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TRANSCRIPT
Glo
bal T
echn
ical
Res
earc
h &
Deve
lopm
ent
INTE
GR
ATE
D D
RU
G D
EVEL
OPM
ENT
PRO
CES
SJu
ly 1
7-19
, 200
6Er
ika
Zann
ou, P
h.D
. & T
ony
Tong
, Ph.
D.,
Nov
artis
Pha
rmac
eutic
als
Cor
p.
•D
evel
opab
ility
Ass
essm
ent S
uppo
rtin
g D
rug
Can
dida
te S
elec
tion
•Pr
ofili
ng o
f key
Phy
sico
chem
ical
Pro
pert
ies
•B
ioph
arm
aceu
tical
Ass
essm
ent
•Pr
efor
mul
atio
n•
Solu
bilit
y, S
tabi
lity,
Dis
solu
tion
Rat
e an
d So
lid S
tate
Pro
pert
ies
•Sa
lt an
d Fo
rm S
cree
ning
and
Sel
ectio
n•
Exci
pien
tCom
patib
ility
•D
osag
e Fo
rm D
esig
n•
Con
vent
iona
l•
Non
-Con
vent
iona
l•
Form
ulat
ion
Dev
elop
men
t, Ev
alua
tion
and
Scal
e-up
•Eq
uipm
ent a
nd P
roce
ssin
g •
Reg
ulat
ory
Con
side
ratio
ns
Glo
bal T
echn
ical
Res
earc
h &
Deve
lopm
ent
INTE
GR
ATE
D D
RU
G D
EVEL
OPM
ENT
PRO
CES
S
ND
APr
e-C
linic
alPh
ase
IPh
ase
IIPh
ase
IIIIN
D
Tole
rabi
lity
Phas
e III
D
osag
e Fo
rm
Dos
e Fi
ndin
gEf
ficac
yEf
ficac
y Sa
fety
Ph I
Bat
chPh
ase
II B
atch
Com
mer
cial
Cam
paig
n
Com
mer
cial
Dos
age
Form
Phas
e I
Dos
age
Form
Con
cept
GM
PB
atch
Phas
e III
B
atch
Dru
g Su
bsta
nce
Phas
e II
Dos
age
Form
Dru
g Pr
oduc
t
Clin
ical
Stu
dies Acu
te A
nim
al T
oxic
olog
yC
arci
noge
nici
ty T
oxic
olog
y
** C
olor
s us
ed fo
r Dru
g Su
bsta
nce,
Dru
g Pr
oduc
t and
Clin
ical
stu
dies
are
mat
chin
g
Glo
bal T
echn
ical
Res
earc
h &
Deve
lopm
ent
INTE
GR
ATE
D D
RU
G D
EVEL
OPM
ENT
PRO
CES
S
Glo
bal T
echn
ical
Res
earc
h &
Deve
lopm
ent
INTE
GR
ATE
D D
RU
G D
EVEL
OPM
ENT
PRO
CES
S
The
CD
ERH
andb
ook
Glo
bal T
echn
ical
Res
earc
h &
Deve
lopm
ent
INTE
GR
ATE
D D
RU
G D
EVEL
OPM
ENT
PRO
CES
S
•Ph
ase
IPh
arm
acok
inet
ics
and
Safe
tySm
all n
umbe
r of H
ealth
y Vo
lunt
eers
•Ph
ase
II Safe
ty a
nd E
ffica
cy
Larg
er p
atie
nt p
opul
atio
n
•Ph
ase
III –
Pivo
tal S
tudi
esLo
ng-te
rm S
afet
y an
d Ef
ficac
ySe
vera
l tho
usan
ds o
f pat
ient
s in
mul
tiple
clin
ical
cen
ters
•Fu
ture C
linic
al T
rials
Sim
ulat
ions
Seam
less
Clin
ical
Tria
l Des
igns
Bio
-Mar
kers
Glo
bal T
echn
ical
Res
earc
h &
Deve
lopm
ent
DO
SAG
E FO
RM
DES
IGN
•B
alan
ce o
f Dos
age
Form
Req
uire
men
tsB
ioph
arm
aceu
tics,
Phy
sica
l/Che
mic
al, P
roce
ss, M
arke
ting,
R
egul
