Tieng Anh -Du thao huong dan ASEAN ve dang ky thay doi doi voi duoc pham.rtf

8/21/2019 Tieng Anh -Du thao huong dan ASEAN ve dang ky thay doi doi voi duoc pham.rtf

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ASEAN VARIATION GUIDELINE FORPHARMACEUTICAL PRODUCTS

6TH DRAFTJULY 2011


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LIST OF CONTENTS Page

1 INTRODUCTION 1

2 SCOPE OF THIS GUIDELINE 1

3 DEFINITION 1

3.1 Major Variation (MaV) 13.2 Minor Variation (MiVP! " MiVN) 1

# PROCEDURE !ND TIMELINE 1

$ CH!NGES LE!DING TO ! NE% PRODUCT REGISTR!TION 13

& OTHERS 3

' MAJOR VARIATION (MaV)

MaV1 Can* an+,or a++itiona- in+iation,+o/in r*i0*n,ati*nto-ation,in-/ion o -inia- inor0ation *4t*n+in t* /a* ot* ro+t

#

MaV2 Can* o ont*nt o ro+t -a5*-in #

MaV3 Can* an+,or a++ition o a-t*rnati6* 0anatr*r,/it* o +r/5/tan* (7*r* Ero*an Par0aoo*ia C*rtiiat* o Sita5i-it8(CEP) i/ not a6ai-a5-*)

$

MaV# !++ition or r*-a*0*nt o t* 0anatrin /it* o t* +rro+t

&

MaV$ !++ition or r*-a*0*nt o t* a-t*rnati6* /it* or t* ri0ar8a9ain (+ir*t ontat 7it +r ro+t)

&

MaV& Can* o t* /*iiation +r /5/tan* an+,or +r ro+t '

MaV' Can* o 5at /i:* o /t*ri-* +r ro+t '

MaV; Can* o 5at /i:* o non/t*ri-* +r ro+t ;

MaV< Major an* in t* 0anatrin ro*// or t* +r ro+t ;MaV1= R*-a*0*ntCan* or >antitati6* an* o an *4ii*nt <

MaV11 ?antitati6* an* in t* oatin 7*it o ta5-*t/ or 7*it an+,or/i:* o a/-* /*--/

1=

MaV12 ?a-itati6* an+ >antitati6* an* in o0o/ition an+,or t8* oontain*r an* or in-/ion o ri0ar8 a9ain 0at*ria- or +rro+t

1=

MaV13 Can* or a++ition o i-- 6o-0* an+,or an* o /a* or+i0*n/ion o ontain*r or -o/r* or a /t*ri-* /o-i+ an+ -i>i+ +rro+t

11

MaV1# In-/ion@ r*-a*0*nt or +*-*tion o o0on*nt/ t* /o-6*nt,+i-*ntor t* +r ro+t/ in-+in +i-*nt/

11

MaV1$ Can* o E4t*n/ion o /*- -i* o t* +r ro+t 12

MaV1& Can* o /tora* on+ition/ o t* +r ro+t (Lo7*rin ro0 t*rr*nt aro6*+ /tora* on+ition)

13

; MINOR VARIATION PRIOR APPROVAL (MiVPA)

MiVP!1 Can* o +r ro+t na0* 1#

MiVP!2 Can* in na0* an+,or a++r*// o t* 0ar9*tin atori:ationo-+*r

1#

MiVP!3 Can* o ro+t -a5*-in (in aor+an* to ontr8 /*ii

-a5*-in r*>ir*0*nt)

1$

MiVP!# !++ition or r*-a*0*nt o t* o0an8 or art8 r*/on/i5-* or5at r*-*a/*

1$

2


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MiVP!$ Can* an+,or a++ition o a-t*rnati6* 0anatr*r ,/it* o +r/5/tan* A7*r* Ero*an Par0aoo*ia C*rtiiat* o Sita5i-it8(CEP) i/ a6ai-a5-*B

1&

MiVP!& Can* o 5at /i:* o +r /5/tan* A*4-+in +r /5/tan*o6*r*+ 58 a C*rtiiat* o Sita5i-it8 (CEP)B

1&

MiVP!' Can* o inro*// ontro-/ a-i*+ +rin t* 0anatr* o t*+r /5/tan* (in-+in tit*nin an+ a++ition o n*7 inro*//t*/t)

1'

MiVP!; Can* o 0anatrin ro*// o t* +r /5/tan* 1;

MiVP!< Can* o t* /*iiation o +r /5/tan* 1<

MiVP!1= R*6i/ion o C*rtiiat* o Sita5i-it8 (CEP) o +r /5/tan* 1<

MiVP!11 Can* o t* t*/t ro*+r* o nono0*n+ia- +r /5/tan* 2=

MiVP!12 Can* o /*--i* or r*t*/t *rio+ or +r /5/tan* 2=

MiVP!13 Can* o /tora* on+ition or +r /5/tan* 2=

MiVP!1# Can* o 5at /i:* o non/t*ri-* +r ro+t 21

MiVP!1$ R*+tion or r*0o6a- o o6*ra* 21

MiVP!1& R*-a*0*nt Can* or >antitati6* an* o an *4ii*nt 22

MiVP!1' ?antitati6* an* in oatin 7*it o ta5-*t/ or 7*it an+,or/i:* o a/-* /*--

23

MiVP!1; Can* o t* o-orin,-a6orin a*nt o t* ro+t Aa++ition@+*-*tion or r*-a*0*nt o o-orant(/),-a6or(/)B

23

MiVP!1< Can* o inro*// ontro-/ a-i*+ +rin t* 0anatr* o t*+r ro+t (in-+in tit*nin an+ a++ition o n*7 inro*//t*/t)

2#

MiVP!2= Minor an* o t* 0anatrin ro*// or non/t*ri-* ro+t/. 2$

MiVP!21 Can* o /*iiation/ o an *4ii*nt 2&

MiVP!22 Can* o a t*/t ro*+r* or an *4ii*nt@ in-+in r*-a*0*nto an aro6*+ t*/t ro*+r* 58 a n*7 t*/t ro*+r*

2&

MiVP!23 Can* in t* /or* o *0t8 ar+ a/-* 2'

MiVP!2# Can* o r*-*a/* an+ /*--i* /*iiation/ o t* +r ro+t 2'

MiVP!2$ Can* o i0rint/@ 5o//in or ot*r 0ar9in/ on t* ta5-*t/ orrintin on a/-*/ in-+in a++ition or an* o in9/ /*+ orro+t 0ar9in

2;

MiVP!2& Can* o +i0*n/ion/ an+,or /a* o ta5-*t/@ a/-*/@/o/itori*/ or *//ari*/ 7itot an* in >a-itati6* an+>antitati6* o0o/ition an+ 0*an 0a//

2<

MiVP!2' Can* in t* t*/t ro*+r* o t* +r ro+t (in-+inr*-a*0*nt or a++ition o a t*/t ro*+r*)

3=

MiVP!2; ?a-itati6* an+ >antitati6* an* in t* o0o/ition o ri0ar8a9ain 0at*ria- or non/t*ri-* ro+t/

3=

MiVP!2< !++ition or r*-a*0*nt o a 0anatr*r or /*on+ar8 a9ain 31

MiVP!3= Can* o a9 /i:*,6o-0* an+,or /a*,+i0*n/ion o a9ain0at*ria- or 6o-0* o non/t*ri-* ro+t

31

MiVP!31 Can* o ot*r arton a9 /i:*/ or a +r ro+t 31

MiVP!32 Can* in an8 art o t* (ri0ar8) a9ain 0at*ria- not inontat 7it t* ini/*+ ro+t or0-ation (/ a/ o-or o -i

o a/@ o-or o+* rin/ on a0o-*/@ an* o n**+-* /i*-+(+i*r*nt -a/ti /*+)

32

MiVP!33 !++ition or r*-a*0*nt o 0*a/rin +*6i* or ora- -i>i+ +o/a* 32

3


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or0/ an+ ot*r +o/a* or0

MiVP!3# R*+tion o /*- -i* o t* +r ro+t 33

MiVP!3$ Can* o /tora* on+ition/ o t* +r ro+t (Inr*a/in ro0t* rr*nt aro6*+ /tora* on+ition)

33

< MINOR VARIATION NOTIFICATION (MiVN)

MiVN1 Can* o ro+t o7n*r 3#

MiVN2 Can* in o7n*r/i o 0anatr*r 3#

MiVN3 Can* o t* na0* or a++r*// (*.. o/ta- o+*@ /tr**t na0*) ot* 0anatr*r o +r ro+t

3$

MiVN# Can* o t* na0* or a++r*// (*.. o/ta- o+*@ /tr**t na0*) ot* o0an8 or 0anatr*r r*/on/i5-* or 5at r*-*a/*

3$

MiVN$ Can* o t* na0* an+,or a++r*// (or *4a0-* o/ta- o+*@/tr**t na0*) o a 0anatr*r o t* +r /5/tan*

3$

MiVN& %it+ra7a-,+*-*tion o t* a-t*rnati6* 0anatr*r(/) (or +r/5/tan* an+,or +r ro+t an+,or a9a*r)

3&

MiVN' R*n*7a- o C*rtiiat* o Sita5i-it8 (CEP) 3&

MiVN; Can* o r*-*a/* an+ /*--i* /*iiation/ o t* +r ro+tan+,or +r /5/tan* an+,or *4ii*nt@ o--o7in t* +at*/ in t*o0*n+i0

3&

MiVN< D*-*tion o a9 /i:* or a ro+t 3&

1= GLOSS!R 3'

11 REFERENCES 3'

4


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ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS

1! INTRODUCTION

Troot t* -i* o a ar0a*tia- ro+t@ t* 0ar9*tin atori:ation o-+*r i/r*/on/i5-* or t* ro+t tat i/ -a*+ in t* 0ar9*t an+ i/ a-/o r*>ir*+ to ta9* intoaont t*nia- an+ /i*ntii ror*//@ an+ to 0a9* an8 a0*n+0*nt/ tat 0a8 5*r*>ir*+ to *na5-* t* ar0a*tia- ro+t/ to 5* 0anatr*+ an+ *9*+ 580*an/ o *n*ra--8 a*t*+ /i*ntii 0*to+/. S a0*n+0*nt/ a6* to 5*aro6*+ 58 t* r*-ator8 a*n8.

Ti/ i+an* +o0*nt i/ int*n+*+ to ro6i+* /orti6* inor0ation on t*r*>ir*0*nt/ or /50i//ion o a 6ariation a-iation to i0-*0*nt a an* to a

ar0a*tia- ro+t. Variation a-iation/ ar* at*ori:*+ into 0ajor 6ariation@0inor 6ariation (rior aro6a-) an+ 0inor 6ariation (notiiation). U+atin o ti/i+*-in* 7i-- 5* +on* on a *rio+i 5a/i/ a/ r*>ir*+.

2! SCOPE OF THIS GUIDELINE

Ti/ !SE!N Variation Gi+*-in* on*rn/ t* 6ariation a-iation/ /50itt*+ 58 t*0ar9*tin atori:ation o-+*r or ar0a*tia- ro+t/ or 0an /* on-8 an+ notin-+in 5iot*no-o8,5io/i0i-ar ro+t/.

"! DEFINITION

"!1 Ma#$% &a%ia'i$ (MaV)

Variation to a r*i/t*r*+ ar0a*tia- ini/*+ ro+t tat 0a8 a*t /iniiant-8an+,or +ir*t-8 t* a/*t/ o >a-it8@ /a*t8 an+ *ia8 an+ it +o*/ not a-- 7itin t*+*inition o 0inor 6ariation an+ n*7 r*i/tration.

"!2 Mi$% Va%ia'i$ (MiVN MiVPA)

Variation to a r*i/t*r*+ ar0a*tia- ini/*+ ro+t in t*r0/ o a+0ini/trati6* +ataan+,or an*/ 7it 0ini0a-,no /iniiant i0at on t* a/*t/ o *ia8@ >a-it8@an+ /a*t8.

*! PROCEDURE AND TIMELINE

Variation a-iation i/ /50itt*+ a-on 7it a +*-aration -*tt*r n+*r/in*+ 58 ?a-it8 !//ran* Mana*r an+ H*a+ o R*-ator8 Oi*r tat +*-ar*/ t*r* i/ no ot*ran* *4*t or t* roo/*+ 6ariation

5 Proposal: ASEAN Variation Guideline for Pharmaceutical Products, 2011


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*!1 Mi$% Va%ia'i$ + N$'i,i-a'i$

T8* o 6ariationMinor 6ariation

(Notiiation)MiVN

Pro*+r*

NotiiationI t* notiiation -i-/ t* r*>ir*0*nt/ (on+ition/an+ /ortin +o0*nt/) a/ *r +*/ri5*+ n+*r MiVN@ t* R*-ator8 !*n8 /a-- a9no7-*+*

r**it o a 6a-i+ notiiation.

Ti0*-in* or R*-ator8 !*n8 to *6a-at*6ariation notiiation

Do " T*-- !9no7-*+*0*nt o notiiation 7i-- 5* /*nt to a-iant

7itin 3= 7or9in +a8/ a +ration /5j*t to ontr8 /*iiroo/a-@ o--o7in 6a-i+ r**it o notiiation.

*!2 Mi$% Va%ia'i$ +P%i$% A..%$&a/ a Ma#$% Va%ia'i$

T8* o 6ariation

Minor 6ariation

(Prior aro6a-)MiVP!

Major 6ariationMaV

Pro*+r*

Prior aro6a-

I t* a-iation -i-/ t*r*>ir*0*nt/ (on+ition/ an+/ortin +o0*nt/) a/ *r +*/ri5*+ n+*r MiVP!@ t*

R*-ator8 !*n8 /a--a9no7-*+* r**it o a 6a-i+

a-iation.

Prior aro6a-

I t* a-iation -i-/ t*r*>ir*0*nt/ (on+ition/ an+/ortin +o0*nt/) a/ *r

+*/ri5*+ n+*r MaV@ t*R*-ator8 !*n8 /a--

a9no7-*+* r**it o a 6a-i+a-iation.

Ti0*-in* or R*-ator8 !*n8 to *6a-at* t*

6ariation a-iation

%itin 3= 7or9in +a8/ a+ration /5j*t to ontr8

/*ii roo/a- on r**ito a 6a-i+ a-iation.

an+ anot*r 3= 7or9in +a8/i a++itiona- +ata i/ r*>ir*+.

