following sentence in the dmf guidance, section vii.b.1, has confused some dmf holders: “a dmf is required to contain a complete list of persons authorized to incorporate information in the dmf by reference .” it does not mean to say that a company must list all individuals in the dmf holder's company who are authorized to submit information to the dmf. the language in the cfr is clearer: “the drug master file is required to contain a complete list of 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 is authorized to incorporate.” types of dmfs type i dmfs (category 1) the fda no longer accepts type i dmfs, per a final rule published on january 12, 2000 (65 fr 1776). see type v dmfs below. holders of type ii, iii, and iv dmfs must not place information regarding facilities, personnel, or general operating procedures in these dmfs. they should only submit dmf holder addresses, manufacturing sites, and contact personnel. see administrative information in a dmf. type ii dmfs (category 1) for type