Kuwait - 361 Ph. Registration Requirements

Download as pdf or txt
Download as pdf or txt
You are on page 1of 78

ig4

AA
‘gaiSV
aels as
MA% Si
'Newir-
aare

Ministry of Health
NEWKUWAIT
Minister's Office -4_13a

Date: / / Ref. : \°\

I %<-\\ saJ

u..430 Lys, Alkuall ejlalJ.. vi 1996 ta...128 4, j3U1ietssi


udazzt, 2016
cibban jai141,,a...1 rArt, ct,bszlasitS,, J 4-i 1983 as-I 744, ctaa

46111,14.1L.i...1 eAsk,2411.31ca9iA1lAsiS. ,44 1987 zu..148


A, kaLsn, A.A..th km)ye.sb satc.1.4 2005 %sal 319 ãj
31 j931 ,k fl'iI

261."0 WJSCJI
.JAI6:171
.A1 .L.,913.41 cWit .,6o
lsaj 0.1).t tht 1/,4 4 2019 L..45434 4,UyI jyai
di
26 4, ac.4....1
, theit, 2—balk...la La% ks.....23:3 cal=
.2019 :1/43-1
.4,11 d&la 11#1
,11111 ;41
.1r4...11 Je-a .146_1)
LA.41 Jct....11SM .4-111141c. A...kue Li43.all ;jai. .L144.31. ,sla V.1.33

— ii

:40 4J1 40,1 **Al 4,041 411.i.11 alallasa114 asaio. OA.


c".•11s.y.as• , ji 3.AA Ls.• :u.sija um/A.1—n
74.4 jI 41I•
31 ;t4,..k9A cns ea&a,z çj. j afl C).4 •4d11311 31

.saLIS-t, e-,41 S "kejli...waill La:Alain

.4.:U4L.,alt j.tt..al c.41.41 tea e3.4 J SII Sc 1/4rip 'a -;.-41 :14),111 •

:i4sLa AS:),111J1iIA....L%..11 :411,111 kcy:all 44.• -11 34,11 •


1.3471 oty 1+1
4459tan cJictiAti .p 1431-4.3

Cm9SI I ;404 -riAlriov . 0.Alb-rt/otrovt- tAWIA1 apin - 13001„isihacKot -00 • .y - 45121.11-blial I - Zu_301

Kuwait - Sulaibikhat - P.O.Box: (5) - Postal Code: 13001 - Tel : 24863686- 24863574 - Fax : 24863457- Cable: Health Kuwait
7540 HA0001982
T.L4gtaVSV
adi
Ministry of Health
NEWKUWAIT
Minister's Office CiesS112-lia

Date: / / Ref. : ; ti)1:611

ji .2.3431 31 cy.. 1/45:11jall 4214-all

;LI Lab

4313.113 Za./A11 on:451 3.411 van k1:31.3311 Ls.• ;LCILI 2.5j1zin •

;4.t3l 3 i 1.to t 45j..t.11 49. C.k.u.a


42319.111 1-11 34.p. cp. ;ALAS 4431,4.4 441.4 LLI.S:13 tctty.alt,"
11 ;Liti
ltill cJIcflyt iL3t3..:111 aat4 Alsytkic1649
luyInA L.5. i
s 35asa

J•2--1--11 1-4JQ cs:131 Lbait e5 Life kiNsi ;chi:4D


JS Liait a,A1l js j.k.. 5_35W1 S :t.‘.-11;t53.111 a1.3 cr• •Laall 43 •
.44:1V
as)k e1i ate sL k. jjss j j • *--•-•1, allfi..21 j . • 11 •

tzsit* cara
;t :44_,.....112LIaL11 •

c.:Th31 2l..15 cf,--.111 to: ;Lball i5 L-92_,...:111 as ;t4sL-• ;di


al

cos, .u._•. U„• • -•••• •


,• - U „friv4au Ls.,2 oak” sAa1.1

EN-L3/ U 2:—trs e-Ind3 atth.t-% itta CLIb •


4.5:43dsJa.aI_91 ciylo. (1-01 c}.. ta....3. . 3j iLateaSi 1.3 CJ'tatiBb e...111 • h.4•14

ei SJ.
• .tdati
.. - i141.0 Lin. ji 4.14 j•-•14-1 ) 14:14 Lgic

Laid A. ...p..11

114_9a 4)Alt L.141 Atuktli-an ,L3* b. *---1-11 ae.. ..:1" iaLe


.J1;0 141 Lai cli-2_411

4:44_4.11 2Lnsa I 1+3,4 -11Allet AV s 041.11- AlrlAI (01113 - 130014J-1,41 j.41411 - (*) s a...I %pa - Cal:".141.4a11 - Cia_411
Kuwait - Sulaibikhat - P.O.Box: (5) - Postal Code: 13001 - Tel : 24863686- 24863574- Fax : 24863457 - Cable: Health Kuwait
7540 HA0001982
aftlei
Ministry of Health
NEWKUWAIT
Minister's Office C.1-3_3-C11

Date: / / Ref. : :

J L)LJS.AJ3.?_J:. 111 u_95,3 1


9:12,9 :WA Bale
A.S.),111 4L1:1411 al4 LEO (7.323.-.1 r at.
.47.41531.3 ltdifi I Atibai Lie-a (.14 Cr* c..s_Art Va.) I AT0,111
cili*. flu i43t 4J6 gan

ka..12—.11 —113 ziotit un— lua12 :,-Aarob eat..


1aan LiSSAO Latin t....11.11/1:Wi 1

u"' ita 411°4 _9/ "Call CLb..a.‘-''' 49 "1/41_9'M &AI ""lib° L1'2.451 1.1
r1)14:1-31
Ail bl:19 °a. jai.... zi.natil 0...4V 1 2
bljj 0.c,4*.ja 1 3
.A.1.12.11 Ls_itu :14?dil :t5j.111 ;1.-; alalc.1 .1.4
Lsic. cL3:9-Cit A=11-*.3 4)43 A-if* 34 LiS'" LA1; 6 , 31:15 • 1-5

&Yc 33.43 Asaiji

ja31,3 aSia k31.14,11

9.‘,111js taLa ;;S_4JL Lali11 St.614.1 2

41,..411 J4;1 (>14 Z.2)14a11 k1it11 c-a_14 A.1411 ylii& .2.1


-*Z5..A15
.*L1:1.111 ‘ca By1a-c, ;15,111 0..4;-J ;.114.4., .2.2
spi c..-111-L11 si
aLa ASJ.111 441 tp, -111 cfr9.10:3 3..)1÷1 .2.3
*L16-.11 al,
74.5i
..111 c.,12—a-, c.ALc aS .2.4

cu_scsi 43rt/otriov oat" tm rovt-Y1 /onto , a013 130014,9)1,/i jkoti - ( e) .9 .usa - caorli
Kuwait - Sulaibikhat - P.O.Box: (5) - Postal Code: 13001 - Tel : 24863686- 24863574 - Fax : 24863457 - Cable: Health Kuwait
7540 HA0001982
At
itAkoe u.,57
rtg,
V, alSV

Ministry of Health
NEWKUWAIT Minister's Office C.,e_95-11

Date: / / Ref. : : L—tay-1.1 :

tfe kcAllal-51411j ;Lcyfail 3 i4LZ5J241


11.126.3 tj:3 .2.4.1
;Loa :td_CIA CJI CLIAS
c, cii1+123Lici Zcyfal ASiLadaii
CtOlt J&I
t\-11 cs 51,1•43 (cF51)5) La1/41-4 41-2";rj .2.4.4
ch,141.01 ticsgi
,I245
13.1243
4181 ..),:a43 j: 34.p.11 ;491pli oba•
-Ai
,Ltila,h7 1J .2.4.6
tL":3t-C G1.3.4 C"^Il leXy. LS Cil)& U .2.4.7
3t.
1,s12,..1 &ski71.4>111 C4y c14.4 L),-,11 cila1431 f.LAII.A...513 .2.4.8

01-1.4Agrtin 5 4.)1.31; Jsu-11 .2.4.9


jao_, c.•'al.? 411.1)1 LJUaLJI 43c.
14-.11Cirsidalt,
340 3j.6.2.4•10
A.C.):11 4111,131 -141:411 elia3 -a-01 ,-11.112 4 11
A.1-.113J ,L3e9..
. ipc•
ks.j.›.11,1 f•VAidt, :CO

.;
2.5
kijk, catAll AJ3. j1L,>c c...114111 0:ut, Jj 1 ,,A51/34 *
C.11.11 6).41

t 1.21aita oor t ov atä- WOV I - AlriAl • agja.13 130014-9)..4ssuts (*) a .y %pa - aZiUsyteLall
Kuwait - Sulaibikhat - P.O.Box: (5) - Postal Code: 13001 - Tel : 24863686- 24863574 - Fax: 24863457. Cable: Health Kuwait
7540 HA0001982
44 Ministry of Health
v

NEWKUWAIT
Minister's Office 11€3.511 `

Date: / / Ref. :

A41+111 5.)1-1
,34 4111 "C.19.1ti I .41131i-4_9 5-)1 4 Ceml ..2C;A:-)L •

.d111 jt LA csaA .it Li+WAI (3.46:1 Cya Still

tha. ;WU S4J iA.SS jla :taSe


MAII ASAIL C.L.1'
12.1411 3
: 4:frs Vain

11 A-p-6atii CA:LLD Cya La a.; —11 2.4y,fii j.as4 at .3.1


*Laall
aet A.Sysll
- L•iLdizi 34.1 .3.2
*t.t.,ali cfe
Agi111 ki)6.11 Lt...etp 3.544 .3.3

.7,j,i&til ()a 5.)41....


cLuj_CI '11.1.641I
3...)14-4 (Das leklassal C- el% jj...ai a.MJ J3

Ll
acill ise b14:111
1041011 (enim.411 ynal-o.4.11 L4jfl aiLlithal
sI 4
udl,. 3-, 40-4,31 L:JILI5LiZLI cpSaall Sl ft3.-Cal .4.1

L.,2t-L
cJI;11-1,11 JAIS JsAai3 4..A11?171 a _bill (3.%.1.4 cjaa.:d.i.j 4 2
.asi
all ysa.1
11 LSD 41 Lail;
,p;a11 *ball eI5121 ob.? 35se L44.11 Xnat171 LII,N.Laa) csy. 43
crk. :0:1-‘41 kaall j••--,
1-• al 1294 u- LAII
4441&11
. u.4.4 ussa '." JA Istsi L1/4431

C40.071 Lissa s 1,4.3_As tAIrt OV s °ALI YEAlrovt- A Int A t 6.0.13 - 130014-y.)4s jajts (6) g - y .use L.elewt
. telsat I Ceini

Kuwait - Sulaibikhat - P.O.Box: (5) - Postal Code: 13001 - Tel : 24863686- 24863574- Fax : 24863457 - Cable : Health Kuwait
7540 HA0001982
cit-4:23
7
afeli

iAagru-
NEWKUWAIT
Ministry of Health
Minister's Office YyJSJI 149

Date: / / Ref. :

;4)131 4.5A 4,11 Yti5 ?dab ( k21 3:.15.511) J.:. 'MI Lsi=L '4114116 LILO

.47.6171:115 4.3131 A-.-471;1


1 41bA_, 32, °All OA 3-";41 .4.=1Aa
..:11144.11 cai je..1_,.:7

4S1 4.1Yal 1 y e 1 anwl 1 7y:ii.otai 6.1..431-y

C-1,4.53 CJISii-,,LA Lrab "1..410.1 1̀4.1 )49 ei)14 Asa's balm


erstii cAtt-til „let, bbyt csai c4)14-1&.i )

libj.}aj 4,21.01 As....11 ts.al L;jr, iiaLo


er.lifiA ja }4I ita latais.A
Ditt. Eviq I j# uaja1. atai U J SU1S
c.,1)

Lfficl ;04;3 'Aeical ;


111/4.9 Lsit• eaL0
stri tak asiLL Vi Lrla 1.A:121 lA ji
ult. EDI* ALaits... csic.

Ll...s..:12,4.1:14s5La:U bale

DIA A4Isa ;L5,1i,L.14.O3,...A 3s 1, 141s. Asisllct iltaLa


A.S.)11.1 usa.sjAj cats:.
ctitztai 3ii.‘41111 3s A.S.11...

;41141.3 1172._thi (..$2":3S1

-r win ev s ussui.ttAlrovt-ttnlruct • (Jan 130014-tahalskjil -0) I .y -


Kuwait - Sulaibikhat - P.O.Box: (5)- Postal Code: 13001 - Tel : 24863686- 24863574- Fax :24863457 - Cable: Health Kuwait
7540 HA0001982
gttalSW
Neramer
Ministry of Health
NEWKUWAIT
Minister's Office -4_13

Date: / / Ref. :

t) (sic 443.,..0.411:4).111_, 4..A46.11 ;alai L.:As..? • "al& ;so Ala baLe


4rsl cya jell 1 J3 -0j141 J.cya .1,3311-.11 ylth eaid
All Zpta

L.4-11 J-153 C.JA 24 .431.59 Jj a3z ‘74N7'. ' 1 oak


1;
:Utill cJia‘,..11 edii;
aks-s? 3s lieL..A.5j2,11 c.).4 Fv.g....sk3r11;1.114,11 .1
..111 41? cria3 (J7.15,3
3.a
( :14).131 t).4 3i1...,11 3441 Zsjsa.21 01.4
.*A.31SJII &.)1.1L,,4
kcjAtAl jaL.s1.114,11 ;;...513 .3
jicsill 4)41 ralUê aja 3.yafl 3s 5,4s1.....
LICtill
kiji
o c_11.2_411 zt.1.0 1444a. C-1i4.f.0 DIA Jja.al Mi *
Lta.121 ;Sall

J ". LI2e-d-1 Cia23 A.P141119 74.431 AUhl 4- 1)49 (127N-1-5 3.)14 ;as &IA agie
JI ja1l J 44ahLa Sj..1.3 ) Vjaa
3
.}.011 C:41

C41 1-A-11 ()A A.53.111 j••-•--, —11 ) 131 .1


t211-0
tlasai,i1;y5,4ta3 74411.si eat. csti
kuii I A411).” Si Z4a7i.411 LE.i ‘,.s.31:111
-kCJ141.1b

1:95.113-...sa • Laj4 -Y in‘r I v oars - t A 11" OV - I A IrlAI ,1021.13 - 3001 ,s..u..j.gs joust - (*) I ..ce - I - Cu_itt I

Kuwait - Sulaibikhat - P.O.Box: (5) - Postal Code: 13001 - Tel : 24863686- 24863574 - Fax : 24863457 - Cable : Health Kuwait
7540 HA0001982
S
:4
iit.,\?.(Acr1/4 Ministry of Health
NEWKUWAIT
Minister's Office c..6,33S-11 4_.1

Date: / / Ref. : : WI

;)+12111 AT.3 _941 I.47111.}49 C:3191,9 4'11 4 ailS-4 c I:11

j1j.ca...
H1 eac.C.i 131 .c

4431).43 JJiaaU 4_91.4 c:45..4 (sal J21-.ItIJai j14:4.1 rt.

