Seminar On Drug Master File 4h491c

Seminar on

Submitted by

Kuldeep Saikia M.Pharm 2nd semester Roll No:01

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What is it actually

• A Drug Master File (DMF) is a reference document that provides information about specific processes or components used in the manufacturing, processing, and packaging of a drug. • Drug Master File (DMF) is a document containing complete information on an active pharmaceutical ingredient(API) and finished drug dosage form.

But why? • Maintain confidentiality of proprietary information (e.g., Manufacturing procedure) for the holder • Permit review of information by reviewers in the Center for Drug Evaluation and Research (CDER) to applications submitted by one or more applicants

Type of DMFs • Originally Five Types i. Manufacturing plant information ii. Drug substance, drug product, intermediates and material used in their manufacture iii. Packaging iv. Excipients v. Other Usually clinical, toxicological

Current Types of DMFs • Now Four Types (Numbering retained to avoid confusion) i. Drug substance, drug product, intermediates and material used in their manufacture ii. Packaging iii. Excipients iv. Other Sterile manufacturing plants, biotech contract facilities, clinical, toxicological

dmf contents A. Types of DMFs Type I: Manufacturing plant information Type I DMF is recommended for a person outside of the United States to assist FDA in conducting on site inspections of their manufacturing facilities. The DMF should describe the manufacturing site, equipment capabilities, and operational layout. The description of the site should include acreage, actual site address, and a map showing its location with respect to the nearest city. An aerial photograph and a diagram of the site may be helpful. A diagram of major production and processing areas is helpful for understanding the operational layout. Major equipment should be described in of capabilities, application, and location. Make and model would not normally be needed unless the equipment is new or unique.

Type ƖƖ: Drug substance, drug product, intermediates and material used in their manufacture It is limited to a single drug intermediate, drug substance, drug product, or type of material used in their preparation. 1.Drug Substance Intermediates, Drug Substances, and Material Used in Their Preparation Summarize all significant steps in the manufacturing and controls of the drug intermediate or substance. Detailed guidance on what should be included in a Type II DMF for drug substance. 2.Drug Product Manufacturing procedures and controls for finished dosage forms should ordinarily be submitted in an IND, NDA, ANDA, or Export Application. If this information cannot be submitted in an IND, NDA, ANDA, or Export Application, it should be submitted in a DMF.

Type III: Packaging Material Data ing the acceptability of the packaging material for its intended use should also be submitted as outlined in the "Guideline for Submitting Documentation for Packaging for Human Drugs and Biologics." Type IV: Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation Each additive should be identified and characterized by its method of manufacture, release specifications, and testing methods. Type V: FDA Accepted Reference Information FDA discourages the use of Type V DMF's for miscellaneous information, duplicate information, or information that should be included in one of the other types of DMF's. If any holder wishes to submit information and ing data in a DMF that is not covered by Types I through IV, a holder must first submit a letter of intent to the Drug Master File Staff. FDA will then the holder to discuss the proposed submission.

B.General Information and Suggestions  Environmental Assessment Type II, Type III, and Type IV DMF's should contain a commitment by the firm that its facilities will be operated in compliance with applicable environmental laws.  Stability Stability study design, data, interpretation, and other information should be submitted,

Some definitons  Agency: the Food and Drug istration.  Agent or representative: any person who is appointed by a DMF holder to serve as the for the holder.

 Applicant: any person who submits an application or abbreviated

application or an amendment or supplement to them to obtain FDA approval of a new drug or an antibiotic drug and any other person who owns an approved application.

 Drug product: a finished dosage form, for example, tablet, capsule,

or solution, that contains a drug substance, generally, but not necessarily, in association with one or more other ingredients.

 Drug substance: an active ingredient that is intended to furnish

pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the human body, but does not include intermediates used in the synthesis of such ingredient.

 Export application: an application submitted under section 802 of the Federal Food, Drug, and Cosmetic Act to export a drug that is not approved for marketing in the United States.

 Holder : a person who owns a DMF.  Letter of authorization: a written statement by the holder or designated agent or representative permitting FDA to refer to information in the DMF in of another person's submission.

 Person:

includes individual, partnership, corporation, and association. (Section 201(e) of the Federal Food, Drug, and Cosmetic Act.).

