F e a t u r e s

Integrity testing of hydrophobic membrane fdters Sartorius replaces so lvent -based t e s t ing with new water pressure integri ty tes t . So lvent -based integri ty t e s t ing of hydrophobic filters used in pharmaceut ica l and biological appl icat ions is difficult to perform in s i tu fo l lowing s ter i l izat ion because o f the risk of downstream s o l v e n t c o n t a m i n a t i o n . Sartorius has deve loped an a l ternat ive tes t m e t h o d m the Water Pressure Integrity Test m which o v e r c o m e s th i s diff iculty and is c la imed to be e a s y to perform, sens i t ive and reliable.

Ster i l iz ing g r a d e h y d r o p h o b i c f i l ters a re u t i l i zed for t he s te r i l e f i l t ra t ion of a i r s t r e a m s a n d g a s e s in m a n y p h a r m a c e u t i c a l a n d bio logica l a p p l i c a t i o n s . The in t eg r i ty of t h e s e f i l ters a n d the i r ability to r e t a i n b a c t e r i a a r e t r a d i t i o n a l l y c o r r e l a t e d to a n o n - d e s t r u c t i v e in t eg r i ty tes t , C u r r e n t m e t h o d s r equ i r e t h e u s e of so lven t s (e thanol , i s o p r o p a n o l , freon) to we t the m e m b r a n e s in o rde r to pe r fo rm b u b b l e p o i n t a n d d i f fus ion in t eg r i t y t e s t s a n d the u s e of t h e s e so lven t s p o s e s seve ra l p r o b l e m s .

In s i tu i n t eg r i t y t e s t i ng u s i n g so lven t we t t ed m e m b r a n e s r e q u i r e s e l a b o r a t e b y p a s s valve s y s t e m s to p r e v e n t d o w n s t r e a m c o n t a m i n a t i o n b y so lven t r e s i d u a l s . After t e s t i n g g r e a t ca re m u s t be t a k e n to a s s u r e comple t e r emova l of t he so lvents . So lven t s m a y r e d u c e the ac t ive f i l t ra t ion a r e a t h r o u g h p a r t i c u l a t e m e d i a t e d m e m b r a n e fouling, r e d u c i n g filter p e r f o r m a n c e a n d p o t e n t i a l l y l e ad i ng to d a m a g e of t he v e n t e d vessel . Here a lso , i n c o m p l e t e so lven t r e m o v a l d u r i n g d ry ing can c a u s e t he filter to rewet , r e n d e r i n g i t h y d r o p h i l i c a n d no longer c a p a b l e of a c t i n g a s a h y d r o p h o b i c vent .

For t h e s e r e a s o n s so lven t in tegr i ty is u s u a l l y n o t p e r f o r m e d in s i tu post s te r i l i za t ion , b u t r a t h e r presterflization. Then, s te r i l i ty a s s u r a n c e c a n on ly be g u a r a n t e e d if a fi l ter i n t eg r i t y t e s t is p e r f o r m e d i m m e d i a t e l y p r io r to u s e b u t i t p roves e x t r e m e l y

diff icult to pe r fo rm the r e q u i r e d t e s t a n d to ins ta l l the filter a s s e m b l y on the p r o c e s s e q u i p m e n t a sep t i ca l ly .

To overcome t h e s e p r o b l e m s a t e a m a t S a r t o r i u s (2) h a s b e e n deve lop ing a n d t e s t i ng a n a l t e rna t i ve in t eg r i ty t e s t i ng m e t h o d b a s e d on wa te r i n t r u s i o n a n d p e n e t r a t i o n . Their work h a s s h o w n t h a t t he 'Water P r e s s u r e In tegr i ty Test ' (WPIT) m a y be p e r f o r m e d in s l tu p o s t s t e r i l l za t ion w i t h o u t a n y d o w n s t r e a m m a n i p u l a t i o n s a n d c a n b e d i rec t ly co r r e l a t ed to the r e t e n t i o n of b a c t e r i a l cha l l enges . O the r a d v a n t a g e s c l a imed for W~IT inc lude : • app l i c ab i l i t y to a n y ven t ing or