Ai-11,635 11:4611-4-2941

.4,3--i,(111 c_alJaesziAllagi2411 LAIL 45.6 .t

JiI ljabaj J.s 4.17.


153.11EZIa J6 .a

;4)2 uscaLctia_,:l L91 ms-ci p;04.1113

.3.1.4.12.411
- Calimil Cya 4.14:6-111

L.,51 (-)--3?- 1 401 k3:111111b 341`1,11}49 B.J;Si Oat*


c41'Asa-. as jai ji j-aD bJLSJ.ta c.sL!p

:443. La 0)41

111411 Lfa AS:>111 *WI

(.03 4_ilAtis,14:12.111;411i11 c,11,4.41.1

.10141
,
'66.,..e.411;t5j.111 4,11= '11*.0 sai

Z•Ziabe J1>•.:01 C-tia III

cfe 4i.a?:5 OF-


;LAP kjib..j 347%-471 Løsi iJI CjIti,.I cra j:01 c41 131 .t
AriAsini
L5.11 y14J.111 4,1
. 14...J CD] c).41 Cjii.tua C.u.a.* 1 31 t

.ca jSiI;dia

Cityttl aama 3 - AI t *V 03511 - YtAlroVt- Asir% Al Asa" - 1300141.4jtt I jou.t1 0) .y .0ea - I - Cte#11

Kuwait- Sulaibikhat- P.O.Box: (5) - Postal Code: 13001 - Tel : 24863686- 24863574 - Fax : 24863457- Cable: Health Kuwait
7540 HA0001982
s4 4i
de a•
a Hat111
lkii
"fierraise S.);\,:a

icAltAs." e4 Ministry of Health


NEWKUWAIT
Minister's Office a6.2.5.5212-45a

Date: / / Ref. : : tr-2,17oll

3$z5 ,At eac.

341.ti1i ()A mei Csial Sia aJt


c3;ak) 11:411113 k.4,31 ;171.34144)49 Je 3.).57 334 41;" 'O'DEA' jai.
0:.ej „I! Ls:41i LA,sacii zsi.1 ji J .
132,'"`11

1.1
1,-zi oak) Jt ib141 L,1c. L,1l La t ;awls bal..
as., :);,ths

L19 LDS 414 _91 32, ::;11 3414 31 4.u


..1,
1-45.3"191
4 ;143 ffia.d 446.3 jbill tuaiti cya ;6)el

11--1).1 Lcit• 0:9 4)1 ca.4.172.3

aci.1113 A.1.1,111 2-.044.—.11 C.1 b, ••••••1 • alat.I.A I j2, • ;COWLS bale

4.1411 4)13)31 j911 W- i-

rt.131,111 ;41'14;11 Lgic- bale


zptio djjAU
cAta71 r\i, csio
'
btu Lsic.

Lsk1:19 '..)1.3a_19-1a-a &a.31.-1 bviti 44 Lid4DT.P_, 0arIr..3171 (>4 jiYil 1:1/4 t-341 Q.011.6 bale
- 441 3.12.1Ø1 Jaj _ha 13A el-(J tea 0:"..)141.0-'3 91 ..ba
4

tismallaj.aa JsI /AZ


' .1.11

2
p4W1t2f,.\-\
Julia

CW-WiPt iC 9
ejsarsail.).—j39
asoca adousa t t Alt tov oath YIAIrOVt- tAIrtAl t Lai 13009‘jaaj..J1 j.‘11 -(0) - Cu_JS/1
Kuwait - Sulaibikhat - P.O.Box: (5) - Postal Code: 13001 - Tel : 24863686- 24863574 - Fax : 24863457- Cable : Health Kuwait
7540 HA0001982
.4431)111A9 a4+0-a4u 4.),3411 J1)
j. '41 4..0
.1 .4.4V,1
.1.5.4...all

STATE OF KUWAIT
MINISTRY OF HEALTH
DRUG AND FOOD CONTROL

Pharmaceutical & Herbal Medicines Registration & Control


Administration

MINISTERIAL DECREE FOR REGISTRATION


OF PHARMACEUTICAL MEDICINAL
PRODUCTS

Dr Abdullah M. AI-Bader
e.„.„--.4sgistant llersecretary
For Drug & ood Coning
26-17.--Z-0‘5
Introduction

In accordance with Pharmacy Law in the State of Kuwait, a pharmaceutical


product can only be placed in the local market if registered by Pharmaceutical
and Herbal Medicines Registration and Control Administration.
Each pharmaceutical product must be represented by local pharmaceutical
company which will be referred to as Local Agent.
Local agent will be responsible for providing the documents set by this M.D.
in order to finalize the registration of the pharmaceutical product and its
manufacturing company.
Documents required for registration of pharmaceutical product must be in
compliance with CTD (Common Technical Document) Structure [i.e.
applicants (Local Agents) must not modify the overall organization of the
CTD as outlined in this ministerial decree], however, applications might differ
according to product type; for example: New Chemical Entity (NCE),
Biologicals and Biosimilars ALL CTD Modules are required, while in case of
Generic products certain modules or sections of the CTD would generally not
be applicable and must be marked as such (not to be deleted).

(Biological medicinal products are made of biological sources such as living


cells or organisms (human, animals and microorganisms) and are often
produced by biotechnology. Biosimilars are therapeutics biologicals that
follow previously approved innovator biologicals medicinal products.
Biosimilar denote drugs produced by means of recombinant DNA technology
following the foot steps of an innovator products. With regard to safety,
efficacy and quality biological drugs and biosimilars must fulfilled and satisfy
the technical and product class specific provision GHC guidelines and
requirements. Furthermore, all biological drugs and biosimilars must be
registered in one of the reference authorities, such as GHC, EMEA, USFDA
or other approved reference regulatory authority)*.

Dr Abdullah M. Al-Bader
ndersecretary
Avcicflnt u
Wage For Drug & C r
Z —I—0 3
In some cases such as GCC centrally registered products or others, customized
set of requirement will be applicable, and in such cases the Administration
will set these requirements and will be communicated via Memo's to Local
Agent.
For Locally manufactured pharmaceutical products or when the marketing
authorization holder is a local pharmaceutical company, The Pharmaceutical
and Herbal Medicines Registration and Control Administration is the
authorized body to issue CPP, Manufacturing License, Good Manufacturing
Practice certificate and any certificate related to pharmaceutical product
registration.

For Registration of Pharmaceutical Product , the Following requirements must


be fulfilled:

1. Local Agent requirements:


If the Local Agent is new local pharmaceutical company, the following must be
submitted:
Copy of valid License from Ministry of Commerce in which the company activity
includes the sale of medicines.
Copy of valid license issued from Drug Inspection Administration.
Copy of valid Store License issued from Drug Inspection Administration.
Copy of authorized personal signatures legalized from Kuwait Chamber of
Commerce and Industry.
Any other documents set by the administration in accordance with other MD's.

2. Marketing Authorization Holder (MAR) Registration (including


manufacturing company/ companies):
Legalized and original letter of appointment from MAH Stating that the Local
Agent is the sole and/or exclusive agent in The State of Kuwait.
Original legalized Manufacturing License from country of origin for each
manufacturing site issued from Health Authority in country of origin.
Dr Abdullah-114; AikBacler
21 Page
d,erscretary
ForOru ood Con
5
Original legalized "Good Manufacturing Practice" (GMP) certificate from
Health Authority in country of origin.
Site master file which contain the following:
4.1.General information and history of the company.
4.2.Capital and turnover for the past three years.
4.3.Layout and diagrams of manufacturing sites.
4.4.Quality control unit and quality management.
4.5.Personnel information including number of employees in each department
and their qualification.
4.6.Premises and equipment, including manufacturing sites owned by the
company, manufacturing lines, and manufacturing machines.
4.7.List of products manufactured by the company and exporting countries.
4.8.Distribution problems, complaints, product defects and recalls from any
authorities worldwide.
4.9. Contract manufacturing information.
4.10. Pharmacovigilance Master File.
4.11. Recognized global approvals for the company such as USFDA, EMA,
MHRA, GCC.

The Pharmaceutical and Herbal Medicines Registration and Control Administration


may request a GMP inspection visit for any manufacturing site.

N.B: Legalization must be done by the following:


Kuwait embassy/consulate in the country of origin and when it is not possible,
by an authorized Arabian embassy/consulate in the country.
Arab chamber of commerce of the country of origin.
Kuwait chamber of commerce.

3.Pharmaceutical Product Reeistration:

1. Pharmaceutical product registration file must be submitted in CTD structure


as per GCC guidelines:

CTD Modules Description

Dr Abdullah M. Al-lader
Assistant Undersecretary
3 I P
r - a°
Mitrol----_,
For Dru & Food Co
Module 1: Regional Administrative Information;

This module includes the regional required information specific


to Kuwait Pharmaceutical &Herbal Medicines Registration And
Control Administration, such as administrative information and
certificates.

Module 2: Common Technical Document Summaries;

Must reflect the information provided in modules 3, 4 and 5.

Module 3: Quality

Module 4: Non-Clinical Study Reports

Module 5: Clinical Study Reports

Module 1: Administrative Information


Section Requirements

1.0 Cover letter

1.1 Comprehensive Table of content

1.2 Application Form

1.3 Product Information

1.3.1 Summary of Product Characteristics (SPC)

1.3.2 Labeling

1.3.3 Patient information leaflet (PIL)

1.3.3.1 Arabic leaflet

1.3.3.2 English leaflet

1.3.4 Artwork (Mock-ups)

1.3.5 Samples

Dr Abdullah M. Al-Bader
A • s retary
Wage

,
1.4 Information on the experts

1.4.1 Quality

1.4.2 Non-Clinical

1.4.3 Clinical

1.5 Environmental Risk Assessment

1.5.1 Non-Genetically Modified Organism (Non-GMO)

1.5.2 GMO

1.6 Pharmacovigilance

1.6.1 Pharmacovigilance System

1.6.2 Risk Management Plan

1.7 Certificates and Documents

1.7.1 GMP Certificate

1.7.2 CPP or Free-sales

1.7.3 Certificate of analysis — Drug Substance

1.7.4 Certificate of analysis — Excipients

1.7.5 Alcohol-content declaration

1.7.6 Pork- content declaration

1.7.7 Certificate of suitability for TSE

1.7.8 The diluents and coloring agents in the product formula

1.7.9 Patent Information

1.7.10 Letter of access or acknowledgment to DMF

1.8 Pricing

1.8.1 Price list

Dr Abdullah M. Allader
Wage
ssistan ndersectgary
For D.4.& Food Contre>--..
— —1,2, /3
1.8.2 Other documents related

1.9 Responses to questions

Module 2: Common Technical Document Summaries


Section Requirements

2.1 Table of Contents of Module 2-5

2.2 Introduction

2.3 Quality Overall Summary

Introduction

2.3.5 Drug substance

2.3.5.1 General Information

2.3.S.2 Manufacture

2.3.S.3 Characterization

2.3.S.4 Control of Drug Substance

2.3.5.5 Reference Standards or Materials

2.3.S.6 Container/Closure System

2.3.S.7 Stability

2.3.P Drug Product

2.3. P. 1 Description and Composition of the Drug Product

2.3.P.2 Pharmaceutical Development

2.3.P.3 Manufacture

2.3.P.4 Control of Excipients

2.3.P.5 Control of Drug Product

2.3.P.6 Reference Standards or Materials

2.3.P.7 Container/Closure System

6IPage
Dr Abdullah M. Al-Bader
e../Asisista5PUndersecitacy,
or Drug & Food Control
Zs' - 12 - /
2.3.P.8 Stability

2.3.A Appendices

2.3.A.1 Facilities and Equipment

2.3.A.2 Adventitious Agents Safety Evaluation

2.3.A.3 Novel Excipients

2.3.R Regional Information

2.4 Nonclinical Overview

2.5 Overview of the Nonclinical Testing Strategy

2.5.1 Product Development Rationale

2.5.2 Overview of Biopharmaceutics

2.5.3 Overview of Clinical Pharmacology

2.5.4 Overview of Efficacy

2.5.5 Overview of Safety

2.5.6 Benefits and Risks Conclusions

2.5.7 References

2.6 Non clinical written and tabulated summaries: Pharmacology, pharmacokinetics


Toxicology

2.6.1 Introduction

2.6.2 Pharmacology Written Summary

2.6.2.1 Brief Summary

2.6.2.2 Primary Pharmacodynamics

2.6.2.3 Secondary Pharmacodynamics

2.6.2.4 Safety Pharmacology

2.6.2.5 Pharmacodynamic Drug Interactions

Dr Abdullah M. Al-Bader
7IPage Assistaatljndersecretary
c___Lor Drug aood Cord
ThThl"---

2-6 — 2_ -2-0
2.6.2.6 Discussion and Conclusions

2.6.2.7 Tables and Figures

2.6.3 Pharmacology Tabulated Summary

2.6.4 Pharmacokinetics Written Summary

2.6.4.1 Brief Summary

2.6.4.2 Methods of Analysis

2.6.4.3 Absorption

2.6.4.4 Distribution

2.6.4.5 Metabolism (interspecies comparison)

2.6.4.6 Excretion

2.6.4.7 Pharmacokinetic Drug Interactions

2.6.4.8 Other Pharmacokinetic Studies

2.6.4.9 Discussion and Conclusions

2.6.4.10 Tables and Figures

2.6.5 Pharmacokinetics Tabulated Summary

2.6.6 Toxicology Written Summary

2.6.6.1 Brief Summary

2.6.6.2 Single-Dose Toxicity

2.6.6.3 Repeat-Dose Toxicity

2.6.6.4 Genotoxicity

2.6.6.5 Carcinogenicity

2.6.6.6 Reproductive and Developmental Toxicity

2.6.6.7 Local Tolerance

2.6.6.8 Other Toxicity Studies (if available)

DrJbdullahJVI1 Al•Bader
8[Page Assistant U epecretary
For Drug & Food Control
Lé --17_— to f 7
1-

