KDMF Regulations - Apec-ahc.org

DMF Regulation and Management
in Korea
Introduction Introduction
Introduction
Drug Drug Evaluation Evaluation Department
Department
Korea Korea Food Food and and Drug Drug Administration Administration (KFDA)
(KFDA)
• Korea Korea Drug Drug Master Master File File (KDMF)
(KDMF)
Ο Evaluates designated drug substances
by reviewing data on their characteristics,
manufacturing facilities, manufacture and quality
control
Ο Only publicly announced drug substances can be
used for drug production
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KDMF KDMF Regulations
Regulations
Regulations Regulations
Contents
Contents
The The The Enforcement Enforcement Regulation of
the the Pharmaceutical Affairs Affairs Act
clause clause 3, 3, 3, Article Article Article 26 26
26
The The Enforcement Enforcement Regulation Regulation of
the the Pharmaceutical Affairs Act,
Article Article 3( 3(Manufacturer 3( Manufacturer obligations obligations) obligations
)
No. No. No. 15
The The Enforcement Enforcement Regulation Regulation of of
the the Pharmaceutical Affairs Affairs Act,
Article Article 43(Manufacturer
3(Manufacturer Obligations Obligations) Obligations
)
No. No. 16
Guidance Guidance for Drug Master Master Files
(Announced (Announced (Announced by by the the KFDA KFDA) KFDA
Anyone Anyone who who intends intends to to manufacture manufacture or or import import
import
designated designated drug drug substances substances should should submit submit DMF
DMF
application application Form Form and and data data to to the the KFDA KFDA Commissioner
Commissioner
Commissioner
A A drug drug manufacturer can can only use drug substances
publicly publicly announced announced by by the the KFDA KFDA Commissioner
Commissioner
Commissioner
A A DMF DMF holder holder must must notify any changes of DMF data
to to the the KFDA KFDA Commissioner Commissioner by by the the end end of of January January
January
every every year
year
List List of of designated designated drug drug substance, substance, substance, data preparatio preparatio
method, method, extent extent and and requirements requirements of of data, data, KDMF
KDMF
process process flow
flow
Designated Designated Drug Drug Substances
Substances
1. Active ingredients of New drug (since Jul 1, 02)
2. Human placenta- derived drug substance
3. Drug substances specified by KFDA
123 ingredients 141 ingredients(Jan 1, 11)
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KDMF KDMF Exemption
Exemption
1. Orphan Drugs
2. Recombinant DNA Drugs
3. Cell- Cultured Drugs
4. Biological Medicines
5. Cell Therapy products
6. Gene Therapy products
7. Radiopharmaceuticals
8. Inactive Pharmaceutical Ingredients
(e.g. excipients)
The The Expansion Expansion of of KDMF
KDMF
� Jul 1, 2002 Active ingredients of new drug
� Sep 1, 2005 77 ingredients including gliclazide
� Jul 1, 2006 Human placenta- derived drug substance
� Jan 1, 2008 22 ingredients including domperidone
� Jan 1, 2009 14 ingredients including norfloxacin
� Jan 1, 2010 10 ingredients including cefmetazole sodium
� Jan 1, 2011 18 ingredients including sulpiride
(including salt ∙hydrate for existing ingredients)
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Documents Documents for for KDMF
KDMF
1. Data on facilities for manufacture and quality control
2. Data on physicochemical properties and stability
3. Data on manufacturing method, packaging, container,
precautions in handling
4. Supporting evidence that manufacturing and quality
control system is good for Korea Good Manufacturing
Practice (KGMP) or better
5. Data on drug substance specification and test
method, test result report, used solvents
6. Drug substance for test purposes
※ The
The The original original original manufacturer manufacturer can can directly directly directly submit submit data data to the KFDA KFDA
KFDA
when when the the data data need need need to to be be protected.
protected.
Documents Documents for for for DMF
DMF
Facility Facility
Facility
and
and
GMP
GMP
Characterization
Characterization
and and Stability Stability
Stability
KDMF
KDMF
Manufacturing
Manufacturing
process process process and and control
control
Container Container Closure
Closure
System
System
Quality
Quality
Control
Control
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Dossier Dossier for for for KDMF KDMF Submission(1)
Submission(1)
1. Data on facilities for manufacturing quality control
▶Facility should be acceptable to presidential decree which is
established separately for manufacturer ∙
1.1 Facility layout (including laboratory, depository, door and
corridor)
1.2 A diagram showing environmental control area (including
Cleanliness Level)
1.3 Air handling unit diagram, compressed air diagram and
water utility diagram
Data ※
based on PIC/ S’s Site Master File guideline may
replace data(described above).
Dossier Dossier for for KDMF KDMF submission(2)
submission(2)
2. Data on physicochemical properties
2.1. Data on origin, details of discovery and background
physicochemical
2.2 Data on structure determination properties
2.2.1 Structure determination : data that proves chemical structure ∙
2.2.2 Physicochemical Properties : scientific basis for specification
- appearance, solubility, pH of solution, melting point,
hygroscopy, Pka, partition coefficient, partition ratio,
polymorphism, optical rotation, isomer (including optical
isomer), related substance etc.