%itin


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Not*1. T* ti0*-in* an+ i0-*0*ntation o t* 6ariation i/ /5j*t to ontr8 /*ii

roo/a-/.2. T* r*-ator8 a*n8 r*/*r6*/ t* rit to r*at*ori:* t* a-iation t8*@ 7*r*

+**0*+ aroriat*. S5j*t to ontr8 /*ii ro*+r*@ r*at*ori:ation 0a8r*>ir* t* 0ar9*tin atori:ation o-+*r to 7it+ra7 t* oriina- a-iation an+r*/50it a n*7 a-iation aor+in to t* orr*t at*or8.

! CHANGES LEADING TO A NE PRODUCT REGISTRATION

Can*/ r*>irin a n*7 ro+t r*i/tration 0a8 6ar8 ro0 ontr8 to ontr8. C*rtain6ariation/ +*/ri5*+ in ti/ i+*-in* 0a8 r*>ir* a n*7 ro+t r*i/tration in *rtainontri*/. !-iant/ ar* a+6i/*+ to *9 7it in+i6i+a- ontr8 on t* a-ia5i-it8 o ti/ 6ariation i+*-in*

6! OTHERS

&.1 Lea -$3.ei43 r**r/ to riti/ Par0ao*ia (P)@ Unit*+ Stat*/Par0ao*ia (USP) an+ Ero*an Par0ao*ia (EP).

&.2 !n8 6ariation/ not 8*t -i/t*+ in ti/ i+*-in* /o-+ 5* j/tii*+ an+ +*i+*+ 58t* R*-ator8 !*n8. !roriat* r**r*n* an 5* 0a+* to

i. EM! C-a//iiation Gi+an* On Minor Variation/ o T8* I!@ Minor Variation/ o T8* I !n+ Major Variation/ o T8* II@

ii. SUP!CIR I00*+iat*R*-*a/* So-i+ Ora- Do/a* For0/ Sa-*U !n+Po/t!ro6a- Can*/ C*0i/tr8@ Manatrin !n+ Contro-/@ In VitroDi//o-tion T*/tin@ !n+ In Vi6o io*>i6a-*n* Do0*ntation@

iii. %HO Gi+an* On Variation/ To ! Pr*>a-ii*+ Pro+t Do//i*r.

&.3 T* R*-ator8 !*n8 0a8 in *rtain a/*/ r*>*/t or /-*0*ntar8inor0ation@ 7*n +**0*+ n**//ar8.

&.# A55%e&ia'i$7

C J Con+ition/ to 5* -i--*+

D J Do0*nt/ to 5* /50itt*+MaV J Major VariationMiVN J Minor Variation (Notiiation)MiVP! J Minor Variation (Prior !ro6a-)



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8! MAJOR VARIATION

Ma#$% Va%ia'i$ (MaV)

MaV1 C9age a:$% ai'i$a/ ii-a'i$:$ig %egi3e:.a'ie'.$.4/a'i$:i-/4i$ $, -/ii-a/ i,$%3a'i$ e;'eig '9e 4age $, '9e.%$4-'

C 1. Pro+t -a5*-in r**r/ to Pa9a* iIn/*rt (PI)@ Pati*nt iInor0ation -L*a-*t (PIL)@nit arton -a5*-@ inn*r -a5*- an+,or 5-i/t*r /tri/.

2. !/ a /5/*>*nt an* +* to r*6i/ion o S00ar8 o Pro+t Carat*ri/ti/

(S0PC) or *>i6a-*nt +o0*nt (US PI).

D 1. Crr*nt-8 aro6*+ ro+t -a5*-in.2. Proo/*+ ro+t -a5*-in@ a -*an an+ annotat*+ 6*r/ion i-itin t* an*/

0a+*.

3. K/tiiation/ or t* an*/ roo/*+ an+ /ortin -inia- +o0*nt/ 7*na-ia5-*.

4. C-inia- *4*rt r*ort/ an+,or ino/* -inia- tria- r*ort/ (7*r* a-ia5-*).5. !ro6*+ PI,S0PC,PIL ro0 an aro6*+ r**r*n* r*-ator8 a*n8 or t* ontr8

o oriin ontainin t* roo/*+ an*/ (7*r* a-ia5-*).

6. !ro6a- -*tt*r/ ro0 r**r*n* ontri*/ or ontr8 o oriin 7i a6* aro6*+ t*n*7 in+iation or +o/in r*i0*n (7*r* a-ia5-*).

7. C-inia- +o0*nt/ a/ *r !SE!N Co00on T*nia- Do//i*r ( !CTD) art IV (7*r*a-ia5-*).

MaV2 C9age $, -$'e' $, .%$4-' /a5e/ig

C 1. Pro+t -a5*-in r**r/ to Pa9a* In/*rt (PI)@ Pati*nt Inor0ation L*a-*t (PIL)@ nitarton -a5*-@ inn*r -a5*- an+,or 5-i/t*r /tri/.

2. T* an* i/ not a 0inor 6ariation an+ not 7itin t* /o* o MaV'1.3. !/ a /5/*>*nt an* +* to r*6i/ion o S00ar8 o Pro+t Carat*ri/ti/

(S0PC) or *>i6a-*nt +o0*nt (US PI).

D 1. Crr*nt-8 aro6*+ ro+t -a5*-in.2. Proo/*+ ro+t -a5*-in@ a -*an an+ annotat*+ 6*r/ion i-itin t* an*/

0a+*.

3. K/tiiation/ or t* an*/ roo/*+ an+ /ortin -inia- +o0*nt/ 7*na-ia5-*.

4. !ro6*+ PI,S0PC,PIL ro0 an aro6*+ r**r*n* r*-ator8 a*n8 or t* ontr8o oriin ontainin t* roo/*+ an*/ (7*r* a-ia5-*).



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MaV" C9age a:$% ai'i$ $, a/'e%a'i&e 3a4,a-'4%e%:i'e $, %4g45'a-e (CEP) i $' a&ai/a5/e?

F$//$=ig ACCS@ PPG Mee'ig i Siga.$%e '9e Mee'ig ag%ee '9a'=9e%e E4%$.ea P9a%3a-$.$eia Ce%'i,i-a'e $, S4i'a5i/i'> (CEP) i $'a&ai/a5/e '9e &a%ia'i$ 9a// 5e -$ie%e a a MaV a../i-a'i$! P/eae%e,e% '$ MiV PA10 =9e CEP i a&ai/a5/e!

C 1. S*iiation/ o +r /5/tan*/ r*0ain nan*+.

D 1. Co0-*t* CTD /*tion S1S'@ 5ot t* o*n an+ -o/*+ art o t* Dr Ma/t*r Fi-*

an+ t* L*tt*r o !*//.

2. Ta5-ation o t* +i*r*n*/ o0ar*+ 7it t* r*i/t*r*+ 0anatr* inor0ation (ia-ia5-*).

3. at ana-8/i/ +ata (in a o0arati6* ta5-ar or0at) or at -*a/t t7o i-ot 5at*/ ot* +r /5/tan* ro0 t* rr*nt an+ roo/*+ 0anatrin /it*/.

4. ! -*tt*r o o00it0*nt ro0 ro+t -i*n/* o-+*r to on+t r*a- ti0* an+a*-*rat*+ /ta5i-it8 /t+i*/ or t* +r ro+t 0anatr*+ 7it t* +r/5/tan* ro0 t* roo/*+ 0anatrin /it*@ an+ r*ort i an8 r*/-t/ a-- ot/i+*/*- -i* /*iiation/ (7it roo/*+ ation) or 7*n r*>*/t*+.



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MaV* Ai'i$ $% %e./a-e3e' $, '9e 3a4,a-'4%ig i'e $, '9e %4g .%$4-'

C 1. Not a-ia5-* to an*/ r*-atin to 0anatr*r r*/on/i5-* or 5at r*-*a/* or a/it* 7*r* on-8 5at r*-*a/* ta9*/ -a*.

2. I t*r* ar* an*/ to t* 0anatrin ro*//@ MaV;*/t or r*ort*+ i ot/i+* /*iiation/ (7it roo/*+ ation).

3. Sta5i-it8 +ata a/ *r !SE!N Gi+*-in* On Sta5i-it8 St+8 O Dr Pro+t an+ r*ort i an8 r*/-t/ a-- ot/i+* /*- -i* /*iiation/ (7it roo/*+ ation).

4. R*6i/*+ +rat/ o t* a9a* in/*rt an+ -a5*-in inororatin t* roo/*+ 6ariation(7*r* a-ia5-*).

5. For /t*ri-* +r ro+t/@ Va-i+ation +ata o t* 0anatrin ro*// a/ *r !SE!NGi+*-in* on S50i//ion o Manatrin Pro*// Va-i+ation Data or DrR*i/tration at t* roo/*+ /it* or ro+t/ /o-+ 5* ro6i+*+ on /50i//ion.Va-i+ation +ata /o-+ 5* r*/*nt*+ or 6a-i+ation rotoo- (/*0*) /o-+ 5*/ii*nt.

6. Co0arati6* +i//o-tion roi-* +ata 0anatr*+ in t* rr*nt-8 aro6*+ an+roo/*+ 0anatrin /it* or ora- /o-i+ +o/a* or0/ a/ *r o0*n+i0 an+6a-i+ation 5at*/.

7. Pro+t or0-a.8. R*-*a/* an+ *n+o/*- -i* /*iiation/ o +r ro+t.9. at n05*rin /8/t*0 (7*r* a-ia5-*).10. S*iiation o +r /5/tan*.11. Ho-+ ti0* /t+i*/ t*/tin o 5-9 a9 +rin /tora* an+ tran/ortation 5*t7**n t*

5-9 ro+tion /it* an+ ri0ar8 a9a*r (i a-ia5-*).

12. Oiia- -*tt*r atori:in t* roo/*+ /it* to 0anatr* t* ro+t.

MaVAi'i$ $% %e./a-e3e' $, a/'e%a'i&e i'e ,$% .%i3a%> .a-Bagig (i%e-'-$'a-' =i'9 %4g .%$4-')

C 1. No ot*r an*/ *4*t or t* a++ition or r*-a*0*nt o a-t*rnati6* /it* or ri0ar8a9ain (+ir*t ontat 7it +r ro+t).

D 1. Proo tat t* roo/*+ /it* i/ aroriat*-8 atori:*+ or t* a9ain ati6it8 o t*ar0a*tia- or0 on*rn*+ a 6a-i+ GMP C*rtiiat*.or a CPP 7i o6*r/ GMP*rtiiation.

2. L*tt*r o aoint0*nt an+ -*tt*r o a*tan* or Oiia- -*tt*r atori:in t*roo/*+ /it* to a9a* t* ro+t an+ /tatin t* t8*/ o ati6it8 to 5* *ror0*+58 t* a9a*r (or ontrat 0anatr*r,a9a*r).

3. Va-i+ation +ata on ri0ar8 a9ain ro*//*/ to 5* ro6i+*+ on /50i//ion o 6ariation an* (7*r* a-ia5-*).


5. Sta5i-it8 +ata a/ *r !SE!N Gi+*-in* On Sta5i-it8 St+8 O Dr Pro+t an+ r*ort i an8 r*/-t/ a-- ot/i+* /*- -i* /*iiation/ (7it roo/*+ ation).



11/46

6 thdraft

6. Ho-+ti0* /t+i*/ t*/tin o 5-9 a9 +rin /tora* an+ tran/ortation 5*t7**n t*5-9 ro+tion /it* to ri0ar8 a9a*r (7*r* a-ia5-*).

MaV6 C9age $, '9e .e-i,i-a'i$ $, %4g 45'a-e a:$% %4g .%$4-'

a) S.e-i,i-a'i$ /i3i' a%e =ieeb) De/e'i$ $, 'e' .a%a3e'e% a /i3i'

C (a) S.e-i,i-a'i$ /i3i' a%e =iee1. T*/t ro*+r*/ r*0ain nan*+.2. Not a-ia5-* to o0*n+ia- +r /5/tan*/,+r ro+t/.

(b) De/e'i$ $, 'e' .a%a3e'e% a /i3i'1. T*/t ro*+r*/ o t* ot*r ara0*t*r/ in t* +r ro+t /*iiation/ r*0ain

nan*+.

2. Not a-ia5-* to o0*n+ia- +r /5/tan*/,+r ro+t/.

D (a) S.e-i,i-a'i$ /i3i' a%e =iee1. K/tiiation or an* /5/tantiat*+ 7it /i*ntii +ata to 5* ro6i+*+.2. Co0arati6* ta5-at*+ or0at ta5-ation o t* rr*nt-8 aro6*+ an+ r*6i/*+

/*iiation o +r /5/tan*,+r ro+t 7it an*/ i-it*+.

3. R*6i/*+ /*iiation o +r /5/tan* , +r ro+t.4. at ana-8/i/ o t* +r /5/tan*,+r ro+t or a-- t*/t/ in t* n*7 /*iiation

or 2 i-ot or ro+tion /a-* 5at*/.

5. Sta5i-it8 +ata a/ *r !SE!N Gi+*-in* On Sta5i-it8 St+8 O Dr Pro+t an+ r*ort ian8 r*/-t/ a-- ot/i+* /*- -i* /*iiation/ (7it roo/*+ ation).

(b) De/e'i$ $, 'e' .a%a3e'e% a /i3i'In a++ition to t* a5o6* +o0*nt/ *4*t D$@

6. C*rtiiat* o ana-8/i/ o t* +r /5/tan*,+r ro+t or a-- t*/t/ 7it t* n*7/*iiation.

MaV8 C9age $, 5a'-9 ie $, 'e%i/e %4g .%$4-'

C 1. T* an* +o*/ not a*t on/i/t*n8 o ro+tion.

2. R*-*a/* an+ *n+o/*- -i* /*iiation/ o +r ro+t r*0ain nan*+.3. Va-i+ation /*0* or r*ort i/ a6ai-a5-* or 6a-i+ation o t* 0anatrin ro*// a/

5**n /*//--8 arri*+ ot aor+in to rotoo- 7it at -*a/t tr** 5at*/ at t*roo/*+ n*7 5at /i:* in aor+an* 7it t* !SE!N Gi+*-in* on S50i//ion oManatrin Pro*// Va-i+ation Data.

D 1. Pro*// 6a-i+ation /*0* or r*ort aroriat* to t* 5at /i:* an*/.2. Co0arati6* ta5-at*+ or0at o roo/*+ an+ rr*nt-8 aro6*+ 5at 0anatrin

or0-a.

3. at ana-8/i/ +ata (in a o0arati6* ta5-*) o +r ro+t o at -*a/t 2 ro+tion5at*/ aor+in to rr*nt-8 aro6*+ an+ roo/*+ 5at /i:*/.

