Hài hòa GMP toàn cầu - Góc nhìn từ Nhật Bản

ISPE Prague September 19-21 2005 1
Global GMP Harmonisation –
A Japanese Perspective
Yukio Hiyama, Ph.D.
Chief, Third Section, Division of Drugs,National
Institute of Health Sciences,
The Ministry of Health Labour and Welfare,JAPAN

Presentation Key Points
Changes in Pharmaceutical Affairs Law
Quality Regulations under the Revised
Pharmaceutical Affairs Law
Commitment of Manufacturing Process as
Approval Matters
Role of ICH Pharmaceutical Development
Role of the Quality Overall Summary
GMP Regulations and related Guidelines

Revision of the Pharmaceutical
Affairs Regulation
(effective April 2005)
Revision of the Approval and Licensing System
= From Manufacturing (or Importation)
Approval/License to Marketing Authorization
Enhancement of Post-marketing Measures
= To clarify the Market Authorization Holder’s
(MAH) responsibility of the safety measures as well
as quality management (GVP, GQP)

Revision of the Quality Regulation
1. MAH’s＊ responsibility for the Quality
management ＊Marketing Authorization Holder
2. Requirement Changes in Approval Matters
3. Drug Master File system to support CTD based
application
4. Consolidation of the Legal Positioning of GMP
5. Revision and Consolidation of GMP standards

Revision of approval and license system for
pharmaceuticals and medical devices
Attention to
manufacturing
Prefecture
1. Companies are supposed to have their own
manufacturing establishment
2. “Approval” is for “manufacturing”, not for
“marketing” (Minister manufacturing approval)
3. Final manufacturing “license” is issued, based on
approval. (Mainly prefectural manufacturing
licensing)
Attention to whole process
( from manufacturing to
PMS)
1. Introduction of “Marketing Approval” for overall evaluating quality, safety & efficacy and
manufacturing for marketing
2. Manufacturing establishment license is separated from product authorisation process, which
allows companies to subcontract whole manufacturing process
3. Instead, company’s ability of pharmacovigilance is subject to review for Marketing Approval
Holder (MAH)
MHLW
Research & Development
From Development to Use
Evaluation of quality, effect & safety
(manufacturing approval for each product)
Manufacturing
（manufacturinglicense）
New System
Old system
Use
Sale

Manufacturing
Approval
Manufacturing
Application (MHLW)
Licensed
Establishment
1-Step process
Start production
Comparison Flowcharts of Approval and License
Product
OLD system
Product
REVISED system
Quality, Safety & Efficacy
Establishment
G
GM
MP
P
Requirement
• Companies’ PMS
compliance system
• Companies’ Quality
Assurance System
Self production
OR
Subcontracting
Establishment
• MHLW inspection :
New drug &
Partial
subcontracting
biologics
• Prefectural inspection: Others
: Recurred for each product
Start manufacturing
Points: (1) MAH’s requirements for PMS system, (2) Allow complete subcontract
manufacturing, (3) Introduce marketing approval system
Partial License
Establishment License
inspection
(5 yearly renewal) ）
License application
(Prefecture)
Start marketing
Marketing Approval
inspection
( Renewal) Every 5 years
2-Step process
Marketing Application
(MHLW)
Licensed Marketing
Approval Holder

ISPE Prague September 19-21 2005
軽微変更届出
7
Framework for
Review and Inspection
Application of
partial change
Review
Application
form
Review
Approval
letter
Notification of
minor partial
change
G
GM
MP
P
i
in
ns
sp
pe
ec
ct
ti
io
on
n
Pilot scale data
New Drug
Application
Collection of
production
scale data
Re-submission
of application
form
Pre-approval
GMP Inspection
Commercial
Production
Minor
Change
Partial
Change
Minor
Change
Partial
Change
Validation Data etc.

From Multi sets to One set of
regulations
Previously: No inspections at foreign GMP
sites/Under GMPI →Foreign inspections by PMDA
Previously: Approvals given to API and Product.
Only specs are set for API of imported products
→Approvals only to products including API specs
and manufacturing process
Previously: Whole Manufacture contracts NOT
allowed for domestic industry→ Contracts allowed
everyone

1. MAH’s＊ responsibility for quality management
＊Marketing Authorization Holder
2. Requirement changes in Approval Matters
application

1. MAH’s responsibility for quality
management (GQP)
Supervise and manage the manufacturer, and
ensure the compliance with GMP of all
manufacturing sites
Ensure proper product release to the market
Respond quickly with complaints and recall, etc.
Conduct quality management based on post-
marketing information, etc.