2.6.6.9 Discussion and Conclusions

2.6.6.10 References

2.6.7 Toxicology Tabulated Summary

2.7 Clinical Summary

2.7.1 Summary of Biopharmaceutic and Associated Analytical Methods

2.7.1.1 Background and Overview

2.7.1.2 Summary of Results of Individual Studies

2.7.1.3 Comparison and Analyses of Results Across Studies

2.7.1.4 Appendix

2.7.2 Summary of Clinical Pharmacology Studies

2.7.2.1 Background and Overview

2.7.2.2 Summary of Results of Individual Studies

2.7.2.3 Comparison and Analyses of Results Across Studies

2.7.2.4 Special Studies

2.7.2.5 Appendix

2.7.3 Summary of Clinical Efficacy

2.7.3.1 Background and Overview of Clinical Efficacy

2.7.3.2 Summary of Results of Individual Studies

2.7.3.3 Comparison and Analyses of Results Across Studies

2.7.3.3.1 Study Populations

2.7.3.3.2 Comparison of Efficacy Results Across All Studies

2.7.3.3.3 Comparison of Results in Sub-Populations

2.7.3.4 Analysis of Clinical Information Relevant to Dosing Recommendations

2.7.3.5 Persistence of Efficacy and/or Tolerance Effects

9IPage Dr Aikullah M. A Bader


Ass' . .1 •

ro
26— 12_-2_0/q
2.7.3.6 Appendix

2.7.4 Summary of Clinical Safety

2.7.4.1 Exposure to the Drug

2.7.4.1.1 Overall Safety Evaluation Plan and Narratives of Safety Studies

2.7.4.1.2 Overall Extent of Exposure

2.7.4.1.3 Demographic and Other Characteristics of Study Population

2.7.4.2 Adverse Events

2.7.4.2.1 Analysis of Adverse Events by Organ System or Syndrome

2.7.4.2.2 Narratives

2.7.4.3 Clinical Laboratory Evaluations

2.7.4.4 Vital Signs, Physical Findings, Observations Related to Safety

2.7.4.5 Safety in Special Groups and Situations

2.7.4.5.1 Intrinsic Factors

2.7.4.5.2 Extrinsic Factors

2.7.4.5.3 Drug Interactions

2.7.4.5.4 Use in Pregnancy and Lactation

2.7.4.5.5 Overdose

2.7.4.5.6 Drug Abuse

2.7.4.5.7 Withdrawal and Rebound

2.7.4.5.8 Effects on Ability to Drive or Operate Machinery or Impairment of Mental


Ability

2.7.4.6 2.7.4.6 Post-Marketing Data

2.7.4.7 2.7.4.7 Appendix

2.7.5 2.7.5 References

Dr i bdull. h M. Al-Bader
10Page
For Drug & Food Control
2_6 — 1 2 — 2_0 / q
2.7.6 2.7.6 Synopses of Individual Studies

Module 3: Quality
Section Requirements

3.1 Table of Contents of Module 3

3.2 Body of data

3.2.S Drug Substance

3.2.S.1 General Information

3.2.S.1.1 Nomenclature

3.2.S.1.2 Structure

3.2.S.1.3 General Properties

3.2.S.2 Manufacture

3.2.S.2.1 Manufacturer(s)

3.2.5.2.2 Description of Process and Process Controls

3.2.S.2.3 Control of Materials

3.2.5.2.4 Control of Critical Steps and Intermediates

3.2.S.2.5 Process Validation and/or Evaluation

3.2.S.2.6 Manufacturing Process Development

3.2.S.3 Characterization

3.2.S.3.1 Elucidation of Structure and Other Characteristics

3.2.S.3.2 Impurities

3.2.S.4 Control of Drug Substance

3.2.S.4.1 Specifications

3.2.S.4.2 Analytical Procedures

Dr Abdullah M. Al-Bader
11IPage a-cretary
3.2.5.4.3 Validation of Analytical Procedures

3.2.5.4.4 Batch Analyses

3.2.5.4.5 Justification of Specification

3.2.S.5 Reference Standards or Materials

3.2.S.6 Container/Closure Systems

3.2.S.7 Stability

3.2.5.7.1 Stability Summary and Conclusions

3.2.S.7.2 Post-approval Stability Protocol and Commitment

3.2.S.7.3 Stability Data

3.2.P. Drug Product

3.2.P.1 Description and Composition of the Drug Product

3.2.P.2 Pharmaceutical Development

3.2.P.2.1 Components of the Drug Product

3.2.P.2.1.1 Drug substance

3.2.R2.1.2 Excipients

3.2.P.2.2 Drug Product

3.2.P.2.2.I Formulation Development

3.2.P.2.2.2 Overages

3.2.P.2.2.3 Physiochemical and Biological Properties

3.2.P.2.3 Manufacturing Process Development

3.2.P.2.4 Container Closure System

3.2.P.2.5 Microbiological Attributes

3.2.P.2.6 Compatibility

3.2.P.3 Manufacture

Dr Abdullah M. Al-Bader
12IPage
As ' n erseci'itaty----
& kood nirol
'o —
2 6 -)Q_-2o/9
3.2.P.3.1 Manufacturer(s)

3.2.P.3.2 Batch Formula

3.2.P.3.3 Description of Manufacturing Process and Process Controls

3.2.P.3.4 Controls of Critical Steps and Intermediates

3.2.P.3.5 Process Validation and/or Evaluation

3.2.P.4 Control of Excipients

3.2.P.4.1 Specifications

3.2.P.4.2 Analytical Procedures

3.2.P.4.3 Validation of Analytical Procedures

3.2.P.4.4 Justification of Specifications

3.2.P.4.5 Excipients of Human or Animal Origin

3.2.P.4.6 Novel Excipients

3.2.P.5 Control of Drug Product

3.2.P.5.1 Specifications

3.2.P.5.2 Analytical Procedures

3.2.P.5.3 Validation of Analytical Procedures

3.2.P.5.4 Batch Analyses

3.2.P.5.5 Characterization of Impurities

3.2.P.5.6 Justification of Specifications

3.2.P.6 Reference Standards or Materials

3.2.P.7 Container/Closure System

3.2.P.8 Stability

3.2.P.8.1 Stability Summary and Conclusions

3.2.P.8.2 Post-Approval Stability Protocol and Stability Commitments

13 I Page
Abdullah M. Al-BadE
As istant UnderfriTh-r+tsr
For Drug 84 Food Control
gg -2_<2 /9
3.2.P.8.3 Stability Data

3.2.A Appendices

3.2.A.1 Facilities and Equipment

3.2.A.2 Adventitious Agents Safety Evaluation

3.2.A.3 Excipients

3.2.R Regional Information

3.2.R.1 Alcohol Content Declaration

3.2.R.2 Porcine/Pork — content/origin

3.2.R.3 The diluents and coloring agents in the product formula

3.3 Literature References

Module 4: Non-Clinical Study Reports


Section Requirements

4.1 Table of Contents of Module

4.2 Study Reports

4.2.1 Pharmacology

4.2.1.1 Primary Pharmacodynamics

4.2.1.2 Secondary Pharmacodynamics

4.2.1.3 Safety Pharmacology

4.2.1.4 Pharmacodynamic Drug Interactions

4.2.2 Pharmacokinetics

4.2.2.1 Analytical Methods and Validation Reports

4.2.2.2 Absorption

4.2.2.3 Distribution

4.2.2.4 Metabolism

14lPage lah M. Al-Bader


Assistan Under
••
orIpro & Food Com
2_6 12-20 /9
4.2.2.5 Excretion

4.2.2.6 Pharmacokinetic Drug Interactions

4.2.2.7 Other Pharmacokinetic Studies

4.2.3 Toxicology

4.2.3.1 Single-Dose Toxicity

4.2.3.2 Repeat-Dose Toxicity

4.2.3.3 Genotoxicity

4.2.3.3.1 In vitro Studies

4.2.3.3.2 In vivo Studies

4.2.3.4 Carcinogenicity

4.2.3.4.1 Long Term Studies

4.2.3.4.2 Short or medium term studies

4.2.3.4.3 Other studies

4.2.3.5 Reproductive and Development Toxicity

4.2.3.5.1 Fertility and Embryonic Development

4.2.3.5.2 Embryo-Fetal Development

4.2.3.5.3 Pm- and Post-natal Development & Maternal Function

4.2.3.5.4 Offspring, Juvenile, Second & Third-Generation Studies

4.2.3.6 Local Tolerance

4.2.3.7 Other Toxicity Studies

4.2.3.7.1 Antigenicity

4.2.3.7.2 Immunogenicity

4.2.3.7.3 Mechanistic Studies (not included elsewhere)

4.2.3.7.4 Dependence

15 [Page I !1 I ullah M, i
• ary
r
2 - 2_- 2_013
I

4.2.3.7.5 Metabolites

4.2.3.7.6 Impurities

4.2.3.7.7 Other

4.3 Literature References

Module 5: Clinical Study Reports


Section Requirements

5.1 Table of Contents of Module 5

5.2 Tabular Listing of All Clinical Studies

5.3 Clinical Study Reports

5.3.1 Reports of Biopharmaceutic Studies

5.3.1.1 Bioavailability (BA) Study Reports

5.3.1.2 Comparative BA & BE Study Reports

5.3.1.3 In vitro/In vivo Correlation (IV/IVC) study reports

5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human studies

5.3.2 Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials

5.3.2.1 Plasma Protein Binding Study Reports

5.3.2.2 Reports of Hepatic Metabolism and Drug Interactions studies

5.3.2.3 Reports of Studies Using other Human Biomaterials

5.3.3 Reports of Human Pharmacokinetic Studies

5.3.3.1 Healthy Subject PK and Tolerability

5.3.3.2 Patient PK and Initial Tolerability

5.3.3.3 Intrinsic Factor PK Study Reports

5.3.3.4 Extrinsic Factor PK Study Reports

5.3.3.5 Population PK Study Reports

Abdu rah M. Al-Bader


16IPage
A •
For Drug & Food Control

2_6-12—L00
5.3.4 Reports of Human Pharmacodynamic (PD) Studies

5.3.4.1 Healthy Subject PD and PK/PD Study Reports

5.3.4.2 Patient PD and PIC/PD Study Reports

5.3.5 Reports of Efficacy and Safety Studies

5.3.5.1 Study reports of Controlled Clinical Studies pertinent to the claimed Indication

5.3.5.2 Study reports of Uncontrolled Clinical Studies

5.3.5.3 Reports of Analyses of Data from More than One Study

5.3.5.4 Other Study Reports

5.3.6 Reports of Post-Marketing Experience

5.3.7 Case Report Forms and Individual Patient Listings

5.4 Literature References

The following is detailed description of repuirements:

Module 1 Regional Administrative Information

1.0 Cover letter


The agent shall include a cover letter for each submission stating the following:
Subject
Date of submission
submission type
name of marketing authorization holder
name of product (dosage form and strengths)
singed by the authorized person
1.1 Comprehensive table of content
Must list all documents included in all Modules.
1.2 Application Form
The completed and signed application form.
1.3 Product Information

Dr Abdullah M. Al-Bader
ASSIS4flt Undersec a ry
17IPage

7 t(- 12- Zs) (5


This section contains the Summary of Product Characteristics (SPC), Labeling,
Patient Information Leaflet (PIL) in Arabic and English, Artwork and the Samples.
1.3.1. Summary of Product Characteristics (SPC)
The SPC must include the name of the product, strength, pharmaceutical form,
quantity of active ingredients, posology, method of administration, indications,
contraindications, excipients, shelf-life and any special warnings and precautions for
use.
SPC must be submitted as per the GCC Guidance for Presenting the SPC, PIL and
Labeling Information.

1.3.2. Labeling
The labeling content must be in compliance with the SPC and must be submitted as
per the GCC Guidance for Presenting the SPC, PIL and Labeling Information.

1.3.3. Patient Information Leaflet (PIL)


1.3.3.1. Arabic leaflet
1.3.3.2. English leaflet
The PIL content must be in compliance with the SPC.
PIL must be submitted as per the GCC Guidance for presenting the SPC, PIL and
Labeling Information.

1.3.4. Artwork (Mock-ups)


A mock-up is a flat artwork design in full color, presented so that, following cutting
and folding, where necessary, it provides a full-size replica of both the outer and
immediate packaging so that the two-dimensional presentation of the label text is
clear. The application for a marketing authorization must include one or more mock-
ups of the outer packaging and of the immediate packaging of the product.
Artworks must be submitted as per the GCC Guidance for Presenting the SPC, PIL
and Labeling Information.

1.3.5. Samples
A sample from each strengths and presentation must be submitted.
Pharmaceutical and Herbal Medicines Registration and Control Administration have
the right to request whenever needed samples in order to perform complete analysis.
Dr Abdullah M. Al-Bader
Asststan • dersecr
18IPage For D I g & Food Control
— t_ —2_t 19
The submitted samples must represent the final finished product to be marketed in
Kuwait.

1.4. Information on the experts


1.4.1. Quality
1.4.2. Non-Clinical
1.4.3. Clinical
It is important to emphasize that well prepared expert reports greatly facilitate the
task of the pharmaceutical and herbal medicines registration and control
administration in evaluating the dossier and contribute towards the speedy
processing of applications.
Authors of expert reports must be chosen based on their relevant qualifications and
their recognized expertise in the field concerned. The experts must not preferably
been personally involved in the conduct of the tests included in the dossier.
Each expert report must consist of:
An abbreviated product profile.
A critical evaluation of the dossier.
The opinion of the expert as to whether sufficient guarantees have been
provided as to the suitability of the product for its proposed use.
A summary of all the important data
The signature of the expert and the place and date of the report's issue
The expert's curriculum vitae and a declaration of the expert's professional
relationship to the applicant.
It is essential to note that the expert reports must include a critical discussion of the
properties of the product as demonstrated by the contents of the dossier.
The expert is expected to take and defend a clear position on the final product, in the
light of current scientific knowledge.
A simple factual summary of the information contained in the application is not
sufficient and the expert reports must not be a repetition of other parts of the dossier,
although important data will need to be summarized in the expert report in some
form, both expert reports and summaries must contain precise references to the
information contained in the main documentation. If experts wish to supplement
their report by reference to additional literature, they must indicate clearly that the
applicant has not included this information in the relevant part of the dossier.

19IPage Dr Abdullah M ader


For D
ntroi
6—
1.5. Environmental Risk Assessment
1.5.1. Non-Genetically Modified Organism (Non-GMO)
1.5.2. Genetically Modified Organism (GMO)
The applicant shall include an evaluation for any potential risks of the product to the
environment. This must include risks to the environment arising from use, storage
and disposal of products and not for risks arising from the synthesis or manufacture
of products.

1.6. Pharmacovigilance
1.6.1. Pharmacovigilance System
It shall contain a detailed description of the pharmacovigilance system including the
proof that the applicant has the services of a qualified person responsible for
pharmacovigilance and the necessary means for the notification of any adverse
reaction.
1.6.2. Risk Management Plan
A detailed description of the risk management system which the applicant will
introduce must be provided, where appropriate.

1.7. Certificates and Documents


1.7.1. GMP Certificate
A valid original and legalized GMP Certificate must be submitted reflecting the
manufacturing lines certified.
1.7.2. CPP
Original and legalized certificate of pharmaceutical product (CPP) issued from
health authority in the country of origin must be submitted in accordance with WHO
guidelines.
1.7.3. Certificate of analysis — Drug Substance/Finished Product
Certificates of analysis for more than one batch of the drug substance must be
submitted from the API supplier & finished product manufacturer.
Certificates of analysis for more than one batch of the finished product must be
submitted from the finished product manufacturer.
1.7.4. Certificate of analysis — Excipients
Dr Abdullah I Al-Bader
20IPage
AssistO tt Undersec tary
For Dru RE Fanti
2_ — Z. —2_0 /9
Certificates of analysis for more than one batch of the excipients may be submitted
to support the application.