4. R*-*a/* an+ *n+o/*- -i* /*iiation/ o t* +r ro+t.5. Sta5i-it8 +ata a/ *r !SE!N Gi+*-in* On Sta5i-it8 St+8 O Dr Pro+t an+ r*ort i

an8 r*/-t/ a-- ot/i+* /*- -i* /*iiation/ (7it roo/*+ ation).



12/46

6 thdraft



13/46

6 thdraft

MaV C9age $, 5a'-9 ie $, $'e%i/e %4g .%$4-'

C 1. Ti/ i/ a-ia5-* to an* o 5at /i:* 0or* tan 1=o-+ o0ar*+ to t* rr*nt-8r*i/t*r*+ 5at /i:*.For Can* o 5at /i:* to 1=o-+ o0ar*+ to t* rr*nt-8 r*i/t*r*+ 5at/i:*@ -*a/* r**r MiVP! 31#.

2. T* an* +o*/ not a*t on/i/t*n8 o ro+tion.3. R*-*a/* an+ /*--i* /*iiation/ o +r ro+t r*0ain nan*+.4. Pro*// 6a-i+ation /*0* or r*ort i/ a6ai-a5-* or 6a-i+ation o t* 0anatrin

ro*// a/ 5**n /*//--8 arri*+ ot aor+in to rotoo- 7it at -*a/t tr**5at*/ at t* roo/*+ n*7 5at /i:* in aor+an* 7it t* !SE!N Gi+*-in* onS50i//ion o Manatrin Pro*// Va-i+ation Data.

D 1. Pro*// 6a-i+ation /*0* or r*ort aroriat* to t* 5at /i:* an*/.

2. Co0arati6* ta5-at*+ or0at o roo/*+ an+ rr*nt 5at 0anatrin or0-a.3. at ana-8/i/ +ata (in a o0arati6* ta5-*) o +r ro+t o at -*a/t 2 on a

0ini00 o on* ro+tion 5at*/ aor+in to rr*nt-8 aro6*+ an+ roo/*+5at /i:*/ an+ -*tt*r o n+*rta9in to /50it 5at +ata on t* n*4t on* --ro+tion 5at.


5. R*-*a/* an+ /*- -i* /*iiation/ o t* +r ro+t.6. For ora- /o-i+ +o/a* or0/@ o0arati6* +i//o-tion roi-* or at -*a/t on* ro+tion

5at (7*r* a-ia5-* a/ *r o0*n+ia- r*>ir*0*nt).

MaV Ma#$% -9age i '9e 3a4,a-'4%ig .%$-e ,$% %4g .%$4-'

C 1. T* /a0* rr*nt-8 aro6*+ 0anatrin /it*. I t*r* i/ a an* in 0anatrin/it*@ MaV# i/ a-/o a-ia5-*.

2. T* an* +o*/ not a/* a n*ati6* i0at on t* >a-it8@ /a*t8 an+ *ia8 o t*+r ro+t.

D 1. D*/rition o t* n*7 0anatrin ro*//.2. Pro*// 6a-i+ation o 3 ro+tion 5at*/@ or at a 0ini00@ 2i-ot 5at*/ -/ on*

ro+tion 5at 7it a o00it0*nt to on+t t7o 0or* 6a-i+ation 5at*/ on

aro6a- o t* 6ariation.3. Co8 o rr*nt-8 aro6*+ r*-*a/* an+ *n+o/*- -i* /*iiation/. Or@

a-t*rnati6*-8@ o8 o roo/*+ r*-*a/* an+ *n+o/*- -i* /*iiation/ tat /ort/tat t* n*7 ro*// 0/t -*a+ to an i+*ntia- or 5*tt*r ro+t r*ar+in a-- a/*t/ o >a-it8@ /a*t8 an+ *ia8.

4. Co0arati6* 5at ana-8/i/ +ata o +r ro+t or a 0ini00 o on* ro+tion5at at -*a/t t7o ro+tion 5at*/ (or on* ro+tion 5at an+ t7o i-ot 5at*/)0anatr*+ aor+in to rr*nt-8 r*i/t*r*+ an+ roo/*+ ro*//*/.


6. Co0arati6* +i//o-tion roi-* +ata 5*t7**n t* ro+t/ 0anatr*+ in t*rr*nt-8 aro6*+ an+ roo/*+ 0anatrin ro*// or ora- /o-i+ +o/a* or0/ a/

*r o0*n+i0 an+ 6a-i+ation 5at*/.7. K/tiiation or not /50ittin a n*7 5io*>i6a-*n* /t+8 aor+in to !SE!N

Gi+*-in*/ or t* Con+t o ioa6ai-a5i-it8 an+ io*>i6a-*n* St+i*/ (7*r*a-ia5-*).



14/46

6 thdraft



15/46

6 thdraft

MaV10 Re./a-e3e'C9age $% 4a'i'a'i&e -9age $, a e;-i.ie'

a) F$% i33eia'e %e/eae $%a/ $age ,$%3(a .e% Le&e/ 2 a " Pa%' III C$3.$e' a C$3.$i'i$ SUPACg4ie/ie)

b) F$% 3$i,ie %e/eae $%a/ $age ,$%3c) F$% $'9e% -%i'i-a/ $age ,$%3 4-9 a 'e%i/e .%e.a%a'i$!

C 1. Can* 7i-- n**+ to o0-8 7it t* ini/*+ ro+t /*iiation/ or *4a0-* r*-*a/*an+ *n+o/*- -i* /*iiation/ o t* +r ro+t r*0ain/ t* /a0*@ *4-+inro+t +*/rition.

2. Va-i+ation /*0* or r*ort i/ a6ai-a5-* or 6a-i+ation o t* 0anatrin ro*// a/5**n /*//--8 arri*+ ot aor+in to rotoo- 7it at -*a/t tr** 5at*/ o t*roo/*+ n*7 ro+t or0-a in aor+an* 7it t* !SE!N Gi+*-in* on S50i//ion

o Manatrin Pro*// Va-i+ation Data.3. T*r* i/ no an* in +i//o-tion roi-* or ora- /o-i+ +o/a* or0/. T* +i//o-tion

roi-* o t* roo/*+ ro+t i/ o0ara5-* to tat o t* rr*nt aro6*+ ro+t.

4. R*-a*0*nt o an *4ii*nt 7it a o0ara5-* *4ii*nt o t* /a0* ntiona-arat*ri/ti/.

D 1. K/tiiation or t* an* 0/t 5* i6*n 58 aroriat* +*6*-o0*nt oar0a*ti/.


3. Co0arati6* +i//o-tion roi-* +ata o at -*a/t on* r*r*/*ntati6* i-ot,ro+tion 5at

o t* +r ro+t 5*t7**n t* rr*nt-8 aro6*+ an+ roo/*+ /o-i+ +o/a* or0/or0-ation (7*r* a-ia5-*).

4. K/tiiation or not /50ittin a n*7 5io*>i6a-*n* /t+8 aor+in to !SE!NGi+*-in*/ or t* Con+t o ioa6ai-a5i-it8 an+ io*>i6a-*n* St+i*/ (7*r*a-ia5-*).

5. Co0arati6* ta5-at*+ or0at ta5-ation o t* rr*nt an+ r*6i/*+ ro+t or0-ation7it a--at*+ an*/ i-it*+ (-*a/* /tat* an*/ in t* *r*nta* o t*roo/*+ *4ii*nt ot o t* tota- tar*t +o/a* or0 7*it@ 7*r* a-ia5-*).

6. R*-*a/* an+ /*- -i* /*iiation/.7. at ana-8/i/ +ata (in a o0arati6* ta5-*) o +r ro+t o at -*a/t 2 ro+tion (or

on* ro+tion 5at an+ t7o i-ot 5at*/) aor+in to rr*nt-8 aro6*+ an+roo/*+ ro+t or0-a.


9. S*iiation/ o t* roo/*+ *4ii*nt.10. For roo/*+ *4ii*nt/ 0a+* o r0inant/ /or*@ Tran/0ittin !ni0a- Sonior0

En*a-oat8 (TSE)r** *rtiiat* or o6in* Sonior0 En*a-oat8 (SE)r***rt i//*+ ro0 r*-*6ant 6*t*rinar8 atorit8 o t* i//in ontr8 (7*r* a-ia5-*).

11. R*6i/*+ 5at 0anatrin or0-a.12. Pro*// Va-i+ation /*0* or r*ort aroriat* to t* roo/*+ an* in ro+t

or0-a.

13. R*6i/*+ !CTD S*tion P3.2 to P3.$ (7*r* a-ia5-*).



16/46

6 thdraft

MaV11 @4a'i'a'i&e -9age i -$a'ig =eig9' $, 'a5/e' $% =eig9' a:$% ie $,-a.4/e 9e//

C 1. !-ia5-* on-8 or 0o+ii*+ r*-*a/* ora- +o/a* or0.2. T*r* i/ no an* in +i//o-tion roi-* or ora- /o-i+ +o/a* or0/. T* +i//o-tion

roi-* o t* roo/*+ ro+t i/ o0ara5-* to tat o t* rr*nt aro6*+ ro+t.

3. T* ro+t r*-*a/* an+ *n+o/*- -i* /*iiation/ a6* on-8 5**n +at*+ inr*/*t o ro+t +*/rition (7*r* a-ia5-*).

4. For i00*+iat* r*-*a/* ora- /o-i+ +o/a* or0/ -*a/* r**r to MiVP! 1; 1'.

D 1. Co0arati6* +i//o-tion roi-* +ata o at -*a/t on* i-ot,ro+tion 5at o t* +rro+t 5*t7**n t* rr*nt-8 aro6*+ an+ roo/*+ o0o/ition.

2. K/tiiation or not /50ittin a n*7 5io*>i6a-*n* /t+8 aor+in to t* !SE!NGi+*-in*/ For T* Con+t o ioa6ai-a5i-it8 an+ io*>i6a-*n* St+i*/ (7*r*a-ia5-*).

3. R*6i/*+ r*-*a/* an+ *n+o/*- -i* /*iiation/ o t* +r ro+t.4. ! +*-aration tat t* an* +o*/ not int*r*r* 7it t* +r ro+t r*-*a/* an+ /*-

-i* /*iiation/ t*/t 0*to+.

5. Crr*nt an+ roo/*+ ro+t an+ 5at 0anatrin or0-a.6. R*6i/*+ +rat o ro+t -a5*- inororatin t* roo/*+ an* (7*r* a-ia5-*).7. Sta5i-it8 +ata a/ *r !SE!N Gi+*-in* On Sta5i-it8 St+8 O Dr Pro+t an+ r*ort i


I4e ,$% AMS '$ -$33e'7D87 Vie'a3 .%$.$e '$ a D8!

MaV12 @4a/i'a'i&e a 4a'i'a'i&e -9age i -$3.$i'i$ a:$% '>.e $,-$'aie% -9age $% i-/4i$ $, .%i3a%> .a-Bagig 3a'e%ia/ ,$% 'e%i/e %4g .%$4-'

C 1. R*-*a/* an+ *n+o/*- -i* /*iiation/ o t* +r ro+t r*0ain nan*+.2. For >a-itati6* an+ >antitati6* an* in t* o0o/ition o ri0ar8 a9ain

o0on*nt or non/t*ri-* +r ro+t@ -*a/* r**r to MiVP!2;.

D 1. For /t*ri-* +r ro+t/@ Pro*// 6a-i+ation +ata o t* 0anatrin an+ /t*ri-i:ationro*//.2. Sta5i-it8 +ata a/ *r !SE!N Gi+*-in* On Sta5i-it8 St+8 O Dr Pro+t an+ r*ort i


3. Proo 0/t 5* ro6i+*+ tat no int*ration 5*t7**n t* ont*nt an+ t* a9ain0at*ria- or/ (7*r* a-ia5-*).

4. Co0arati6* ta5-at*+ or0at o /*iiation/ o t* roo/*+ an+ rr*nt ri0ar8a9ain 0at*ria-.


6. R*6i/*+ !CTD S*tion/ P3 an+,or P' (7*r* a-ia5-*).7. !roriat* /i*ntii +ata on n*7 a9ain.



17/46

6 thdraft

MaV1" C9age $% ai'i$ $, ,i// &$/43e a:$% -9age $, 9a.e $% i3ei$ $,-$'aie% $% -/$4%e ,$% a 'e%i/e $/i a /i4i %4g .%$4-'

C 1. R*-*a/* an+ *n+o/*- -i* /*iiation/ o t* +r ro+t ar* not a*t*+@ *4*ti-- 6o-0* /*iiation.

2. T* roo/*+ a9 /i:* i/ on/i/t*nt 7it t* +o/a* r*i0*n an+ +ration o /* a/aro6*+ in t* a9a* in/*rt.

3. T* a9ain 0at*ria- r*0ain/ t* /a0*.

D 1. K/tiiation tat t* roo/*+ a9 /i:* i/ on/i/t*nt 7it t* +o/a* r*i0*n an++ration o /* a/ aro6*+ in t* a9a* in/*rt.

2. Va-i+ation +ata o t* 0anatrin ro*//@ /t*ri-i:ation an+ ontain*r -o/r* /8/t*0(7*r* a-ia5-*).

3. Sta5i-it8 +ata a/ *r !SE!N Gi+*-in* On Sta5i-it8 St+8 O Dr Pro+t an+ r*ort ian8 r*/-t/ a-- ot/i+* /*- -i* /*iiation/ (7it roo/*+ ation).4. R*6i/*+ +rat/ o t* a9a* in/*rt an+ -a5*-in inororatin t* roo/*+ 6ariation@

7*r* a-ia5-*.

MaV1* I-/4i$ %e./a-e3e' $% e/e'i$ $, -$3.$e' '9e $/&e':i/4e' ,$%'9e %4g .%$4-' i-/4ig i/4e'

F$//$=ig ACCS@ PPG Mee'ig i Siga.$%e '9i &a%ia'i$ i '$ 5e%e&ii'e ,$% ,4%'9e% i-4i$ 5> AMS

C

1. T* roo/*+ an* +o*/ not r*/-t in an8 an* in t* +o/a* r*i0*n@ in+iation@0*to+ o a+0ini/tration o t* ro+t.

2. T* roo/*+ an* i/ a-ia5-* on-8 i t* rr*nt or0 o r*/*ntation a9a*+ or /a-* 7i-- not 5* 0ar9*t*+ at*r t* rr*nt /to9/ ar* *4a/t*+.

3. For an* o /*- -i* an+,or /tora* on+ition o t* +r ro+t at*r ir/t o*ninan+,or at*r +i-tion,r*on/tittion@ -*a/* a-/o r**r to MaV1$ an+,or MaV1& (7*r*a-ia5-*)

D 1. Co0-*t* /*tion P or t* /o-6*nt,+i-*nt/ an+ r*on/tittion /ta5i-it8 +ata (7*r*a-ia5-*).

