Ster

ile p

acka

ging

of l

iqui

d ph

arm

aceu

tical

sU

sing

rom

mel

ag b

otte

lpac

kbl

ow-fi

ll-se

al m

achi

nes

Moh

amm

ad S

adeg

hiV.

P. R

&D

Hol

opac

k In

tern

atio

nal C

orp.

1 Te

chno

logy

Circ

leC

olum

bia,

SC

292

03Te

l: (8

03) 8

06-3

300

Con

tent

s

�bo

ttlep

ack

His

tory

�B

low

Fill

Sea

l pro

cess

�M

anuf

actu

ring

�C

onta

iner

Des

ign

botte

lpac

kH

isto

ry

botte

lpac

k®B

FS m

achi

ne h

isto

ry

�196

0s-I

nven

tion

of th

e B

FS p

roce

ss

-Firs

t bot

telp

ack

prot

otyp

e 19

63

-Low

cap

acity

with

one

mol

d

-Rel

ay c

ontr

olle

d

-No

asep

tic s

yste

ms

-Big

ger f

ill v

olum

e

-Cus

tom

ers

in G

erm

any

and

Euro

pe

�197

0s-M

ediu

m-h

igh

capa

city

mac

hine

with

2-1

0 m

olds

-Mac

hine

for s

mal

l fill

vol

umes

(0.2

-50

mL)

-Mac

hine

des

igns

for a

sept

ic fi

lling

(pro

duct

filte

rs,

CIP

, SIP

)-P

isto

n do

sing

/tube

dos

ing

syst

ems

for b

ig/s

mal

l

volu

mes

-rel

ay-c

ontr

olle

d m

achi

nes

-Wor

ldw

ide

mac

hine

exp

ort;

licen

se p

rodu

ctio

n in

U

SA

�198

0s-H

igh

capa

city

mac

hine

for s

mal

l fill

vol

umes

with

15

mol

ds (t

ype

4010

M)

-Aut

omat

ic m

achi

ne p

rogr

am c

hang

es

-Tim

e pr

essu

re d

osin

g as

sta

ndar

d sy

stem

-PLC

con

trol

led

mac

hine

s -A

larm

mes

sage

on

disp

lay

-Pro

duct

ion

docu

men

tatio

n

�19

90s

-New

bot

telp

ack®

mac

hine

gen

erat

ion

(Typ

es 3

21/3

21M

-36

0/36

0M)

-Cle

an/D

irty

conc

ept m

achi

ne d

esig

n-I

ncre

ased

leve

l of a

utom

atio

n us

ing

PLC

s-D

evel

opm

ent o

f Co-

extr

usio

n an

d PE

T pr

oces

sing

tech

niqu

e fo

r BFS

-I

SO 9

001

Cer

tific

ate

botte

lpac

k®B

FS m

achi

ne ty

pes

-tod

ay

�Sin

gle

paris

on ty

pes

for b

ottle

man

ufac

turin

g

(50

-200

0ml).

Mac

hine

Typ

es:

-301

2 (o

ne m

old)

-321

(one

mol

d)

-360

(tw

o m

olds

)

Cap

acity

rang

e: ~

250

-4,

000

bottl

es/h

�Mul

tiple

par

ison

type

s fo

r am

poul

e m

anuf

actu

ring

(0,2

-50

ml).

Mac

hine

Typ

es:

-301

2 M

(one

mol

d)

-321

M (o

ne m

old)

-360

M (t

wo

mol

ds)

-401

0 M

(fift

een

mol

ds)

Cap

acity

rang

e: ~

2,5

00 -

30,0

00 a

mpo

ules

/h

botte

lpac

k®m

odel

301

2/32

1C

apac

ities

up

to 9

,000

via

ls p

er h

our

botte

lpac

k®m

odel

360

Hig

her c

apac

ities

up

to 1

8,00

0 vi

als

per h

our

Blo

w F

ill S

eal P

roce

ss

Con

vent

iona

l vs.

BFS

Supp

ly of

con

tain

ers

Tran

spor

t int

o ste

rile ro

om

Cont

aine

r clea

ning

Cont

aine

r ste

riliza

tion

Tran

spor

t pro

cess

und

erst

erile

cond

itions

Prep

. fillin

g pr

oduc

t for

ste

rile

fillin

g

Asep

tical

ly o

pera

ting

filler

Tran

sp. u

nder

ste

rile c

ondit

ion

Capp

ing

unde

r ste

rile

cond

ition

Clos

ure

part

supp

ly, c

leanin

g,st

eriliz

atio

n

Out

put f

rom

ster

ile ro

om

Supp

ly o

fpl

astic

gran

ulate

Prep

arat

ion

ofpr

oduc

t for

ster

ile fil

ling

Asep

tic m

anuf

actu

ring,

fillin

g an

d clos

ing

in th

ebl

owin

g m

old w

ithou

t cha

ngin

g the

pla

ce

BFS

Pro

cess

Ove

rvie

w

Par

ison

Ex

trut

ion

Mol

din

g by

bl

owin

g an

d va

cuu

m

Filli

ng

Con

tain

er

seal

ing

Pro

duct

�Pl

astic

mel

ting

and

ext

rusi

on (1

70-2

30°C

; up

to 3

50

bar)

