1. What is a Drug Master File?
DR ANTHONY MELVIN CRASTO
An introduction with case study of an API

2. LEADS: 1. Introduction to DMFs 2. Drug master file process
3. Drug master file format
4. Drug Master File contents
4.1 Submission of DMF
4.2 Authorization to refer to a drug master file
4.2.1 Format for Letter of authorization to review DMF
4.3. Processing and reviewing policies
4.4. Changes in DMFs
4.5. Closure of a drug master file
4.6. Retiring DMFs
5.Electronic Filing of DMFs and CTD
6. Changes in DMF system:
7.Application
8. Difference in European DMFS compare to us DMFs
9. European DMFs
10. Difference in European DMFS compare to US DMFs
11. Case study
12. References

3. Agenda Executive Summary: Drug Master Files Closed DMFs: The FDA Way
Mixed ASMFs: The European Way
Harmonizing: the eCTD challenge
Global Trends: The Future of DMFs
Questions
Agenda

4. 2) Drug product Submitted in a DMF.
Manufacturing procedures and controls for finished dosage forms
10/21/2014
If cannot be submitted in an IND, NDA, ANDA, or Export Application.
Submitted in an IND, NDA, ANDA, or Export Application.
Submitted in a DMF.
DR ANTHONY

5. Drug Submissions: US, Canada, EU
TYPES OF DRUG SUBMISSIONS: US, Canada, EU
USA
New Drug Application (NDA), for new drugs
Accelerated New Drug Application (ANDA)-for generics
Biologic License Application (BLA), for biologic
Canada
New Drug Submission (NDS)―for both drugs and biologic products EU
Marketing Authorization Application (MAA)―via the Centralized Procedure for eligible products. For other products, via the decentralized, mutual recognition or national authorization are applicable.

6. Role of DMFs
Supporting documents for the registration / approval of drug products
In the Chemistry, Manufacturing and Controls (CMC) sections of the drug submission, the DMF documents the drugs identity, purity, strength and quality.
Protect Proprietary and Confidential Information

7. DMFs Globally
Highly Regulated Markets (Drug Master Files used to support approval process)
United States:
Canada:
Australia
Japan
Europe: China is developing its own DMF system
Nearly Regulated Markets (Technical Package / Registration Dossier)
Brazil
Russia
South Africa
Less Regulated Markets (No Drug Master Files used in registration process)
India and many others

8. Drug Master Files: USA
Drug Master File (DMF): is a submission to the Food and Drug Administration (FDA) 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.
There is no legal or regulatory requirement to file a DMF.
A DMF may be filed to provide CMC information that the FDA reviews instead of including this information in the Application (IND, NDA, ANDA).
A DMF is neither approved nor disapproved by the FDA.
It is provided for in 21 CFR (Code of Federal Regulations)
CMC-Chemistry, Manufacturing & Controls

9. The US DMF System “Closed”

10. DMF – US: Important Facts
DMFs are Confidential (Closed)
DMF Stakeholders
DMF Holder: Company or Person who submits the DMF
Applicant: Company or person who references the DMF in an application or another DMF
Information contained in a DMF may be used to :
Support an Investigational New Drug Application (IND))
Support a New Drug Application(NDA)
Support an Abbreviated New Drug Application (ANDA)
Support another DMF
Support an Export Application
Support amendments and supplements to any of these.

11. How the US DMF System Works
Filing the DMF
Holder sends two copies of the DMF to FDA
DMF is reviewed for administrative purposes only by Central Document Room staff
DMF entered into database, assigned a number and acknowledgment letter sent to holder
A DMF is neither approved or disapproved
Accessing the DMF: Letter of Authorization (LOA)

12. The DMF will be reviewed only when it is referenced in an Application or another DMF
The Holder must submit a two copies of the LOA to the DMF, plus a copy to the Applicant
The Applicant submits a copy of the LOA in their Application
The LOA is the only mechanism to trigger a review of the DMF by the FDA
DMF Review Procedure
The DMF is reviewed only if referenced by an Applicant or another DMF
If the reviewer finds deficiencies in the DMF, the deficiencies are detailed in a letter to the Holder
The Applicant will be notified that deficiencies exist, but the nature of the deficiencies are not communicated to the Applicant

13. US DMFs - Types
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.
Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel
No longer accepted by the FDA (as of January 2000)
Type II – Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product
Type III – Packaging
Type IV – Excipients, Colorant, Flavor, Essence, or Material Used in Their Preparation
Type V – FDA Accepted Reference Information
Used for sterile manufacturing plants and contract facilities for biotech products

14. The EU DMF (ASTM) System “Open & Closed”

15. EU DMF (EDMF or ASMF)
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.
Established in
Revised in 2005 and became ASMF (Active Substance Master File) after implementation of CTD in EU
Applicable only to active substances
Has been divided into 2 parts
Applicant Part (Open)
ASM Restricted Part (Closed / Confidential)

