1. DRUG MASTER FILE(DMF) AND ITS TYPES
Presented by
B.JAHNAVI(M.Pharm)
V.BHARATH NAIK(M.Pharm)
G.ABHINAYA(M.Pharm)
Department of Pharmaceutical Analysis and Quality Assurance
2. What is DMF ?
Why DMF is required ?
DMF usually not necessary when
Who’s who in DMF ?
Supplement VS Amendment
Acknowledgement letter
Letter of Authorization
Annual updates
DMF review procedure
Types of DMF
Conclusion
References
Contents
3. What is DMF ?
Drug master file – “DMF(314.420-21 CFR) is a submission of
information, usually concerning with the chemistry,
manufacturing and controls(CMC) of a drug product (or) Other
component of drug product to permit the FDA to review this
information in support of third party’s submission”.
Non CMC information may be filed in a DMF.
4. Why DMF is Required
To support regulatory requirements and to prove quality, safety,
and efficacy of medicinal products.
Required to supply bulk materials to United States but FDA
does not require all manufacturers to submit DMF.
Document containing complete information on an API
(OR) Finished drug dosage form.
5. Normally CMC for a compendial excipient is not reviewed.
DMF must be current to review. To ensure the DMF is current
FDA sent a ONLs to the holder.
CMC information is not reviewed for OTC drug products
marketed with out prior approval by FDA.
CMC information is reviewed for non OTC drug products which
are marketed after approval of A/NDAs.
DMF usually not necessary when
6. Who’s who:
Holder : Person (or) company who submits a DMF.
Agent : person (or) company who represents a DMF holder.
Applicant/Authorized party/customer : person (or) company
who references the DMF.
Applications :
IND : Investigational new
drug application.
NDA : New drug application.
ANDA : Abbreviated new drug
application.
7. Supplement to an A/NDA :A report of a change in an approved
A/NDA since a DMF is not approved ,there can be no
supplements to a DMF , only amendments.
Amendment to an application : Additional information to an
existing IND, a pending A/NDA (OR) a pending A/NDA
supplement.
Supplement to an application : A report of change in an approved
application.
Difference between supplement and amendment
8. Assigns number and type.
Reminder of obligations of holder.
Submit all changes as amendments
Notify FDA of change in holder name
(OR) address
Notify FDA of change in
agent/representative
Submit annual update
Submit LOA for each item referenced
for each customer
Notify authorized parties of changes
Acknowledgment letter
9. DMF reviewed only when it is referenced in application (OR)
another DMF.
Holder must submit an LOA (2copies) to DMF.
Send a copy to the applicant.
Applicant submits copy of LOA in their application – trigger
review of DMF.
In Europe , permission to reference a DMF is called letter of
access.
LOA is a specific reference to a particular item in DMF.
Letter of authorization (LOA)
10. Letter of Authorization(LOA)
USFDA DMF HOLDER
Send 2 copies of LOA to
the FDA
1 Copy of LOA to the applicant
The applicant submits this copy
of LOA in their application
Send a letter to
remind holder
delegators
11. Annual Updates
List of authorized parties, what they are authorized to reference,
and the date of LOA.
List of changes during the past year.
This is not a list of changes made but a list of changes already
reported.
Stability updates should be reported as amendments.
If anniversary date is missed FDA will not send a reminder.
12. DMF Review Procedure
DMF is reviewed when
referenced.
If there are deficiencies the detailed
deficiencies are communicated to the
holder.
The applicant is notified that deficiencies exist ( in
an Information Request (IR) , Approvable and Not
Approvable (NA) letter) but nature of deficiencies is
not communicated to the applicant.
If no deficiencies, no
letter ,applicant not filed.
13. Types of DMFs
European DMFs
US – DMFs
Active substance master file(ASMF) is a term
recognized in Europe also called as European Drug
Master File(EDMF).US –DMF in United States.
14. DMF
Applicants part of DMF ASM restricted part of DMF
Open Part Closed Part
( Available to applicant) (Not available to applicant)
EUROPE DMF CLASSIFICATION
16. Type I DMFs:
Type I DMFs are no longer accepted . Final rule
published January 11, 2000(65 FR 1776).
Type II DMFs:
Drug substance and drug substance intermediates.
Type II DMFs for drug substance should be submitted in the
format for “Drug substance” in the “Guidance for Industry
M4Q: The CTD Quality”.
17. It is not necessary to include methods validation package.
GDUFA includes requirements for Type II DMFs for Active
Pharmaceutical Ingredients.
The term active pharmaceutical ingredient means in GDUFA :
A substance, or a mixture when the substance is unstable or
cannot be transported on its own, intended –
- To be used as a component of drug.
- To furnish pharmacological activity.
18. Type III DMFs
The applicable guidance for Type III DMFs is the “Guidance
for Industry: Container Closure Systems for Packaging,
Human Drugs and biologics: chemistry, manufacturing, and
controls Documentation”.
Manual of policies and procedures covering reviewer
responsibilities for review of Type III DMFs has been
implemented.
19. Packaging material intended for which use
It’s components an composition
Names of suppliers or fabricators of the components
used in preparing packaging material.
Acceptance specification.
Toxicological data on these materials.
20. CMC for a compendial Excipient is usually not reviewed and
therefore a DMF is not necessary.
Exceptions: New route of administration or total dosing that may
affect safety and efficacy, e.g. RESPITOSE
CMC requirements for a novel Excipient (one not used in an
approved drug product) are the same as those for a new drug
substance.
Type IV DMFs
21. DMF holders should send the request to FDA governments
with following
An explanation of necessity for filling the information in a
type V DMF.
The proposed subject (Title) of the DMF
The rationale for not submitting the information in an IND,
NDA, ANDA.
Type V DMFs
22. The clinical division that will be reviewing the information if
applicable.
Information regarding the manufacturing sites, facilities,
operating procedures and personnel for sterile manufacturing
plants can be filed as Type V DMFs without clearance.
23. Conclusion
DMF System presents challenges for both Industry and the
FDA.
Problems can be minimized if holders and applicants
- Understand their responsibilities
- Adhere to regulations
- Follow the recommendations in the guidances
- Communicate with each other
24. References
Food and Drug Administration http://www.FDA.Gov
James D. Vidra, Ph.D, FDA/Industry container closure
Guidance training session, OCTOBER 26 1999 , DRUG
MASTER FILES. CDER
http://www.FDA.GOV /Drugs/ Development approval
process/ forms submission requirements/Drug Master
Files/default.htm
druginfo@FDA.hhs.gov