�Ex

trus

ion

prov

ides

ste

riliz

atio

n an

d de

pyro

gena

tion

Proc

ess

step

1 Extr

uder

H

ead

Paris

on

Paris

on

head M

old

Mul

tiple

par

ison

ex

trus

ion

Sing

le p

aris

on

extr

usio

n

Sing

le/M

ultip

le p

aris

on e

xtru

sion

Paris

on

�M

ain

mol

d se

als

the

low

er p

aris

on e

nd

�Th

e pa

rison

is s

epar

ated

by

a kn

ife

�St

erile

air

kept

in th

e pa

rison

Proc

ess

step

2 Hol

ding

jaw

Hea

d M

old

Esca

ping

st

erile

air

Ster

ile a

ir sh

ower

bo

x

�R

apid

mol

d m

ovem

ent t

o fil

ling

posi

tion

�St

erile

air

show

er b

ox (1

00) p

rote

cts

fillin

g po

int

�Blo

win

g/fil

ling

unit

at re

st p

ositi

on

Proc

ess

step

3

Air s

uppl

y

Pre-

filte

r

Ster

ile a

ir fil

ter

Ster

ile a

ir sh

ower

bo

x

Filli

ng

poin

t

Ster

ile F

illin

g Sp

ace

Blo

w &

Fill

pip

e

�Low

ered

blo

win

g/fil

ling

unit

is p

lace

d tig

htly

on

top

of m

ain

mol

d

�Blo

w m

oldi

ng b

y st

erile

air

and/

or v

accu

m

Proc

ess

step

4a

Ster

ile P

rodu

ct

�Fill

ing

-Tim

e pr

essu

re d

osin

g

Proc

ess

step

4b

Filli

ng

Asep

tic P

ipin

g an

d St

erile

filtr

atio

n

�Pr

oduc

t Filt

ers

-0.

2 m

icro

n�

Paris

on A

ir Fi

lter

�St

erile

spa

ce A

ir Fi

lters

Prod

uct

supp

ly

Con

stan

t bu

ffer a

ir

Prod

uct

tank

Dos

ing

bloc

k, ti

mer

co

ntro

lled

Con

tain

er

Tim

e Pr

essu

re D

osin

g

Hea

d m

ould

se

aled

�Fill

ing

need

les

with

draw

into

the

ster

ile s

pace

�Hea

d m

old

seal

s co

ntai

ner h

erm

etic

ally

Proc

ess

step

5

Seal

ing

Man

ufac

turin

g

Ove

rvie

w

Man

ufac

turin

g C

ompo

nent

s

�Fi

ll Su

ite�

Mac

hine

Qua

lific

atio

n�

Bul

k So

lutio

n�

Util

ities

Fill

Suite

Fill

Suite

Env

ironm

ent

�Fi

ll su

ites

are

desi

gned

to s

epar

ate

the

BFS

m

achi

ne�s

ase

ptic

par

t fro

m it

s ut

ilitie

s

Bas

ic b

otte

lpac

k® m

achi

ne la

y-ou

t

Plas

tic

gran

ulat

e ho

pper

Mec

hani

cal c

abin

et

Elec

tron

ic

cabi

net

Filli

ng

syst

em

Buf

fer

tank

Mai

n fr

ame

Paris

on

head

Mol

d m

ovem

ent

Fill

Suite

Seg

rega

tion

The

�Dirt

y� S

ide

�Se

para

ting

pote

ntia

l sou

rces

of c

onta

min

ants

fr

om th

e fil

ling

envi

ronm

ent

Stai

nles

s St

eele

Bar

rier W

all

Fill

Suite

Seg

rega

tion

The

�Dirt

y� S

ide

�Se

para

ting

pote

ntia

l sou

rces

of c

onta

min

ants

fr

om th

e fil

ling

envi

ronm

ent.