1.7.5. Alcohol-free declaration


This section must contain a declaration letter in an official company letterhead
stating that the product is free from alcohol.
In case the medicinal product contains alcohol, justification must be submitted and
must be in accordance with the Guidelines for importing and handling ethyl alcohol
and any material that is manufactured with it in accordance to Ministerial decree
(603 / 2000).

1.7.6. Pork-free declaration


This section must contain a declaration letter in an official company letterhead
stating that the product is free from any material of pork/ porcine source.
In case the medicinal product contains any materials of pork/ porcine source
justification must be submitted.

1.7.7. Certificate of suitability for TSE


This section must contain a valid TSE Certificate of Suitability issued by the
European Directorate for the Quality of Medicines (EDQM), which confirms the
compliance of a substance to the relevant monograph of the European
Pharmacopoeia or equivalent certificate from reference authority.

1.7.8. The diluents and coloring agents in the product formula


This section must contain a declaration letter in an official company letterhead
stating the diluents and coloring agents used in the product formula.

1.7.9. Patent Information


This section must contain a declaration letter in an official company letterhead
stating the patent status of the product in GCC patent office accompanied by patency
letter from GCC patent office.

1.7.10. Letter of access or acknowledgment to DMF


A letter written by the DMF Owner or authorized Agent permitting Kuwait ministry
of health to reference information in the DMF on behalf of the Applicant.
21IPage

M. Al-Bader
44331S Undersecretrey
For Drug & Food Control
2- zo/9
1.8. Pricing
The agent shall include the price of the product in countries listed in the GCC
Guidance for Submission.

1.9. Responses to questions


The response document must follow the same presentation as the initial dossier.
The applicant must include in this section a document which lists the questions with
the corresponding response for each question.
This section will not be used for supporting technical documentation which will be
included to the relevant Modules. Each question must be followed by the name of
section, page number and a hyperlink where the answer can be found in the
concerned Module.

Module 2 Common Technical Document Summaries

Table of Contents of Module 2-5


The table of content must list all documents included in Modules 2 to 5.

Quality Overall Summary


The Quality Overall Summary (QOS) is a summary that follows the scope and the
outline of the Body of Data in Module 3. The QOS must not include information,
data or justification that was not already included in Module 3 or in other parts of
the CTD. The QOS must include sufficient information from each section to provide
the Quality reviewer with an overview of Module 3.
The QOS must include a discussion of key issues that integrates information from
sections in the Quality Module and supporting information from other Modules (e.g.
qualification of impurities via toxicological studies discussed under module 4),
including cross referencing to volume and page number in other Modules.

Non-Clinical Overview

Dr Abdullah M. AI-Bader
22IPage Assistan nders retary
For

ZS— /2_ —7—a(9


The Nonclinical Overview must provide an integrated overall analysis of the
information in the CTD. The nonclinical testing strategy must be discussed and
justified.
There must be comment on the GLP status of the studies submitted. Any association
between nonclinical findings and the quality characteristics of the human
pharmaceutical, the results of clinical trials, or effects seen with related products
must be indicated, as appropriate.
Except for biotechnology-derived products, an assessment of the impurities and
degradants present in the drug substance/active substance and product must be
included along with what is known of their potential pharmacological and
toxicological effects. This assessment must be part of the justification for proposed
impurity limits in the drug substance/active substance and product, and be
appropriately cross-referenced to the quality documentation.
The implications of any differences in the chirality, chemical form, and impurity
profile between the compound used in the nonclinical studies and the product to be
marketed must be discussed. For biotechnology-derived products, comparability of
material used in nonclinical studies, clinical studies, and proposed for marketing
must be assessed. If a drug product/medicinal product include a novel excipient, an
assessment of the information regarding its safety must be provided.
The Nonclinical Overview must be presented in the following sequence:
Overview of the nonclinical testing strategy.
Pharmacology.
Pharmacolcinetics.
Toxicology.
Integrated overview and conclusions.
List of literature references.

Clinical Overview
The Clinical Overview is intended to provide a critical analysis of the clinical data
in the Common Technical Document. The Clinical Overview will refer to
application data provided in the comprehensive Clinical Summary, the individual
clinical study reports (ICH E3), and other relevant reports; but it must primarily
present the conclusions and implications of those data and must not recapitulate
them. Specifically, the Clinical Summary must provide a detailed factual

231Page
bdullah
!stunt Underspnrn
For Drug & Food Control
a —/a_zo
summarization of the clinical information in the CTD, and the Clinical Overview
must provide a succinct discussion and interpretation of these findings together with
any other relevant information (e.g., pertinent animal data or product quality issues
that may have clinical implications).

The Clinical Overview must:


Present the strengths and limitations of the development program and study
results
Analyze the benefits and risks of the medicinal product in its intended use
Describe how the study results support critical parts of the prescribing
information.

Non-Clinical Written and Tabulated Summaries


Whenever appropriate, age- and gender-related effects must be discussed. Relevant
findings with stereoisomers and/or metabolites must be included, as appropriate.
Consistent use of units throughout the Nonclinical Written Summaries will facilitate
their review. When available, in vitro studies must precede in vivo studies. Where
multiple studies of the same type are summarized within the Pharmacokinetics and
Toxicology sections, studies must be ordered by species, by route, and then by
duration (shortest duration first). Species must be ordered as follows:

I. Mouse.
Rat.
Hamster.
Other rodent.
Rabbit.
Dog.
Non-human primate.
Other non-rodent mammal.
Non-mammals.

Routes of administration must be ordered as follows:

24IPage
Dr Abduliah M. Al-Bader
Assistan nders
For ug & Food Control
The intended route for human use.
Oral.
Intravenous.
Intramuscular.
Intraperitoneal
Subcutaneous
Inhalation
Topical
Other

Clinical Summary
The Clinical Summary is intended to provide a detailed, factual summarization of
all the clinical information in the Common Technical Document.
This includes information provided in ICH E3 clinical study reports; information
obtained from any meta-analyses or other cross-study analyses for which full reports
have been included in Module 5; and post-marketing data for products that have
been marketed in other regions. The comparisons and analyses of results across
studies provided in this document must focus on factual observations (In contrast,
the CTD Clinical Overview document must provide critical analysis of the clinical
study program and its results, including discussion and interpretation of the clinical
findings and discussion of the place of the test drug in the armamentarium).

Module 3 Quality
3.1 Table of Contents of Module 3
3.2 Body of data
3.2.5 Drug Substance
The number of Active Pharmaceutical Ingredients (API) suppliers must not exceed
two sources for each API, unless reasonably justified.
The drug substance information can be submitted in one of the following options:
Certificate of suitability (CEP); or
Drug master file (DMF); or
Complete information on the "3.2.S drug substance" sections.

Dr Abdullah M. Al-Bader
25IPage
The drug substance information submitted must include the following for each of
the options used:

1. Certificate of Suitability (CEP)


Certificate of suitability submitted must clearly state the validity period.
A complete copy of the CEP (including any annexes) must be provided in Module 1.
Along with the CEP, the applicant must submit the following:
3.2.S.1.3 General properties
Discussions on any additional applicable physicochemical and other relevant
drug substance properties that are not controlled by the CEP and Ph. Eur.
monograph, e.g. solubilities and polymorphs.
3.2.S.3.1 Elucidation of structure and other characteristics
Studies to identify polymorphs (exception: where the CEP specifies a
polymorphic form) and particle size distribution, where applicable.
3.2.S.4.1 Specification
The specifications of the finished product manufacturer including all tests and
limits of the CEP and Ph. Eur. monograph and any additional tests and
acceptance criteria that are not controlled in the CEP and Ph. Eur. monograph,
such as polymorphs and/or particle size distribution.
3.2.S.4.2 / 3.2.S.4.3 Analytical procedures and validation
For any tests in addition to those in the CEP and Ph. Eur. monograph.
3.2.S.4.4 Batch analysis
Results from three batches of at least pilot scale, demonstrating compliance
with the finished product manufacturer's API specifications.
3.2.S.5 Reference standards or materials
Information on the finished product manufacturer's reference standards.
3.2.S.6 Container closure system
The specifications including descriptions and identification of primary
packaging components must be included in this section, except where the CEP
specifies a re-test period.
3.2.S.7 Stability
The stability must be included in this section, except where the CEP specifies
a re-test period that is the same as or of longer duration than the re-test period
proposed by the applicant.
Dr Abdullah M. AI-Bader
26IPage ssis desecretary
tor urug &

16 —12--Zoty
Note: In the case of sterile drug substances, data on the sterilization process of the
drug substance, including validation data must be included in the dossier.

2. Drug Master File (DMF)


Full details of the chemistry, manufacturing process, quality controls during
manufacturing and process validation for the drug substance may be submitted as
DMF. In such cases, the Open part needs to be included in its entirety in the dossier
as an annex to 3.2.S.
In addition, the applicant/finished product manufacturer must complete the
following sections:
General information 5.1.1 through S.1.3
Manufacture S.2
Manufacturer(s) S.2.1
Description of manufacturing process and process controls S.2.2
Controls of critical steps and intermediates 5.2.4
Elucidation of structure and other characteristics S.3.1
Impurities S.3.2
Control of the API 5.4.1 through 5.4.5
Reference standards or materials S.5
Container closure system S.6
Stability 5.7.1 through S.7.3
A copy of the letter of access must be provided in Module 1.

3. Complete Information on the "3.2.S Drug Substance" Sections.


Information on the 3.2.S Drug Substance sections, including full details of
chemistry, manufacturing process, quality controls during manufacturing and
process validation for the drug substance, must be submitted in the dossier.

3.2. S.1 General Information


3.2. S.1.1 Nomenclature
Information on the nomenclature of the drug substance(s) must be provided. For
example:
Recommended International Nonproprietary Name (INN);
Compendial name (if relevant);
Chemical name(s);
It I. I M. Al-Bader
27IPage 'It cre
For Drug & Food Control

6 -1a_2_0
Company or laboratory code;
Other non-proprietary name(s), e.g., National Name, United States Adopted
Name (USAN), British Approved Name (BAN),
Chemical Abstracts Service (CAS) registry number.

3.2.S.1.2 Structure
The structural formula, including relative and absolute stereochemistry, the
molecular formula, and the relative molecular mass must be provided.
For drug substance(s) existing as salts, the molecular mass of the free base or acid
must be provided.
For Biotech: In addition to the above, the schematic amino acid sequence
indicating glycosylation sites or other post-translational modifications and relative
molecular mass must be provided, as appropriate.

3.2.S.1.3 General Properties


A list must be provided of physicochemical and other relevant properties of the drug
substance.
This includes the physical description, solubilities in common solvents,
polymorphism, pH and pKa values, UV absorption maxima and molar absorptivity,
melting point, refractive index (for liquids), hygroscopicity, partition coefficient, ...
etc.
For Biotech: In addition to the above, the biological activity must be provided.

3.2.S.2 Manufacture
3.2.5.2.1 Manufacturer(s)
The name, address, and responsibility of each manufacturer, including contractors,
and each proposed production site or facility involved in manufacturing and testing
must be provided. In addition, a valid manufacturing license for the production of
drug substance(s) and a certificate of (IMP compliance must be provided.

3.2.S.2.2 Description of Process and Process Controls


Dr Abdullah M. Al-Bader
28IPage Assistant Undersecretary
d Control

Z -)
The description of the drug substance manufacturing process represents the
applicant's commitment for the manufacture of the drug substance. Information
must be provided to adequately describe the manufacturing process and process
controls.
For example:
A flow diagram of the synthetic process(es) must be provided that includes
molecular formulae, weights, yield ranges, chemical structures of starting
materials, intermediates, reagents and drug substance reflecting stereochemistry,
and identifies operating conditions and solvents.
A sequential procedural narrative of the manufacturing process must be
submitted. The narrative must include, for example, quantities of raw materials,
solvents, catalysts and reagents reflecting the representative batch scale for
commercial manufacture, identification of critical steps, process controls,
equipment and operating conditions (e.g., temperature, pressure, pH, time...
etc).
Alternate processes must be explained and described with the same level of detail
as the primary process. If applicable, reprocessing steps must be identified and
justified. Any data to support this justification must be either referenced or filed
in 3.2.S.2.5.
In case there are multiple manufacturing sites for one drug substance manufacturer,
a comprehensive list in tabular form must be provided comparing the processes
at each site and highlighting any differences.
For Biotech: In addition to the above, information must be provided on the
manufacturing process, which typically starts with a vial(s) of the cell bank, and
includes cell culture, harvest(s), purification and modification reactions, filling,
storage and shipping conditions;
Batch(es) and scale definition
An explanation of the batch numbering system, including information regarding
any pooling of harvests or intermediates and batch size or scale must be provided.
Cell culture and harvest
A flow diagram must be provided that illustrates the manufacturing route from
the original inoculum (e.g. cells contained in one or more vials(s) of the Working
Cell Bank) up to the last harvesting operation. The diagram must include all steps
(i.e., unit operations) and intermediates. Relevant information for each stage,
Dr Abdullah M. Al•Bader
29IPage Undersecreat-tiL,..,
Fur Dr ug & Fuud-Gm.I
such as population doubling levels, cell concentration, volumes, pH, cultivation
times, holding times, and temperature, must be included. Critical steps and
critical intermediates for which specifications are established (as mentioned in
3.2.S.2.4) must be identified.
A description of each process step in the flow diagram must be provided.
Information must be included on, for example, scale; culture media and other
additives (details provided in 3.2.S.2.3); major equipment (details provided in
3.2.A.1); and process controls, including in-process tests and operational
parameters, process steps, equipment and intermediates with acceptance criteria
(details provided in 3.2.S.2.4). Information on procedures used to transfer
material between steps, equipment, areas, and buildings, as appropriate, and
shipping and storage conditions must be provided (details on shipping and
storage provided in 3.2.S.2.4.).
Purification and modification reactions:
A flow diagram must be provided that illustrates the purification steps (i.e., unit
operations) from the crude harvest(s) up to the step preceding filling of the drug
substance. All steps and intermediates and relevant information for each stage
(e.g., volumes, pH, critical processing time, holding times, temperatures and
elution profiles and selection of fraction, storage of intermediate, if applicable)
must be included. Critical steps for which specifications are established as
mentioned in 3.2.S.2.4 must be identified.
A description of each process step (as identified in the flow diagram) must be
provided.
The description must include information on, for example, scale, buffers and
other reagents (details provided in 3.2.S.2.3), major equipment (details provided
in 3.2.A.1), and materials.
For materials such as membranes and chromatography resins, information for
conditions of use and reuse also must be provided (equipment details in 3.2.A.1;
validation studies for the reuse and regeneration of columns and membranes in
3.2.S.2.5.). The description must include process controls (including in-process
tests and operational parameters) with acceptance criteria for process steps,
equipment and intermediates (details in 3.2.S.2.4.). Reprocessing procedures
with criteria for reprocessing of any intermediate or the drug substance must be
described (details must be given in 3.2.S.2.5.). Information on procedures used
to transfer material between steps, equipment, areas, and buildings, as
30IPage
E ___Dr_Abcruilaq,1, A
A...a:scant Underse
For Drug & Food Control
- I _2_09
appropriate, and shipping and storage conditions must be provided (details on
shipping and storage provided in 3.2.5.2.4.).
Filling, storage and transportation (shipping)
A description of the filling procedure for the drug substance, process controls
(including in process tests and operational parameters), and acceptance criteria
must be provided (details in 3.2.S.2.4.). The container closure system(s) used for
storage of the drug substance (details in 3.2.S.6.) and storage and shipping
conditions for the drug substance must be described.