2. Do0*ntar8 *6i+*n* to *rti8 t* 0anatrin /it* o +i-*nt/ o0-i*/ 7it rr*nta-ia5-* GMP /tan+ar+/.

3. at n05*rin /8/t*0 (7*r* a-ia5-*).4. !tori:ation -*tt*r ro0 ro+t o7n*r to atori:* t* 0anatrin /it* to

0anatr* an+ a9a* t* /o-6*nt,+i-*nt/ (7*r* a-ia5-*).

5. R*6i/*+ art7or9/ or t* +r ro+t -a5*-/ inororatin t* an*/.6. ! +*-aration ro0 t* a-iant tat t* r*-*a/* an+ /*- -i* /*iiation/ o +r

ro+t ar* not a*t*+.

7. K/tiiation or t* +*-*tion o t* /o-6*nt,+i-*nt.8. ! -*tt*r o +*-aration tat rr*nt ro+t /to9/ 7i-- 5* *4a/t*+ 5*or* t* roo/*+

r*/*ntation i/ 0ar9*t*+@ in+iatin t* t*ntati6* +at* or *4a/tion o t* rr*nt/to9.


I4e ,$% AMS '$ -$33e'7D7 Vie'a3 .%$.$e '$ a D! H$=e&e% '9e ACCS@ PPG 3ee'ig ag%ee '9a'



18/46

6 thdraft

D$-43e' 1 3a> 4,,i-e a '9e 4gge'e D 3a> $' 5e e-ea%>!

MaV1 C9age $, E;'ei$ $, 9e/, /i,e $, '9e %4g .%$4-'1) A a .a-Bage ,$% a/e a:$% 2) A,'e% ,i%' $.eig a:$%

3) A,'e% i/4'i$:%e-$'i'4'i$

Ma/a>ia .%$.$e %e4-'i$ $, 9e/, /i,e '$ 5e ./i' i'$ MiVPA!F$//$=ig ACCS@ PPG Mee'ig i Siga.$%e i' 9a 5ee ag%ee '9a'%e4-'i$ $, 9e/, /i,e '$ 5e ./i' ,%$3 MaV1 '$ MiV PA"* =i'9 a3e Ca D! (E&a/4a'i$ $, 9e/, /i,e %e4-'i$ ee '$ 5e $e i 9$%'e% 'i3e,%a3e $ .%$3.' a-'i$ -a 5e 'aBe 5> MAH)

C 1. For (1) " (2) T* /t+i*/ 0/t /o7 onor0an* to t* rr*nt-8 aro6*+ *n+o/*- -i* /*iiation.

2. For (3) T* /t+i*/ 0/t /o7 onor0an* to t* rr*nt-8 aro6*+ /*- -i*/*iiation or t* r*on/titt*+ ro+t.

3. For r*+tion o /*- -i*@ -*a/* r**r to MiVP!3#.

D 1. R*/-t/ o aroriat* r*a- ti0* /ta5i-it8 /t+i*/ o6*rin t* +ration o roo/*+/*--i* o at -*a/t 2 i-ot,ro+tion /a-* 5at*/ o t* ro+t in t* atori:*+a9ain 0at*ria-1) a/ a a9a* or /a-* an+,or 2) at*r ir/t o*nin an+,or 3) at*r t* +i-tion,r*on/tittionin aor+an* 7it t* !SE!N Gi+*-in*/ on Sta5i-it8 St+8 o Dr Pro+t r*/-t/ o

aroriat* 0iro5io-oia- t*/tin /o-+ 5* in-+*+ (7*r* aroriat*).2. R*6i/*+ +rat/ o t* a9a* in/*rt an+ -a5*-in inororatin t* roo/*+ 6ariation

(7*r* a-ia5-*).

3. K/tiiation -*tt*r or t* an* o /*- -i* o t* +r ro+t (7*r* a-ia5-*).



19/46

6 thdraft

MaV16 C9age $, '$%age -$i'i$ $, '9e %4g .%$4-' (L$=e%ig ,%$3 '9e-4%%e' a..%$&e '$%age -$i'i$)

1) A a .a-Bage ,$% a/e a:$% 2) A,'e% ,i%' $.eig a:$% 3) A,'e% i/4'i$:%e-$'i'4'i$

Ma/a>ia .%$.$e i-%eaig $, '$%age -$i'i$ '$ 5e ./i' i'$ MiVPA!F$//$=ig ACCS@ PPG Mee'ig i Siga.$%e i' 9a 5ee ag%ee '9a'i-%eaig ,%$3 '9e -4%%e' a..%$&e '$%age -$i'i$ '$ 5e ./i' ,%$3MaV16 '$ MiV PA" =i'9 a3e C a D!

C 1. T* /t+i*/ 0/t /o7 onor0an* to t* rr*nt-8 aro6*+ *n+o/*- -i*/*iiation.

1. For (1) " (2) T* /t+i*/ 0/t /o7 onor0an* to t* rr*nt-8 aro6*+ *n+o/*- -i* /*iiation.


3. For an* o /tora* on+ition (inr*a/in ro0 t* rr*nt aro6*+ /tora*on+ition)@ -*a/* r**r to MiVP!3$.

D 1. R*/-t/ o aroriat* r*a- ti0* /ta5i-it8 /t+i*/ o6*rin t* +ration o rr*nt-8aro6*+ *n+o /*--i* (at roo/*+ /tora* on+ition) o at -*a/t 2 i-ot,ro+tion/a-* 5at*/ o t* ro+t an+ in t* atori:*+ a9ain 0at*ria- in aor+an*7it t* !SE!N Gi+*-in*/ on Sta5i-it8 St+8 o Dr Pro+t.




20/46

6 thdraft

! MINOR VARIATIONPRIOR APPROVAL

Mi$% Va%ia'i$ (MiVPA)P%i$% A..%$&a/

MiVPA1

C9age $, %4g .%$4-' a3e

C 1. T*r* i/ no an* to t* ro+t (or0-ation@ r*-*a/* an+ *n+o/*- -i*/*iiation/@ 0anatrin /or* an+ ro*//) *4*t or t* ro+t na0* an*.

2. No on/ion 7it anot*r +r ro+t *it*r 7*n /o9*n or 7ritt*n.3. T* n*7 na0* +o*/ not (1) /*/t r*at*r /a*t8 or *ia8 tan /ort*+ 58 -inia-

+ata (2) i0-8 a t*ra*ti /* (3) i0-8 /*riorit8 o6*r anot*r /i0i-ar ro+t (#)i0-8 t* r*/*n* o /5/tan*(/) not r*/*nt in t* ro+t.

D 1. Oiia- -*tt*r ro0 ro+t o7n*r or 0ar9*tin atori:ation o-+*r atori:in t*an* o ro+t na0* (7*r* a-ia5-*) an+ o00ittin to inor0 /*r/ o t*r*-*6ant an*/ an+ tat t* rr*nt ro+t /to9 7i-- 5* *4a/t*+ 5*or* t*ro+t -a5*-*+ 7it t* n*7 na0* i/ 0ar9*t*+.

2. ! +*-aration ro0 t* a-iant tat t*r* i/ no ot*r an*/ to t* ro+t,-a5*-*4*t or t* +r ro+t na0* an*.

3. R*6i/*+ +rat a9a* in/*rt an+ -a5*-in inororatin t* roo/*+ 6ariation.4. U+at*+ C*rtiiat* o Par0a*tia- Parti-ar/Pro+t (CPP) i a-ia5-* (ro0

ontr8 o oriin).

5. Oiia- -*tt*r o o00it0*nt to inor0 /*r/ o t* r*-*6ant an*/ an+ tat t* rr*ntro+t /to9/ 7i-- 5* *4a/t*+ 5*or* t* ro+t -a5*-*+ 7it t* n*7 na0* i/0ar9*t*+.

6. $. Tra+*0ar9 *rtiiat* (7*r* a-ia5-*).

MiVPA2

C9age i a3e a:$% a%e $, '9e 3a%Be'ig a4'9$%ia'i$ 9$/e%

F$//$=ig ACCS@ PPG Mee'ig i Siga.$%e '9i &a%ia'i$ i '$ 5e %e-a'eg$%ie a MiVPA ,%$3 MiVN!

C 1. T* na0* an* r**r/ to t* r*na0in o a o0an8 or orani:ation.2. T* an* +o*/ not in-+* tran/*r o ro+t -i*n/* to anot*r o0an8.

D 1. L*tt*r 58 t* ro+t o7n*r atori:in t* n*7 na0* o 0ar9*tin atori:ation o-+*r to o-+ t* ro+t -i*n/*.

2. Stattor8 +o0*nt o na0* an+,or a++r*// an*.



21/46

6 thdraft

MiVPA"

C9age $, .%$4-' /a5e/ig (i a--$%a-e '$ -$4'%> .e-i,i- /a5e/ig%e4i%e3e')

In-+*/

a) Can* o t* -a8ot,art7or9 7itot a-t*rin 0*anin an+,or b) !++ition,+*-*tion,r*-a*0*nt o itr*/@ +iara0/@ 5ar o+*@ -oo/ an+,or t*4t/ tat

+o not i0-8 an naro6*+ in+iation an+,or

c) !++ition,/tr*nt*nin o 7arnin/@ r*ation/@ ontrain+iation/ or a+6*r/**6*nt/,**t/ to t* aro6*+ ro+t -a5*--in

d) Tit*nin o ro+t/ tar*t o-ation an+,or e) D*-*tion o in+iation.f) Can* o +i/tri5tor/ +*tai-/

C 1. T* an* i/ not a MaV an+ +o*/ not ontain ro0otiona- inor0ation.

D 1. Crr*nt aro6*+ ro+t -a5*-in.2. Proo/*+ ro+t -a5*-in@ a -*an an+ annotat*+ 6*r/ion i-itin t* an*/

0a+*.

3. L*tt*r o +*-aration ro0 t* a-iant /tatin tat no ot*r an*/ on t* -a5*- *4*tor t* int*n+*+ an*.

4. R*-*6ant +o0*nt,r**r*n* to /ort t* an*/ (7*r* a-ia5-*).

MiVPA*

Ai'i$ $% %e./a-e3e' $, '9e -$3.a> $% .a%'> %e.$i5/e ,$% 5a'-9%e/eae


C1. On-8 a-ia5-* or 5at r*-*a/*.2. M*to+ tran/*r ro0 t* rr*nt-8 aro6*+ to t* roo/*+ /it* or t*/t -a5orator8 a/

5**n /*//--8 o0-*t*+.

3. T* 0anatr*r o t* +r ro+t r*0ain/ t* /a0*.

D1. Oiia- -*tt*r ro0 ro+t o7n*r atori:in t* o0an8,0anatr*r to 5*

r*/on/i5-* or 5at r*-*a/*.

2. ! 6a-i+ GMP *rtiiat* or CPP 7i o6*r/ t* GMP *rtiiat* o t* roo/*+ /it*.3. R*6i/*+ +rat/ o t* a9a* in/*rt an+ -a5*-in inororatin t* roo/*+ 6ariation

(7*r* a-ia5-*).



22/46

6 thdraft

MiVPA

C9age a:$% ai'i$ $, a/'e%a'i&e 3a4,a-'4%e% :i'e $, %4g 45'a-e (CEP) ia&ai/a5/e?

F$//$=ig ACCS@ PPG Mee'ig i Siga.$%e '9e Mee'ig ag%ee '9a'=9e%e E4%$.ea P9a%3a-$.$eia Ce%'i,i-a'e $, S4i'a5i/i'> (CEP) i $'a&ai/a5/e '9e &a%ia'i$ 9a// 5e -$ie%e a a MaV a../i-a'i$! P/eae%e,e% '$ MaV "!

C 1. S*iiation/ o +r /5/tan*/ r*0ain nan*+.

D 1. 1. ! 6a-i+ Ero*an Par0aoo*ia C*rtiiat* o Sita5i-it8 (CEP) or t* +r

/5/tan*@ -at*/t 6*r/ion@ 7it a-- ann*4*/ i//*+ 58 ED?M. or Dr Ma/t*r Fi-* orr*-*6ant +at*+ +r /5/tan* (DS) /*tion or *>i6a-*nt,a+it +o0*nt.

2. Pro6i+* t* +i*r*n*/ o0ar*+ 7it t* r*i/t*r*+ +r /5/tan* 0anatr*rinor0ation (7*r* a-ia5-*).

3. 2. at ana-8/i/ +ata (in a o0arati6* ta5-ar or0at) or at -*a/t t7o i-ot 5at*/(0ini00 i-ot /a-* o t* +r /5/tan* ro0 t* rr*nt an+ roo/*+0anatr*r/, 0anatrin /it*/).3. I t* r*t*/t *rio+ i/ not /tat*+ in t* CEP@ at -*a/t /i4 0ont/ r*a- ti0* an+a*-*rat*+ /ta5i-it8 +ata on t7o i-ot 5at*/ o t* +r /5/tan* 0anatr*+ ro0t* roo/*+ 0anatrin /it*/ /o-+ 5* ro6i+*+.#. ! -*tt*r o o00it0*nt ro0 ro+t -i*n/* o-+*r to on+t aroriat* r*a- ti0*an+ a*-*rat*+ /ta5i-it8 /t+i*/ or t* +r ro+t 0anatr*+ 7it t* +r

/5/tan* ro0 t* roo/*+ 0anatrin /it*@ an+ r*ort i an8 r*/-t/ a-- ot/i+*/*--i* /*iiation/ (7it roo/*+ ation) or 7*n r*>*/t*+.

MiVPA6

C9age $, 5a'-9 ie $, %4g 45'a-e


23/46

6 thdraft

MiVPA 8

C9age $, i.%$-e -$'%$/ a../ie 4%ig '9e 3a4,a-'4%e $, '9e %4g45'a-e (i-/4ig 'ig9'eig a ai'i$ $, e= i.%$-e 'e')

C

1. Inro*// -i0it/ ar* tit*n*+ or a++ition o n*7 t*/t/.2. R**r to MiVP!1= i t* 6ariation i/ o6*r*+ 58 a C*rtiiat* o Sita5i-it8 (CEP).3. T* an* i/ not a on/*>*n* o an8 o00it0*nt ro0 r*6io/ a//*//0*nt/ to

r*6i*7 /*iiation -i0it/.

4. T* an* +o*/ not r*/-t ro0 n*4*t*+ *6*nt/ ari/in +rin 0anatr* *..n*7 n>a-ii*+ i0rit8 an* in tota- i0rit8 -i0it/.

5. !n8 n*7 t*/t 0*to+ +o*/ not on*rn a no6*- non/tan+ar+ t*ni>* or a /tan+ar+t*ni>* /*+ in a no6*- 7a8.