Fill

Suite

Seg

rega

tion

The

�Cle

an�

Side

�H

ouse

s th

e pa

rison

ext

rusi

on, a

nd s

teril

e fil

ling

spac

e un

der a

ste

rile

lam

inar

air

hood

LUW

A C

urta

in

Ster

ile la

min

ar a

ir ho

od

�R

oom

Cla

ss 1

00,0

00

�LU

WA,

Lam

inar

Ste

rile

Air S

how

er, C

lass

10

,000

�St

erile

Fill

ing

Spac

e,

Cla

ss 1

00

Mac

hine

Qua

lific

atio

n

Mai

n ac

tiviti

es o

f Mac

hine

Qua

lific

atio

n

�In

stal

latio

n Q

ualif

icat

ion

(IQ)

-Che

ck o

f the

mai

n co

mpo

nent

s fo

r cor

rect

ness

acco

rdin

g sp

ecifi

catio

n (m

ater

ial a

nd ty

pe)

�O

pera

tiona

l Qua

lific

atio

n (O

Q)

-Che

ck o

f mai

n fu

nctio

ns o

f the

equ

ipm

ent

�Pe

rfor

man

ce Q

ualif

icat

ion

(PQ

)-C

heck

of p

roce

sses

func

tions

and

effi

cien

cies

, ou

tput

, cap

abili

ties

etc.

�Pro

cess

Qua

lifca

tions

-3 x

Med

ia fi

lls

-3 x

SIP

-Val

idat

ion

(Ste

riliz

atio

n in

Pla

ce) w

ith

biol

ogic

al in

dica

tors

(BI)

-3 x

CIP

-Val

idat

ion

(Cle

anin

g in

Pla

ce)

Bul

k So

lutio

n

Bul

k So

lutio

n

�So

lutio

n is

tran

sfer

red

into

th

e H

oldi

ng ta

nk th

roug

h a

0.2

mic

ron

Pall

Filte

r

�So

lutio

n in

the

Hol

ding

ta

nk is

mai

ntai

ned

unde

r po

sitiv

e pr

essu

re w

ith

ster

ile a

ir

Util

ities

Stab

le s

uppl

y an

d qu

ality

of u

tiliti

es

�Ele

ctric

pow

er:

!C

onne

ctio

n: 3

5-10

0 kW

, dep

endi

ng o

n m

achi

ne

type

!C

onsu

mpt

ion:

25-

60 k

W, d

epen

ding

on

mac

hine

ty

pe

�Com

pres

sed

air:

oil a

nd m

oist

ure

free

qua

lity,

8 b

ar

min

.

�Coo

ling

wat

er:~

1.3

-2.

0 m

3 /h a

t 12°

C a

nd 4

bar

; di

rt fi

ltere

d at

55

mic

ron

�Pur

e st

eam

(SIP

):~

25-4

0 kg

/h p

artic

le fi

ltere

d

Con

tain

er D

esig

n

Poin

ts to

con

side

r for

con

tain

er d

esig

n:

�Res

in ty

pe fo

r BFS

�N

eed

for a

utoc

lavi

ng�O

xyge

n / V

apor

per

mea

tion

�Lig

ht s

ensi

tivity

�Fill

vol

ume

-dos

age

volu

me

�Clo

sure

des

igns

�Lab

elin

g O

ptio

ns

Res

in f

or B

FS te

chno

logy

Low

den

sity

poly

ethy

lene

(LD

PE)

Hig

h de

nsity

poly

ethy

lene

(HD

PE)

Polyp

ropy

lene

(PP)

Den

sity

(g/c

m3 )

0,91

5-0,

930,

94-0

,95

0,89

5-0,

905

Mel

ting

inde

x(g

/10

min

)0,

2-2

~2

~2

Cla

rity

good

poor

good

Gas

per

mea

tion

med

ium

med

ium

med

ium

Vapo

r per

mea

tion

good

exce

llent

exce

llent

Dro

p re

sist

ance

exce

llent

good

satis

fact

ory

Sque

ezab

ility

exce

llent

satis

fact

ory

poor

Reg

ulat

ory

conf

orm

ityEP

III,

Ed 1

997

3.1.

4U

SP, c

lass

VI

FDA,

CFR

177-

1520

(c) 2

.2

EP II

I, Ed

199

7 3.

1.5

USP

cla

ss V

IEP

III,

Ed 1

997

3.1.