1. MAH’s＊ responsibility for quality management
＊Marketing Authorization Holder
2. Requirement changes in Approval Matters
application

2. Application Form and
Approval Matters
Contents provided in the NDA
application form are dealt with as
“matters subject to approval.”
Contents described in approval letter are
“legal binding” approval matters.

Approval Matters
General name (for drug substance)
Brand name
Composition
Dosage and administration
Manufacturing process, including control
of materials
Indications
Storage condition and shelf-life
Specifications and analytical procedures

No change:
Approval Letter
• Approval letter system
Changes:
• From manufacturing approval to marketing approval
• Requirement of detailed description in application
form regarding manufacturing process and control
Encourage industry to better controlqualityof products
Link assessment and inspection
• Introduction of a notification system pertaining to
minor change
Effective regulatorysystem

Application Form after the Enforcement of
Revised Pharmaceutical Affairs Law
High
OLD APPLICATION
Manufacturing Application
CTD-BASED APPLICATION
Marketing Application
Specification＋
Manufacturing
(Process Control)
Low QualityInformation Module 3
Quality Information
Application
form
GAIYO
Batch Data etc
Approval
Matter
(Specification)
Module 2
Minor change
(notification)
Partial Change
(application)
Batch Data etc
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Approval Matters Policy
Notification from Director of Review Management,
0210001 February 10, 2005
Manufacturing Process: Principles and end points
of the critical manufacturing steps with key
operational parameters of commercial scale will
become approval matters. Principle and quality
end point for each manufacturing step will be
subject to pre-approval review.
In-process procedure is pre-approval matter if it
replaces final specification test.

Approval Matters Policy (continued)
A pilot scale manufacturing processes may be
submitted at Application.
The commercial scale processes will be subject to
Pre-approval GMP inspection and the commercial
scale must be described in the approval.
Pre-approval vs. notification classification may be
determined through the review process

Matter Subject to Approval under
(Chemical drug substance and drug product)
Manufacturing site
Manufacturing method
Detailed information about:
• Manufacturing process and process
control
• Control of material
• Container-closure system

Matter to Be Described in Application Form
-Drug Products-
All processes from raw material(s) to
packaging process
– A flow diagram of manufacturing process
including:
• Raw materials
• Charge-in amount
• Yield
• Solvent
• Intermediate materials
• Process parameter (e.g. Target Value and Set Value)
– A narrative description of manufacturing process

Narrative Description of
Manufacturing Process
– Matters needed for assuring the quality consistency
should be selected
Quantities of raw materials, critical processes,
process control, equipment, process parameter
(speed, time, temp., pressure, pH, etc)
Test and acceptance criteria of critical step and
intermediate
Identity and specification of primary packaging
material (or manufacturer and type number of the
packaging material)

Case１
Observed
Value A
Case ２
Observed
Value B
Target
Value/Set
Value
Target Value and Set Value
In cases where target value/set value are set:
– Permissible range of target value/set value must be
described on the master production documents or SOPs.
Case 2:
– The suitability of product should be judged based on GMP.
Temp
Permissible range

Hydroxypropylcellulose Process Control 1
Blending Kakikukekon
Calcium Carmellose
Lactose
Flow Diagram of Manufacturing process (Tablet)
Step Operation Raw Material In-process Test
1st Step Content Unifomity
particle size
Content Unifomity
Dissolution
2nd Step
Drying
Size Granulation
Screenφ1mm
Process Control 2
Temp. of exhaust air
Water act.
Stability of dissolution
Quality
endpoint
criteria
Granulation
Quality endpoint
criteria

Distinctions between Partial Change
Approval Application and Minor
Change Notification
Partial Change
Approval Application
Minor Partial Change
Notification
Change in the principle of
unit operation of critical
process
Process parameter to
control the quality
endpoint criteria
Change in process control
criteria as quality endpoint
criteria

Examples of Matter Subject to a
Partial Change Application
Change in principle of unit operation of critical
process: matter subject to approval
• In that case, the evaluation methods which was approved at
the time of previous submission might be invalidated.
Change in materials of primary packaging component
Change in matters for aseptic manufacturing
Change in specification of intermediate product in
case that the test is performed instead of release test of
final drug product

Some matters are subject to application of
partial change, based on the information
described in P2.
The Role of P2 Document in Reviewing
New Drug Application (NDA) under
(PAL)

Matters described
in Module3
P2
Matters subject
to approval
Matters not subject
to approval
The Role of P2 document in
reviewing NDA under revised PAL
P2
Partial change approval application
Minor partial change
notification

The new requirement regarding the approval
letter is applicable to:
1. market applications after April 2005
2. renewals of existing licenses, which may occur by
2010
for case 2, the manufacturing section of approval letter
may be rewritten without review/assessment.
For most of those approvals, CTD information was NOT
submitted (did not exist).