16. European Master File
The DMF contains information which includes valuable know-how which should be kept confidential and submitted to the authorities only. Therefore, it should be divided into 2 parts – an applicant’s part and an ASM Restricted Part. The applicant’s part of a DMF is provided by the ASM (Active Substance Manufacturer) to the applicant directly and becomes part of the application for marketing authorization. Both the applicant’s part and the ASM Restricted Part of the DMF are submitted to the authorities.
Applicant’s part of a DMF – opening part
The applicant must be supplied by the ASM with sufficient information to be able to take responsibility for an evaluation of the suitability of the active substance specification to control the quality of the substance. This normally includes a brief outline of the manufacturing method, information on potential impurities originating from the manufacturing method, from the isolation procedure (natural products) or from degradation and, where applicable, information on the toxicity of specific impurities.
ASM Restricted Part of DMF – closing part
Detailed information on the individual steps of the manufacturing method such as reaction conditions, temperature, validation and evaluation data for certain critical steps of the manufacturing method, etc. and on quality control during manufacture may contain valuable know-how. Such information may therefore be supplied to the authorities only.

17. EU: Documenting Quality: 4 Options
In Europe there are four ways to document the quality of the drug substance for the purpose of marketing authorization:
Certificate of Suitability of the pharmacopoeia monograph (CEP)
Full details of manufacture (according to CTD Module 3 - Quality of Drug Substance)
European Active Substance Master File (ASMF; former Drug Master File, DMF)
Other evidence of suitability of the pharmacopoeial monograph

18. Generic Drug Approval: Act 505 (j)
Brand Name Drug Generic Drug
NDA Requirements ANDA Requirements
1. Chemistry Chemistry
2. Manufacturing 2. Manufacturing
3. Controls Controls
4. Labeling Labeling
5. Testing Testing
6. Animal Studies
7. Clinical Studies Bioequivalence
8. Bioavailability

19. INTRODUCTION
A Drug Master File (DMF) is a set of documents that provides detailed information concerning facility protocols and procedures used in the manufacturing, packaging and storing of pharmaceuticals.
A Drug Master File (DMF) is a submission to the FDA of information, usually concerning the Chemistry, Manufacturing and Controls (CMC) of a component of a drug product, to permit the FDA to review this information.
Drug product information or other non-CMC information may be filed in a DMF.
Generally DMFs have two parts:
(1) Applicant’s part : which contain non-confidential information that the license-holder needs to assess for the marketing.
(2)Restricted part: which contains confidential information about the manufacturing procedure that only needs to be disclosed to the authorities

20. Drug Master file Process
Two copies of the Drug Master File with one signed original of the covering letter and other necessary documents are send to the FDA’s Central Drug Evaluation and Research (CDRL). [1]
The Drug Master File staff will audit the non-technical information for completeness and adequacy for submission. If the key elements are missing, the staff will contact the proposed holder to try to obtain the necessary documents in order to file the DMF.
Once the DMFs are determined to be acceptable for filing, the document room staff assigns a DMF number and a letter is sent to the contact person listed in the DMF.
All DMF submitted in CTD format is accepted by any authorities.

21. WHO MUST FILE DMF?
NOBODY
There is no legal or regulatory requirement to file a DMF. A DMF may be filed to provide Chemistry, Manufacturing and Controls (CMC) information that the FDA reviews.
It is only for Maintain confidentiality of proprietary information (e.g., Manufacturing procedure, key ingredients, etc.) for the holder

22. In EU, ASMF must be submitted in different sections in CTD modules
EU ASMF Structure: CTD
In EU, ASMF must be submitted in different sections in CTD modules
Module 1: Contains administrative and prescribing information (administrative information is only required for an ASMF)
Module 2: Contains common overall summaries (QOS) of an “Applicant’s part” (open part) and “Restricted part” (close part). It is nothing but summary of the information provided in module 3.
Module 3: Contains all Quality information. It contains applicant’s part and restricted part. Applicant’s Part contains information required for marketing authorization. The Restricted Part contains information that is extremely confidential for the ASMF holder and can share with the health authority only.

23. 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 DMF 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.

24. 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.
GENERAL INFORMATION
1. General properties 2. Structure 3. Nomenclature
B. MANUFACTURE 1. Manufacture(s). 2. Description of Manufacturing Process and Process Control. a) Flow Chart of Manufacturing Process b) Synthetic Route of Manufacturing Process c) Manufacturing Method. 3. Control of Material a) List of Materials. b) Specification and routine tests of the Raw Materials. 4. Control of Critical Steps and Intermediates. a) Critical Steps. b) Process Validation and/or evalution. 5. Specifications and Test method for the Intermediates. 6. Manufacturing Process Development.