gas f i l t ra t ion s y s t e m • f i l ters c a n be t e s t e d af ter

s t e a m i n g or au toc l av ing in s i tu • i n sens i t i v i t y to t e m p e r a t u r e

f l u c t u a t i o n s • ab i l i ty to t e s t in h a r d to r e a c h

l oca t i ons • s impl i c i ty of t e s t i ng rou t i ne

Background theory The wa te r p r e s s u r e in t eg r i ty t e s t is b a s e d on the s a m e p r inc ip l e s a s the 'Mercu ry I n t r u s i o n ' tes t . By def ini t ion, h y d r o p h o b i c m e m b r a n e s r e s i s t we t t ing b y water . The wa te r r e p e l l a n t forces m a y b e overcome t h r o u g h the u s e of suf f ic ient p r e s s u r e to 'wet out '

t he pores . The force r e q u i r e d is r e l a t e d to t he po re d i ame te r :

4 o cos 0 D = x K

P

w h e r e D is po re d iamete r , o is t he s u r f a c e t e n s i o n ( d y n e s / c m ) , 0 is t h e c o n t a c t angle , p is a b s o l u t e pressure, a n d K is a co r r ec t i on fac tor ( cap i l l a ry to m e m b r a n e pore). As c a n be seen , t he pore size is i nve r se ly p r o p o r t i o n a l to the pressure r e q u i r e d to wet or i n t r u d e the capi l la ry . In p rac t i ce th i s m e a n s t h a t t he u p s t r e a m vo lume of t he h o u s i n g or t i l ter m u s t b e c o m p l e t e l y f looded, t h e n p r e s s u r e a p p l i e d a n d the r a t e of w a t e r p e r m e a t i o n d e t e r m i n e d .

Wate r p e r m e a t i o n or i n t r u s i o n is s een a s a n u p s t r e a m p r e s s u r e drop . The p r e s s u r e d rop c a n be conve r t ed into a d i f fus iona l flow w h i c h c a n b e u s e d to d e t e r m i n e the i n t eg r i t y of t h e m e m b r a n e . The l imi ted c o m p r e s s i b i l i t y of w a t e r m e a n s t h a t a n y p e r m e a t i o n of w a t e r t h r o u g h t h e m e m b r a n e u n l i k e a i r d i f fus ion d u r i n g the t r a d i t i o n a l p r e s s u r e ho ld t e s t s - - will exh ib i t i t se l f a s a r e la t ive ly la rge (volume d e p e n d e n t ] p r e s s u r e drop . This is t he b a s i s for t he s ens i t i v i t y a n d a c c u r a c y of the n e w t e s t m e t h o d .

Development and proving The S a r t o r i u s t e a m h a s u n d e r t a k e n a n ex tens ive se r i e s of t e s t s a s p a r t of i t s d e v e l o p m e n t p r o g r a m m e a n d s o m e of t he m a i n f e a t u r e s a n d r e s u l t s a r e d e s c r i b e d below. Fu l l de t a i l s of t h e d e v e l o p m e n t p r o g r a m m e , cover ing m e t h o d s , r e s u l t s a n d a n a l y s i s - - s t a b i l i z a t i on t ime, select ivi ty , e n v i r o n m e n t a l i n f luences , c o m p a r i s o n wi th t he t r a d i t i o n a l d i f fus ion tes t , co r r e l a t i on wi th t he d e s t r u c t i v e b a c t e r i a l cha l l enge in t eg r i ty t e s t - - a r e ava i l ab le f rom S a r t o r i u s .

(2) Mlchael Dosmar, Peter Wolber, Karl Bracht, Helmut Tr6ger and Peter Walbel.