ator
y
•Ev
olut
ion
with
Tim
e of
Dos
age
Form
Req
uire
men
ts &
Kno
wle
dge
Phas
e I t
hrou
gh P
hase
III,
Com
mer
cial
For
m,
Prod
uct L
ine
Exte
nsio
ns
•C
lass
ifica
tion
of V
ario
us D
osag
e Fo
rms
Rou
te o
f Adm
inis
trat
ion
Tim
e C
ours
e of
Dru
g D
eliv
ery
Targ
et O
rgan
, Tis
sue
of C
ell f
or D
rug
Del
iver
y
Glo
bal T
echn
ical
Res
earc
h &
Deve
lopm
ent
DO
SAG
E FO
RM
DES
IGN
B
alan
ced
Nee
ds
Dos
age
Form
D
esig
nP
hysi
cal/C
hem
ical
Pro
cess
ing
Mar
ketin
g
Bio
phar
mac
eutic
al
Reg
ulat
ory
Glo
bal T
echn
ical
Res
earc
h &
Deve
lopm
ent
INTE
GR
ATE
D D
RU
G D
EVEL
OPM
ENT
PRO
CES
S
ND
APr
e-C
linic
alPh
ase
IPh
ase
IIPh
ase
IIIIN
D
Tole
rabi
lity
Dos
e Fi
ndin
gEf
ficac
yEf
ficac
y Sa
fety
Ph I
Bat
chPh
ase
II B
atch
Com
mer
cial
Cam
paig
n
Bra
nded
Tab
lets
Size
, Col
or
Diff
eren
tiate
dPo
wde
r-in
-a-B
ottle
Han
d Fi
lled
Cap
sule
Con
cept
GM
PB
atch
Phas
e III
B
atch
Dru
g Su
bsta
nce
Sam
e Si
ze,
Shap
e, C
olor
Ta
blet
s
Mac
hine
Fill
edC
apsu
les
Dru
g Pr
oduc
t
Clin
ical
Stu
dies
** C
olor
s us
ed fo
r Dru
g Su
bsta
nce,
Dru
g Pr
oduc
t and
Clin
ical
stu
dies
are
mat
chin
g
Glo
bal T
echn
ical
Res
earc
h &
Deve
lopm
ent
DO
SAG
E FO
RM
DES
IGN
Dru
g Pr
oduc
t Attr
ition
Cur
ve •
Attr
ition
Cur
ve
Man
agin
gA
ttriti
onC
urve
Goo
d
Indu
stry
Ave
rage
Bad
Ref
: R.L
. Lip
per,
Mod
ern
Dru
g D
isco
very
, Jan
-Feb
199
9, 5
5-60
Glo
bal T
echn
ical
Res
earc
h &
Deve
lopm
ent
DO
SAG
E FO
RM
DES
IGN
Evol
utio
n of
Dos
age
Form
Nee
ds
•Pr
eclin
ical
(Tox
icol
ogy)
Dos
age
Form
s–
Bio
phar
mac
eutic
s-E
mph
asis
is o
n Ex
posu
re, H
igh
Dru
g C
once
ntra
tion
»Su
spen
sion
s (N
aCM
C),
Dru
g/Fe
ed M
ixtu
res
»Sp
ecia
lized
For
ms
(Yog
urt)
•Ph
ase
I Clin
ical
Dos
age
Form
s–
Bio
phar
mac
eutic
s-S
impl
e, F
lexi
ble
Dos
ing
»Si
ngle
/Mul
tiple
Dos
e To
lera
bilit
y St
udie
s, H
ealth
y Vo
lunt
eers
»Ef
ficac
y M
arke
r -Pr
oof o
f Con
cept
, Attr
ition
Cur
ve»
Solu
tions
, Pow
der-
in-a
-Bot
tle, H
ard
Gel
atin
Cap
sule
s
•Ph
ase
II C
linic
al D
osag
e Fo
rms
–B
ioph
arm
aceu
tics,
Phy
sico
-Che
mic
al, P
roce
ssin
g-L
arge
r, Lo
nger
St
udie
s»
Patie
nts,
Dos
e Fi
ndin
g an
d Pr
oof o
f Con
cept
»B
linde
d C
apsu
les
or T
able
ts
Glo
bal T
echn
ical
Res
earc
h &
Deve
lopm
ent
DO
SAG
E FO
RM
DES
IGN
Evol
