integrated drug development -...

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(%

)