Some ※
properties can be omitted in case they are unnecessary
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Dossier Dossier for for for KDMF KDMF submission(3)
submission(3)
3. Data on Stability
▶Stability data need to meet ‘Standard for Stability testing of
medinie’.
▶Stability data should include test methods and raw data
Type Type
Data
New New drug drug or or Human Human placenta-
placenta
derived derived drug drug substance
substance
Ingredients Ingredients recognized to be
changed changed by by by time time time and antibiotics
Drug Drug substances
substances
Except Except Except for for for the the the above above
above
long long- long term term storage storage studies
studies
and and severity severity studies studies
studies
long long- long term term storage storage studies
studies
accelerated accelerated stability stability studies
studies
(long long long- long term term storage storage storage studies studies studies data data
data
for for at at least least six six months months) months
Dossier Dossier for for KDMF KDMF submission(4)
submission(4)
submission(4)
4. Manufacturing Process and Process Control
4.1. Provide detailed information on the whole
manufacturing process(including in- process control
for each step)
4.2 Data on quantities of raw materials, solvents and
reagents used for each process
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Dossier Dossier for for for KDMF KDMF submission(4)
submission(4)
4. Manufacturing Process and Process Control
4.3. Provide detailed information on key intermediates(e.g.
nomenclature, structural formula and yield for intermediates
isolated during the process) and specification and test
method
♣Key intermediates
- substance of which basic chemical structure has changed
through chemical reaction – they can be separated in a solid
form.
Dossier Dossier for for KDMF KDMF submission(5, submission(5, 6)
6)
5. Data on Container Closure System
5.1. Provide detailed information on packaging, reason for
choosing the container, the specification and test result of
each primary packaging component
5.2. Data on packaging at the time of release (including the
secondary packaging component)
6. Precautions in handling
Information on storage conditions(e.g. room temperature, cool
and dark place) should be given. Expiration date should be set
based on stability testing data
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Dossier Dossier for for for KDMF KDMF submission(7)
submission(7)
7. Data on specification and test method, test result report and
used solvents
7.1. Specification and test method should be written
following the way of official compendium like Korean
Pharmacopoeia. Other test methods should be validated.
7.2. Test result report : conducted more than 3 sequential lots
based on specification and test methods
7.3. Data on types of organic solvents, reason for use, criteria of
residual solvents for final products, the content of solvents in
products and test methods
The data should be suitable for guideline ‘Guideline for residual solvents’ ※
Dossier Dossier for for for KDMF KDMF submission(8, submission(8, 9)
9)
8. Data on Evidence that manufacturing and quality control system
is good for Korea Good Manufacturing Practice (KGMP) or better
☞GMP certificate
9. Drug substance for test
In principle, amounts for three repeated tests
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KDMF KDMF Work Work Work Flow
Flow
inspection schedule [Applicant] submit
No
schedule reply Request
receipt review supplement? request review Application Need and
Request Supplementary data submission supplement reply Pharmaceutical standardi zationdivision Yes
completion (return) Yes No request review reply zationdivision standardi Pharmaceutical review data Supplementary Review Acceptable?
inspection Acceptable? Receive submission and site
announcement Yes Public
Request Reply No
completion (return) Pharmaceutical quality division Review
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KDMF KDMF Holder Holder Holder Obligations(1)
Obligations(1)
• Annual Update
KDMF holder should submit an annual report to
KDFM by the end of Jan. every year. This report
should include all changes to the DMF data.
KDMF KDMF Holder Holder Obligations(2)
Obligations(2)
▶ Amendment is necessary when you have any changes
such as ...
ⓐ manufacturing site
ⓑ storage condition(including packaging material) and
expiration date
ⓒ major manufacturing process
ⓓ batch size(more than 10 times)
ⓔ specification and test methods different from
Official Compendium such as KP and USP
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Public Public Notified Notified Drug Drug Substances Substances
Substances
Type No. of item
No. of notified
substance
Total 253 1000
New drug substance 127 173
Human placentaderived
drug
substance
Ingredients specified
by KFDA
3 16
123 811
(as (as of of Dec. Dec. 31, 31, 2009)
2009)
Public Public notification notification by by years
years
(as (as (as of of Dec Dec 31, 31, 2009)
2009)
Type / Year Total 2003 2004 2005 2006 2007 2008 2009
Total 1000 9 12 475 71 138 139 156
New Drug
Substance
Human placenta-
derived drug
substance
Ingredients
specified by
KFDA
173 9 12 18 21 28 30 55
16 6 6 3 1
811 457 44 104 106 100
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Thank Thank You.
You. You. You.
Korea Korea Korea Korea Korea Food Food Food Food and and Drug Drug Administration
Administration
Jeoung Jeoung- Jeoung Gen Gen Kim Kim (kjk12@korea.kr)
(kjk12@korea.kr)
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