Method and device for testing the permeability of membrane filters

The invention pertains to a method and device for testing the permeability of membrane filters by submitting a wetted membrane filter on its inlet side to a predetermined testing gas pressure within a first closed system and by measuring pressure variation over time within the closed system. The object of the method of the invention is a sensitive testing method permitting permeability, and thus pore size, of a membrane filter to be determined exclusively by measurements performed on the inlet side of the membrane filter. Such measurement is performed by measuring a pressure differential with respect to a reference pressure, or by measuring the quantity of gas per unit of time flowing with respect to a reference pressure system, or else by measuring the pressure differential twice and draining, during the second measurement, a predetermined quantity of gas from the space being tested.

DESCRIPTION 
This invention pertains to a method permitting the permeability of membrane 
filters to be tested by subjecting, within a first closed system, a wetted 
membrane filter on its intake side to a predetermined testing gas pressure 
and by measuring, over time, the pressure differential occurring within 
said closed system. 
Membrane filters are increasingly relied upon for sterilizing liquids 
whenever heat sterilization is impossible, e.g. because of damage to the 
liquid itself. By way of example, the pore size of such filters might be 
approximately 0.2 .mu.m, and the pore density may be approximately 
4.times.10.sup.9 pores per square centimeter. 
In order to test the integrity of this type of membrane filter and to 
verify the fact that there are no pores having a size exceeding a certain 
predetermined limit, wetted membrane filters are subjected to bubble-point 
or gas-diffusion testing. Bubble-point testing of membrane filters in a 
filter housing is normally done by creating a head of gas pressure on the 
inlet side of the membrane filter to be tested, and thus a pressure 
differential across said membrane filter. One end of a tube is connected 
to the outlet side of the filter housing of said membrane filter, the 
other end of the tube is submerged in a liquid contained in a vessel. In 
this test method, gas pressure on the inlet side of the membrane filter is 
gradually increased, which causes more and more gas to permeate through 
the filter as the pressure keeps mounting. Initially, the rate of gas flow 
measured on the outlet side is proportional to the increasing gas pressure 
on the inlet side. As soon as the rate of gas flow measured on the outlet 
side of the membrane filter increases at a greater rate than does the gas 
pressure on the inlet side--as indicated by a substantial increase in the 
quantity of gas bubbles escaping--the bubble point has been reached. 
However, the visual determination of this point must be performed 
subjectively; thus, it is subject to a relatively high degree of 
imprecision. 
Gas diffusion testing is performed in practically the same manner except 
that, in any individual case, the gas quantities permeating through the 
membrane filter are collected within an up-ended graduated cylinder filled 
with liquid for the purpose of measuring the gas quantity penetrating the 
membrane filter per unit of time. It is true that this gas-diffusion, or 
forward-flow, test is more precise; however, the procedure is more 
complicated. A constant pressure is applied across a wetted membrane 
filter and actual flow of gas on the outlet side of the membrane filter is 
measured by determining the rate of flow of the water displaced from the 
graduated cylinder. In principle, gas diffusion is measured across a 
continuous layer of water as represented by the wetted membrane. The 
quantity (J) of gas diffusing is proportional to the pressure differential 
(.DELTA.p) occurring between inlet and outlet sides, and inversely 
proportional to the thickness (d) of the water layer or membrane; reduced 
to a formula: 
EQU J.about..DELTA.p/d 
For diffusion testing, the pressure applied on the inlet side are lower 
than those at which the so-called bubble point is reached. The pressures 
used here are normally approx. 80% of those attained during bubble-point 
testing. 
Both processes described above are subject to the serious drawback that 
testing the permeability of the membrane filter implies measurements on 
the outlet side of the filter, thus creating the quite serious danger of 
causing, in the event of sterile filtration, secondary impurities on the 
sterile side. This is the reason why pharmacists manufacturing or using 
any filter will refrain from testing the system subsequent to its having 
been sterilized or, if testing is required nevertheless, will have to rely 
on a very insensitive testing method to be performed on the inlet side. 
This method consists in automatically increasing the pressure prevailing 
within the space on the inlet side of the membrane filter up to a 
predetermined testing gas pressure within the so-called diffusion range, 
below the pressure prevailing at the bubble point. As soon as the testing 
gas pressure has been reached, all valves on the inlet side are closed, 
and any changes in the gas pressure prevailing on the inlet side of the 
membrane filter are monitored by means of a recorder. However, this 
process is highly insensitive; therefore, only serious system damage, such 
as any leaking O rings, can be identified with it. Owing to this lack of 
sensitivity inherent in the so-called pressure keeping or pressure decay 
test, bubble point testing from the inlet side is also performed. To do 
so, testing gas pressure levels are increased until the pressure drop per 
unit of time becomes more than proportional. However, this test method has 
likewise been found to be highly insensitive. Tests run in 
parallel--determining the bubble point from the inlet side, and 
determining the bubble point according to the visual method described 
above and characterized by observing gas bubbles having passed the 
membrane filter--demonstrated that values obtained by employing the inlet 
side bubble point test method are at least 0.2 bar greater than those 
found when bubble points are determined by visual methods. Nevertheless, 
numerous pharmacists are still using this method since it is the best one 
currently available if integrity and permeability of a sterile membrane 
filter is to be checked. 