Opportunities by ICH CTD based application
Complete description of product specific quality
system
Better knowledge transfer tool within the sponsor
organization, between industry and regulator, and
within the regulator organizations---QoS:Module 2
plays important roles
ICH Pharmaceutical Development Q 8 (step 2 in
Yokohama)

Role of Module 2 in Japan
Module 2 bridges NDA Application Form
and Module 3
Module 2 is one of the key review
documents
• Reviewers evaluate Module 2 and then narrow
down into Module 3, 4, or 5 when they need
more detailed information.
• Module 1 and 2 together with reports written
by reviewers are evaluated in Pharmaceutical
Affairs and Food Sanitation Council.

Relationship between
Application Form and CTD format
Module 3
Module 2
• Tabulated summary of
specifications
• Analytical procedures
• Tabulated summary of
batch analyses
• Justification etc.
Raw data
3.2.S4.1Specification
3.2.S4.2Analytical Procedures(SOP)
3.2.S4.3Validation of Analytical
Procedures
3.2.S4.4Batch Analyses
3.2. S4.5 Justification of Specification
Application
form
Approval
Matters

4. Legal position of GMP
Flowchart of Approval and License
Manufacturer Holder Company
Requirement:
Human Resource
Facility
Requirement:
Human resource
GVP/GQP compliance
(renewal/ X years)
Self production
or
Subcontracting
(renewal/ X years)
Product
Manufacturing Start
Pre-approval inspection
Post-approval inspection
Requirement:
GMP compliance
Product Marketing
Approval
(every 5 years)
Marketing Start
Product Marketing
Application
Manufacturing
License
MAH License
Manufacturing
License Application
MAH License
Application

Manufacturing
License Application
Flowchart of Approval and License
(old system)
< Approval scheme > < License scheme >
Product
Manufacturer
Requirement:
Quality, Safety, & Efficacy
Manufacturing License
Pre-licenseinspection
Requirement:
Human resources, Facility
GMP compliance
(renewal/5years)
Manufacturing
License
Product Manufacturing
Approval
Application
Manufacturing Start
License Application

1. MAH’s＊ responsibility for the quality
2. Approval Matters Requirements Change
application

4. Consolidation of the Legal
Positioning of GMP
Became a requirement for product approval
GMP inspection prior to approval, and
periodical GMP inspection in post-marketing
phase
GMP inspection at the time of application for
partial change of the approval matters
GMP inspection at foreign sites

1. MAH’s＊ responsibility for the quality
2. Approval Matters Requirements Change
application

5. Revision and Consolidation of GMP
Standards
Revised Pharmaceutical Affairs Law (passed July 2002,
Effective April 2005)
MHLW Ministerial Ordinance No. 179 on GMP (published
December 2004)
Notification on GMP (March 30, 2005) – “Instructions to
inspection body RE the Ministerial Ordinance, revision of
Validation standards”
Major Changes:
Content of Approval Letters (Manufacturing Processes, Container
Closure etc)-define where GMP applies “legally”
Change control and Deviation control

Perceived Problems
Superficial approaches to GMP -non validated
procedures, little connection with QC results,
procedures override science
Regulations might not encourage good practices
Poor communication between R&D and
Manufacturing Plant
Poor development and or change control of
manufacturing
Detail GMP related guidance and inspection
manuals are NOT readily available in Japan

GMP related guidelines
Product GMP Guideline: Level is similar to ICH
Q7A, with emphasis of Periodical Quality Review
Technology Transfer, Process Validation Strategy,
and Site Qualification of Pharmacopoeia Tests
Technology Transfer Guideline: R&D
responsibility and on Study Report ←ICH Q8
Laboratory Control Guideline
The guidelines are posted at NIHS web site.