utio
n of
Dos
age
Form
Nee
ds
•Ph
ase
III C
linic
al D
osag
e Fo
rms
–B
ioph
arm
aceu
tics,
Phy
/Che
mic
al, P
roce
ssin
g-E
ven
Larg
er, L
onge
r St
udie
s»
Patie
nts,
Piv
otal
Effi
cacy
and
Saf
ety
»C
apsu
les
or T
able
ts, B
linde
d or
Bra
nded
(Dou
ble
Dum
my)
•M
arke
ted
Form
s–
Bio
phar
mac
eutic
s, P
hy/C
hem
ical
, Pro
cess
ing,
Mar
ket,
Reg
ulat
ory
»C
onsu
mer
s»
Size
, Sha
pe, C
olor
, Bra
nded
Tab
lets
or C
apsu
les
•Pr
oduc
t Lin
e Ex
tens
ions
–B
ioph
arm
aceu
tics,
Phy
/Che
mic
al, P
roce
ssin
g, M
arke
t, R
egul
ator
y»
Prot
ectio
n fr
om G
ener
ic E
rosi
on»
Con
trol
led
Rel
ease
, Fix
ed C
ombi
natio
n, A
ltern
ate
Del
iver
y Fo
rms
Glo
bal T
echn
ical
Res
earc
h &
Deve
lopm
ent
DO
SAG
E FO
RM
DES
IGN
•B
ioph
arm
aceu
tical
–M
echa
nism
of A
ctio
n–
Targ
et O
rgan
–D
ose
(Pot
ency
)–
Perm
eabi
lity
(Pas
sive
, Act
ive,
Effl
ux)
–Ph
arm
acok
inet
ics
»A
bsor
ptio
n »
Dis
trib
utio
n»
Met
abol
ism
»D
istr
ibut
ion
Glo
bal T
echn
ical
Res
earc
h &
Deve
lopm
ent
DO
SAG
E FO
RM
DES
IGN
B
ioph
arm
aceu
tics
Cla
ssifi
catio
n Sy
stem
Hig
h So
lubi
lity
Low
Sol
ubili
ty
Hig
h Pe
rmea
bilit
yC
lass
I
Dis
solu
tion
rate
limits
abs
orpt
ion
Cla
ss II
Solu
bilit
y lim
itsab
sorp
tion
Low
Per
mea
bilit
yC
lass
III
Perm
eabi
lity
limits
abso
rptio
n
Cla
ss IV
Sign
ifica
ntpr
oble
ms f
or o
ral
deliv
ery
expe
cted
G. L
. Am
idon
et a
l., P
harm
. Res
. (19
95),
12, 4
13-4
20
Glo
bal T
echn
ical
Res
earc
h &
Deve
lopm
ent
DO
SAG
E FO
RM
DES
IGN
Bio
phar
mac
eutic
al P
artic
le S
ize
Nee
ds
•Pa
rtic
les
larg
er th
an 6
µm
depo
sit i
n m
outh
and
trac
hea.
•Pa
rtic
les
betw
een
6-2
µm
depo
sit i
nbr
onch
i & b
ronc
hiol
es.
•Pa
rtic
les
less
than
2 µ
mde
posi
t in
te
rmin
al b
ronc
hiol
es a
nd a
lveo
li.
Glo
bal T
echn
ical
Res
earc
h &
Deve
lopm
ent
DO
SAG
E FO
RM
DES
IGN
Phys
iolo
gica
l pH
Gas
tric
pH
in th
e fa
sted
sta
te a
nd a
fter
food
in
take
(pH
6, 4
58 c
alor
ies
and
400
ml t
otal
vo
lum
e) in
10
heal
thy
volu
ntee
rs
0123456
-20
24
6
hour
s
pH
Duod
enal
pH
in th
e fa
sted
sta
te a
nd a
fter
food
in
take
(pH
6, 4
58 c
alor
ies
and
400
ml t
otal
vo
lum
e) in
10
heal
thy
volu
ntee
rs
4
4.55
5.56
6.57
7.58
-10
12
34
hour
spH
Hor
terD
, Dre
ssm
anJB
. 199
7 A
dvan
ced
Dru
g D
eliv
ery
Rev
iew
s 25:
3-14
.