6 Membrane Technology

F e a t u r e s

Diffusion (ml/lO rain) 300

25O

200

180

100

80

0 0

Intrusion Poi~ /

/ Diffusion / .J

2 3 4 Pressure (bar) l 5 6

Figure 1: Results f rom a water intrusion test on a Sartofluor GA 0.2 w-n fllter cartridge.

Water P e n e t r a t i o n P ressu re (bar )

6 -

_

2

0 1 2 3 4 5

Cartridge Number

0 . 4 5 m }J ~ 0 . 2 m p

Figure 2: Water penetration values obtalned f rom a series of tests on 0.2 ~m and 0.45 ~m SartoJluor GA fllter cartridges.

Tes t s were p e r f o r m e d on Sa r to f l uo r GA 0.2 ~rn a n d 0.45 ~m fil ter c a r t r i d g e s t a k e n f rom a va r i e ty of p r o d u c t i o n lots . These c a r t r i d g e s a r e c o n s t r u c t e d wi th Gore e x p a n d e d PTFE m e m b r a n e s . A d r y ca r t r i dge w a s i n s e r t e d into a h o u s i n g a n d the u p s t r e a m vo lume w a s fi l led w i th water . A S a r t o c h e c k II a u t o m a t i c fi l ter i n t eg r i t y tester w a s u s e d to con t ro l a n d m o n i t o r t he p r e s s u r e t e s t a n d p r o g r a m m e d to m e a s u r e wa te r i n t r u s i o n a s a p e r m e a t i n g flow over a r a n g e of p r e s s u r e s .

In t he t e s t i n g t e rmino logy , water intrusion is t he po in t w h e r e w a t e r forc ibly s t a r t s to en t e r a n d p e r m e a t e t he po re s t r u c t u r e , The p e r m e a t i o n of w a t e r d u r i n g the i n t r u s i o n s t age in i t ia l ly s h o w s a l i nea r r e s p o n s e to i n c r e a s i n g p r e s s u r e (Figure 1). For t he 0 .2 ~m fil ters, for example , t he r a t e of w a t e r i n t r u s i o n i n c r e a s e s l i nea r ly wi th i n c r e a s i n g p r e s s u r e u p to a b o u t 3 .7 bar , w h e n t h e r e is a r a p i d i n c r e a s e in flow a n d wa te r p e n e t r a t i o n beg ins . The water penetration va lue (4.5 ba r ) is w h e r e t he m e m b r a n e b e c o m e s we t t ed a n d free w a t e r flow begins .

For a n y in t eg r i ty t e s t to be use fu l i t m u s t be ab l e to d e t e r m i n e g r o s s f a i lu res a n d a lso b e ab le to d i s t i n g u i s h the d i f ference b e t w e e n a d j a c e n t po re s izes . The in t eg r i t y t e s t for a 0 .2 ~m m e m b r a n e m u s t the re fo re be ab le to recognize une qu ivoca l l y a 0 .45 ~m m e m b r a n e a s a n in t eg r i ty fa i lure . F igu re 2 s h o w s t h a t t h e r e is a n u n m i s t a k e a b l e d i f ference b e t w e e n the w a t e r p e n e t r a t i o n v a l u e s of 0 .45 ~-n a n d 0.2 ~m fi l ters a n d th i s is a re l i ab le b a s i s for d i f fe rent ia t ion . F u r t h e r ev idence of th i s is g iven in Table 1, w h i c h c o m p a r e s w a t e r i n t r u s i o n v a l u e s o b t a i n e d for 0.2 ~un a n d 0 .45 ~m m e m b r a n e c a r t r i dges u n d e r t he t e s t c ond i t i ons spec i f ied for t he 0 .2 ~m pore size (Table 2)

The t e s t i ng p a r a m e t e r s p r e s e n t e d In Table 2 a r e p r e s e n t e d for gene ra l i n f o r m a t i o n only. One c a n n o t a s s u m e t h a t t h e s e va lue s a r e va l id for f i l ters of o t h e r origin. The m a x / m u m i n t r u s i o n a l flow v a l u e s a r e r e l a t e d to m a x i m u m flows for s te r i l e f i l t ra tes o b t a i n e d

M e m b r a n e Technology 7

Features

Table 1. Results of testlng both fllters under the conditions suggested for testing the 0.2 ~m cartridge.