Challenges
Training for reviewers and inspectors on
process/manufacturing sciences
Industry side
•Reluctant or unable to give a complete story
•Regulatory personnel training
•Superficial development (meeting specs is all)

Establishment of
Pharmaceuticals and Medical Devises
Agency (PMDA)
Integration of review division, safety information
management division, and GMP inspection division
Strengthening resources for review and inspection
Established in April 2004
 Efficient review system
 More emphasis on pharmaceuticals with high risks

PMDA
New Office:6th-10th
FLOOR
Introduction of PMDA

The Feature of PMDA
Effective operation under “Mid-term Plan” for 5
years’ activities
Subject to regular evaluation of performance by
Independent “ Administrative Agency Evaluation
Committee”
Financial resources are consist of
• User fee (Review and inspection)
• Contribution Funds (Post-marketing, Relief)
• National Budget

ＰＭＤＡ
GMP Inspection
OPSR/KIKO
Establishing the PMDA
Equivalency Review, Clinical trial
consultation, compliance audit, safety
information (Drug)
PMDEC
Substantial NDA review
（excluding the duties of OPSR/KIKO）
JAAME
Equivalency Review (Device)
Law for the incorporated Administrative
agency-Pharmaceuticals and Medical
Devices Agency
Regional Bureau of MHLW
ＰＭＤＡ

Office of Conformity
Audit
（GLP, GCP/ On-site Audit and
Document Audit）
（GMP & Standards/GL）
PMDA Organizational Structure（Outline）
Office of General Affairs/Office
of Planning and Coordination
Auditor
Auditor
Office of ReliefFunds
Review system
8 Office/ 1 Director
Senior
Executive
Director Office of Biologics
Office of OTC/GenericDrugs
Office of Medical Devices
Executive
Director
Executive
Director
Office of Safety
Office of Compliance
and Standards
Post-Marketing system
Director,
Center for
Product
Evaluation
Office of New Drug I - III
Office of Review Administration
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Enforcement of New Regulations
２００２２００３．４２００４．４２００５．４
PAL revision
Marketing Authorization
GMP Strengthening
New Biologics regulation
everything else
PMDA establishment ●
New GMP Standards ●
●： Publication
：Enforcement
●
●
●
●

Japanese CMC Review System with
the Quality overall Summary
Yukio Hiyama, Ph.D.
Section Chief, Division of Drugs, National Institute of
Health Sciences, Ministry of Health, Labour and
Welfare, JAPAN
9/6/2005 AAPS workshop on Pharm Quality 1
Assessment

experts
Review & Advisory
Approval letter
team
Advisory
experts
Flowchart of Reviewing Process
Meeting
Meetingon
key issues
Review
team
Consultation
Advice
NIHS scientists
Academia
* PAFSC: The Pharmaceutical
Affairs and Food Sanitation
Council
Committeeson New drugs, PAFSC*
9/6/2005 2
Applicant
Review report-2
Review report-1
Evaluation and Licensing Division in Pharmaceutical
and Food Safety Bureau, MHLW
Revised QOS
Application form
Module2 (QOS)
Module3 (4,5)
Pharmaceuticals andMedical
Devices Agency (PMDA)
Application form
Module2 (QOS)
Module3 (4.5)

9/6/2005 AAPS workshop on Pharm Quality
Assessment
3
Ensure Product Quality and
Consistency
• Thorough product characterization during
development (*including manufacturing process)
• Appropriate specifications
• Adherence to GMP;
suitable facilities, a validated manufacturing
process, validated test procedure, raw material
testing, in-process testing, stability testing
FROM ICH Q6A &B

Assessment
4
Quality (CMC) Review Areas
Risk Evaluation Phase:Identify basis for Quality
• Design and establishment of product
• Design and establishment of process and quality
control of drug substance and products
Risk Control Phase:
• Commitment of control methods of process and
quality control of drug substance and products
(This phase was NOT well reviewed in Japan for system
reasons before April 2005)

Assessment
5
Basis for Quality(CMC) Review
 ICH Guidelines are the basis for NDA review.
• PMDA has a CTD-based GRP(Good Review
Practices).
 There are some domestic guides for those not covered
by ICH Guidelines.
 The Japanese Pharmacopoeia (JP) is also the basis for
setting specifications and acceptance criteria of drug
substances and drug products.
• “General methods described in the JP, and
internationally harmonized methods are considered to
be validated.”

Assessment
6
Basis for Quality Review
ICH Q8 concept (minimum; identify risk,
additional; Design Space) may be used to
classify approval matters in the manufacturing
process.