Glo
bal T
echn
ical
Res
earc
h &
Deve
lopm
ent
DO
SAG
E FO
RM
DES
IGN
•Ph
ysic
al/C
hem
ical
–So
lubi
lity
(Dis
solu
tion)
–lo
g P,
PSA
, H-d
onor
s, H
-acc
epto
rs–
mw
–St
abili
ty (H
eat,
Hum
idity
, Lig
ht)
–pH
(Dru
g Su
bsta
nce
and
Exci
pien
ts)
–Ex
cipi
ent C
ompa
tibili
ty–
Mor
phol
ogy
–D
ensi
ty (B
ulk
and
Tap)
–Pa
rtic
le S
ize
–W
ettin
g (S
urfa
ce E
nerg
y)–
Stat
ic P
rope
rtie
s–
Flow
Pro
pert
ies
–C
ompr
essi
bilit
y an
d C
ompa
ctab
ility
–H
ygro
scop
icity
–Po
lym
orph
ism
Glo
bal T
echn
ical
Res
earc
h &
Deve
lopm
ent
DO
SAG
E FO
RM
DES
IGN
•Pr
oces
sing
–C
ost o
f Goo
ds»
Cap
ital I
nves
tmen
ts»
Dos
age
Form
(Tab
let v
s. H
ard
Gel
atin
Cap
sule
s)»
Size
(6m
m T
able
t vs.
11m
m T
able
t)»
Shap
e (R
ound
Tab
let v
s. U
niqu
e Sh
aped
-K
eyed
Too
ls)
»Ex
cipi
ents
(Alte
rnat
e Su
pplie
rs)
»Pr
oces
sing
Effi
cien
cy (N
umbe
r of P
roce
ss S
teps
, Spe
ed o
f Pro
cess
ing,
Vo
lum
e of
Pro
cess
)»
Failu
re R
ate
(Rej
ecte
d B
atch
es)
Glo
bal T
echn
ical
Res
earc
h &
Deve
lopm
ent
DO
SAG
E FO
RM
DES
IGN
•M
arke
ting
–Ti
me
for D
evel
opm
ent
–Pa
tent
Pro
tect
ion
–C
ompe
titiv
e A
dvan
tage
»A
esth
etic
s (S
ize,
Sha
pe, C
olor
, Tas
te, P
ainl
ess)
»Pa
tient
Com
plia
nce
(Onc
e-A
-Day
vs
bid)
»Pr
ice
(Cos
t of G
oods
)
Glo
bal T
echn
ical
Res
earc
h &
Deve
lopm
ent
DO
SAG
E FO
RM
DES
IGN
•R
egul
ator
y–
Doc
umen
ted
Form
ula,
Pro
cess
and
Pac
kagi
ng»
Act
ive
Ingr
edie
nts
»Ex
cipi
ents
»Te
stin
g M
etho
ds»
Spec
ifica
tions
»
Equi
pmen
t»
Uni
t Ope
ratio
ns»
In-P
roce
ss C
ontr
ols
–Va
lidat
ion
of th
e Pr
oces
s–
Valid
atio
n of
the
Rel
ease
and
Sta
bilit
y Te
stin
g M
etho
ds–
Stab
ility
Rep
ort o
n Pa
ckag
e D
rug
Prod
uct (
Bul
k, P
rimar
y)–
Doc
umen
ts»
IND
, ND
As,
Val
idat
ion
Rep
orts
Glo
bal T
echn
ical
Res
earc
h &
Deve
lopm
ent
DO
SAG
E FO
RM
DES
IGN
Type
s of
For
mul
atio
ns
•R
oute
of A
dmin
istr
atio
n–
Ora
l–
Inje
ctab
le–
Topi
cal
–In
hala
tion
•Ti
me
Cou
rse
of D
rug
Rel
ease
–Im
med
iate
Rel
ease
–Su
stai
ned
Rel
ease
–C
ontr
olle
d R
elea
se–
Puls
ed R
elea
se•
Targ
eted
Rel
ease
–O
rgan
Spe
cific
–Ti
ssue
Spe
cific
(Tum
or)
–C
ell S
peci
fic
Glo
bal T
echn
ical
Res
earc
h &
Deve
lopm
ent
Dec
isio
n Tr
ee L
ogic
for F
irst i
nto
Man
For
mul
atio
n
Glo
bal T
echn
ical
Res
earc
h &
Deve
lopm
ent
Con
side
ratio
ns fo
r CSF
Dev
elop
men
t
•C
SF
= C
apsu
le
form
ulat
ion
–10
mg,
50
mg,
100
mg
–Fa
st d
isso
lutio
n ra
te–
Che
mic
ally
sta
ble
–N
o ch
ange
of d
isso
lutio
n up
on s
tabi
lity
•C
halle
nges
:–
Ver
y lim
ited
drug
su
bsta
nce
supp
ly (2
80 g
fo
r dev
elop
men
t and
cl
inic
al) -
Flex
ibili
ty w
ith
form
ulat
ion
requ
ired
•P
hysi
co-c
hem
ical
P
rope
rties
•Lo
g P
= 3
.4•
Log
D (p
H 6
.0) =
3.4
•(p
Ka1
~ 1.