25. C. CHARACTERISATION 1. Elucidation of Structure and other characteristics. a) Elemental Analysis b) IR Spectrum of Drug Substance. c) NMR Spectrum of Drug Substance. d) Mass Spectrum of Drug Substance. e) U.V. Spectrum of Drug Substance. f) X-Ray Diffraction. g) Thermal Analysis. h) Comprehensive Illustration.
2. Impurities a) Sources of Potential Impurities. b) Types of impurities. c) Test Procedure for determining impurities.
D. CONTROL OF DRUG SUBSTANCES 1. Specifications 2. Analytical procedure (STP) 3. Validation of Analytical procedure 4. Batch Analysis a) Description of Batches b) Certificate of Analysis 5. Justification of Specification

26. E. REFERENCE STANDARDS OF MATERIAL
F. CONTAINER CLOSURE SYSTEM
G. STABILITY 1. Stability summary and Conclusions 2. Post-Approval Stability protocol and Stability Commitment. 3. Stability data a) Accelerated Stability b) Long Term Stability Studies c) Forced Degradation Studies
H. MATERIAL DATA SAFETY SHEET
I. APPENDICES 1. FACILITIES AND EQUIPMENTS a) Building and Utilities
2. EQUIPMENTS DESIGN AND LOCATION a. Equipment List b. Equipment Flow Chart
3. ADVENTITIOUS AGENTS SAFETY EVALUATIONS STATEMENT OF COMMENT

27. MANUFACTURING SECTION IN DMFS
(a) Data of inputs (Raw materials/Packaging materials)
and Sources
List all RMs and PMs with sources
Identify Key Starting Materials (KSMs)
Complex materials do not qualify as KSMs
(b) Manufacturing Process details
Synthetic scheme
Process flow diagram
Detailed Process write up
10/21/2014
DR ANTHONY

33. 1. Manufacturing Section
FOLLOWING GENERAL POINTS INCLUDED IN TYPE II DMFS
1. Manufacturing Section
2. Quality Controls
a. Input (Raw/Packaging Materials)
b. Intermediates and In-process
c. Finished Drug Substance
3. Validations
4. Stability data
5. Impurities
6. Packaging and labeling
10/21/2014
DR ANTHONY

34. (2) QUALITY CONTROLS’ SECTION IN DMFS
Objective: To ensure quality at every stage of processes.
Gradual increase in checks as the process progresses.
Specification and test methods.
Complete analytical data of study batches.
Sampling procedures adopted.
Analytical Reference Standard (ARS).
Test batches vs. ARS.
10/21/2014
DR ANTHONY

35. NMR

36. (3) ANALYTICAL VALIDATIONS
Done accordance to reference guidelines: ICH Q 2A and B.
Validation of In-house methods.
Validation of Pharmacopoeial methods.
10/21/2014
DR ANTHONY

37. (4) IMPURIRTIES’ SECTION
10/21/2014
(4) IMPURIRTIES’ SECTION
Objective: To prove that quality obtained is by design of process, not by chance.
Justification for limits applied.
Assay/Impurities’ determination.
Forced Degradation Studies.
Three consecutive commercial scale batches.
Accelerated studies.
Long term studies.
Study include all susceptible parameters.
All validated methods.
Labeled unidentified impurities.
DR ANTHONY

39. (5) PACKING AND LABELING
10/21/2014
(5) PACKING AND LABELING
Detailed description of complete packing configuration.
Food-grade certification of inner-most Packing Materials.
Stability sample packing must be identical.
Specification and Test methods for all Packing Materials.
Specimen label must be submitted.
Clear mention of recommended storage conditions.
DR ANTHONY

41. REMEMBER
There is no legal or regulatory requirement to file a DMF.
The information contained in DMF may be used to support an
- Investigational New Drug Application (IND),
- New Drug Application (NDA),
- Abbreviated New Drug Application (ANDA)
- An Export Application
DMF is NOT a substitute for IND / NDA / ANDA or export application.

42. It is not the responsibility of DMF HOLDER.
10/21/2014
BUT REMEMBER THAT,
Most of the type III DMF holders are ISO (International Organization of Standardization) certified, but the rules for ISO and those of CDER are not always the same. The needs of the applicant should also be considered.
Responsibility for compatibility and safety of packaging components in finished drug product is the responsibility of the AUTHORISED PARTY(AP).
It is not the responsibility of DMF HOLDER.
DR ANTHONY

43. which is not covered in type I to IV DMF
10/21/2014
To submit the data
which is not covered in type I to IV DMF
A holder
must first submit
a letter of intent
to the drug master file staff
FDA will then contact the holder
to discuss the proposed submission
DR ANTHONY