3.2.5.2.3 Control of Materials


Materials used in the manufacture of the drug substance (e.g., raw materials, starting
materials, solvents, reagents, catalysts) must be listed identifying where each
material is used in the process. For each starting material, the name, manufacturing
site, and the address of each manufacturer must be indicated. Information on the
quality and control of these materials must be provided.
Information demonstrating that materials (including biologically-sourced materials,
e.g., media components, monoclonal antibodies, enzymes) meet standards
appropriate for their intended use (including the clearance or control of adventitious
agents) must be provided, as appropriate.
For biologically-sourced materials, this can include information regarding the
source, manufacture, and characterization (details in 3.2.A.2).
A letter must be provided confirming that the drug substance, starting materials and
reagents used to manufacture the drug substance are without risk of transmitting
agents of Bovine Spongiform Encephalopathy (BSE)/Transmissible Spongiform
Encephalopathy (TSE).
When available, a CEP demonstrating TSE-compliance must be submitted. A
complete copy of the CEP (including any annexes) must be provided in Module 1.
For Biotech: "In addition to the above"
Control of source and starting materials of biological origin
Summaries of viral safety information for biologically-sourced materials must be
provided (details in 3.2.A.2.).
Source, history, and generation of the cell substrate
Information on the source of the cell substrate and analysis of the expression
construct used to genetically modify cells and incorporated in the initial cell clone

Dr Abdullah M. Al•Bader
31IPage is an II a • ecreta ry
For Drug & F rrn Control
r—

- 2_ — 2_ c2/3
used to develop the Master Cell Bank must be provided (as described in Q5B and
Q5D).
Cell banking system, characterization, and testing
Information on the cell banking system, quality control activities, and cell line
stability during production and storage (including procedures used to generate
the Master and Working Cell Bank(s)) must be provided (as described in Q5B
and Q5D).

3.2. S.2.4 Control of Critical Steps and Intermediates


Critical Steps:
Tests and acceptance criteria (with justification including experimental data)
performed at critical steps identified in 3.2.S.2.2 of the manufacturing process to
ensure that the process is controlled must be provided.
Intermediates:
Information on the quality and control of intermediates isolated during the
process must be provided.
For Biotech: In addition to the above, stability data supporting storage conditions
must be provided.

3.2. S.2.5 Process Validation and/or Evaluation


Process validation and/or evaluation studies for aseptic processing and sterilization
must be included.
For Biotech: Sufficient information must be provided on validation and evaluation
studies to demonstrate that the manufacturing process (including reprocessing steps)
is suitable for its intended purpose and to substantiate selection of critical process
controls (operational parameters and in-process tests) and their limits for critical
manufacturing steps (e.g., cell culture, harvesting, purification, and modification).
The plan for conducting the study (protocol) must be described and the results,
analysis and conclusions from the executed study(ies) must be provided.
The analytical procedures and corresponding validation must be cross-referenced
(e.g., 3.2.S.2.4, 3.2.S.4.3) or provided as part of justifying the selection of critical
process controls and acceptance criteria.
For manufacturing steps intended to remove or inactivate viral contaminants, the
information from evaluation studies must be provided in 3.2.A.2.

32IPage Dr Abdullah M. Al-Bader

2_6- I 2._ -2 0/5


3.2.S.2.6 Manufacturing Process Development
The developmental history of the manufacturing process, as described in 3.2.S.2.2,
must be provided.
In addition, A description and discussion must be provided of the significant changes
made to the manufacturing process and/or manufacturing site of the drug substance
used in producing nonclinical, clinical, scale-up, pilot, and, if available, production
scale batches. Reference must be made to the drug substance data provided in
section 3.2.S.4.4.
For Biotech: The developmental history of the manufacturing process, as described
in 3.2.S.2.2, must be provided. The description of change(s) made to the
manufacture of drug substance batches used in support of the marketing application
(e.g., nonclinical or clinical studies) must be include, for example, changes to the
process or to critical equipment, where the reason for the change must be explained.
Relevant information on drug substance batches manufactured during development,
such as the batch number, manufacturing scale, and use (e.g., stability, nonclinical,
reference material) in relation to the change, must be provided. The significance of
the change must be assessed by evaluating its potential to impact the quality of the
drug substance (and/or intermediate, if appropriate).For manufacturing changes that
are considered significant, data from comparative analytical testing on relevant drug
substance batches must be provided to determine the impact on quality of the drug
substance.
A discussion of the data, including a justification for selection of the tests and
assessment of results, must be included.Testing used to assess the impact of
manufacturing changes on the drug substance(s) and the corresponding drug
product(s) can also include nonclinical and clinical studies. Cross-reference to the
location of these studies in other modules of the submission must be included.
Reference must be made to the drug substance data provided in section 3.2.S.4.4.

3.2.S.3 Characterization
3.2.S.3.1 Elucidation of Structure and Other Characteristics
Confirmation of structure based on e.g., synthetic route and spectral analyses must
be provided. This must include copies of the spectra, peak assignments and a detailed
interpretation of the data of the studies performed to elucidate and/or confirm the
structure of the drug substance.

Dr Abdullah M. Al-Bader
33IPage ssistant Unj etar
; • •
oo on ex)
For non-pharmacopoeial drug substance(s), these studies normally include
elemental analysis, infrared (IR), ultraviolet (UV), nuclear magnetic resonance
(NMR) and mass spectra (MS) studies. Other tests could include X-ray
diffraction (XRD) and differential scanning calorimetry (DSC).
For pharmacopoeial drug substance(s), it is generally sufficient to provide copies
of the IR spectrum of the drug substance run concomitantly with a reference
standard.
Information such as the potential for isomerism, the identification of
stereochemistry, or the potential for forming polymorphs must also be included.
For Biotech:In addition to the above, details (for the desired product and product-
related substances) must be provided on primary, secondary and higher-order
structure, post-translational forms (e.g., glycoforms), biological activity, purity, and
immunochemical properties, when relevant.

3.2.5.3.2 Impurities
Information on impurities must be provided, including a discussion on the potential
and actual impurities arising from the synthesis, manufacture, or degradation of the
drug substance.
This must cover starting materials, by-products, intermediates, chiral impurities and
degradation products and must include the chemical names, structures and origins.

3.2.S.4 Control of Drug Substance


3.2.5.4.1 Specifications
Copies of the drug substance specifications, dated and signed by the concerned
individual(s) must be provided, including specifications from each drug substance
manufacturer as well as those of the finished product manufacturer.

3.2.S.4.2 Analytical Procedures


The analytical procedures used for testing the drug substance must be provided.
Copies of the non-compendial analytical procedures used to generate testing results
34IPage anieL
g&-F
Ze —12_-2019
provided in the dossier, as well as those proposed for routine testing of the drug
substance by the finished product manufacturer, must be provided. Unless modified,
it is not necessary to provide copies of the compendial analytical procedures.

3.2.8.4.3 Validation of Analytical Procedures


Analytical validation information, including experimental data for the analytical
procedures used for testing the drug substance, must be provided. Copies of the
validation reports for the analytical procedures used to generate testing results
provided in the dossier, as well as those proposed for routine testing of the drug
substance by the finished product manufacturer, must be provided.

3.2.S.4.4 Batch Analyses


Description of batches and results of batch analyses must be provided. Analytical
results must be provided from at least two batches of at least pilot scale from each
proposed manufacturing site of the drug substance. A pilot-scale batch must be
manufactured by a procedure fully representative of and simulating that to be applied
to a full production-scale batch.
For quantitative tests (e.g. assay test, individual and total impurity tests), it must be
ensured that actual numerical results are provided rather than vague statements such
as "within limits" or "conforms".

3.2.8.4.5 Justification of Specification


Justification for the drug substance specification must be provided. This must
include a discussion on the inclusion of certain tests, evolution of tests, analytical
procedures and acceptance criteria, etc. If the compendial methods have been
modified or replaced, a discussion must be included.

3.2.S.5 Reference Standards or Materials


Information on the reference standards or reference materials used for testing of the
drug substance must include the following:
The source of reference standards or reference materials (e.g., House, USP, BP,
Ph. Fur.).
Certificate of analysis for reference standards or reference materials.

Dr Abdullah Ni. AI-Bader


35IPage Undersecretary

Z._ 6- -12_-z_oty
3. Characterization and evaluation of non-official (e.g., non-compendial) reference
standards or reference materials (e.g., method of manufacture, elucidation of
structure, certificate of analysis, calibration against an official standard

3.2.5.6 Container/Closure Systems


A description of the container closure system(s) must be provided, including the
identity of materials of construction of each primary packaging component, and their
specifications. The specifications must include description and identification (and
critical dimensions with drawings, where appropriate). Non-compendia! methods
(with validation) must be included, where appropriate.

3.2.5.7 Stability
3.2.S.7.1 Stability Summary and Conclusions
The GCC guidelines for "Stability Testing of Active Pharmaceutical Ingredients
(APIs) and Finished Pharmaceutical Products (FPPs)" and ICH (Q1A-Q1F) must be
followed for recommendations on the stability data required for the drug
substance(s).

3.2.5.7.2 Post-approval Stability Protocol and Commitment


The stability of the drug substance must be monitored according to a continuous and
appropriate program that will permit the detection of any stability issue (e.g. changes
in levels of degradation products). For this purpose, the ongoing stability program
must include at least one production batch per year of drug substance (unless none
is produced during that year).
In certain situations, additional batches must be included. Therefore, a written
commitment (signed and dated) for ongoing stability studies must be included in the
dossier. Any differences in the stability protocols used for the primary batches and
those proposed for the commitment batches or ongoing batches must be
scientifically justified.

3.2.S.7.3 Stability Data


Results of the stability studies must be presented in a tabular format.

Dr Abdullah M. Al-Bader
36IPage aders
ug ood Control
The results of all testing parameters related to each batch for the entire testing period
must be presented in one table (i.e. presenting the results of one parameter of all
batches in one table is not acceptable).
For quantitative tests (e.g. individual and total degradation product tests and assay
tests), it must be ensured that actual numerical results are provided rather than vague
statements such as "within limits" or "conforms".
Information on the analytical procedures used to generate the data and validation of
these procedures must be included.

3.2P Drug Product


3.2.P.1 Description and Composition of the Drug Product
A description of the drug product and its composition must be provided. The
information provided must include:
Description of the dosage form;
Composition, i.e., list of all components of the dosage form, and their amount on
a per-unit basis (including overages, if any), the function of the components, and
a reference to their quality standards (e.g., compendial monographs or
manufacturer's specifications);
Description of accompanying reconstitution diluent(s); and
Type of container and closure used for the dosage form and accompanying
reconstitution diluent, if applicable.

3.2.P.2 Pharmaceutical Development


The pharmaceutical development section must contain information on the
development studies conducted to establish that the dosage form, the formulation,
manufacturing process, container closure system, microbiological attributes and
usage instructions are appropriate for the purpose specified in the application.
The studies described here are distinguished from routine control tests conducted
according to specifications. Additionally, this section must identify and describe the
formulation and process attributes (critical parameters) that can influence batch
reproducibility, product performance and drug product quality.
Supportive data and results from specific studies or published literature can be
included within or attached to the pharmaceutical development section. Additional

Dr Abduliah M. Al-Bader
37IPage ("Cks;Ria-rn)Urid tn.e cretary
For Dt ug & Fee4I-Can
supportive data can be referenced to the relevant nonclinical or clinical sections of
the application.

3.2.P.2.1 Components of the Drug Product


3.2.P.2.1.1 Drug substance
The compatibility of the drug substance with excipients listed in 3.2.P.1 must be
discussed. Additionally, key physicochemical characteristics (e.g., water content,
solubility, particle size distribution, polymorphic or solid state form) of the drug
substance that can influence the performance of the drug product must be discussed.
For combination products, the compatibility of drug substances with each other must
be discussed.

3.2.P.2.1.2 Excipients
The choice of excipients listed in 3.2.P.1, their concentration, and their
characteristics that can influence the drug product performance must be discussed
relative to their respective functions. Where relevant, compatibility study result must
be included to justify the choice of excipients. Where antioxidants are included in
the formulation, the effectiveness of the proposed concentration of the antioxidant
must be justified and verified by appropriate studies. Where relevant, the
antimicrobial preservatives must be discussed in 3.2.P.2.5.

3.2.P.2.2 Drug Product


3.2.P.2.2.1 Formulation Development
A brief summary describing the development of the drug product must be provided,
taking into consideration the proposed route of administration and usage. The
differences in the formulations for the batches used the in the in vivo studies (e.g.,
pivotal clinical, comparative bioequivalence) and the formulation (i.e. composition)
described in 2.3.P.1 must be discussed.
Summary of the results from comparative in vitro studies (e.g., dissolution) or
comparative in vivo studies (e.g., bioequivalence) must be discussed when
appropriate, including the description of batches (e.g., batch number, strength, type
of the study ... etc.) used in these studies.
The discussion must include the results of studies justifying the choice of in vitro
dissolution or drug release conditions (e.g. apparatus, rotation speed, medium).

38IPage
Dr Abdullah Al-Bader
Assistallnders
'rug
a6 z.
Furthermore, the submitted data must demonstrate whether the method is sensitive
to changes in manufacturing processes and/or changes in grades and/or amounts of
critical excipients and particle size where relevant.
Scored Tablets
In order to ensure that the patient will receive the intended dose, the efficacy of the
break mark(s) must be assessed during the development of the product, in respect of
uniformity of mass of the subdivided parts.
If the proposed finished product is a scored tablet or the applicant indicates that it
may be divided, the following must be submitted:
A justification/rationale for the tablet scoring, and
Results of the appropriate compendial tests demonstrating equivalence in
characteristics/correct dosing (i.e. results demonstrating that the proposed tablet
breaks evenly).
The submitted data must include a description of the test method, individual values,
mean and relative standard deviation (RSD) of the results.