5 (b
ase)
)•
pKa2
= 5.
33 (b
ase)
•pK
a3=
8.57
(aci
d)
•M
W fr
ee b
ase
= 40
0
•S
alt s
elec
tion
Glo
bal T
echn
ical
Res
earc
h &
Deve
lopm
ent
pH-S
olub
ility
Pro
file
•B
esyl
ate
coun
ter i
on
•S
o=
0.00
08 m
g/m
L at
25°
C•
pKa
= 5.
33•
MW
= 4
00
•pH
max
~ 2.
2•
pH o
f sat
urat
ed s
olut
ion
~ 2.
3 (0
.57
mg/
mL)
Bes
ylat
eM
onoh
ydra
teS
alt
Free
Bas
e
Solid
Pha
se:
pH max
0.0
0.5
1.0
1.5
2.0
03
69
pH
DRUG (mg/mL Base eq.)
Theo
retic
alFr
ee B
ase
Mal
eate
Sal
t
Glo
bal T
echn
ical
Res
earc
h &
Deve
lopm
ent
Solid
Sta
te C
hara
cter
izat
ion
No
chan
ge in
bes
ylat
e sa
lt up
on m
illing
Glo
bal T
echn
ical
Res
earc
h &
Deve
lopm
ent
Solid
Sta
te C
hara
cter
izat
ion
Siev
e d
Mille
d
Bes
ylat
e S
alt
•D
ehyd
ratio
n ~
130o C
•m
.p. ~
194
o C
Siev
ed
Mille
d
QA
D17
1 Fr
ee B
ase
•m
.p. =
296
.30o C
Sto
ichi
omet
ric m
onoh
ydra
te c
onfir
med
by:
–TG
A (~
3%
)–
DSC
Glo
bal T
echn
ical
Res
earc
h &
Deve
lopm
ent
Che
mic
al S
tabi
lity
•E
xcel
lent
sol
id s
tate
sta
bilit
y af
ter 1
wee
k at
:–
80o C
in ti
ght c
onta
iner
–80
o C/7
5% R
H
•N
on-h
ygro
scop
ic
•N
o de
tect
able
deg
rada
tion
afte
r 2 w
eeks
at 5
0o C w
ith 2
0% w
ater
(c
lose
d gl
ass
cont
aine
r)(1
mon
th d
ata
poin
t thi
s w
eek)
•pH
-rat
e pr
ofile
–N
o m
ajor
inst
abili
ty o
ver p
H 1
-13
afte
r:»
2 w
eeks
(4°C
to 5
0°C
)»
1 da
y at
RT
unde
r lig
ht–
Som
e in
stab
ility
over
pH
1-1
3 un
der h
igh
inte
nsity
ligh
t
Glo
bal T
echn
ical
Res
earc
h &
Deve
lopm
ent
Exci
pien
t Com
patib
ility
•N
o m
ajor
inco
mpa
tibili
ty w
ith d
iluen
ts a
nd lu
bric
ants
not
ed b
y m
icro
calo
rimet
ry
•C
onve
ntio
nal H
PLC
stu
dies
–1%
dru
g lo
adin
g, 5
0°C
wet
and
dry
con
ditio
ns–
No
maj
or in
com
patib
ility
afte
r 2 w
eeks
–1
mon
th d
ata
this
wee
k
Ingr
edie
nts
Form
ulat
ion
12
34
56
78
910
1112
1314
1516
1718
1920
Ran
ge (%
)D
rug
5-50
ND
ND
ND
ND
ND
ND
ND
ND
ND
0.1
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
Lact
ose
30-8
0M
anni
tol
30-8
0A
vice
l10
-80
Star
ch 1
500
10-5
0M
g St
0.5-
2St
earic
ac.
2-5
Cut
ina
2-4
Cro
spov
idon
e2-
5C
rosc
arm
ello
se N
a2-
5N
a st
arch
gly
cola
te2-
8C
SD0.
1-0.
5T
alc
1-10
Povi
done
0.5-
5H
PMC
2-5
HPC
2-5
Gel
atin
Cap
sule
Deg
rada
tion
Pro
duct
s af
ter
2 w
eek
s at
50°
C w
ith
20%
Wat
er(%
)