The critical information about the CMC (Chemistry, Manufacturing and Control) aspect of an active pharmaceutical ingredient or a finished pharmaceutical product is detailed in the Drug Master File. This document is not compulsory to submit but when submitted can play an essential role in the drug approval process. Let’s find out more about DMF, its structure, types and more.
What Is A Drug Master File?
FDA states that “A Drug Master File is a submission to the Food and Drug Administration that may be used to provide confidential detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of one or more human drugs.”
It is not mandatory as per the FDA regulation but is submitted solely at the discretion of the holder. A DMF is not approved or disapproved. DMF is used as a support document for IND, NDA, ANDA, other master files, export documents or any amendments and supplements to any of these.
Drug Master File Structure
eCTD is the standard format for submitting DMF. Paper submissions take time for FDA to receive the file ranging from a few days to weeks. When a new submission is made through the FDA’s electronic submissions gateway system, the FDA receives the submission within 24hrs and will confirm it by sending a letter within 10 days of receipt. The submission must be formatted to the eCTD structure, which is:
Module 1: Region Specific information
Module 2: Summaries and overviews of quality, non-clinical and clinical information
Module 3: Quality Information
Module 4: Non-clinical Study Reports
Module 5: Clinical Study Reports
Types Of Drug Master File
In 2000, Type I was discontinued. Although it was discontinued the numbering of them remained the same.
There are four types of DMF's:
Type II: Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product
Normally, this type of DMF should be limited to a single intermediate of the drug, drug substance, drug product, or material type used in their preparation.
Type III: Packaging Material
Each packaging material must be identified by the use it is intended for, components, composition, and controls for its release. The names of the suppliers of the components that are used in the preparation of the packaging material along with the acceptance specifications should be given.
Data that is supporting the acceptability of the packaging material for the use it is intended for should be submitted as well, as mentioned in the "Guideline for Submitting Documentation for Packaging for Human Drugs and Biologics." Toxicological data about these materials, if not available by cross reference to another document, would be included in this type of DMF.
Type IV: Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation
Each and every additive used must be identified and characterized by its method of manufacture, release specifications, and testing methods. Toxicological data about these materials, if not available by cross reference to another document, would be included in this type of DMF. The DMF should involve other supporting information or data that are not available by cross reference to another document.
Type V: FDA Accepted Reference Information
The FDA does not encourage the use of Type V DMF for any miscellaneous information, duplicate information or information that should be included in one of the other types of DMF's. If the holder decides to submit information and supporting data in a DMF that is not covered by the other 4 types, a letter of intent must be submitted by the holder to the Drug Master File Staff. FDA contacts the holder to discuss about the proposed submission.
Each DMF must have only one type of information and every supporting data regarding that information. Supporting information and data in a DMF can be cross indexed to any other DMF.
Requirements For The Submission Of A DMF
Rejection of the submission happens if these key requirements are not followed:
Submission must be in the Electronic Common Technical Format.
Submissions that are sized 10GB or less should be submitted via the Electronic Submission Gateway of the FDA.
Submissions greater than 10GB, can be submitted via ESG or on physical media like the CD-ROM. While making a submission through ESG, it is essential to make an appropriate choice, CDER or CBER, from the menu of choices to allow the proper routing of the DMF.
To submit an original DMF in eCTD format, the DMF holder must have a pre-assigned number. Each DMF submission must have a transmittal letter, administrative information regarding the submission, and other specifications mentioned.
Moreover, the DMF must be in the English language and if a submission contains information in other language, an accurate certified English translation must also be included along with it. Every page of each copy of the DMF should be dated and numbered. An updated version of the table of contents should be incorporated with each submission.
DMF review is done if it is referred to in any other application or DMF. FDA only reviews the DMF after submitting a copy of LOA (Letter of Authorization) to the FDA and another copy to the applicant/ holder or sponsor.
Benefits Of Submitting A DMF
Some major benefits of submitting DMF is as follows:
Act as a central reference document for multiple drug applications.
Serves as a support document for regulatory applications like NDA, IND, ANDA, etc.
It provides quality, safety and efficacy information regarding the drug substance or drug product.
It makes sure that the product is in compliance with regulatory as well as GMP standards.
Streamlines the process of regulatory drug approval
Provides the benefit of competitive advantage and improves global sales.
Confidentiality of proprietary information.
Challenges In DMF Preparation
Some common challenges in the preparation of the drug master file include:
Incomplete or inaccurate data
Compliance with the complex and constantly changing regulations.
Making timely submissions as well as annual updates.
Difference in the rules and regulations for filing a DMF in different countries.
Facing these challenges without a proper idea of how to navigate through these can be a very draining process. Artixio Consulting is here to help you make sure that all the data is complete and accurate. As we stay updated with the ever-changing regulatory requirements, we can assure you of a smooth experience in the DMF preparation and submission. Connect with us through info@artixio.com
FAQs About Drug Master Files
Q1: Can a Drug Master File be used for multiple drug applications?
A: Yes, the DMF can be used as a support information to IND, NDA, ANDA, export application, other DMF’s, and any supplements or amendments made to them.
Q2: What is the difference between DMF and NDA? A: NDA is a mandatory regulatory application submitted for marketing a drug product whereas DMF acts as a supporting document for any of the regulatory applications including NDA. DMF submission is not mandatory.
Q3: How often should a DMF be updated? A: DMF holder must update the DMF annually or whenever any changes occur. If unchanged is the subject matter of the DMF, then the holder shall provide a statement that the subject matter is current. If left unattended, it can cause delay in the regulatory application approval and can even lead to the closure of DMF.
Q4: What happens if a DMF is incomplete? A: The DMF undergoes a completeness assessment and if it fails the assessment, a DMF incompleteness letter is issued to the DMF holder describing the information that is needed in the DMF to pass the assessment.
Q5: What are the policies for processing and reviewing Drug Master Files (DMFs)?
A: When the reviewer receives an application that references DMF, they request for the DMF from CDR (Central Document Room). After having the DMF, they start the reviewing procedure and if any deficiencies are found it is the applicant is notified but communicated in detail to the DMF holder. The holder then must submit the requested information in response to the deficiency letter along with a transmittal letter stating the subject matter.
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