3.2.P.2.2.2 Overages
In general, use of an overage of a drug substance to compensate for degradation
during manufacture or a product's shelf life, or to extend shelf life, is discouraged.
Any overages in the manufacture of the drug product whether they appear in the
final formulated product or not, must be justified considering the safety and efficacy
of the product. Information must be provided on the following.
amount of overage
reason for the overage (e.g., to compensate for expected and documented
manufacturing losses)
Justification for the amount of overage.
The justification of an overage to compensate for loss during manufacture must be
provided, including the step(s) where the loss occurs, the reasons for the loss and
batch analysis (assay results).
The overage must be included in the amount of drug substance listed in the batch
formula (3.2.P.3.2).

3.2.P.2.2.3 Physiochemical and Biological Properties


Parameters relevant to the performance of the drug product, such as pH, ionic
strength, dissolution, redispersion, reconstitution, particle size distribution,
39IPage Dr ;el -11.A1eBaL
c
3313telll t • I rsecre ary
aggregation, refractive index, polymorphism, rheological properties, biological
activity or potency, and/or immunological activity, must be addressed.

3.2.P.2.3 Manufacturing Process Development


The scientific rationale for the selection, optimization and scale-up of the
manufacturing process described in 3.2.P.3.3, in particular its critical aspects, must
be explained. Where relevant, the method of sterilization must be explained and
justified. The justification for selecting aseptic processing or other sterilization
methods over terminal sterilization must be provided. Differences between the
manufacturing process(s) used to produce pivotal clinical batches/ comparative
bioavailability batches and the process described in 3.2.P.3.3 that can influence the
performance of the product must be discussed.

3.2.P.2.4 Container Closure System


The suitability of the container closure system (described in 3.2.P.7) used for the
storage, transportation (shipping) and use of the drug product must be discussed.
This discussion must consider, e.g., choice of materials, protection from moisture
and light, compatibility of the materials of construction with the dosage form
(including sorption to container and leaching), and performance (such as
reproducibility of the dose delivery from the device when presented as part of the
drug product).
For a device accompanying a multidose container, the discussion must provide the
results that demonstrate the reproducibility of the device (e.g. consistent delivery of
the intended volume), generally at the lowest intended dose.

3.2.P.2.5 Microbiological Attributes


Where appropriate, the microbiological attributes of the dosage form must be
discussed, including, for example, the rationale for not performing microbial limits
testing for non-sterile products, the selection and effectiveness of preservative
systems in products containing antimicrobial preservatives.
A single primary stability batch of the finished product must be tested for
effectiveness of the antimicrobial preservative (in addition to preservative content)
at the proposed shelf-life for verification purposes, regardless of whether there is a
difference between the release and shelf-life acceptance criteria for preservative
content.
40IPage
ah M. AI-Bader
Assistant der r
For Drug & Food Contro

Z6-12_-2-019
For sterile products, the integrity of the container closure system to prevent
microbial contamination must be addressed.

3.2.P.2.6 Compatibility
The compatibility of the drug product with reconstitution diluent(s) or dosage
device(s) (e.g., precipitation of drug substance in solution, sorption on injection
vessels, stability) must be addressed to provide appropriate and supportive
information for the labeling. Where sterile reconstituted products are to be further
diluted, compatibility must be demonstrated with all diluents over the range of
dilution proposed in the labeling. These studies must preferably be conducted on
aged samples. Where the labeling does not specify the type of containers,
compatibility (with respect to parameters such as appearance, pH, assay, levels of
individual and total degradation products, subvisible particulate matter and
extractables from the packaging components) must be demonstrated in glass, PVC
and polyolefm containers.
However, if one or more containers are identified in the labeling, compatibility of
admixtures needs to be demonstrated only in the specified containers.
Where the labeling specifies co-administration with other finished products,
compatibility must be demonstrated with respect to the principal finished product as
well as the co-administered finished product (i.e. in addition to other aforementioned
parameters for the mixture, the assay and degradation levels of each co-administered
finished product must be reported).

3.2.P.3 Manufacture
3.2.P.3.1 Manufacturer(s)
The name, address, and responsibility of each manufacturer, including contractors,
and each proposed production site or facility involved in manufacturing and testing
must be provided.
A valid manufacturing license must be submitted.
A GMP certificate must be submitted for each manufacturing site where the major
production step(s) are carried out.

3.2.P.3.2 Batch Formula


A batch formula must be provided that includes a list of all components of the dosage
form to be used in the manufacturing process (including those that may not be added
41IPage
Dr Abdullah M. Al-Bader
ersecreta
For Druz &
26- .-- 12_ --z_o
to every batch [e.g. acid and alkali], those that may be removed during processing
[e.g. solvents] and any others [e.g. nitrogen, silicon for stoppers]), and their amounts
on a per batch basis, including overages.
The components used in the manufacturing process must be declared by their proper
or common names and a reference to their quality standards (e.g. BP, IJSP).

3.2.P.3.3 Description of Manufacturing Process and Process Controls


A flow diagram must be presented giving the steps of the process and showing where
materials enter the process. The critical steps and points at which process controls,
intermediate tests or final product controls are conducted must be identified.
A narrative description of the manufacturing process, including packaging that
represents the sequence of steps undertaken and the scale of production must also be
provided.
Novel processes or technologies and packaging operations that directly affect
product quality must be described with a greater level of detail.
Equipment must, at least, be identified by type (e.g., tumble blender) and working
capacity, where relevant. Steps in the process must have the appropriate process
parameters identified, such as time, temperature, or pH. Associated numeric values
can be presented as an expected range. Numeric ranges for critical steps must be
justified in Section 3.2.P.3.4. In certain cases, environmental conditions (e.g., low
humidity for an effervescent product) must be stated. For the manufacture of sterile
products, the class of the areas (e.g. A, B, ...etc) must be stated for each activity
(e.g. compounding, filling, ...etc), as well as the sterilization parameters for
equipment, container/closure, terminal sterilization ...etc. Proposals for the
reprocessing of materials must be justified. Any data to support this justification
must be either referenced or filed in this section. Detailed information on Biotech
facilities and equipment must be provided in 3.2.A.1.

3.2.P.3.4 Controls of Critical Steps and Intermediates


Critical Steps: Tests and acceptance criteria must be provided (with
justification, including experimental data) performed at the critical steps
identified in 3.2.P.3.3 of the manufacturing process, to ensure that the process is
controlled.

Dr Abdullah M. Al-Bader
42IPage
r Foistant Unatrsecretary
r Drug & Food Contr---___
Intermediates: Information on the quality and control of intermediates isolated
during the process must be provided.

3.2.P.3.5 Process Validation and/or Evaluation


Description, documentation, and results of the validation and/or evaluation studies
must be provided for critical steps or critical assays used in the manufacturing
process (e.g., validation of the sterilization process or aseptic processing or filling).
Viral safety evaluation must be provided in 3.2.A.2, if necessary.
The following information must be provided:
A copy of the process validation protocol, specific to this finished product,
that identifies the critical equipment and process parameters that can affect the
quality of the finished product and defines testing parameters, sampling plans,
analytical procedures and acceptance criteria
A commitment that three consecutive, production-scale batches of this
finished product will be subjected to prospective validation in accordance
with the above protocol
If the process validation studies have already been conducted (e.g. for sterile
products), a copy of the process validation report must be provided in the
dossier

3.2.P.4 Control of Excipients


3.2.P.4.1 Specifications
The specifications must be provided for all excipients, including those that may not
be added to every batch (e.g. acid and alkali), those that do not appear in the finished
product (e.g. solvents) and any others used in the manufacturing process (e.g.
nitrogen, silicon for stoppers).
For excipients of natural origin, microbial limit testing must be included in the
specifications. For oils of plant origin (e.g. soybean oil, peanut oil) the absence of
aflatoxins or biocides must be demonstrated.
The colors permitted for use are limited to those listed in the EU "List of permitted
food colors" and the US FDA "Inactive ingredient guide".
For proprietary mixtures, the supplier's product sheet with the qualitative
formulation must be submitted, in addition to the finished product manufacturer's
specifications for the product including identification testing.
43IPage
Dr Abduliah M. AlBac1E
For Drug & Food Control
3.2.P.4.2 Analytical Procedures
The analytical procedures used for testing the excipients must be provided. Copies
of the non compendial analytical procedures used to generate testing results must be
provided. Unless modified, it is not necessary to provide copies of the compendial
analytical procedures.

3.23.4.3 Validation of Analytical Procedures


Analytical validation information, including experimental data, for the non-
compendial analytical procedures used for testing the excipients must be provided,
where appropriate.

3.2.P.4.4 Justification of Specifications


Justification for the proposed excipient specifications must be provided, where
appropriate. This must include a discussion on the tests that are supplementary to
those appearing in the compendial monograph.

3.2.P.4.5 Excipients of Human or Animal Origin


List of excipients that are of human or animal origin (including country of origin).
Summary of the information (e.g., sources, specifications, description of the testing
performed, viral safety data) regarding adventitious agents for excipients of human
or animal origin (details must be located in 3.2.A.2).
For excipients obtained from sources that are at risk of transmitting Bovine
Spongiform Encephalopathy (BSE)/Transmissible Spongiform Encephalopathy
(TSE) agents (e.g., ruminant origin), a letter of attestation (with supporting
documentation) must be provided confirming that the material is not from a
BSE/TSE affected country/area.
Along with a CEP demonstrating TSE-compliance must be submitted. A complete
copy of the CEP (including any annexes) must be provided in Module 1.

3.2.P.4.6 Novel Excipients


44IPage
Dr Abdullah IV. AbBader
rug Food Control
zs - -z_al 9
For excipient(s) used for the first time in a drug product or by a new route of
administration, full details of manufacture, characterization, and controls, with cross
references to supporting safety data (nonclinical and/or clinical) must be provided
according to the drug substance format (details in 3.2.A.3).

3.2.P.5 Control of Drug Product


3.2.P.5.1 Specifications
The specification(s) for the drug product must be provided. A copy of the finished
product specification(s) (release and shelf-life specifications) dated and signed by
authorized personnel (i.e. the person in charge of the quality control or quality
assurance department), must be provided.
The specification(s) sheet must include, but not be limited to, the following:
The tests;
Acceptance criteria;
The standard declared by the applicant (e.g. compendial or in-house standard);
The specification reference number and version (e.g. revision number and/or
date)
Analytical procedures, including their type (e.g. visual, IR, HPLC ...), source
(e.g. Ph.Eur., BP, USP, in-house) and version (e.g. code number/version/date).
Specifications must include, at minimum, tests for appearance, identification, assay,
purity, pharmaceutical tests (e.g. dissolution), physical tests (e.g. loss on drying,
hardness, friability, particle size, apparent density), uniformity of dosage units,
identification of coloring materials, identification and assay of antimicrobial or
chemical preservatives (e.g. antioxidants) and microbial limit tests (refer to ICH
Q6A).
Any differences between release and shelf-life tests and acceptance criteria must be
clearly indicated and justified. Note that such differences for parameters such as
dissolution are normally not accepted.

3.2.P.5.2 Analytical Procedures


The analytical procedures used for testing the drug product must be provided. Copies
of the non-compendial analytical procedures used during pharmaceutical
development (if used to generate testing results provided in the dossier) as well as
those proposed for routine testing must be provided.
Dr Abdullah M. Al-Bader
451 page ssistan ersentry-
or Drug & F4e4Control
Unless modified, it is not necessary to provide copies of the compendial analytical
procedures.

3.2.P.5.3 Validation of Analytical Procedures


Analytical validation information, including experimental data, for the analytical
procedures used for testing the drug product, must be provided. Copies of the
validation reports for the non-compendial analytical procedures used during
pharmaceutical development (if used to support testing results provided in the
dossier) as well as those proposed for routine testing must be provided. Verification
of compendial methods can be necessary. The compendial methods, as published,
are typically validated based on a drug substance or a finished product originating
from a specific manufacturer.
Different sources of the same drug substance or finished product can contain
impurities and/or degradation products or excipients that were not considered during
the development of the monograph. Therefore, the monograph and compendia!
method(s) must be demonstrated suitable for the control of the proposed finished
product. For compendial assay methods, verification must include a demonstration
of specificity, accuracy and repeatability (method precision), Linearity, and Range.
If a compendial method is used to control related substances that are not specified in
the monograph, full validation of the method is expected with respect to those related
substances.
If a compendial standard is claimed and an in-house method is used in lieu of the
compendial method (e.g. for assay or related substance), equivalency of the in-house
and compendial methods must be demonstrated. This could be accomplished by
performing duplicate analyses of one sample by both methods and providing the
results from the study. For related substance methods, the sample analyzed must be
the placebo spiked with related substances at concentrations equivalent to their
specification limits.

3.2.P.5.4 Batch Analyses


A description of batches and results of batch analyses must be provided. The
information provided must include strength, batch number, batch size, batch type,
date and site of production. Analytical results tested by the company responsible for
the batch release of the finished product must be provided for not less than two
batches of at least pilot scale batches. These batches must be manufactured by a
46IPage
Dr Abdullah M. Al.Bader
SIStA I)
ec
r Orti 2 &
- Food
procedure fully representative of and simulating that to be applied to a full
production-scale batch.
The discussion of results must focus on observations noted for the various tests,
rather than reporting comments such as "all tests meet specifications". For
quantitative tests it must be ensured that actual numerical results are provided rather
than vague statements such as "within limits" or "conforms". Dissolution results
must be expressed at minimum as both the average and range of individual results.
A discussion and justification must be provided for any incomplete analyses (e.g.
results not tested according to the proposed specification).

3.22.5.5 Characterization of Impurities


Information on the characterization of impurities must be provided, if not previously
provided in "3.2.S.3.2 Impurities". The discussion must be provided for all
impurities that are potential degradation products and finished product process-
related impurities.

3.2.P.5.6 Justification of Specifications


Justification for the proposed drug product specification(s) must be provided. The
discussion must be provided on the omission or inclusion of certain tests, evolution
of tests, analytical procedures and acceptance criteria, differences from the
compendial standard. If the compendial methods have been modified or replaced, a
discussion must be included.
The justification for certain tests, analytical procedures and acceptance criteria (e.g.
degradation products) may have been discussed in other sections of the dossier and
does not need to be repeated here, although a cross-reference to their location must
be provided.