M e m b r a n e p o r e s ize (~trn) W a t e r i n t r u s i o n v a l u e s ( m l / i 0 min )

P a s s / fal l i n t e g r i t y t e s t

0 .2

0 . 4 5

9 P a s s 8 P a s s i 0 P a s s 9 P a s s 10 P a s s

3 4 0 Fa i l 3 1 0 Fa l l 3 4 0 Fa i l 2 0 0 Fa i l 2 2 0 Fa i l

Table 2. Testing parameters established for Sartorlus 0.2 I~m Sartofluor GA filter cartridges.

Tes t c o n d i t i o n s

M a x i m u m i n t r u s i o n a l f low

S o l u t i o n P r e s s u r e S t a b i l i z a t i o n t ime Tes t t i m e

0. i m 2 c a p s u l e 0 .2 m 2 c a p s u l e

i0" S a r t o f l u o r GA 20" S a r t o f l u o r GA 30" S a r t o f l u o r GA

W a t e r 20°C 2.5 b a r (36 ps i ) 5 to 10 m i n u t e s 10 m i n u t e s

4 m l / 1 0 m i n 6 m l / 1 0 m i n 15 m l / 1 0 m i n 30 m l / 1 0 m i n 45 ml / I 0 m i n

from destruct ive bacter ia l challenge integri ty tests .

A final series of comparat ive tes ts were u n d e r t a k e n to es tabl i sh tha t WPIT was as sensi t ive and accura te as the cur ren t diffusion tes t method. All filters meet ing the specificat ions for the diffusion tes t also met the specif icat ions for WPIT. Fur thermore , those filters outside the cri ter ia for re lease for either tes t also failed the bacter ia l challenge.

Summary The water p ressu re integri ty tes t e l iminates many of the obstacles presented by t radi t ional integri ty tests. WPIT has been shown to be an accura te and reproducible tes t in evaluat ing hydrophobic membrane filter cartr idges.

Patents This is a list of recent ly publ i shed pa ten t s covering des igns and inventions of re levance to synthet ic m e m b r a n e technology. Where the same device has been pa ten ted in several countr ies , we normal ly give the Bri t ish pa ten t number . If there is no UK patent , we give the n u m b e r of an English- language patent , if one exists.

The pa ten t s l ist is compiled from in te rna t iona l sources by BHR Group 's informat ion service. The facility can also be used to carry out retrospect ive pa ten t searches - - to tes t the validity, novelty or infr ingement of existing pa ten ts or new ideas. BHR Group Cranfleld, Bedford MK43 0AJ, UK, will provide free es t imates on request .

Countr ies can be identified by the code in front of the number as follows:

AT Austria AU Australia BE Belgium BR Brazil CH Switzerland DD East Germany DE West Germany DK Denmark EP European Patent ES Spain FI Finland FR France GB Britain HU Hungary IL Israel IR Eire IT Italy JP Japan KP North Korea LI Liechtenstein LU Luxembourg NL Netherlands NO Norway RO Romania SE Sweden US United States SU Soviet Union WO World Patent

(Patent Treaty Cooperation publication)

BHR Group does not operate a documen t delivery service for pa tents , b u t full copies of the original pa ten t documen t s can be ob ta ined from the following addresses :

The Bri t ish Library Patent Express 25 S o u t h a m p t o n Buildings London WC2A IAW, UK Fax: 071 323 7230

(The Bri t ish Library will also supp ly a list of UK l ibraries inc luded in the Patent Information Network.)

US Patent Office Scientific Library 15th and Eas t Streets , NW Washington, DC 20231, USA

8 M e m b r a n e Technology