DRUG
MASTER FILE (DMF)
Drug Master File (DMF) : is a document prepaired by a pharmaceutical manufacturer
and submittedsolely at its discretion to the appropriate regulatory agency.DMF
contains confidential and factual information about facilities,
processes(includes drug product's chemistry, manufacture, stability, purity,
impurity profile etc.) or articles used in the manufacturing, processing,
packaging, and storing of one or more human drugs.DMF helps the manufacturer to
keep relevant information secret and at the same time to sell the product to
different customers using this drug within there final application.The information
contained in the DMF may be used to support an Investigational New Drug
Application (IND), a New Drug Application (NDA), an Abbreviated New Drug
Application (ANDA), A DMF is NOT a substitute for an IND, NDA, ANDA, or Export
Application. It is not approved or disapproved. Technical contents of a DMF are
reviewed only in connection with the review of an IND, NDA, ANDA, or an Export
Application.
DMF contains complete information on an Active Pharmaceutical Ingredient (API) or finished drug dosage form. In Europe it is known as European Drug Master File (EDMF) or Active Substance Master File (ASMF) and in US it is known as US-Drug Master file (US-DMF).
DMF’s are mostly prepared following the rules of Common Technical Documentation (CTD).
Prerequisites
DMF contains complete information on an Active Pharmaceutical Ingredient (API) or finished drug dosage form. In Europe it is known as European Drug Master File (EDMF) or Active Substance Master File (ASMF) and in US it is known as US-Drug Master file (US-DMF).
DMF’s are mostly prepared following the rules of Common Technical Documentation (CTD).
Prerequisites
Production process is well established and fixed in writing
(Master production instructions).
Specifications of raw materials as well as of the final product are defined including specification of packaging material.
Inprocess controls, sampling points and procedures are clearly outlined.
Critical process steps are validated, equipment is qualified.
Analytical methods are validated.
Impurity profile is established.
Stability program is set up and first data are available.
Basic GMP requirements are fullfilled.
Specifications of raw materials as well as of the final product are defined including specification of packaging material.
Inprocess controls, sampling points and procedures are clearly outlined.
Critical process steps are validated, equipment is qualified.
Analytical methods are validated.
Impurity profile is established.
Stability program is set up and first data are available.
Basic GMP requirements are fullfilled.
Data required for the CTD are
General Information
Nomenclature
Structure Description
General Properties
Manufacture
Manufacturer(s)
Description of manufacturing process and process controls
Control of materials
Controls of critical steps and intermediates
Process validation and/or evaluation
Manufacturing process development.
Characterisation
Elucidation of structure and other characteristics
Impurities
Control of drug substance
Specification
Analytical Procedures
Validation of analytical procedures
Batch analyses
Justification of Specification
Reference Standards or Materials
Container Closure System
Stability
US-DMF
In United states DMFs are submitted to the FDA.The main objective of the DMF is to support regulatory requirements and prove the quality,safety and efficacy of the medicinal product.
In US there are five types of DMF's:
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
Type I
Manufacturing Site, Facilities, Operating Procedures, and PersonnelA 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 terms of capabilities, application, and location. Make and model would not normally be needed unless the equipment is new or unique.
A diagram of major corporate organizational elements, with key manufacturing, quality control, and quality assurance positions highlighted, at both the manufacturing site and corporate headquarters, is also helpful.
Type II
Drug Substance, Drug Substance Intermediate, and Material
Used in Their Preparation, or Drug ProductA
Type II DMF should, in general, be limited to a single drug intermediate, drug
substance, drug product, or type of material used in their preparation.It
Summarize all significant steps in the manufacturing and controls of the drug
intermediate or substance.
Type III
Type III
Packaging MaterialEach
packaging material should be identified by the intended use, components,
composition, and controls for its release. The names of the suppliers or
fabricators of the components used in preparing the packaging material and the
acceptance specifications should also be given. Data supporting the acceptability
of the packaging material for its intended use should also be submitted.
Type IV
Type IV
Excipient, Colorant,
Flavor, Essence, or Material Used in Their PreparationEach additive should be identified and characterized by its
method of manufacture, release specifications, and testing methods.
Toxicological data on these materials would be included under this type of DMF, if not otherwise available by cross reference to another document.
Type V
Toxicological data on these materials would be included under this type of DMF, if not otherwise available by cross reference to another document.