3.2.P.6 Reference Standards or Materials


Information on the reference standards or reference materials used for testing of the
drug product must include the following, if not previously provided in "3.2.S.5
Reference Standards or Materials":

47IPage
Or Abdullah KAI-Bader
rxssistant retsv_s_
or Drug' dersec
ood Control
The source of reference standards or reference materials (e.g., House, USP, BP,
Ph. Bur.).
Certificate of analysis for reference standards or reference materials.
Characterization and evaluation of non-official (e.g., non-compendial) reference
standards or reference materials (e.g., method of manufacture, elucidation of
structure, certificate of analysis, calibration against an official standard

3.2.P.7 Container/Closure System


A description of the container closure systems must be provided, including unit
count or fill size, container size or volume, the identity of materials of construction
of each primary packaging component, its specification and the supplier's name and
address.
The specifications must include description and identification (and critical
dimensions, with drawings where appropriate).
The specifications for the primary packaging components must include a specific
test for identification (e.g. TR). Specifications for film and foil materials must include
limits for thickness or area weight. Non-compendial methods (with validation) must
be included where appropriate.
The suitability of the container closure system used for the storage, transportation
(shipping) and use of the drug product must be located in 3.2.P.2.4. Information to
establish the suitability (e.g. qualification) of the container closure system must be
discussed in Section 3.2.P.2.4.
Comparative studies may be provided for certain changes in packaging components
(e.g. comparative delivery study "droplet size" for a change in manufacturer of
dropper tips).

3.2.P.8 Stability
3.2.P.8.1 Stability Summary and Conclusions
The GCC guidelines for "Stability Testing of Active Pharmaceutical Ingredients
(APIs) and Finished Pharmaceutical Products (FPPs)" and ICH (Q1A-Q1F) must be
followed for recommendations on the stability data required for the finished
product(s).
For registration of reference (innovator) or generic products long term stability
studies covering the complete shelf life and accelerated stability studies covering 6
months are requested.
ullah M. Al-Bader
48IPage
Assistan Undersecretary
FrD
The types of studies conducted, protocols used, and the results of the studies must
be summarized.
The summary must include information on storage conditions, strength, batch
number (including the drug substance batch number(s) and manufacturer(s)), batch
size, batch type, batch manufacturing date, container closure system (including
where applicable the orientation e.g. inverted) and completed (and proposed) testing
intervals, results, as well as conclusions with respect to storage conditions and shelf-
life, and, if applicable, in-use storage conditions and shelf-life.
The discussion of results must focus on observations noted for the various tests,
rather than reporting comments such as "all tests meet specifications".
For quantitative tests (e.g. individual and total degradation product tests and assay
tests), it must be ensured that actual numerical results are provided rather than vague
statements such as "within limits" or "conforms". Dissolution results must be
expressed at minimum as both the average and range of individual results. Where
the methods used in the stability studies are different from those described in
3.2.P.5.2, descriptions and validation of the methodology used in stability studies
must be provided.

3.2.P.8.2 Post-Approval Stability Protocol and Stability Commitment


The stability of the drug product must be monitored over its shelf-life to determine
that the product remains within its specifications and to detect any stability issue
(e.g. changes in levels of degradation products). For this purpose, the ongoing
stability program must include at least one production batch per year of product
manufactured in every strength and every container closure system (unless none is
produced during that year). Therefore, a written commitment (signed and dated) for
ongoing stability studies must be included in the dossier.
Any differences in the stability protocols used for the primary batches and those
proposed for the commitment batches or ongoing batches must be scientifically
justified.

3.2.P.8.3 Stability Data


Results of the stability studies must be presented in a tabular format. The results of
all testing parameters related to each batch for the entire testing period must be
49IPage Dr K AI-Bader
natant Under ecre a .
r &F Control

— I 2_-7__c,/,5
presented in one table (i.e. presenting the results of one parameter of all batches in
one table is not acceptable).
The actual stability results/reports used to support the proposed shelf-life must be
provided in the dossier. For quantitative tests (e.g. individual and total degradation
product tests and assay tests), it must be ensured that actual numerical results are
provided rather than vague statements such as "within limits" or "conforms".
Dissolution results must be expressed at minimum as both the average and range of
individual results.
Information on the analytical procedures used to generate the data and validation of
these procedures must be included. Information on characterization of impurities is
located in 3.2.P.5.5.

3.2.A Appendices 3.2.A.1 Facilities and Equipment


For Biotech:
A diagram must be provided illustrating the manufacturing flow including
movement of raw materials, personnel, waste, and intermediate(s) in and out of the
manufacturing areas. Information must be presented with respect to adjacent areas
or rooms that may be of concern for maintaining integrity of the product.
Information on all developmental or approved products manufactured or
manipulated in the same areas as the applicant's product must be included.
A summary description of product-contact equipment and its use (dedicated or
multi-use) must be provided. Information on preparation, cleaning, sterilization, and
storage of specified equipment and materials must be included, as appropriate.
Information must be included on procedures (e.g., cleaning and production
scheduling) and design features of the facility (e.g., area classifications) to prevent
contamination or cross contamination of areas and equipment, where operations for
the preparation of cell banks and product manufacturing are performed.

3.2.A.2 Adventitious Agents Safety Evaluation


Information assessing the risk with respect to potential contamination with
adventitious agents must be provided in this section.
For non-viral adventitious agents:
Detailed information must be provided on the avoidance and control of non-viral
adventitious agents (e.g., transmissible spongiform encephalopathy agents, bacteria,

50IPage Dr Ab ullah M AI ader


Assistant

Z-6 Z__
mycoplasma, fungi). This information can include, for example, certification and/or
testing of raw materials and excipients, and control of the production process, as
appropriate for the material, process and agent.
For viral adventitious agents:
Detailed information from viral safety evaluation studies must be provided in this
section. Viral evaluation studies must demonstrate that the materials used in
production are considered safe, and that the approaches used to test, evaluate, and
eliminate the potential risks during manufacturing are suitable.
Materials of Biological Origin
Information essential to evaluate the virological safety of materials of animal or
human origin (e.g. biological fluids, tissue, organ, cell lines) must be provided (See
related information in 3.2.S.2.3, and 3.2.P.4.5). For cell lines, information on the
selection, testing, and safety assessment for potential viral contamination of the cells
and viral qualification of cell banks must also be provided (See related information
in 3.2.S.2.3).
Testing at appropriate stages of production
The selection of virological tests that are conducted during manufacturing (e.g., cell
substrate, unprocessed bulk or post viral clearance testing) must be justified. The
type of test, sensitivity and specificity of the test, if applicable, and frequency of
testing must be included. Test results to confirm, at an appropriate stage of
manufacture, that the product is free from viral contamination must be provided (See
related information in 3.2.S.2.4 and 3.2.P.3.4).
Viral Testing of Unprocessed Bulk
In accordance with ICH Q5A(R1) and Q6B, results for viral testing of unprocessed
bulk must be included.
Viral Clearance Studies
In accordance with ICH Q5A(R1), the rationale and action plan for assessing viral
clearance and the results and evaluation of the viral clearance studies must be
provided.
Data can include those that demonstrate the validity of the scaled-down model
compared to the commercial scale process; the adequacy of viral inactivation or
removal procedures for manufacturing equipment and materials; and manufacturing
steps that are capable of removing or inactivating viruses (See related information
in 3.2.S.2.5 and 3.2.P.3.5).
Dr Abdullah M. Al-Bader
511Page
Assistant Un
ontro

Z6 — z_ z_c20
3.2.A.3 Excipients
3.2.R Regional Information
Any additional information must be provided in this section.

3.3 Literature References


A list and copies of all bibliographical references cited in support of this application
must be provided. References that have not been provided must be available upon
request.

Module 4 Non-Clinical Study Reports

4.1 Table of Contents of Module 4


A Table of Contents must be provided that lists all of the nonclinical study reports
and gives the location of each study report in the CTD.

4.2 Study Reports


The study reports must be presented in the following order:
4.2.1 Pharmacology
This section must begin with a description of the content of the pharmacologic data
package, pointing out any notable aspects such as the inclusion/exclusion of
particular data (e.g., lack of an animal model).

4.2.1.1 Primary Pharmacodynamics

Dr Abdullah M. Al-Bader
52IPage
Studies on primary pharmacodynamics must be provided and evaluated. Where
possible, it would be helpful to relate the pharmacology of the drug to available data
(in terms of selectivity, safety, potency ... etc.) on other drugs in the class.

4.2.1.2 Secondary Pharmacodynamics


Studies on secondary pharmacodynamics must be provided by organ system, where
appropriate, and evaluated in this section.

4.2.1.3 Safety Pharmacology


Safety pharmacology studies must be provided and evaluated in this section. In some
cases, secondary pharmacodynamic studies can contribute to the safety evaluation
when they predict or assess potential adverse effect(s) in humans. In such cases,
these secondary pharmacodynamic studies must be considered along with safety
pharmacology studies.

4.2.1.4 Pharmacodynamic Drug Interactions


If they have been performed, pharmacodynamic drug interaction studies must be
provided in this section.

4.2.2 Pharmacokinetics
4.2.2.1 Analytical Methods and Validation Reports
This section must contain the methods of analysis for biological samples, including
the detection and quantification limits of an analytical procedure. If possible,
validation data for the analytical method and stability of biological samples must be
discussed in this section.
The potential impact of different methods of analysis on the interpretation of the
results must be discussed in the following relevant sections.

4.2.2.2 Absorption
The following data must be provided in this section:
Absorption (extent and rate of absorption, in vivo and in situ studies).

Dr Abdullah M. Al-Bader
53 1Page ersecr ars'
r rTrfl.Th

7- 6 - - o
Kinetic parameters, bioequivalence and/or bioavailability (serum/plasma/blood
PK studies). 4.2.2.3 Distribution The following data must be provided in this
section:
Tissue distribution studies.
Protein binding and distribution in blood cells.
Placental transfer studies.

4.2.2.4 Metabolism
The following data must be provided in this section:
Chemical structures and quantities of metabolites in biological samples.
Possible metabolic pathways.
Pre-systemic metabolism (GI/hepatic first-pass effects).
In vitro metabolism including P450 studies.
Enzyme induction and inhibition.

4.2.2.5 Excretion
The following data must be provided in this section:
Routes and extent of excretion.
Excretion in milk.

4.2.2.6 Pharmacokinetic Drug Interactions


If they have been performed, nonclinical pharmacokinetic drug-interaction studies
(in vitro and/or in vivo) must be provided in this section.

4.2.2.7 Other Pharmacokinetic Studies


If studies have been performed in nonclinical models of disease (e.g., renal impaired
animals), they must be provided in this section.

4.2.3 Toxicology
4.2.3.1 Single-Dose Toxicity
The single-dose data must be provided, in order by species, by route. In some cases,
it may be helpful to provide the data in the form of a table.

54IPage
Dr Abdullah M. AI der
re
ntrol

z_ -2_ cily
4.2.3.2 Repeat-Dose Toxicity
Studies must be provided in order by species, by route, and by duration, giving
details of the methodology and highlighting important findings (e.g., nature and
severity of target organ toxicity, dose (exposure)/response relationships, no observed
adverse effect levels, ...etc).

4.2.3.3 Genotoxicity
Studies must be provided in the following order:
In vitro non-mammalian cell system.
In vitro mammalian cell system.
In vivo mammalian system (including supportive toxicokinetics evaluation).
Other systems.

4.2.3.4 Carcinogenicity
The choice of the studies and the basis for the high-dose selection must be explained.
Individual studies must be provided in the following order:
4.2.3.4.1 Long-term Studies
Long-term studies must be provided in order by species; including range-finding
studies that cannot appropriately be included under repeat-dose toxicity or
pharmacokinetics.

4.2.3.4.2 Short- or medium-term studies


Short- or medium-term studies must be provided including range-finding studies that
cannot appropriately be included under repeat-dose toxicity or pharmacokinetics.

4.2.3.4.3 Other studies


4.2.3.5 Reproductive and Development Toxicity
Studies must be provided in the following order, giving details of the methodology
and important findings:
4.2.3.5.1 Fertility and Embryonic Development
4.2.3.5.2 Embryo-Fetal Development
4.2.3.5.3 Pre- and Post-natal Development & Maternal Function
4.2.3.5.4 Offspring, Juvenile, Second & Third-Generation Studies
Dr Abdullah M, Al-Bader
55f Page tant Un ecretary
For I ntro

2- C— I 2__
If modified study designs are used, the sub-headings must be modified accordingly.

4.2.3.6 Local Tolerance


If local tolerance studies have been performed, they must be provided in order by
species, by route, and by duration, giving details of the methodology and important
findings.

4.2.3.7 Other Toxicity Studies


If other studies have been performed, they must be provided in the following order,
and where appropriate, the rationale for conducting the studies must be provided.
4.2.3.7.1 Antigenicity
4.2.3.7.2 Immunogenicity
4.2.3.7.3 Mechanistic Studies
4.2.3.7.4 Dependence
4.2.3.7.5 Metabolites
4.2.3.7.6 Impurities
4.2.3.7.7 Other
4.3 Literature References
A list and copies of all bibliographical references cited in support of this application
must be provided. References that have not been provided must be available upon
request.

Module 5 Clinical Study Reports

5.1 Table of Contents of Module 5


A Table of contents for the clinical study reports must be provided.

5.2 Tabular Listing of All Clinical Studies


A tabular listing of all clinical studies and related information must be provided. For
each study, this tabular listing must generally include the type of information
identified in Table 5.1. Other information can be included in this table if the
applicant considers it useful. The sequence in which the studies are listed must
follow the sequence described in Section 5.3. Use of a different sequence must be
noted and explained in an introduction to the tabular listing.
56IPage Dr Abdullah M. Al der
Control
5.3 Clinical Study Reports
5.3.1 Reports of Biopharmaceutic Studies
BA studies evaluate the rate and extent of release of the active substance from the
medicinal product.
Comparative BA or BE studies may use PK, PD, clinical, or in vitro dissolution
endpoints, and may be either single dose or multiple dose.
When the primary purpose of a study is to assess the PK of a drug, but also includes
BA information, the study report must be submitted in Section 5.3.1, and referenced
in Sections 5.3.1.1 and/or 5.3.1.2.

5.3.1.1 Bioavailability (BA) Study Reports


BA studies in this section must include:
Studies comparing the release and systemic availability of a drug substance from
a solid oral dosage form to the systemic availability of the drug substance given
intravenously or as an oral liquid dosage form,
Dosage form proportionality studies, and
Food-effect studies.

5.3.1.2 Comparative BA & BE Study Reports


Studies in this section compare the rate and extent of release of the drug substance
from similar drug products.
5.3.1.3 In vitro/In vivo Correlation (IV/IVC) study reports
In vitro dissolution studies that provide BA information, including studies used in
seeking to correlate in vitro data with in vivo correlations must be placed in this
section.
Reports of in vitro dissolution tests used for batch quality control and/or batch
release must be placed in the Quality section of the CTD.

5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human studies


Bioanalytical and/or analytical methods for biopharmaceutical studies or in vitro
dissolution studies must ordinarily be provided in individual study reports. Where a
method is used in multiple studies, the method and its validation must be included
once in Section 5.3.1.4 and referenced in the appropriate individual study reports.