Comparison of Application Forms
before and after the Revision
All matters were
for partial change
application
Former manufacturing
application
CTD-based marketing
application
9/6/2005
Quality information 7
GAIYO
Application
Form
Specification &
Manufacturing
(Process Control)
Matters for
partial change
application
Matters for
minor change
notification
Module 2
(QOS)
Quality information
Module 3
(Batch data
etc)
Batch data etc
Application
Form
Specification

Revised
Former Revised
Balance between “Specification” and
“Control of Manufacturing”
◼ Implementation of ICH-CTD (July, 2003)
◼ Revision of Pharmaceutical Affairs Law
(April, 2005)
Specifications Manufacturing
Manufacturing

 Considered as a summary;
not reviewed; not used as the
basis for approval decision
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 QOS is main review document.
•
•
Applicants are expected to
summarizecritical data in
module 3 into QOS, along with a
sufficient discussion on every
critical point for ensuring the
quality, efficacy and safety of
the drug.
QOS makes it possible for
reviewers to understand the
characteristicsof the drug
within a short time, and to
review the NDA application
efficiently.
Comparison of Purposes of QOS
between EU/USA and Japan
EU/USA Japan

Assessment
10
Characteristics of Japanese QOS
• Within CTD guideline
• Include many figures and tables which
summarize critical data
• Include narrative summary and/or
discussion on data
• Should be written in Japanese :Tables &
Figures may be in English

Assessment
11
QOS is main Document for Reviewing
NDA in Japan
1. Expert team in PMDA reviews NDA application using
module 2 (QOS) as main review document and referring
to module 3, and prepares a review report.
2. (Final)QOS and review report are submitted to the
Committees on new drugs in the Pharmaceutical Affairs
and Food Sanitation Council (PAFSC).
3. The committee members discuss quality, efficacy and
safety of the drug based on the review report and QOS.
(Usually, the committee members do not review module
3.)
4. The opinion of the committee is sent to MHLW together
with the review report, then the Minister of Health,
Labor and Welfare grants the new drug approval to the
applicant.

1) Determination of structure
2) Physicochemical properties
3) Manufacturing process (brief
outline)
4) Specifications and test methods
5) Stability: stress test, accelerated
test, long-term test
Requirements for Mockup of QOS
Preparation of
Mockup of
Module 2 (QOS)
What to describe?
How to describe?
Former NDA Dossier CTD-based NDA Dossier
3.2.S.2 (P.2) Manufacture
3.2.S.6 (P.7) Container closure
system
3.2.P.2 Pharmaceutical
development
3.2.P.4 Control of excipients
3.2.S.1 General information
3.2.S.3 Characterization
3.2.S.4 (P.5) Control of drug
substances (products)
3.2.S.5 (P.6) Reference standards or
materials
3.2.S.7 (P.8) Stability

Mockup of Japanese QOS
• Published by Pharmaceutical Manufacturers
Association of Tokyo, Osaka Pharmaceutical
Manufacturers Association and Japan Health Sciences
Foundation in July 2002
• Merely shows an example of description for each
module 2 section and just a reference for an applicant
to prepare QOS.
• Not covers all information required for each NDA,
nor shows acceptance criteria for each categories.
• NEED more description on pharmaceutical
development and on justification of manufacturing
process according to ICH Q8 and the revised PAL.
Assessment

Applicationform
(in Japanese)
Analytical
procedures
(JP style) &
acceptance
criteria
Manufacturi
ng process
Relationship between Application Form and
CTD Documents
Module 2 (QOS)
(in Japanese)
Module 3 (in Japanese
or English)
•Specifications
• Analytical procedures
•Pharmaceutical
Development
•Manufacturing Process
• batch analyses
• Justification etc.
3.2.S4.1 Specification
3.2.S4.2 Analytical procedures
3.2.S4.3 Validation of analytical
procedures
3.2.S4.4 Batch analyses
3.2.S4.5 Justification of specification
Raw data

Assessment
軽微変更届出
15
Revised Framework for Review
and GMP Inspection
Application of
partial change
Review
Application
form
Review
Approval
letter
Notification of
minor partial
change
GMP
inspection
New drug
application
Collection of
commercial
scale data
Re-submission
of application
form
Pre-approval
inspection
Commercial
production
Minor
change
Partial
change
Minor
change
Partial
change
Validation data etc
Pilot scale data