Type V
FDA Accepted Reference InformationFDA 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
supporting 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 (for
address, see D.5.a. of this section). FDA will then contact the holder to
discuss the proposed submission.
General Requirements for Filling Type I,II,III,IV,V DMF's
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 study design, data, interpretation, and other information should be submitted.
A DMF is required to contain a complete list of persons authorized to incorporate information in the DMF by reference.
EDMF
In Europe DMFs are submitted to EMEA. The main objective of the Active Substance Master File (ASMF) procedure, commonly known as the European Drug Master File (EDMF), is to allow valuable confidential intellectual property or 'know-how' of the manufacturer of the active substance (ASM) to be protected, while at the same time allowing the Applicant or marketing authorisation (MA) holder to take full responsibility for the medicinal product and the quality and quality control of the active substance. Competent Authorities/EMEA thus have access to the complete information that is necessary for an evaluation of the suitability of the use of the active substance in the medicinal product.
The scientific information in the EDMF should be physically divided into two separate parts, namely the Applicants Part (AP) and the Restricted Part (RP). The AP contains the information that the EDMF holder regards as non-confidential to the Applicant/MA holder, whereas the RP contains the information that the EDMF holder regards as confidential.
It is emphasized that the AP is still a confidential document that cannot be submitted by anyone to third parties without the written consent of the EDMF holder. In all cases the AP should contain sufficient information to enable the Applicant/MA holder to take full responsibility for an evaluation of the suitability of the specifications for the active substance to control the quality of this active substance for use in the manufacture of a specified medicinal product. The RP may contain the remaining information, such as detailed information on the individual steps of the manufacturing method (reaction conditions, temperature, validation and evaluation data of critical steps) and the quality control during the manufacture method of the active substance.
General Requirements for Filling Type I,II,III,IV,V DMF's
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 study design, data, interpretation, and other information should be submitted.
A DMF is required to contain a complete list of persons authorized to incorporate information in the DMF by reference.
EDMF
In Europe DMFs are submitted to EMEA. The main objective of the Active Substance Master File (ASMF) procedure, commonly known as the European Drug Master File (EDMF), is to allow valuable confidential intellectual property or 'know-how' of the manufacturer of the active substance (ASM) to be protected, while at the same time allowing the Applicant or marketing authorisation (MA) holder to take full responsibility for the medicinal product and the quality and quality control of the active substance. Competent Authorities/EMEA thus have access to the complete information that is necessary for an evaluation of the suitability of the use of the active substance in the medicinal product.
The scientific information in the EDMF should be physically divided into two separate parts, namely the Applicants Part (AP) and the Restricted Part (RP). The AP contains the information that the EDMF holder regards as non-confidential to the Applicant/MA holder, whereas the RP contains the information that the EDMF holder regards as confidential.
It is emphasized that the AP is still a confidential document that cannot be submitted by anyone to third parties without the written consent of the EDMF holder. In all cases the AP should contain sufficient information to enable the Applicant/MA holder to take full responsibility for an evaluation of the suitability of the specifications for the active substance to control the quality of this active substance for use in the manufacture of a specified medicinal product. The RP may contain the remaining information, such as detailed information on the individual steps of the manufacturing method (reaction conditions, temperature, validation and evaluation data of critical steps) and the quality control during the manufacture method of the active substance.
The EDMF procedure can be used for the following active
substances (except biological active substances)
A. New active substances
B. Existing active substances not included in the European
Pharmacopoeia (Ph. Eur.) or the pharmacopoeia of an EU Member State
C. Pharmacopoeial active substances included in the Ph. Eur.
or in the pharmacopoeia of an EU Member State
DMF (Drug Master File), CoS (Certificate of suitability) as well as CMC (Chemical Manufacturing and Control Documentation) are used for one and the same intention – to give evidence, that the drug substance (API – Active Pharmaceutical Ingredient) is suitable for its intended use and that the manufacturing process is well established and controlled. Content of DMF, CoS, and CMC are nearly equal. There are only differences in the kind of document preparation (forms to use) and the authority you have to contact (USDMF FDA; EDMF EMEA; CoS EDQM; CMC national bodies). Therefore above mentioned procedure is nearly equal for all the three types. Especially CoS does not replace an approval process. Approval authorities can require more information even if CoS is available.