D 1. ! +*/rition o t* ana-8tia- 0*to+ an+ /00ar8 o 6a-i+ation +ata 0/t 5* ro6i+*+

or a-- n*7 ana-8tia- 0*to+/ (7*r* a-ia5-*).2. Co0arati6* ta5-at*+ or0at Ta5-ation o t* roo/*+ an+ rr*nt inro*//ontro-/ an+ t* r*-*6ant an*/.

3. Co0arati6* 5at*/ ana-8/i/ +ata o on* t7o ro+tion 5at*/ o t* +r/5/tan* or a-- t*/t/ in t* roo/*+ /*iiation (i a-ia5-*).



24/46

6 thdraft

MiVPA

C9age $, 3a4,a-'4%ig .%$-e $, '9e %4g 45'a-e

C 1. No a+6*r/* an* in >a-itati6* an+,or >antitati6* i0rit8 roi-* 7i 7o-+ r*>ir*rt*r >a-iiation/ in /a*t8 /t+i*/.

2. S*iiation/ an+ /ta5i-it8 *ror0an* o +r /5/tan* r*0ain nan*+.3. T* /8nt*ti rot* r*0ain/ t* /a0* (or *4a0-*@ int*r0*+iat*/ r*0ain t* /a0*).4. Manatrin ro*// o +r /5/tan* +o*/ not /* an8 0at*ria-/ o 0an , ani0a-

oriin or 7i a//*//0*nt i/ r*>ir*+ o 6ira- /a*t8.

5. P8/ia- ro*rti*/ o +r /5/tan* r*0ain nan*+.6. R**r to MiVP!1= i t* 6ariation i/ o6*r*+ 58 a C*rtiiat* o Sita5i-it8 (CEP).

D 1. C*rtiiat* o Sita5i-it8 (CEP) or Dr Ma/t*r Fi-* (DMF)@ or r*-*6ant +at*+ +r/5/tan* (DS) /*tion or *>i6a-*nt,a+it +o0*nt.

For +r /5/tan*/ 7i ar* nono0*n+ia- an+ *n*ri ro+t/ 7i +o not a6* CEP

2. Co0arati6* ta5-at*+ or0at Ta5-ation o t* rr*nt-8 aro6*+ an+ n*7 ro*//*/7it an*/ i-it*+ (7*r* a6ai-a5-*).

3. C*rtiiat* o ana-8/i/ or 2 5at*/ o t* +r /5/tan*.4. at ana-8/i/ (in o0arati6* ta5-*) o +r ro+t o at -*a/t 2 5at*/

(i-ot,ro+tion /a-*) 0anatr*+ aor+in to t* rr*nt-8 aro6*+ an+ roo/*+ro*//*/.

5. ! -*tt*r o +*-aration ro0 0ar9*tin atori:ation o-+*r /tatin tat no n*7 i0riti*/

a6* 5**n intro+*+ at or a5o6* t* a*t*+ tr*/o-+ or >a-iiation o i0riti*/or tat t*r* i/ no inr*a/* in t* -*6*-/ o i0riti*/@ 7i r*>ir* rt*r /a*t8/t+i*/.

6. ! -*tt*r o +*-aration ro0 t* 0ar9*tin atori:ation o-+*r /tatin tat t*/*iiation/ o t* +r /5/tan* a6* not an*+ or i t*r* i/ an8 an* to t*/*iiation ( or *4a0-*@ tit*nin)@ t* t*4t/ o t* rr*nt-8 aro6*+ an+ roo/*+/*iiation/ /o-+ 5* ro6i+*+ (in a o0arati6* ta5-at*+ or0at ta5-* 7*r*o//i5-*).

7. Sta5i-it8 +ata a/ *r !SE!N Gi+*-in* On Sta5i-it8 St+8 O Dr Pro+t an+ r*ort ian8 r*/-t/ a-- ot/i+* /*- -i* /*iiation/ (7it roo/*+ ation). T$ 5e i-4e.%$.$e '$ ,$//$= Siga.$%e HSA 'a'e3e'! ! +*-aration ro0 t* a-iant tatt* r*-*6ant /ta5i-it8 /t+i*/ o t* +r /5/tan* in aor+an* 7it t* r*-*6anti+*-in*/ a6* 5**n /tart*+ an+ tat t* r*-*6ant /ta5i-it8 /t+i*/ 7i-- 5* ina-i:*+ +ata

/o-+ 5* ro6i+*+ on-8 i ot/i+* /*iiation (7it roo/*+ ation).8. For /t*ri-* +r /5/tan*@ ro*// 6a-i+ation r*ort (7*r* a-ia5-*).

I4e ,$% AMS '$ -$33e'7D87 APRIA:APC .%$.$e '$ %e./a-e 'a'e3e' a .e% HSA &a%ia'i$ g4ie/ie!



25/46

6 thdraft

MiVPA

C9age $, '9e .e-i,i-a'i$ $, %4g 45'a-ea) S.e-i,i-a'i$ /i3i' a%e 'ig9'ee5) Ai'i$ $, e= 'e' .a%a3e'e% a /i3i'

Not* Ti/ i/ on-8 a-ia5-* or +r /5/tan*/ 7i ar* nono0*n+ia- an+ *n*ri +r/5/tan*/ 7itot C*rtiiat* o Sita5i-it8 (CEP)

C 1. Ti/ i/ on-8 a-ia5-* or +r /5/tan*/ 7i ar* nono0*n+ia- an+ *n*ri +r/5/tan*/ 7itot C*rtiiat* o Sita5i-it8 (CEP)

2. For (5) a-ia5-* to nono0*n+ia- 0*to+ on-8.3. R**r to MiVP!1= i t* 6ariation i/ o6*r*+ 58 a C*rtiiat* o Sita5i-it8 (CEP).

D

(a) S.e-i,i-a'i$ /i3i' a%e 'ig9'ee

1. Co0arati6* ta5-at*+ or0at Ta5-ation o t* rr*nt-8 aro6*+ an+ r*6i/*+

/*iiation o +r /5/tan* 7it an*/ i-it*+.2. Co0arati6* 5at ana-8/i/ o t* +r /5/tan* or a-- t*/t/ in t* n*7 /*iiationor 2 i-ot or ro+tion /a-* 5at*/.

(5) Ai'i$ $, e= 'e' .a%a3e'e% a /i3i'In a++ition to t* a5o6* +o0*nt/@

3. D*/rition o an8 n*7 ana-8tia- 0*to+ an+ /00ar8 o t* 6a-i+ation +ata.

MiVPA 10

Re&ii$ $, Ce%'i,i-a'e $, S4i'a5i/i'> (CEP) $, %4g 45'a-e

C Non*

D 1. ! o8 o t* +at*+ 6a-i+ Ero*an Par0aoo*ia C*rtiiat* o Sita5i-it8 (CEP) or t* +r /5/tan*@ -at*/t 6*r/ion@ 7it a-- ann*4*/ i//*+ 58 ED?M.

2. S*iiation/ o +r /5/tan* /*iiation/ (7*r* a-ia5-*).3. R*/-t/ o 5at ana-8/i/ ro0 t* +r /5/tan* 0anatr*r +*0on/tratin

o0-ian* 7it t* PEr 0onora an+ in-+in a++itiona- t*/t,-i0it/ -i/t*+ on t*CEP (7*r* a-ia5-*).

4. !++itiona- +ata to a++r*// an8 r*-*6ant ara0*t*r(/) not a++r*//*+ in t* CEP / a//ta5i-it8 +ata (S')@ i a r*t*/t *rio+ i/ not /tat*+ on t* CEP an+ 8/io*0ia-arat*ri/ti/ (*.. arti-* /i:*@ o-80ori/0 *t)@ i a-ia5-*.

I t* +r /5/tan* 0anatr*r i/ CEP *rtii*+ an+ t* +r ro+t 0anatr*r-ai0/ ot*r7i/* (USP@ KP@ Ino/* *t)@ +ata o6*rin S#.1 to S#.$ ro0 t* +r ro+t0anatr*r /o-+ 5* /50itt*+.



26/46

6 thdraft

MiVPA11

C9age $, '9e 'e' .%$-e4%e $, $-$3.eia/ %4g 45'a-e(For +r /5/tan* 7i i/ not -i/t*+ in o0*+i0)

C 1. R*/-t/ o 0*to+ 6a-i+ation /o7 n*7 t*/t ro*+r* to 5* at -*a/t *>i6a-*nt to t*or0*r ro*+r*.

2. R**r to MiVP!1= i t* 6ariation i/ o6*r*+ 58 a C*rtiiat* o Sita5i-it8 (CEP).

D 1. D*/rition o t* ana-8tia- 0*to+o-o8@ a /00ar8 o 6a-i+ation +ata@ an+o0arati6* ana-8tia- r*/-t/ 5*t7**n t* rr*nt-8 aro6*+ an+ roo/*+ t*/t(7*r* a-ia5-*).

2. S*iiation o t* +r /5/tan*.

MiV

PA 12

C9age $, 9e/, /i,e $% %e'e' .e%i$ ,$% %4g 45'a-e

C 1. T* /ta5i-it8 /t+i*/ 0/t /o7 o0-ian* 7it /*iiation.2. No an* in /tora* on+ition.3. R**r to MiVP!1= i t* 6ariation i/ o6*r*+ 58 a C*rtiiat* o Sita5i-it8 (CEP).

D 1. Sta5i-it8 +ata o t* +r /5/tan* /o-+ 5* r*/*nt*+ on at -*a/t t7o i-ot orro+tion /a-* 5at*/ o t* r*>*/t*+ /*- -i* or r*t*/t *rio+.

2. S*iiation/ o t* +r /5/tan*.

MiVPA 1"

C9age $, '$%age -$i'i$ ,$% %4g 45'a-e

C 1. T* /ta5i-it8 /t+i*/ 0/t /o7 o0-ian* 7it /*iiation.2. No an* in /*- -i*,r*t*/t *rio+.3. R**r to MiVP!1= i t* 6ariation i/ o6*r*+ 58 a C*rtiiat* o Sita5i-it8 (CEP).

D 1. Sta5i-it8 +ata o t* +r /5/tan* /o-+ 5* r*/*nt*+ on at -*a/t t7o i-ot orro+tion /a-* 5at*/ o t* r*>*/t*+ /tora* on+ition.

2. S*iiation/ o t* +r /5/tan*.



27/46

6 thdraft

MiVPA1*

C9age $, 5a'-9 ie $, $'e%i/e %4g .%$4-'

C 1. Ti/ i/ a-ia5-* to an* o 5at /i:* to 1=o-+ o0ar*+ to t* rr*nt-8r*i/t*r*+ 5at /i:*.

2. T* an* +o*/ not a*t on/i/t*n8 o ro+tion.3. R*-*a/* an+ *n+o/*--i* /*iiation/ o +r ro+t r*0ain nan*+.4. Pro*// V6a-i+ation /*0* or r*ort i/ a6ai-a5-* or 6a-i+ation o t* 0anatrin

ro*// a/ 5**n /*//--8 arri*+ ot aor+in to rotoo- 7it at -*a/t tr**5at*/ at t* roo/*+ n*7 5at /i:* in aor+an* 7it t* !SE!N Gi+*-in* onS50i//ion o Manatrin Pro*// Va-i+ation Data.

5. For Can* o 5at /i:* or /t*ri-* ro+t/ -*a/* r**r to MaV1= ' an+ or Can*o 5at /i:* 0or* tan 1=o-+ o0ar*+ to t* rr*nt-8 r*i/t*r*+ 5at /i:* -*a/*r**r MaV< ;.

D 1. Pro*// 6a-i+ation /*0* or r*ort aroriat* to t* 5at /i:* an*/.2. Co0arati6* ta5-at*+ or0at ta5-ation o roo/*+ an+ rr*nt 5at 0anatrin

or0-a.

3. at ana-8/i/ +ata (in a o0arati6* ta5-*) o at -*a/t 2 o +r ro+t on a 0ini00o on* ro+tion 5at*/ aor+in to rr*nt-8 aro6*+ an+ roo/*+ 5at /i:*/an+ a -*tt*r o n+*rta9in to /50it 5at +ata on t* n*4t -- ro+tion 5at.


5. R*-*a/* an+ *n+o/*- -i* /*iiation/ o t* +r ro+t.6. R*6i/*+ !CTD,ICTD S*tion P3.23.$ (7*r* a-ia5-*).

MiVPA1

Re4-'i$ $% %e3$&a/ $, $&e%age

C 1. Can*/ o r*6io/-8 aro6*+ 0anatrin o6*ra*/ o +r /5/tan* on-8.2. R*-*a/* an+ *n+o/*--i* /*iiation/ o +r ro+t r*0ain nan*+.

D 1. K/tiiation or t* an*.2. Co0arati6* ta5-at*+ or0at ta5-* o rr*nt-8 aro6*+ an+ roo/*+ 5at

0anatrin or0-a.

3. C*rtiiat* o ana-8/i/ or 2 5at*/ o t* ini/*+ ro+t.




28/46

6 thdraft

MiV +PA 16

Re./a-e3e' C9age $% 4a'i'a'i&e -9age $, a e;-i.ie'

a) F$% i33eia'e %e/eae $%a/ $age ,$%3(a .e% Le&e/ 1 Pa%' III C$3.$e' a C$3.$i'i$ SUPACg4ie/ie)

b) F$% $'9e% $-%i'i-a/ $age ,$%3 eg! $%a/ /i4i e;'e%a/.%e.a%a'i$!

C1. R*-*a/* an+ *n+o/*- -i* /*iiation/ o t* +r ro+t r*0ain nan*+.2. P*rtin*nt Pro*// Va-i+ation. Va-i+ation /*0* or r*ort i/ a6ai-a5-* or 6a-i+ation o t*

0anatrin ro*// a/ 5**n /*//--8 arri*+ ot aor+in to rotoo- 7it at-*a/t tr** 5at*/ o t* roo/*+ n*7 ro+t or0-a in aor+an* 7it t* !SE!NGi+*-in* on S50i//ion o Manatrin Pro*// Va-i+ation Data.

3. T*r* i/ no an* in +i//o-tion roi-* or ora- /o-i+ +o/a* or0/. T* +i//o-tion

roi-* o t* roo/*+ ro+t i/ o0ara5-* to tat o t* rr*nt aro6*+ ro+t.4. R*-a*0*nt o an *4ii*nt 7it a o0ara5-* *4ii*nt o t* /a0* ntiona-

arat*ri/ti/ (7*r* a-ia5-*).

D 1. K/tiiation or t* an* 0/t 5* i6*n 58 aroriat* +*6*-o0*nt oar0a*ti/.