44. V. AUTHORIZATION TO REFER TO A DRUG MASTER FILE
10/21/2014
V. AUTHORIZATION TO REFER TO A DRUG MASTER FILE
A. Letter of Authorization (LoA) to FDA:
The letter of authorization should include the following:
The date.
Name of DMF holder.
DMF number.
Name of person(s) authorized to incorporate information in
the DMF by reference.
Specific product(s) covered by the DMF.
DR ANTHONY

45. Section numbers and/or page numbers to be referenced.
10/21/2014
Section numbers and/or page numbers to be referenced.
Statement of commitment that the DMF is current and that the
DMF holder will comply with the statements made in it.
Signature of authorizing official.
Typed name and title of official authorizing reference to the DMF.
DR ANTHONY

46. LETTER OF AUTHORIZATION (LOA)
10/21/2014
Send a letter to remind holder obligations
US FDA
DMF HOLDER
1 copy of LOA to the APPLICANT
Send 2 copies of LOA to the FDA
The applicant submits THIS copy of LOA in their Application.
DR ANTHONY

47. DRUG MASTER FILE REVIEW:-
10/21/2014
DRUG MASTER FILE REVIEW:-
A DMF IS NEVER APPROVED OR DISAPPROVED.
The agency will review information in a DMF only when an IND sponsor, an applicant
for an NDA, ANDA, or Export Application, or another DMF holder incorporates material
in the DMF by reference.
As noted, the incorporation by reference must be accompanied by a
copy of the DMF holder's letter of authorization.
DR ANTHONY

48. REVIEWER After getting DMF, the Reviewer starts the review procedure
10/21/2014
REVIEWER
When reviewer receives an application (IND/NDA/ANDA) that references DMF
After getting DMF, the Reviewer starts the review procedure
Requests the DMF from
the CDR (central document room)
The DETAILED DEFICIENCIES
are communicated to the holder.
If Reviewer found any deficiency in the content of DMF,
The APPLICANT is also notified but, the nature of the deficiencies is not communicated to the applicant.
HOLDER should submit the REQUESTED INFORMATION to the DMF in response to the agency's deficiency letter along with transmittal letter having subject matter.
DR ANTHONY

49. DMF SEARCH ENGINE
CLICK HERE
DMF search engine

50. Other DMF Systems

51. DMF - Canada Canada has 4 Types of DMFs Type I & 4 have two sections
Type 1: Used for Active Pharmaceutical Ingredients (APIs)
Type II: used for packaging materials
Type III: used for excipients
Type IV: used for products
Type I & 4 have two sections
Sponsor's (Open)
Restricted (Closed)

52. Principal Focus on APIs
DMF: Japan
Principal Focus on APIs

53. Japanese DMF Flow Chart

54. DMF: Australia
In the case of an API used by a producer for a medicine who’s origin is a third party manufacturer, data about its fabrication, quality control and stability can be presented by a Drug Master File (DMF).
The Europena style relavent for the procedure of a Active Substance Master File, adopted by Austrailia’s Therapeutic Goods Administration (TGA), are available on the TGA website.
A DMF format used by the US (FDA) is acceptable if the DMF is prepared according to the Common Technical Document (CTD) format or the older European format if this is not available.

55. China Draft Guidance Issued September 2010
Applicable to marketed drug products registered in China
Not applicable to clinical investigational materials
Does not address exported APIs or excipients manufactured in China
Filings required for:
API, Excipients and Auxiliary Materials (primary, product contact containers or packaging)
SFDA to develop system to administer filings

56. China DMA Requirements
Drug Product manufacturer shall have written agreement with identified suppliers
Drug product manufacturer is primary responsible entity for product quality
Filings will be reviewed in context of drug product filing review, not separately
Permit traceability of constituents and components of drug product
• Filings to remain confidential

57. FDA moving towards eCTD applications
Global DMF Trends
Not Yet Harmonized:
US FDA: 2 copies of each Type II DMF u sing CTD format, but not in CTD module form. FDA format combines Modules 2 & 3 as there is no Applicant vs Restricted part.
FDA moving towards eCTD applications
EU: has separate portions for Modules 2 & 3 (Applicant / Restricted), but some countries in EU have different requirements
EU wants electronic format but there are several formats; some countries still require paper
Overhead: DMFs often run in excess of 1,000 pages. Storage and care of them can be a major burden.

58. Global DMF Challenges Open or Closed? CTD, eCTD
Major advantages of a DMF system for Brasil?
Major disadvantages of a DMF system for Brasil?

59. To take full advantage of  Chemical Web content, it is essential
to use several Software:Winzip,Chemscape Chime, Shockwave,
Adobe Acrobat, Cosmo Player, Web Lab Viewer,
Paint Shop Pro, Rasmol, ChemOffice, Quick Time,et

60. THANK YOU! DR ANTHONY CRASTO amcrasto@gmail.com