Benefits from comprehensive QoS
• Writing Japanese style QoS takes
significant time and energy. BUT it helps
the applicant organizations to understand
own product and process consistently
• QoS can be a vehicle for knowledge
management in regulatory authorities and in
industry
Assessment

AAPS Workshop on Pharmaceutical Quality Assessment -
A Science and Risk-Based CMC Approach in the 21st Century
Co-sponsored with ISPE & FDA
October 6, 2005
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ar
re
ed
d U
Un
nd
de
er
rs
st
ta
an
nd
di
in
ng
g &
& A
Ag
gr
re
ee
em
me
en
nt
ts
s

 R
Re
em
ma
ai
in
ni
in
ng
g C
Ch
ha
al
ll
le
en
ng
ge
es
s

 R
Re
ec
co
om
mm
me
en
nd
da
at
ti
io
on
ns
s

 S
St
tr
ra
at
te
eg
gi
ie
es
s t
to
o i
im
mp
pl
le
em
me
en
nt
t a
ag
gr
re
ee
ed
d-
-u
up
po
on
n i
is
ss
su
ue
es
s

 P
Pr
ro
op
po
os
sa
al
ls
s t
to
o r
re
es
so
ol
lv
ve
e r
re
em
ma
ai
in
ni
in
ng
g c
ch
ha
al
ll
le
en
ng
ge
es
s

I
Is
ss
su
ue
es
s D
Di
is
sc
cu
us
ss
se
ed
d

 W
Wh
ha
at
t a
ar
re
e t
th
he
e p
pr
ro
os
s a
an
nd
d c
co
on
ns
s o
of
f t
th
he
e d
di
if
ff
fe
er
re
en
nt
t Q
QO
OS
S
m
mo
od
de
el
ls
s?
? S
Sh
ho
ou
ul
ld
d Q
QO
OS
S b
be
e r
re
e-
-e
ex
xa
am
mi
in
ne
ed
d?
?
•
• H
Ho
ow
w c
co
ou
ul
ld
d t
th
he
e Q
QO
OS
S b
be
e r
re
ep
pu
ur
rp
po
os
se
ed
d/
/r
re
ed
de
ef
fi
in
ne
ed
d t
to
o b
be
e
a
a m
mo
or
re
e u
us
se
ef
fu
ul
l d
do
oc
cu
um
me
en
nt
t f
fo
or
r i
in
nd
du
us
st
tr
ry
y a
an
nd
d r
re
eg
gu
ul
la
at
to
or
ry
y
a
ag
ge
en
nc
ci
ie
es
s?
?
•
• W
Wh
ha
at
t a
ar
re
e t
th
he
e c
cu
ur
rr
re
en
nt
t c
ch
ha
al
ll
le
en
ng
ge
es
s i
in
n p
pr
re
ep
pa
ar
ri
in
ng
g
Q
QO
OS
Ss
s f
fo
or
r g
gl
lo
ob
ba
al
l s
su
ub
bm
mi
is
ss
si
io
on
ns
s a
an
nd
d w
wh
ha
at
t c
ch
ha
al
ll
le
en
ng
ge
es
s
c
ca
an
n b
be
e a
an
nt
ti
ic
ci
ip
pa
at
te
ed
d i
in
n r
re
ev
vi
is
si
it
ti
in
ng
g t
th
he
e d
do
oc
cu
um
me
en
nt
t t
to
o
a
ac
ch
hi
ie
ev
ve
e a
a b
be
et
tt
te
er
r Q
QO
OS
S?
?
•
• S
Sh
ho
ou
ul
ld
d a
a h
ha
ar
rm
mo
on
ni
iz
ze
ed
d Q
QO
OS
S b
be
e a
an
n I
IC
CH
H t
to
op
pi
ic
c?
?
•
• C
Ca
an
n t
th
he
e Q
QO
OS
S b
be
e u
ut
ti
il
li
iz
ze
ed
d f
fo
or
r p
po
os
st
t-
-a
ap
pp
pr
ro
ov
va
al
l
c
ch
ha
an
ng
ge
es
s?
?