3. Co0arati6* +i//o-tion roi-* +ata o at -*a/t on* r*r*/*ntati6* i-ot,ro+tion 5ato t* +r ro+t 5*t7**n t* rr*nt-8 aro6*+ an+ roo/*+ /o-i+ +o/a* or0/or0-ation.

4. K/tiiation or not /50ittin a n*7 5io*>i6a-*n* /t+8 aor+in to t* !SE!NGi+*-in*/ For T* Con+t o ioa6ai-a5i-it8 an+ io*>i6a-*n* St+i*/.

5. Co0arati6* ta5-at*+ or0at Ta5-ation o t* rr*nt an+ r*6i/*+ ro+t or0-ation7it a--at*+ an*/ i-it*+ (-*a/* /tat* an*/ in t* *r*nta* o t*roo/*+ *4ii*nt ot o t* tota- tar*t +o/a* or0 7*it@ 7*r* a-ia5-*).

6. R*-*a/* an+ /*- -i* /*iiation/.7. at ana-8/i/ +ata (in a o0arati6* ta5-*) o +r ro+t o at -*a/t 2 ro+tion (or

on* ro+tion 5at an+ t7o i-ot 5at*/) aor+in to rr*nt-8 aro6*+ an+roo/*+ ro+t or0-a.


9. S*iiation/ o t* roo/*+ *4ii*nt.

10. For roo/*+ *4ii*nt/ 0a+* o r0inant/ /or*@ Tran/0ittin !ni0a- Sonior0En*a-oat8 (TSE)r** *rtiiat* or o6in* Sonior0 En*a-oat8 (SE)r***rt i//*+ ro0 r*-*6ant 6*t*rinar8 atorit8 o t* i//in ontr8 (7*r* a-ia5-*).

11. R*6i/*+ 5at 0anatrin or0-a.12. ! +*-aration tat t* n*7 *4ii*nt +o*/ not int*r*r* 7it t* +r ro+t r*-*a/* an+

/*- -i* /*iiation/ t*/t 0*to+.

13. R*6i/*+ !CTD,ICTD S*tion P3.23.$ (7*r* a-ia5-*).14. Pro*// 6a-i+ation /*0* or r*ort aroriat* to t* roo/*+ an* in ro+t

or0-a (7*r* a-ia5-*).



29/46

6 thdraft

MiV +PA 18

@4a'i'a'i&e -9age i -$a'ig =eig9' $, 'a5/e' $% =eig9' a:$% ie $,-a.4/e 9e//

C 1. T* +i//o-tion roi-* o t* roo/*+ ro+t i/ o0ara5-* to tat o t* rr*ntaro6*+ ro+t.

2. T* ro+t r*-*a/* an+ *n+o/*--i* /*iiation/ o t* +r ro+t r*0ainnan*+ *4*t or t* ro+t +*/rition.

3. For 0o+ii*+ r*-*a/* ora- /o-i+ +o/a* or0/ -*a/* r**r to MaV1# 11.

D 1. Co0arati6* +i//o-tion roi-* +ata o at -*a/t on* i-ot,ro+tion 5at o t* +rro+t 5*t7**n t* rr*nt-8 aro6*+ an+ roo/*+ o0o/ition.

2. K/tiiation or not /50ittin a n*7 5io*>i6a-*n* /t+8 aor+in to t* !SE!NGi+*-in*/ For T* Con+t o ioa6ai-a5i-it8 an+ io*>i6a-*n* St+i*/ (7*r*

a-ia5-*).3. R*6i/*+ r*-*a/* an+ *n+o/*- -i* /*iiation/ o t* +r ro+t.4. ! +*-aration ro0 0ar9*tin atori:ation o-+*r tat t* an* +o*/ not int*r*r* 7it

t* +r ro+t r*-*a/* an+ /*- -i* /*iiation/ t*/t 0*to+.

5. Co0arati6* ta5-at*+ or0at o rr*nt an+ roo/*+ ro+t an+ 5at 0anatrinor0-a.

6. R*6i/*+ +rat o ro+t -a5*- inororatin t* roo/*+ an* (7*r* a-ia5-*).7. ! +*-aration ro0 t* a-iant tat t* r*-*6ant /ta5i-it8 /t+i*/ o t* +r ro+t in

aor+an* 7it t* r*-*6ant i+*-in*/ a6* 5**n /tart*+ an+ tat t* r*-*6ant /ta5i-it8/t+i*/ 7i-- 5* ina-i:*+ +ata /o-+ 5* ro6i+*+ on-8 i ot/i+* /*iiation (7itroo/*+ ation).

MiV PA1

C9age $, '9e -$/$4%ig:,/a&$4%ig age' $, '9e .%$4-' antitati6* inor0ation o t* rr*nt an+ roo/*+ o-orin,-a6orina*nt in a o0arati6* ta5-*.

2. R*6i/*+ ro+t or0-ation an+ 5at 0anatrin or0-a.3. R*6i/*+ r*-*a/* an+ *n+o/*- -i* /*iiation/ o t* +r ro+t.4. R*6i/*+ +rat/ o t* a9a* in/*rt an+ -a5*-in inororatin t* roo/*+ 6ariation

(7*r* a-ia5-*).


6. For roo/*+ *4ii*nt/ 0a+* o r0inant/ /or*@ Tran/0ittin !ni0a- Sonior0En*a-oat8 (TSE)r** *rtiiat* or o6in* Sonior0 En*a-oat8 (SE)r***rtiiat* i//*+ ro0 r*-*6ant 6*t*rinar8 atorit8 o t* i//in ontr8 (7*r*

a-ia5-*).7. ! -*tt*r o o00it0*nt to inor0 t* /*r/ o r*-*6ant an*/ an+ tat t* rr*nt

ro+t /to9 7i-- 5* *4a/t*+ 5*or* t* n*7 ro+t i/ 0ar9*t*+.

8. ! +*-aration ro0 0ar9*tin atori:ation o-+*r tat t* an* +o*/ not int*r*r* 7itt* +r ro+t r*-*a/* an+ /*- -i* /*iiation/ t*/t 0*to+.



30/46

6 thdraft



31/46

6 thdraft

MiVPA1

C9age $, i.%$-e -$'%$/ a../ie 4%ig '9e 3a4,a-'4%e $, '9e %4g.%$4-' (i-/4ig 'ig9'eig a ai'i$ $, e= i.%$-e 'e')

C 1. R*-*a/* an+ *n+o/*- -i* /*iiation/ o +r ro+t r*0ain nan*+.2. T* an* i/ not a on/*>*n* o an8 o00it0*nt ro0 r*6io/ a//*//0*nt/ to

r*6i*7 /*iiation -i0it/.

3. T* an* +o*/ not r*/-t ro0 n*4*t*+ *6*nt/ ari/in +rin 0anatr* *..n*7 n>a-ii*+ i0rit8 an* in tota- i0rit8 -i0it/.

4. !n8 n*7 t*/t 0*to+ +o*/ not on*rn a no6*- non/tan+ar+ t*ni>* or a /tan+ar+t*ni>* /*+ in a no6*- 7a8.

D 1. ! +*/rition o t* ana-8tia- 0*to+o-o8 an+ /00ar8 o 6a-i+ation +ata 0/t 5*ro6i+*+ or a-- n*7 ana-8tia- 0*to+/ (7*r* a-ia5-*).

2. R*6i/*+ inro*// /*iiation/ to*t*r 7it j/tiiation an+ r*-*6ant ro*//6a-i+ation +ata.3. Co0arati6* 5at ana-8/i/ o +r ro+t o at -*a/t 2 ro+tion,i-ot 5at*/.4. Co0arati6* ta5-at*+ or0at ta5-ation an* o t* inro*// ontro-/.



32/46

6 thdraft

MiV PA20

Mi$% -9age $, '9e 3a4,a-'4%ig .%$-e ,$% $'e%i/e .%$4-'!

C 1. T* /a0* rr*nt-8 aro6*+ 0anatrin /it*.

2. T* o6*ra-- 0anatrin rini-* r*0ain/ t* /a0*.3. T* an* +o*/ not a/* n*ati6* i0at on t* >a-it8@ /a*t8 an+ *ia8 o t*

+r ro+t.

4. R*-*a/* an+ *n+o/*--i* /*iiation/ o +r ro+t r*0ain nan*+.5. T* +i//o-tion roi-* o t* roo/*+ ro+t i/ o0ara5-* to tat o t* rr*nt

aro6*+ ro+t.

D 1. D*/rition o t* n*7 0anatrin ro*//.2. Pro*// 6a-i+ation o tr** ro+tion 5at*/@ or at a 0ini00 2 i-ot 5at*/ -/

on* ro+tion 5at 7it a o00it0*nt to on+t 2 0or* 6a-i+ation 5at*/ on

aro6a- o t* 6ariation (or a/ *r !SE!N i+*-in* on S50i//ion o ManatrinPro*// Va-i+ation +ata).

3. For /o-i+ ora- +o/a* or0/@ o0arati6* +i//o-tion roi-* +ata o at -*a/t on*r*r*/*ntati6* ro+tion 5at o t* +r ro+t 5*t7**n t* rr*nt-8 aro6*+ an+roo/*+ /o-i+ ora- +o/a* or0/ or0-ation.

4. Co8 o rr*nt-8 aro6*+ r*-*a/* an+ *n+o/*- -i* /*iiation/. Or@ a-t*rnat*-8@o8 o r*6i/*+ r*-*a/* an+ *n+o/*- -i* /*iiation/ tat /ort/ tat t* n*7ro*// 0/t -*a+ to an i+*ntia- or 5*tt*r ro+t r*ar+in a-- a/*t/ o >a-it8@/a*t8 an+ *ia8.

5. K/tiiation or not /50ittin a n*7 5io*>i6a-*n* /t+8 aor+in to t* rr*ntioa6ai-a5i-it8 an+ io*>i6a-*n* i+an* (7*r* a-ia5-*).

6. at ana-8/i/ o t* +r ro+t (in a o0arati6* ta5-at*+ or0) o +r ro+t on

a 0ini00 o on* 5at 0anatr*+ to 5ot t* rr*nt-8 aro6*+ an+ t* roo/*+ro*// 5at +ata on t* n*4t 2 -- ro+tion 5at*/ /o-+ 5* 0a+* a6ai-a5-*on r*>*/t.

7. Sta5i-it8 +ata a/ *r !SE!N Gi+*-in* On Sta5i-it8 St+8 O Dr Pro+t an+ r*ort ian8 r*/-t/ a-- ot/i+* /*- -i* /*iiation/ (7it roo/*+ ation). T$ 5e i-4e.%$.$e '$ ,$//$= Siga.$%e HSA 'a'e3e'! ! +*-aration ro0 t* a-iant tatt* r*-*6ant /ta5i-it8 /t+i*/ o t* +r ro+t in aor+an* 7it t* r*-*6anti+*-in*/ a6* 5**n /tart*+ an+ tat t* r*-*6ant /ta5i-it8 /t+i*/ 7i-- 5* ina-i:*+ +ata/o-+ 5* ro6i+*+ on-8 i ot/i+* /*iiation (7it roo/*+ ation).

8. Co0arati6* ta5-at*+ or0at o r*/*nt an+ roo/*+ ro*// 7it an*/i-it*+.

I4e ,$% AMS '$ -$33e'7

D87 APRIA:APC .%$.$e '$ %e./a-e 'a'e3e' a .e% HSA &a%ia'i$ g4ie/ie!D27 T9ai/a .%$.$e D2 9$4/ $' 5e %e4i%e ,$% $'e%i/e .%$4-'! I' i $'%e4i%e i EMA &a%ia'i$ g4ie/ie



33/46

6 thdraft

MiVPA21

C9age $, .e-i,i-a'i$ $, a e;-i.ie'a) S.e-i,i-a'i$ /i3i' a%e 'ig9'ee5) Ai'i$ $, e= 'e' .a%a3e'e% a /i3i'

C 1. !-ia5-* to non o0*n+ia- *4ii*nt/. For o0*n+ia- *4ii*nt/@ -*a/* r**r toMiVN;.

2. R*-*a/* an+ *n+o/*--i* /*iiation/ o +r ro+t r*0ain nan*+.3. T* an* /o-+ not 5* t* r*/-t o n*4*t*+ *6*nt/ ari/in +rin 0anatr*

or 5*a/* o /ta5i-it8 on*rn/.

4. For tit*nin o /*iiation/ on-8

D 1. Co0arati6* ta5-at*+ or0at Ta5-ation o t* rr*nt an+ r*6i/*+ /*iiation o t**4ii*nt 7it an*/ i-it*+.

2. at ana-8/i/ o t* *4ii*nt or a-- t*/t/ in t* n*7 /*iiation. (ot/i+* /o* orr*nt !CTD,!CTR)

3. D*/rition o n*7 0*to+ an+ /00ar8 o ana-8tia- 6a-i+ation (a-ia5-* or a++itiono n*7 ara0*t*r).

4. K/tiiation or roo/*+ an*.

MiVPA22

C9age $, a 'e' .%$-e4%e ,$% a e;-i.ie' i-/4ig %e./a-e3e' $, aa..%$&e 'e' .%$-e4%e 5> a e= 'e' .%$-e4%e

C 1. !roriat* 0*to+ 6a-i+ation /t+i*/ a6* 5**n *ror0*+ in aor+an* 7it t*

!SE!N Gi+*-in*/ For Va-i+ation o !na-8tia- Pro*+r*/.2. R*/-t/ o 0*to+ 6a-i+ation /o7 n*7 t*/t ro*+r* to 5* at -*a/t *>i6a-*nt to t*

or0*r ro*+r*.

3. T*r* a6* 5**n no an*/ o t* tota- i0rit8 -i0it/.4. On-8 a-ia5-* to t* rr*nt-8 aro6*+ t*/t ara0*t*r/.5. No n*7 n>a-ii*+ i0riti*/ ar* +*t*t*+.

D 1. D*/rition o t* ana-8tia- 0*to+o-o8 7it a o0arati6* ta5-ation o t* an*/.2. Va-i+ation +ata i/ on-8 n**+*+ or nono0*n+ia- 0at*ria-/ or 0*to+/ (7*r*

a-ia5-*).

3. V*riiation +ata i/ n**+*+ or o0*n+ia- 0*to+/.(ot o /o* o rr*nt !CTD,!CTR.

3. Co0arati6* 6a-i+ation r*/-t/ /o7in tat t* rr*nt an+ roo/*+ t*/t/ ar**>i6a-*nt.



34/46

6 thdraft

MiVPA2"

C9age i '9e $4%-e $, e3.'> 9a% -a.4/e

C 1. Fro0 ani0a-+*ri6*+ TSEri/9 0at*ria- to 6**ta5-*/or*+ or /8nt*ti *0t8 ar+a/-*/ or 6i* 6*r/a.