 Sponsor: a person who takes responsibility for and initiates a

clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization.

istrative A. Original Submissions a. Names and addresses of the following: (1) DMF holder. (2) Corporate headquarters. (3) Manufacturing/processing facility. (4) for FDA correspondence. (5) Agent(s) if any b. The specific responsibilities of each person listed in any of the categories in Section IV.B.1.a. c. Statement of commitment. A signed statement by the holder certifying that the DMF is current and that the DMF holder will comply with the statements made in it.

B. Amendments a. Name of DMF holder. b. DMF number. c. Name and address for correspondence. d. Affected section and/or page numbers of the DMF. e. The name and address of each person whose IND, NDA, ANDA, DMF, or Export Application relies on the subject of the amendment for . f. The number of each IND, NDA, ANDA, DMF, and Export Application that relies on the subject of the amendment for , if known. g. Particular items within the IND, NDA, ANDA, DMF, and Export Application that are affected, if known.

For whom is necessary? • There is no legal or regulatory requirement to file a DMF. A DMF may be filed to provide CMC ( chemistry, manufacturing and control) information that the FDA reviews. Example: novel excipient

Whom is not necessary? • Normally the CMC for a compendial excipient is not reviewed • CMC for some drug substances used in some Over-the Counter drug products is not reviewed e.g. Some OTC drug products are marketed without prior approval by FDA under the OTC monograph system. e.g. aspirin CMC information for such OTC products is NOT reviewed by FDA

Letter of Authorization (LOA) • The DMF will be reviewed only when it is referenced in an Application or another DMF. • The holder must submit an LOA (2 copies) to the DMF (Don’t Neglect) • Then send a copy to the APPLICANT • The applicant submits copy of LOA in their Application. This is the only mechanism to trigger review of the DMF • In some cases a DMF holder will call the permission to reference a DMF a “Letter of Access.” (Phrase used in Europe). An LOA does not permit anyone except FDA to “Access” i.e. “read” the DMF.

Cont…. • LOA must contain a specific reference to a particular item in the DMF. • This is especially important for large Type III or IV DMFs that contain many products • 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 usually not helpful since volume numbers are generated in CDR

TECHNICAL INFORMATION FOR HOLDERS • Holder must follow appropriate regulations • Recommend that holder follow appropriate Guidances and CTD-Q • Facilities information (former Type I) not necessary. Address is sufficient. Statement of cGMP Compliance is The National Environmental Policy Act (NEPA) requires that all required. government agencies prepare an Environmental Impact Statement • (EIS) Environmental Assessment (EA) not necessary or a Finding of No Significant Impact (FONSI) when they take an e.g., approving a drug application. Companies submitting an • action Completed batch records for Type II are expected application are required to submit an EA to permit FDA to determine whether an EIS or a FONSI is needed. Since DMFs are not approved, FDA does not take an action, therefore no EA needed. DMF should include a statement that holder will comply with all local environmental regulations

TRANSFER OF OWNERSHIP To transfer ownership of a DMF to another party, the holder should so notify FDA and authorized persons in writing. The letter should include the following: 1.Name of transferee 2.Address of transferee 3.Name of responsible official of transferee 4.Effective date of transfer 5.Signature of the transferring official 6.Typewritten name and title of the transferring official.

CLOSING OF DMF  A holder who wishes to close a DMF should submit a request to the Drug Master File Staff stating the reason for the closure.  The request should include a statement that the holder's obligations as detailed in Section VII have been fulfilled.  The Agency may close a DMF that does not contain an annual update of persons authorized to incorporate information in the DMF by reference and a list of changes made since the previous annual report. The holder will be notified of FDA's intent to close the DMF.

RETIRING OF DMF 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. Procedure: • 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 in 90 days, one copy of DMF is sent to Federal Records Center (FRC) and the other is destroyed. • Response: Close DMF or submit annual update to keep it open.

BIBLIOGRAPHY • Guideline for Drug Master Files (DMF); Center for Drug Evaluation and Research Food and Drug istration Department of Health and Human Services; Page Last Updated: 01/30/2011

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DRUG MASTER FILES; Shaw Arthur B, Ph.D. FDA DMF Expert; Adapted from DIA Webinar March 19, 2007, Revised November 7, 2008.