S
Sh
ha
ar
re
ed
d U
Un
nd
de
er
rs
st
ta
an
nd
di
in
ng
g
a
an
nd
d A
Ag
gr
re
ee
em
me
en
nt
ts
s

 Q
QO
OS
S s
sh
ho
ou
ul
ld
d b
be
e r
re
e-
-e
ex
xa
am
mi
in
ne
ed
d

 I
In
nd
du
us
st
tr
ry
y w
wi
il
ll
li
in
ng
g t
to
o r
re
ev
vi
is
si
it
t Q
QO
OS
S

S
Sh
ha
ar
re
ed
d U
Un
nd
de
er
rs
st
ta
an
nd
di
in
ng
g
a
an
nd
d A
Ag
gr
re
ee
em
me
en
nt
ts
s

 Q
QO
OS
S s
sh
ho
ou
ul
ld
d b
be
e r
re
e-
-e
ex
xa
am
mi
in
ne
ed
d

 R
Re
eg
gi
io
on
na
al
l d
di
if
ff
fe
er
re
en
nc
ce
es
s i
in
n h
ho
ow
w Q
QO
OS
S i
is
s p
pr
re
ep
pa
ar
re
ed
d

 N
Ne
ee
ed
d f
fo
or
r c
cl
la
ar
ri
if
fi
ic
ca
at
ti
io
on
n o
on
n h
ho
ow
w Q
QO
OS
S w
wi
il
ll
l b
be
e u
us
se
ed
d

 P
Pr
ri
im
ma
ar
ry
y R
Re
ev
vi
ie
ew
w v
vs
s S
Su
um
mm
ma
ar
ry
y d
do
oc
cu
um
me
en
nt
t

 C
Cu
ur
rr
re
en
nt
t U
US
S/
/E
EU
U a
ap
pp
pl
li
ic
ca
at
ti
io
on
n o
of
f Q
QO
OS
S l
la
ac
ck
ks
s s
su
uf
ff
fi
ic
ci
ie
en
nt
t d
de
et
ta
ai
il
l t
to
o
b
be
e p
pr
ri
im
ma
ar
ry
y r
re
ev
vi
ie
ew
w d
do
oc
cu
um
me
en
nt
t

 I
In
nd
du
us
st
tr
ry
y w
wi
il
ll
li
in
ng
g t
to
o r
re
ev
vi
is
si
it
t Q
QO
OS
S

 P
Po
ot
te
en
nt
ti
ia
al
l b
be
en
ne
ef
fi
it
t i
is
s i
im
mp
pr
ro
ov
ve
ed
d C
CM
MC
C r
re
ev
vi
ie
ew
w e
ef
ff
fi
ic
ci
ie
en
nc
cy
y

 P
Pr
re
ef
fe
er
r s
si
in
ng
gl
le
e g
gl
lo
ob
ba
al
ll
ly
y a
ac
cc
ce
ep
pt
te
ed
d Q
QO
OS
S m
mo
od
de
el
l a
an
nd
d a
a
s
si
in
ng
gl
le
e p
pr
ri
im
ma
ar
ry
y r
re
ev
vi
ie
ew
w d
do
oc
cu
um
me
en
nt
t

R
Re
em
ma
ai
in
ni
in
ng
g C
Ch
ha
al
ll
le
en
ng
ge
es
s
a
an
nd
d O
Ou
ut
ts
st
ta
an
nd
di
in
ng
g I
Is
ss
su
ue
es
s

 R
Re
eg
gi
io
on
na
al
l b
ba
ar
rr
ri
ie
er
rs
s t
to
o g
ge
en
ne
er
ra
al
l s
su
ub
bm
mi
is
ss
si
io
on
n
h
ha
ar
rm
mo
on
ni
iz
za
at
ti
io
on
n

 E
E.
.g
g.
. C
Co
om
mp
pe
en
nd
di
ia
al
l s
st
ta
an
nd
da
ar
rd
ds
s,
, D
DM
MF
Fs
s,
, p
pa
ac
ck
ka
ag
ge
es
s

 C
Cl
la
ar
ri
if
fi
ic
ca
at
ti
io
on
n o
of
f r
re
el
la
at
ti
io
on
ns
sh
hi
ip
p Q
QO
OS
S t
to
o M
Mo
od
du
ul
le
e 3
3

 I
In
nc
cl
lu
ud
de
e P
P2
2 o
or
r n
no
ot
t o
or
r s
su
um
mm
ma
ar
ri
iz
ze
ed
d?
?

 H
Ho
ow
w/
/w
wh
he
en
n/
/w
wh
he
er
re
e s
sh
ho
ou
ul
ld
d d
de
es
si
ig
gn
n s
sp
pa
ac
ce
e b
be
e
c
ca
ap
pt
tu
ur
re
ed
d?
?