6U

SP, c

lass

VI

FDA,

CFR

177-

1520

(c) 3

.2Ap

plic

atio

nex

ampl

esey

e dr

ops

inha

latio

nsoi

ntm

ents

/cre

mes

LVP/

SVP

irrig

atio

n so

lutio

nsor

al s

olut

ions

topi

cal s

olut

ions

irrig

atio

n so

lutio

nsLV

PSV

Pey

e dr

ops

Auto

clav

ing

�PP,

aut

ocla

ving

pos

sibl

e at

121

°C, 1

5 m

in

�PE,

med

ium

den

sity

(0,9

28 -

0,93

), au

tocl

avin

g at

10

6 -1

10°C

, pro

long

ed c

ycle

tim

e

�PE,

low

den

sity

(0,9

15-0

,928

): as

eptic

fill

for h

eat

sens

itive

pro

duct

s

Oxy

gen/

Vap

or p

erm

eatio

n

�PE

, PP

limite

d ba

rrie

r pro

pert

ies

for o

xyge

n an

d C

O2

�M

achi

ne o

pera

tion

with

nitr

ogen

inst

ead

of s

teril

e ai

r�Se

cond

ary

pack

agin

g by

pou

chin

g/ov

er w

rapp

ing

-sup

port

ed b

y ni

trog

en-u

se o

f oxy

gen

abso

rber

Ligh

t sen

sitiv

ity�S

econ

dary

pac

kagi

ng in

to li

ght-p

rote

ctiv

e po

uche

s/ca

rton

s

�Ext

rusi

on o

f col

ored

par

ison

Fill

volu

me

-Mul

ti do

se c

onta

iner

s

�Mul

ti do

se c

onta

iner

-ste

rile

befo

re fi

rst

ap

plic

atio

n-c

ritic

al: p

rese

rvat

ives

-add

ition

al c

ap/in

sert

for

re-c

losu

re fu

nctio

n

Mul

ti-do

se e

ye d

rop

& e

ar d

rop

bottl

es

Rec

losa

ble

bottl

e fo

r con

tact

le

nse

clea

ning

Fill

volu

me

-U

nit d

ose

cont

aine

r

�Uni

t dos

e co

ntai

ner

-no

pres

erva

tives

-no

capp

ing

part

-d

efin

ed d

ose

volu

me

-eas

y to

app

ly

Uni

t-dos

e pa

ckag

es fo

r co

ntac

t len

s ca

reU

nit-d

ose

eye,

ear

&

nose

dro

ps

Oin

tmen

ts &

cre

ams

Bel

ow c

onta

iner

s fo

r rec

tal &

vag

inal

app

licat

ions

Enem

as w

ith c

annu

la o

r thr

eads

Spec

ialty

des

igns

Spec

ialty

Des

igns

Clo

sure

Des

igns

a) S

tand

ard

twis

t-off

b) T

hrea

d fo

r big

ger c

aps/

w

ider

ope

ning

c) T

hrea

d fo

r pin

cap

s

d) M

embr

ane

clos

ure

Inse

rtio

n of

sto

pper

s,

nozz

les,

etc

.

Clo

sure

Des

igns

Labe

ling

Labe

ling

Opt

ions

a)Em

boss

ing

b)Pa

per l

abel

on

tabs

c)D

irect

prin

ting

on ta

bs

d)C

onve

ntio

nal L

abel

s

a) E

mbo

ssin

g-En

grav

ed M

olds

�A

mirr

or im

age

of in

form

atio

n is

en

grav

ed o

n th

e su

rfac

e of

a m

old�

s ca

vity

.

�Sm

all v

acuu

m p

orts

on

the

mol

d su

rfac

e pu

ll in

the

soft

plas

tic

embo

ssin

g th

e co

ntai

ner.

Engr

aved

Mol

d

Embo

ssed

Lab

elin

g

Embo

ssin

g

No

leac

habl

es

Ensu

re e

ach

unit

is

trac

eabl

e

Labe

ls c

an n

ot b

e re

mov

ed

Ensu

res

100%

labe

ling

of c

onta

iner

s

Diff

icul

t to

read

on

clea

r co

ntai

ners

No

mai

nten

ance

of l

abel

in

vent

orie

s

Con

sPr

os

b) P

aper

Lab

els

on T

abs

�Th

e m

old

is d

esig

ned

with

a

tab,

or f

lag

on th

e ta

il or

th

e ca

p.

�Ta

b is

a s

olid

sur

face

pr

ovid

ing

spac

e fo

r pap

er

labe

ls

Pape

r Lab

el o

n Ta

b

Pape

r lab

el o

n Ta

b

Gre

atly

redu

ces

pote

ntia

l lea

chin

g in

to

the

solu

tion

Pote

ntia

l lea

chin

g of

la

bel a

dhes

ive

into

so

lutio

n

Cle

arer

to re

adC

ons

Pros

c) D

irect

Prin

ting

on T

abs

�In

k je

t prin

ting

on ta

bs

with

bar

code

s, a

nd

prod

uct i

nfor

mat

ion

Dire

ct P

rintin

g on

Tab

Dire

ct p

rintin

g on

the

Tab

Allo

ws

for b

arco

de

prin

ting

on li

ne

Gre

atly

redu

ces

pote

ntia

l lea

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