Dr Abdullah M. AlsBader
571Page
r Assistant • rsecretary
5.3.2 Reports of Studies Pertinent to Pharmacokinetics using Human
Biomaterials
Human biomaterials is a term used to refer to proteins, cells, tissues and related
materials derived from human sources that are used in vitro or ex vivo to assess PK
properties of drug substances. Examples include cultured human colonic cells that
are used to assess permeability though biological membranes and transport
processes, and human albumin that is used to assess plasma protein binding.
Of particular importance is the use of human biomaterials such as hepatocytes and/or
hepatic microsomes to study metabolic pathways and to assess drug-drug
interactions with these pathways. Studies using biomaterials to address other
properties (e.g., sterility or pharmacodynarnics) must not be placed in the Clinical
Study Reports Section, but in the Nonclinical Study Section (Module 4).

5.3.2.1 Plasma Protein Binding Study Reports


Ex vivo protein binding study reports must be provided here. Protein binding data
from PK blood and/or plasma studies must be provided in Section 5.3.3.

5.3.2.2 Reports of Hepatic Metabolism and Drug Interactions studies


Reports of hepatic metabolism and metabolic drug interaction studies with hepatic
tissue must be provided in this section.

5.3.2.3 Reports of Studies Using other Human Biomaterials


Reports of studies with other biomaterials must be provided in this section.

5.3.3 Reports of Human Pharmacokinetic Studies


Assessment of the PK of a drug in healthy subjects and/or patients is considered
critical to designing dosing strategies and titration steps, to anticipating the effects
of concomitant drug use, and to interpreting observed pharmacodynamic
differences. These assessments must provide a description of the body's handling of
a drug over time, focusing on maximum plasma concentrations (peak exposure),
area-under-curve (total exposure), clearance, and accumulation of the parent drug
and its metabolite(s), in particular those that have pharmacological activity.

Dr AbsAI ?
58IPage et- reta
istant U
For Drug & Food Control

Z6— z_c19
The PK studies whose reports must be included in Sections 5.3.3.1 and 5.3.3.2 are
generally designed to:
Measure plasma drug and metabolite concentrations over time,
Measure drug and metabolite concentrations in urine or faeces
Measure drug and metabolite binding to protein or red blood cells.
Apart from describing mean PK in normal and patient volunteers, PK studies must
also describe the range of individual variability.
In the ICH E5 guideline on Ethnic Factors in the Acceptance of Foreign Data, factors
that may result in different responses to a drug in different populations are
categorized as intrinsic ethnic factors or extrinsic ethnic factors. In this document,
these categories are referred to as intrinsic factors and extrinsic factors, respectively.
Additional studies can also assess differences in systemic exposure as a result of
changes in PK due to intrinsic (e.g., age, gender, racial, weight, height, disease,
genetic polymorphism, and organ dysfunction) and extrinsic (e.g., drug-drug
interactions, diet, smoking, and alcohol use) factors. Reports of PK studies
examining the influence of intrinsic and extrinsic factors on exposure must be
organized in Sections 5.3.3.3 and 5.3.3.4, respectively.
In addition to standard multiple-sample PK studies, population PK analyses based
on sparse sampling during clinical studies can also address questions about the
contributions of intrinsic and extrinsic factors to the variability in the dose-PK-
response relationship. Because the methods used in population PK studies are
substantially different from those used in standard PK studies, these studies must be
provided in Section 5.3.3.5.

5.3.3.1 Healthy Subject PK and Tolerability


Reports of PK and initial tolerability studies in healthy subjects must be placed in
this section.

5.3.3.2 Patient PK and Initial Tolerability


Reports of PK and initial tolerability studies in patients must be placed in this
section.

5.3.3.3 Intrinsic Factor PK Study Reports


Reports of PK studies to assess effects of intrinsic factors, must be placed in this
section.
Dr Abdullah M. Al-Bader
59IPage A I Idersecre

2-6 - I 2_ 2_ 0 / •
5.3.3.4 Extrinsic Factor PK Study Reports
Reports of PK studies to assess effects of extrinsic factors, must be placed in this
section.

5.3.3.5 Population PK Study Reports


Reports of population PK studies based on sparse samples obtained in clinical trials
including efficacy and safety trials, must be placed in this section.

5.3.4 Reports of Human Pharmacodynamic (PD) Studies


Reports of studies with a primary objective of determining the PD effects of a drug
product in humans must be provided in this section.
Reports of studies whose primary objective is to establish efficacy or to accumulate
safety data, however, must be provided in Section 5.3.5.
This section must include reports of:
Studies of pharmacologic properties known or thought to be related to the desired
clinical effects (biomarkers)
Short-term studies of the main clinical effect
PD studies of other properties not related to the desired clinical effect.
Because a quantitative relationship of these pharmacological effects to dose and/or
plasma drug and metabolite concentrations is usually of interest, PD information is
frequently collected in dose response studies or together with drug concentration
information in PK studies (concentration-response or P1QPD studies).
Relationships between PK and PD effects that are not obtained in well-controlled
studies are often evaluated using an appropriate model and used as a basis for
designing further dose-response studies or, in some cases, for interpreting effects of
concentration differences in population subsets.
Dose-finding, PD and/or PK-PD studies can be conducted in healthy subjects and/or
patients, and can also be incorporated into the studies that evaluate safety and
efficacy in a clinical indication. Reports of dose-finding, PD and/or PIQPD studies
conducted in healthy subjects must be provided in Section 5.3.4.1, and the reports
for those studies conducted in patients must be provided in Section 5.3.4.2.
In some cases, the short-term PD, dose-finding, and/or PK-PD information found in
pharmacodynamic studies conducted in patients will provide data that contribute to

601Page Dr s nutllah NI, 1-13ader


Atd
€ ffXsi ersecre
004 Control
r"-Drat
z;- !a— L°'9
assessment of efficacy, either because they show an effect on an acceptable surrogate
marker (e.g., blood pressure) or on a clinical benefit endpoint (e.g., pain relief).
Similarly, a PD study may contain important clinical safety information. When these
studies are part of the efficacy or safety demonstration, they are considered clinical
efficacy and safety studies that must be included in Section 5.3.5, not in Section
5.3.4.

5.3.4.1 Healthy Subject PD and P1C/PD Study Reports


PD and/or PIC/PD studies having non-therapeutic objectives in healthy subjects must
be provided in this section.

5.3.4.2 Patient PD and PK/PD Study Reports


PD and/or PK/PD studies in patients must be provided in this section.

5.3.5 Reports of Efficacy and Safety Studies


This section must include reports of all clinical studies of efficacy and/or safety
carried out with the drug, conducted by the sponsor, or otherwise available,
including all completed and all ongoing studies of the drug in proposed and non-
proposed indications.
The study reports must provide the level of detail appropriate to the study and its
role in the application. ICH E3 describes the contents of a full report for a study
contributing evidence pertinent to both safety and efficacy. Abbreviated reports can
be provided for some studies (see ICH E3).
Within Section 5.3.5, studies must be organized by design (controlled, uncontrolled)
and, within controlled studies, by type of control. Within each section, studies must
be categorized further, ordered by whether the study report is complete or
abbreviated (ICH E3), with completely reported studies presented first. Published
reports with limited or no further data available to the sponsor must be placed last in
this section.
In cases where the application includes multiple therapeutic indications, the reports
must be organized in a separate Section 5.3.5 for each indication. In such cases, if a
clinical efficacy study is relevant to only one of the indications included in the
application, it must be included in the appropriate Section 5.3.5; if a clinical efficacy
study is relevant to multiple indications, the study report must be included in the

61 IPage Dr Abdullah M. AI4Jc.


ac
As nt Un rsecretary
91.^9
— 12— — a_ca
most appropriate Section 5.3.5 and referenced as necessary in other Sections 5.3.5
(e.g., Section 5.3.5A, Section 5.3.5B).

5.3.5.1 Study reports of Controlled Clinical Studies pertinent to the claimed


Indication
The controlled clinical study reports must be sequenced by type of control:
Placebo control (could include other control groups, such as an active
comparator or other doses)
No-treatment control
Dose-response (without placebo)
Active control (without placebo)
External (Historical) control, regardless of the control treatment.
Within each control type, where relevant to assessment of drug effect, studies must
be organized by treatment duration. Studies of indications other than the one
proposed in the application, but that provide support for efficacy in the proposed
use, must be provided in this section.
Where a pharmacodynamic study contributes to evidence of efficacy, it must be
provided in this section.
The sequence in which studies were conducted is not considered pertinent to their
presentation. Thus, placebo-controlled trials, whether early or late, must be placed
in this section.
Controlled safety studies, including studies in conditions that are not the subject of
the application, must also be reported in this section.
5.3.5.2 Study reports of Uncontrolled Clinical Studies
Study reports of uncontrolled clinical studies (e.g., reports of open label safety
studies) must be included in this section. This includes studies in conditions that are
not the subject of the marketing application.

5.3.5.3 Reports of Analyses of Data from More than One Study


Many clinical issues in an application can be addressed by an analysis considering
data from more than one study. The results of such an analysis must generally be
summarized in the clinical summary documents, but a detailed description and
presentation of the results of such analyses are considered critical to their
interpretation. Where the details of the analysis are too extensive to be reported in a
Dr Abdullah M. A •Bader
62IPage AsStanfThIefleèVeXY

z-S
summary document, they must be presented in a separate report. Such reports must
be provided in this section.
Examples of reports that would be found in this section include: a report of a formal
meta-analysis or extensive exploratory analysis of efficacy to determine an overall
estimate of effect size in all patients and/or in specific subpopulations, and a report
of an integrated analysis of safety that assesses such factors as the adequacy of the
safety database, estimates of event rates, and safety with respect to variables such as
dose, demographics, and concomitant medications.
A report of a detailed analysis of bridging, considering formal bridging studies, other
relevant clinical studies, and other appropriate information (e.g., PK and PD
information), must be placed in this section if the analysis is too lengthy for inclusion
in the Clinical Summary.
5.3.5.4 Other Study Reports
This section can include:
Reports of interim analyses of studies pertinent to the claimed indications.
Reports of controlled safety studies not reported elsewhere.
Reports of controlled or uncontrolled studies not related to the claimed
indication.
Published reports of clinical experiences with the medicinal product that is not
included in Section 5.3.5.1. However, when literature is important to the
demonstration or substantiation of efficacy, it must be included in Section
5.3.5.1.
Reports of ongoing studies.
5.3.6 Reports of Post-Marketing Experience
For products that are currently marketed, reports that summarize marketing
experience (including all significant safety observations) must be provided in this
section.

5.3.7 Case Report Forms and Individual Patient Listings


Case report forms and individual patient data listings that are described in the ICH
clinical study report guideline, must be placed in this section when submitted, in the
same order as the clinical study reports and indexed by study.

5.4 Literature References


111ah M.
----13H1
NI •Bader
63IPage Assista t lindersecret
- • , -

1t- -t o
Copies of referenced documents, including important published articles, official
meeting minutes, or other regulatory guidance or advice must be provided here. Only
one copy of each reference must be provided. Copies of references that are not
included here must be immediately available on request.

4.Variations:
Any changes/ additions made to a registered must be submitted to the
pharmaceutical and herbal medicines registration and control administration for
review and approval.
Specific requirements will be set for each type of change/ addition as a memo.

5.Renewal of Registration:
The registration of pharmaceutical product must be renewed every 5 years from
the date of issuing the registration certificate.
The agent must submit the renewal file 6 months prior to pharmaceutical
registration expiration.
Renewal requirements are set as a memo by the administration.

6.Transfer of Agency:
Legalized original Letter of appointment for the new local agent issued by
marketing authorization holder.
Termination letter of the previous local agent mentioning date of termination
issued from MAR.
List of products that are affected by the transfer, including product name,
concentration, dosage form, and manufacturing company if defer from MAH.

7. Pharmaceutical and herbal medicines registration and control


administration reserve the right to suspend the registration of pharmaceutical
product or company in the following circumstances:
64IPage
Dr Abdullah Al-Bader
sststant 'Lai_ •
I - ,
rug & Food Control

-10/9
If the product or the manufacturing company is suspended in country of origin.
Lack of safety or efficacy of the product.
If the company does not comply with the current GMP standards.
If the product does not comply with the specification issued by the manufacturer
or by the pharmacopoeial specification, upon repeated analysis.
If discrepancy in the documents submitted were observed.
As per marketing authorization holder request.
Non compliance to Pharmaceutical and Herbal Medicines Registration and
Control Administration laws and regulations.
If the Pharmaceutical and Herbal Medicine Control and Registration
administration come to know by any circumstances other than agent about any
warning issued for a specific drug or manufacturing site by FDA, EMA, WHO,
GCC or any other International Health Forums.

8. Pharmaceutical and herbal medicines registration and control


administration reserve the right to Cancel the registration of pharmaceutical
product or company in the following circumstances
If the product or the manufacturing company registration is cancelled in country
of origin.
Pharmaceutical and Herbal Medicines Control and registration administration
reserves the right to cancel the registration of the product if there is any risk
related to safety of the product or it fails to comply with this ministerial decree.
Critical and serious lack of safety or efficacy of the product.
If the registered pharmaceutical product is not imported to the State of Kuwait
for the previous two years.
As requested officially by the Marketing Authorization Holder to cancel the
product registration and mention the reasons.
If the registered product is not renewed after the registration certificate expiry.
If falsified information were submitted as part of the CTD were observed.
If the company fails to submit sufficient data and documents, to support revoke
of suspension within six months.

Dr Abdullah M. Al-Bader
65IPage ndersec
oed Control

267 -1z_. 2-019


Abbreviations

BA Bioavailability

BE Bioequivalence

BP British Pharmacopoeia

BSE Bovine Spongiform Encephalopathy

66 IPage Dr Abdullah M. Al-Bader


ststant rsecre
oControl
a 6— a — 2-0 , 9'
CEP Certificate of Suitability

CPP Certificate of Pharmaceutical Product

CTD Common Technical Document

DMF Drug Master File

EU European Union

EMA European Medicine Agency

GCC Gulf Cooperation Council

GCP Good Clinical Practice

GLP Good Laboratory Practice

GMO Genetically Modified Organism

GNfP Good Manufacturing Practice

ICH International Conference on


Harmonization

NCE New Chemical Entity

Non-GMO Non Genetically Modified Organism

PD Pharmacodynamic

Ph.Eur European Pharmacopoeia

PIL Patient Information Leaflet

PK Pharmacokinetics

RM-13 Risk Management Plan

SPC Summary of Product Characteristic

TSE Transmissible Spongiform


Encephalopathy

67IPage
Dr Abdullah M. Al-Bader
Assistant Under •
For D • ••• . Ito
USFDA United states food and drug
administration

USP United States Pharmacopeia

WHO World Health Organization

Dr Abdullah M. Al-Bader
68IPage

You might also like

pFad - Phonifier reborn

Pfad - The Proxy pFad of © 2024 Garber Painting. All rights reserved.

Note: This service is not intended for secure transactions such as banking, social media, email, or purchasing. Use at your own risk. We assume no liability whatsoever for broken pages.


Alternative Proxies:

Alternative Proxy

pFad Proxy

pFad v3 Proxy

pFad v4 Proxy