 Q
QO
OS
S s
sh
ho
ou
ul
ld
d n
no
ot
t b
be
e a
a d
da
at
ta
a d
du
um
mp
p f
fr
ro
om
m M
Mo
od
du
ul
le
e 3
3

 S
Sh
ho
ou
ul
ld
d Q
QO
OS
S l
le
en
ng
gt
th
h b
be
e d
de
et
te
er
rm
mi
in
ne
ed
d b
by
y p
pr
ro
od
du
uc
ct
t
c
co
om
mp
pl
le
ex
xi
it
ty
y?
?

R
Re
em
ma
ai
in
ni
in
ng
g C
Ch
ha
al
ll
le
en
ng
ge
es
s
a
an
nd
d O
Ou
ut
ts
st
ta
an
nd
di
in
ng
g I
Is
ss
su
ue
es
s

 W
Wh
ha
at
t c
co
on
ns
st
ti
it
tu
ut
te
es
s t
th
he
e r
re
eg
gu
ul
la
at
to
or
ry
y a
ag
gr
re
ee
em
me
en
nt
t
a
an
nd
d r
re
el
la
at
ti
io
on
ns
sh
hi
ip
p t
to
o Q
QO
OS
S?
?

 I
Is
s t
th
he
er
re
e a
a p
po
ot
te
en
nt
ti
ia
al
l u
us
se
e o
of
f Q
QO
OS
S d
du
ur
ri
in
ng
g I
IN
ND
D
P
Ph
ha
as
se
es
s?
?

 R
Ro
ol
le
e i
in
n p
po
os
st
t a
ap
pp
pr
ro
ov
va
al
l s
su
ub
bm
mi
is
ss
si
io
on
ns
s

 P
Po
or
rt
ti
io
on
ns
s v
vs
s.
. n
no
o i
in
nv
vo
ol
lv
ve
em
me
en
nt
t

 I
IC
CH
H Q
Q1
10
0

 I
Is
s Q
QO
OS
S a
a l
li
iv
vi
in
ng
g v
vs
s.
. s
st
ta
at
ti
ic
c d
do
oc
cu
um
me
en
nt
t?
?

R
Re
ec
co
om
mm
me
en
nd
da
at
ti
io
on
ns
s
S
St
tr
ra
at
te
eg
gi
ie
es
s t
to
o i
im
mp
pl
le
em
me
en
nt
t a
ag
gr
re
ee
ed
d-
-u
up
po
on
n i
is
ss
su
ue
es
s

 F
Fu
ur
rt
th
he
er
r d
di
is
sc
cu
us
ss
si
io
on
n
a
an
nd
d c
cl
la
ar
ri
if
fi
ic
ca
at
ti
io
on
n
r
re
eq
qu
ui
ir
re
ed
d f
fo
or
r a
a r
re
e-
-
w
wo
or
rk
ke
ed
d Q
QO
OS
S

 I
If
f t
th
he
er
re
e i
is
s a
a d
de
ec
ci
is
si
io
on
n
t
to
o r
re
ev
vi
is
si
it
t Q
QO
OS
S,
, i
it
t
s
sh
ho
ou
ul
ld
d b
be
e g
gl
lo
ob
ba
al
ll
ly
y
h
ha
ar
rm
mo
on
ni
iz
ze
ed
d t
th
hr
ro
ou
ug
gh
h
t
th
he
e I
IC
CH
H p
pr
ro
oc
ce
es
ss
s

R
Re
ec
co
om
mm
me
en
nd
da
at
ti
io
on
ns
s
P
Pr
ro
op
po
os
sa
al
ls
s t
to
o r
re
es
so
ol
lv
ve
e r
re
em
ma
ai
in
ni
in
ng
g c
ch
ha
al
ll
le
en
ng
ge
es
s
W
Wo
or
rk
k t
to
ow
wa
ar
rd
ds
s
g
gl
lo
ob
ba
al
ll
ly
y h
ha
ar
rm
mo
on
ni
iz
ze
ed
d
r
re
eg
gu
ul
la
at
to
or
ry
y r
re
ev
vi
ie
ew
w p
pr
ra
ac
ct
ti
ic
ce
e &
&
e
ex
xp
pe
ec
ct
ta
at
ti
io
on
ns
s

A
Ac
ck
kn
no
ow
wl
le
ed
dg
ge
em
me
en
nt
t

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