2. No an* in t* or0-ation an+ 0anatrin ro*// o +r ro+t.3. Not a-ia5-* to an* ro0 ar+ a/-* to /ot *-.4. E4ii*nt an+ ini/*+ ro+t r*-*a/* an+ *n+ o /*- -i* /*iiation/ r*0ain t*

/a0*.

D 1. Co0arati6* +i//o-tion roi-* +ata o tr** on* 5at*/ r*r*/*ntati6* oi-ot,ro+tion 5at o t* +r ro+t /in ar+ a/-* 5*t7**n t* t7o /or*/(7*r* a-ia5-*).

2. C*rtiiat* o !na-8/i/ o t* *0t8 ar+ a/-* o t* roo/*+ n*7 /or*.

3. T*nia- /*iiation/ an+ o0o/ition o t* *0t8 ar+ a/-* o t* n*7 /or*.4. Sta5i-it8 +ata a/ *r !SE!N Gi+*-in* On Sta5i-it8 St+8 O Dr Pro+t an+ r*ort ian8 r*/-t/ a-- ot/i+* /*- -i* /*iiation/ (7it roo/*+ ation).

5. For *0t8 ar+ a/-* 0a+* o r0inant/ /or*@ Tran/0ittin !ni0a- Sonior0En*a-oat8 (TSE)r** *rtiiat* or o6in* Sonior0 En*a-oat8 (SE)r** *rt i//*+ ro0 r*-*6ant 6*t*rinar8 o0*t*nt atorit8 o t* i//in ontr8.

6. D*-aration ro0 t* 0anatr*r or t* 0ar9*tin atori:ation o-+*r o t* 0at*ria-tat it i/ r*-8 o 6**ta5-*@ ani0a- or /8nt*ti oriin.

MiVPA2*

C9age $, %e/eae a 9e/,/i,e .e-i,i-a'i$ $, '9e %4g .%$4-'a) S.e-i,i-a'i$ /i3i' a%e 'ig9'ee5) Ai'i$ $, e= 'e' .a%a3e'e% a /i3i'


• Vie'a3 a Ca35$ia .%$.$e '$ i-/4e S'a5i/i'> a'a 9$4/

5e 453i''e (=9e%e a../i-a5/e) a D*!

C 1. !-ia5-* to nono0*n+ia- 0*to+.2. T* an* /o-+ not 5* t* r*/-t o n*4*t*+ *6*nt/ ari/in +rin 0anatr*

or 5*a/* o /ta5i-it8 on*rn/.

3. T* t*/t 0*to+/ r*0ain t* /a0* or an*/ in t* t*/t 0*to+/ ar* 0inor.4. I t*r* ar* an*/ to t* t*/t ro*+r*@ MiVP!2' i/ a-/o a-ia5-*

D (a) S.e-i,i-a'i$ /i3i' a%e 'ig9'ee1. Co0arati6* ta5-at*+ or0at ta5-ation o t* rr*nt an+ r*6i/*+ r*-*a/* an+ /*- -i*

/*iiation/ o t* +r ro+t 7it an*/ i-it*+.

2. Co0arati6* 5at ana-8/i/ o t* +r ro+t or a-- t*/t/ in t* n*7 /*iiation o at-*a/t 2 5at*/.

(5) Ai'i$ $, e= 'e' .a%a3e'e% a /i3i'(I t*r* ar* an*/ to t* t*/t ro*+r*@ MiVP!2' i/ a-/o a-ia5-*)In a++ition to t* a5o6* +o0*nt/

3. D*/rition o an8 n*7 0*to+ an+ /00ar8 o ana-8tia- 6a-i+ation +ata or nono0*n+ia- 0*to+.

4. Sta5i-it8 +ata a/ *r !SE!N Gi+*-in* On Sta5i-it8 St+8 O Dr Pro+t an+ r*ort ian8 r*/-t/ a-- ot/i+* /*- -i* /*iiation/ (7it roo/*+ ation). (7*r*a-ia5-*).



35/46

6 thdraft



36/46

6 thdraft

MiVPA2

C9age $, i3.%i' 5$ig $% $'9e% 3a%Big $ 'a5/e' $% .%i'ig $-a.4/e i-/4ig ai'i$ $% -9age $, iB 4e ,$% .%$4-' 3a%Big

C (a) E;-e.' -$%e:5%eaB/ie1. N*7 0ar9in/ +o not a/* on/ion 7it ot*r r*i/t*r*+ ro+t/.2. !n8 in9 roo/*+ 0/t o0-8 to r*-*6ant ar0a*tia- -*i/-ation or o oo+ ra+*

an+ not a -i/t*+ 5ann*+ /5/tan*.

3. R*-*a/* an+ *n+o/*- -i* /*iiation/ o t* +r ro+t r*0ain nan*+*4*t or a*aran*.

(5) + O -$%e:5%eaB/ieIn a++ition to t* a5o6* on+ition/@

4. Sor*,5r*a9-in* i/ not 0*ant or o/0*ti ro/*.5. !-ia5-* to a++ition or r*0o6a- o /or*,5r*a9-in*.

D (a) E;-e.' -$%e:5%eaB/ie1. D*tai-/ an+ /*iiation/ o t* roo/*+ n*7 in9/ (7*r* a-ia5-*).2. C*rtiiat* o ana-8/i/ o in9 , rintin 0at*ria- (ar0a*tia- ra+* an+ o oo+ ra+*).3. D*tai-*+ +ra7in or 7ritt*n +*/rition o t* rr*nt an+ roo/*+

i0rint,5o//in,0ar9in/.


5. R*-*a/* an+ *n+o/*- -i* /*iiation/ o t* +r ro+t 7it t* n*7 ro+t+*/rition.

6. ! -*tt*r o o00it0*nt to inor0 t* /*r/ o r*-*6ant an*/ an+ tat t* rr*nt

ro+t /to9 7i-- 5* *4a/t*+ 5*or* t* n*7 ro+t i/ 0ar9*t*+.

(5) + O -$%e:5%eaB/ieIn a++ition to t* a5o6* +o0*nt/@

7. K/tiiation or t* an* (i.*. an* in +o/in r*i0*n).8. C*rtiiat* o ana-8/i/ o 2 ro+tion,i-ot /a-* 5at*/.9. Data on t*/t o ont*nt nior0it8 o t* /5+i6i+*+ art/ o t* ta5-*t/ at r*-*a/* /o-+

5* /50itt*+.



37/46

6 thdraft

MiV PA26

C9age $, i3ei$ a:$% 9a.e $, 'a5/e' -a.4/e 4..$i'$%ie $% .ea%ie =i'9$4' -9age i 4a/i'a'i&e a 4a'i'a'i&e -$3.$i'i$ a3ea 3aa) I33eia'e %e/eae $%a/ $/i $age ,$%3 4..$i'$%ie a .ea%ie5) O'9e% '9a i33eia'e %e/eae $%a/ $/i $age ,$%3 4..$i'$%iea .ea%ie!

C 1. I aroriat*@ t* +i//o-tion roi-* o t* roo/*+ ro+t i/ o0ara5-* to tat ot* rr*nt aro6*+ ro+t.

2. R*-*a/* an+ *n+o/*- -i* /*iiation/ o t* +r ro+t r*0ain nan*+*4*t or a*aran* +i0*n/ion an+,or /a*

D (a) I33eia'e %e/eae $%a/ $/i $age ,$%3 4..$i'$%ie a .ea%ie

1. D*tai-*+ +ra7in or 7ritt*n +*/rition o t* rr*nt an+ roo/*+ a*aran*.2. R*-*a/* an+ *n+o/*- -i* /*iiation/ o t* +r ro+t.3. R*6i/*+ +rat/ o t* a9a* in/*rt an+ -a5*-in inororatin t* roo/*+ 6ariation

(7*r* a-ia5-*).

4. Co0arati6* +i//o-tion +ata on at -*a/t on* i-ot,ro+tion 5at o t* rr*nt-8aro6*+ an+ roo/*+ +i0*n/ion/.

5. Data on t*/t o ont*nt nior0it8 o t* /5+i6i+*+ art/ o ta5-*t/ at r*-*a/* a/onor0*+ to o0*n+ia- r*>ir*0*nt /o-+ 5* /50itt*+ (on-8 a-ia5-* or +rro+t 7it /or*,5r*a9-in*).

(5) O'9e% '9a i33eia'e %e/eae $%a/ $/i $age ,$%3 4..$i'$%ie a .ea%ieIn a++ition to t* a5o6* on+ition@

6. K/tiiation or not /50ittin a n*7 5io*>i6a-*n* /t+8 aor+in to t* !SE!NGi+*-in*/ For T* Con+t o ioa6ai-a5i-it8 an+ io*>i6a-*n* St+i*/ (7*r*a-ia5-*).



38/46

6 thdraft

MiVPA28

C9age i '9e 'e' .%$-e4%e $, '9e %4g .%$4-' (i-/4ig %e./a-e3e'$% ai'i$ $, a 'e' .%$-e4%e)

C 1. Dr ro+t /*iiation/ ar* not a+6*r/*-8 a*t*+ n-*// t* /*iiation/ ar*tit*n*+.

2. R*/-t/ o 0*to+ 6*riiation,6a-i+ation /o7 n*7 t*/t ro*+r* to 5* at -*a/t*>i6a-*nt to t* or0*r ro*+r*.

3. T* an* /o-+ not 5* t* r*/-t o n*4*t*+ *6*nt/ ari/in +rin 0anatr*or 5*a/* o /ta5i-it8 on*rn/.

D 1. D*/rition o t* ana-8tia- 0*to+o-o8.2. !roriat* 6*riiation,6a-i+ation +ata an+ o0arati6* ana-8tia- r*/-t/ 5*t7**n t*

rr*nt-8 aro6*+ an+ roo/*+ t*/t.

3. C*rtiiat* o ana-8/i/ o t* ini/*+ ro+t o 2 ro+tion 5at*/ 7*n 0a+*a6ai-a5-*.4. K/tiiation or t* roo/*+ an*.5. Co0arati6* ta5-at*+ or0at ta5-* o t* rr*nt-8 aro6*+ an+ roo/*+ r*-*a/* an+

/*- -i* /*iiation/ o t* +r ro+t.

MiVPA2

@4a/i'a'i&e a 4a'i'a'i&e -9age i '9e -$3.$i'i$ $, .%i3a%>.a-Bagig 3a'e%ia/ ,$% $'e%i/e .%$4-'

C 1. R*-*a/* an+ *n+o/*--i* /*iiation/ o +r ro+t r*0ain nan*+.2. T* roo/*+ a9ain 0at*ria- 0/t 5* at -*a/t *>i6a-*nt to or 5*tt*r tan to t*

aro6*+ 0at*ria- in r*/*t o it/ r*-*6ant ro*rti*/.

3. T* an* on-8 on*rn/ t* /a0* a9ain t8* (or *4a0-* ro0 5-i/t*r to 5-i/t*r).

D 1. K/tiiation or t* an* in a9ain 0at*ria- an+ aroriat* /i*ntii /t+i*/ ont* n*7 a9ain.

2. For /*0i/o-i+ an+ -i>i+ +o/a* or0/@ roo 0/t 5* ro6i+*+ tat no int*ration5*t7**n t* ont*nt an+ t* a9ain 0at*ria- or/ (*.. no 0iration oo0on*nt/ o t* roo/*+ 0at*ria- into t* ont*nt an+ no -o// o o0on*nt/ o t*ro+t into t* a9).

3. Co0arati6* ta5-at*+ or0at ta5-* o t* rr*nt-8 aro6*+ an+ roo/*+/*iiation/ o t* ri0ar8 a9ain 0at*ria- (7*r* a-ia5-*).

4. R*6i/*+ +rat/ o t* a9a* in/*rt inororatin t* roo/*+ 6ariation (7*r*a-ia5-*).




39/46

6 thdraft

MiVPA 2

Ai'i$ $% %e./a-e3e' $, a 3a4,a-'4%e% ,$% e-$a%> .a-Bagig


C Non*

D 1. Proo tat t* roo/*+ /it* i/ aroriat*-8 atori:*+ (ar*+it*+ 58 t* atorit8) or t* a9ain ati6it8 on*rn*+ ! 6a-i+ GMP *rtiiat* or CPP 7i o6*r/ t* GMP*rtiiation.

2. Oiia- -*tt*r ro0 ro+t o7n*r atori:in t* n*7 0anatr* or a9a*r to*ror0 /*on+ar8 a9ain.

3. R*6i/*+ +rat/ o t* a9a* in/*rt an+ -a5*-in inororatin t* roo/*+ 6ariation

(7*r* a-ia5-*).

MiVPA"0

C9age $, .a-B ie :&$/43e a:$% 9a.e:i3ei$ $, .a-Bagig3a'e%ia/ ,$% &$/43e $, $'e%i/e .%$4-'

C1. R*-*a/* an+ *n+o/*- -i* /*iiation/ o t* +r ro+t r*0ain nan*+.2. T* n*7 /i:* i/ on/i/t*nt 7it t* +o/a* r*i0*n an+ +ration o /* a/ aro6*+ in

t* a9a* in/*rt.

3. %it Can* in t* +i0*n/ion o t* ri0ar8 a9ain 0at*ria- (7*r* a-ia5-*).4. For Can* o 6o-0* or a /t*ri-* +r ro+t@ -*a/* r**r to MaV11 13.

5. T* an* on-8 on*rn/ t* /a0* a9ain t8* an+ 0at*ria-.

D1. K/tiiation or t* roo/*+ a9 /i:*.2. R*6i/*+ +rat/ o t* a9a* in/*rt an+ -a5*-in inororatin t* roo/*+ 6ariation

(7*r* a-ia5-*).

3. ! -*tt*r o +*-aration tat /ta5i-it8 /t+8 7i-- 5* on+t*+ in aor+an* 7it t*r*-*6ant i+*-in* or ro+t/ 7*r* /ta5i-it8 ara0*t*r/ o-+ 5* a*t*+. Data to 5*r*ort*+ on-8 i ot/i+* /*iiation/ (7it roo/*+ ation).

MiV PA"1

C9age $, $4'e% -a%'$ .a-B ie ,$% a %4g .%$4-'


C 1. Pri0ar8 a9ain 0at*ria-/ r*0ain nan*+.2. No ot*r an*/ *4*t or t* Can* o ot*r arton a9 /i:*/ or a +r ro+t.3. T* r*0ainin a9 /i:*/ ar* a+*>at* to ao00o+at* t* +o/in r*i0*n a/ *r t*

aro6*+ ro+t -a5*-in.

D 1. R*6i/*+ +rat/ o t* a9a* in/*rt an+ -a5*-in inororatin t* roo/*+ 6ariation

(7*r* a-ia5-*).2. L*tt*r o +*-aration ro0 t* a-iant /tatin tat no ot*r an*/ *4*t or t*

Can* o ot*r arton a9 /i:*/ or a +r ro+t.



40/46

6 thdraft



41/46

6 thdraft

MiVPA "2

C9age i a> .a%' $, '9e (.%i3a%>) .a-Bagig 3a'e%ia/ $' i -$'a-' =i'9'9e ,ii9e .%$4-' ,$%34/a'i$ (4-9 a -$/$4% $, ,/i.$,, -a. -$/$4%-$e %ig $ a3.$4/e -9age $, ee/e 9ie/ (i,,e%e' ./a'i- 4e)

F$//$=ig ACCS@ PPG Mee'ig i Siga.$%e '9e Mee'ig ag%ee '$a--e.' '9i e= &a%ia'i$ .%$.$e 5> Siga.$%e!

C 1. T* an* +o*/ not on*rn a art o t* a9ain 0at*ria-@ 7i a*t/ t*

+*-i6*r8@ /*@ /a*t8 or /ta5i-it8 o t* ini/*+ ro+t.

D 1. !0*n+0*nt o t* r*-*6ant /*tion(/) o t* +o//i*r (r*/*nt*+ in t* CTD or0at)@in-+in r*6i/*+ ro+t inor0ation a/ aroriat*.

MiVPA"" Ai'i$ $% %e./a-e3e' $, 3ea4%ig e&i-e ,$% $%a/ /i4i $age ,$%3a $'9e% $age ,$%3

C 1. T* /i:* an+ 7*r* a-ia5-*@ t* ara8 o t* roo/*+ 0*a/rin +*6i* 0/t 5*o0ati5-* 7it t* aro6*+ o/o-o8.

2. T* n*7 +*6i* i/ o0ati5-* 7it t* +r ro+t.

D 1. D*/rition o t* +*6i* (in-+in a +ra7in)@ 7*r* aroriat*.2. T* o0o/ition o t* +*6i* 0at*ria-. %*r* a-ia5-* t* 0at*ria-/ /o-+ o0-8

7it t* Par0aoo*ia.

3. K/tiiation tat /i:* an+ ara8 o t* +*6i* ar* a+*>at* or t* o/o-o8 a/ i/aro6*+ in t* ro+t -a5*-in.

4. R*6i/*+ +rat o t* a9a* in/*rt an+ -a5*-in inororatin t* roo/*+ 6ariation(7*r* a-ia5-*).



42/46

6 thdraft

MiVPA"*

Re4-'i$ $, 9e/, /i,e $, '9e %4g .%$4-'1) A a .a-Bage ,$% a/e a:$% 2) A,'e% ,i%' $.eig a:$% 3) A,'e% i/4'i$:%e-$'i'4'i$


Vie'a37 S9$4/ '9e -$3.a> 'aBe a> a-'i$ '$=a% .a-Bage ,$% a/e=9i-9 =e%e -i%-4/a'e 5e,$%e '9e e= 9e/, /i,e i a//$=e

C1. For (1) " (2) T* /t+i*/ 0/t /o7 onor0an* to t* rr*nt-8 aro6*+ *n+o

/*- -i* /*iiation.


3. For *4t*n/ion o /*- -i*@ -*a/* r**r to MaV1$.

D 1. R*/-t/ o aroriat* r*a- ti0* /ta5i-it8 /t+i*/ o6*rin t* +ration o roo/*+ /*--i* o at -*a/t 2 i-ot,ro+tion /a-* 5at*/ o t* ro+t in t* atori:*+a9ain 0at*ria-

1) a/ a a9a* or /a-* an+,or 2) at*r ir/t o*nin an+,or 3) at*r t* +i-tion,r*on/tittion

in aor+an* 7it t* !SE!N Gi+*-in*/ on Sta5i-it8 St+8 o Dr Pro+tr*/-t/ o aroriat* 0iro5io-oia- t*/tin /o-+ 5* in-+*+ (7*r*aroriat*).


3. K/tiiation -*tt*r or t* an* o /*- -i* o t* +r ro+t (7*r* a-ia5-*).

MiVPA"

C9age $, '$%age -$i'i$ $, '9e %4g .%$4-' (I-%eaig ,%$3 '9e-4%%e' a..%$&e '$%age -$i'i$)

1) A a .a-Bage ,$% a/e a:$% 2) A,'e% ,i%' $.eig a:$% 3) A,'e% i/4'i$:%e-$'i'4'i$


C 1. For (1) " (2) T* /t+i*/ 0/t /o7 onor0an* to t* rr*nt-8 aro6*+ *n+o/*- -i* /*iiation.


3. For an* o /tora* on+ition (-o7*rin ro0 t* rr*nt aro6*+ /tora* on+ition)@-*a/* r**r to MaV1&..

D 1. R*/-t/ o aroriat* r*a- ti0* /ta5i-it8 /t+i*/ o6*rin t* +ration o rr*nt-8aro6*+ *n+o /*--i* (at roo/*+ /tora* on+ition) o at -*a/t 2 i-ot,ro+tion/a-* 5at*/ o t* ro+t an+ in t* atori:*+ a9ain 0at*ria- in aor+an*7it t* !SE!N Gi+*-in*/ on Sta5i-it8 St+8 o Dr Pro+t.

2. R*6i/*+ +rat/ o t* a9a* in/*rt an+ -a5*-in inororatin t* roo/*+ 6ariation



43/46

6 thdraft

(7*r* a-ia5-*).

! MINOR VARIATION NOTIFICATION

Mi$% Va%ia'i$ (MiVN)

N$'i,i-a'i$

MiV N1 C9age $, .%$4-' $=e%

C 1. T* -i*n/* o-+*r r*0ain/ t* /a0*.2. T* 0anatrin /it* r*0ain/ t* /a0*.

D 1. D*-aration on t* tran/*r o o7n*r/i 5*t7**n o-+ ro+t o7n*r an+ n*7 o7n*r.2. Oiia- -*tt*r ro0 t* n*7 ro+t o7n*r +*-arin t* an*@ an+ atori:in t*

-oa- -i*n/* o-+*r to 5* r*/on/i5-* or t* ro+t -i*n/*.

3. I t* n*7 ro+t o7n*r i/ not t* 0anatr*r o t* +r ro+t@ an oiia- -*tt*r 58t* n*7 ro+t o7n*r atori:in t* 0anatr*r to 0anatr* t* +r ro+ton it/ 5*a-.

4. I t* n*7 ro+t o7n*r i/ not t* 0anatr*r o t* +r ro+t@ -*tt*r oa*tan* ro0 t* 0anatr*r tat it 7i-- 5* *-+ r*/on/i5-* or 0anatrin an+*n/rin t* *ia8@ >a-it8 an+ /a*t8 a/*t o t* +r ro+t.


MiV N2 C9age i $=e%9i. $, 3a4,a-'4%e%

C 1. T* 0anatrin /it* r*0ain/ nan*+.2. No ot*r an*/ *4*t or t* an* in o7n*r/i o 0anatr*r.

D 1. L*tt*r o j/tiiation on t* tran/*r o o7n*r/i / a/ a 6a-i+ GMP *rtiiat*.2. Oiia- -*tt*r /tatin t* tran/*r o o7n*r/i ro0 o-+ 0anatr*r to n*7

0anatr*r (7*r* a-ia5-*).

3. In a/* o a ontrat 0anatr*r@ oiia- -*tt*r ro0 ro+t o7n*r +*-arin t*an* an+ atori:in t* n*7 0anatr*r to 0anatr* t* +r ro+t/ on it/5*a-.

4. In a/* o a ontrat 0anatr*r@ -*tt*r o a*tan* ro0 t* n*7 0anatr*r tatit 7i-- 5* *-+ r*/on/i5-* or 0anatrin an+ *n/rin t* *ia8@ >a-it8 an+ /a*t8a/*t o t* +r ro+t.




44/46

6 thdraft

MiV N" C9age $, '9e a3e $% a%e (e!g! .$'a/ -$e '%ee' a3e) $, '9e3a4,a-'4%e% $, %4g .%$4-'

C 1. T* 0anatrin /it* r*0ain/ t* /a0*.2. Not a-ia5-* to t* a/* in 7i it in6o-6*/ an* in o7n*r/i o t* 0anatr*r.

(For an* in o7n*r/i o 0anatr*r@ -*a/* r**r MiVN2)

3. No ot*r an*/ *4*t or t* an* o t* na0* an+,or a++r*// o a 0anatr*ro t* +r ro+t.

D 1. Oiia- -*tt*r ro0 ro+t o7n*r atori:in t* 0anatr*r 7it n*7 na0*,a++r*//to 0anatr* t* +r ro+t.

2. ! 6a-i+ GMP *rtiiat* or CPP 7i o6*r/ t* GMP *rtiiation 7it n*7 na0*

an+,or a++r*//.3. R*6i/*+ +rat/ o t* a9a* in/*rt an+ -a5*-in inororatin t* roo/*+ 6ariation(7*r* a-ia5-*).

MiVN *

C9age $, '9e a3e $% a%e (e!g! .$'a/ -$e '%ee' a3e) $, '9e-$3.a> $% 3a4,a-'4%e% %e.$i5/e ,$% 5a'-9 %e/eae

C 1. T* 0anatr*r o t* +r ro+t r*0ain/ t* /a0*.2. Not a-ia5-* to t* a/* in 7i it in6o-6*/ an* in o7n*r/i o t* 0anatr*r.

(For an* in o7n*r/i o 0anatr*r@ -*a/* r**r MiVN2)

3. T* 5at r*-*a/* /it* r*0ain/ t* /a0*.

D 1. Oiia- -*tt*r ro0 ro+t o7n*r atori:in o0an8,0anatr*r 7it n*7na0*,a++r*// r*/on/i5-* or 5at r*-*a/*.

2. ! 6a-i+ GMP *rtiiat* or CPP 7i o6*r/ t* GMP *rtiiation 7it n*7 na0* or a++r*// (7*r* aroriat*).


4. ! +*-aration ro0 t* a-iant tat t* an* +o*/ not in6o-6* a an* o 5atr*-*a/* /it*.

MiV

N

C9age $, '9e a3e a:$% a%e (,$% e;a3./e7 .$'a/ -$e '%ee'

a3e) $, a 3a4,a-'4%e% $, '9e %4g 45'a-e

C 1. T* 0anatrin /it* o t* +r /5/tan* r*0ain/ nan*+.2. No ot*r an*/ *4*t or t* an* o t* na0* an+,or a++r*// o a 0anatr*r

o t* +r /5/tan*.

D 1. U+at*+ inor0ation o t* 0anatr*r o t* +r /5/tan*.2. Oiia- +o0*nt,*6i+*n* 7*n r*>ir*+.



45/46

6 thdraft

MiVN6 i'9%a=a/:e/e'i$ $, '9e a/'e%a'i&e 3a4,a-'4%e%() (,$% %4g 45'a-ea:$% %4g .%$4-' a:$% .a-Bage%)

C 1. !n a-t*rnati6* 0anatr*r i/ r*i/t*r*+.

D 1. R*a/on or 7it+ra7a-,+*-*tion.

MiVN8 Ree=a/ $, Ce%'i,i-a'e $, S4i'a5i/i'> (CEP)

C 1. On-8 a-ia5-* i t* r*n*7a- o CEP +o*/ not in6o-6* an8 6ariation.

D 1. ! o8 o t* +at*+ 6a-i+ Ero*an Par0aoo*ia C*rtiiat* o Sita5i-it8 (CEP) or t* +r /5/tan*@ -at*/t 6*r/ion@ 7it a-- ann*4*/ i//*+ 58 ED?M.

MiVN C9age $, %e/eae a 9e/,/i,e .e-i,i-a'i$ $, '9e %4g .%$4-' a:$%%4g 45'a-e a:$% e;-i.ie' ,$//$=ig '9e 4.a'e i '9e-$3.ei43!

C 1. !-ia5-* to o0*n+ia- /*iiation/ on-8.2. Can* i/ 0a+* *4-/i6*-8 to o0-8 7it an +at* o t* r*-*6ant 0onora o t*

o0*n+i0.

D1. Ta5-ation o t* rr*nt an+ r*6i/*+ r*-*a/* an+ /*- -i* /*iiation/ o t* +r

ro+t 7it an*/ i-it*+.

2. at ana-8/i/ o t* +r ro+t or a-- t*/t/ in t* n*7 /*iiation o at -*a/t 25at*/.

3. R*6i/*+ r*-*a/* an+ *n+o/*- -i* /*iiation/.

MiVN De/e'i$ $, .a-B ie ,$% a .%$4-'

C 1. T* r*0ainin a9 /i:*/ ar* a+*>at* to ao00o+at* t* +o/in r*i0*n a/ *r t*aro6*+ ro+t -a5*-in.

D 1. R*a/on or +*-*tion.2. R*6i/*+ +rat/ o t* a9a* in/*rt an+ -a5*-in inororatin t* roo/*+ 6ariation

(7*r* a-ia5-*).



46/46

6 thdraft

10! GLOSSARY

I4e '$ 5e i-4e 7 T$ 'a'e Re,e% '$ ACTD:ACTR G/$a%>!

11! REFERENCES

1. Ero*an M*+iin* !*n8 Variation Gi+*-in*@ 2==;

2. Co00niation ro0 t* Co00i//ion Gi+*-in* on t* +*tai-/ o t* 6ario/at*ori*/ o 6ariation/ to t* t*r0/ o 0ar9*tin atori/ation/ or 0*+iina-ro+t/ or 0an /* an+ 6*t*rinar8 0*+iina- ro+t/ Oiia- Korna- ot* Ero*an Union (C 1',1 o 22.=1.2=1=)

3. Co00i//ion R*-ation (EC) No 123#,2==; Oiia- Korna- o t* Ero*an

Union (L33# o 12 D**05*r 2==;)4. %HO Gi+an* on Variation/ To ! Pr*>a-ii*+ Pro+t Do//i*r@ 2=='

5. SUP!C Gi+*-in* I00*+iat* R*-*a/* So-i+ Ora- Do/a* For0/@ Sa-* an+

o/t aro6a- an*/ C*0i/tr8@ 0anatrin an+ ontro-/@ in 6itro

+i//o-tion t*/tin an+ in 6i6o 5io*>i6a-*n* +o0*ntation@ No6*05*r 1

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