Another method which is known to the art, permits the integrity and 
permeability of any membrane filter to be tested exclusively from the 
inlet side. It is true that this process permits changes in pressure on 
the inlet side to be determined far more precisely, however, with this 
method, pressures applied on the inlet side are all below 1 bar. For this 
reason, the method is subject to the drawback that in view of the low test 
gas pressures on the inlet side of the membrane filter, no reliable 
information as to integrity or actual permeability of any filter can be 
derived because, at pressures below 1 bar, test results for membranes 
having unacceptably high permeability values cannot be distinguished from 
those for membranes of admissible permeability. This means that even if 
there is one, or possibly even several pores the size of which are greater 
than admissible values, these pores will not become noticeable as their 
effects will be drowned out among the huge number of standard-sized 
pores--around 10.sup.9 per square centimeter--since the bubble point of 
any such standard-sized pore has not yet been exceeded. 
A practical example will explain how small the pressure differentials due 
to diffusion losses are on the inlet side of the filter housing. On the 
inlet side, the volume of a 250 mm filter housing will at best be 
approximately 1000 ml; thus, the maximum diffusion pressure differential 
will be 6 mbar/min if N.sub.2 diffusion through the wetted membrane of the 
filter cartridge amounts to approximately 6 ml/min for a 2.5 bar testing 
pressure. However, a very slight increase in the amount of gas passing 
through the filter indicates that the filter is leaking. This is why 
pressure differentials have to be determined by methods which are as 
sensitive and as precise as possible. Electronic averaging of measured 
values obtained with a single pressure transducer will permit, at relevant 
testing pressure levels, no more than a 1 or 2 mbar resolution, resulting 
in a correspondingly high lack of precision as regards absolute values. 
It is the object of this invention to present a testing method which is as 
sensitive as possible and which permits the permeability, and thus the 
pore size, of a membrane filter to be determined exclusively by 
measurements performed on the inlet side of said membrane filter. 
According to the invention and based on a method of testing the 
permeability of membrane filters of the kind mentioned initially, this 
object is achieved by bringing up, at the beginning of any measurement, a 
reference pressure system to the testing gas pressure and by measuring the 
change in pressure by way of obtaining the pressure differentials between 
the first system and said reference pressure system. 
For one thing, this method is characterized by the advantage that 
measurements can be perfomed at relatively high testing gas pressures, 
i.e., directly below or even at the bubble point which may mean, by way of 
example, absolute pressure of between 2.5 and 3.5 bars; this is what 
really permits distinguishing between membrane filters having admissible 
permeability and those subject to unacceptable values. Another important 
advantage of this method consists in the fact that, despite this high 
level of absolute pressures, values measured for pressure gradients within 
the space on the inlet side of the membrane filter can be made 
substantially more sensitive and precise by measuring the differential 
between the pressure prevailing within the system on the inlet side of the 
membrane filter and the one obtaining within the reference pressure 
system. According to the invention, sensitivity and precision values of 
approximately 0.1 mbar can be achieved irrespective of testing pressure 
levels. This means that measuring sensitivity has been improved 
substantially. Measurements as such can be performed exclusively on the 
inlet side. 
The testing method will preferentially be performed so as to link, prior to 
any measurement, a first system and reference pressure system, separating 
them whenever a measurement is initiated. This permits the testing gas 
pressure to be determined and read off only once prior to any measurement; 
moreover, the procedure ensures that at the beginning of any test the 
pressure level prevailing within the reference pressure system is 
identical to the level of pressure tested within the measuring system. 
Whenever any test is initiated, it will be sufficient to simply separate 
the first system and said pressure reference system. 
The pressure reference system may of course be connected directly to the 
source of gas pressure, and be brought up independently from the measuring 
system proper to any predetermined testing gas pressure. Even in this 
case, the reference pressure system ought to be separated from said source 
of gas pressure at the beginning of any measurement so as to preclude the 
subsequent occurrence of pressure variations due to, say, changes in 
temperature. 
Since the pressure measuring system is extremely sensitive, testing it 
first for its integrity will be indicated in order to prevent pressure 
measuring equipment from being damaged by rapid loss of pressure through 
possible leaks. For pretesting the integrity of the membrane filter, it 
will be preferable to connect the first system and the reference pressure 
system and to bring them up to a predetermined test gas pressure prior to 
measuring the loss of pressure for the entire system. In this manner, no 
pressure variations will reach the sensitive measuring equipment used to 
measure the pressure differential prevailing between the first system and 
reference pressure system so that it will be protected against being 
damaged. Only if the system has been found to contain no major leaks, can 
the testing process proper be performed. 
This invention relates, moreover, to a device permitting the testing method 
to be performed, which device is characterized in that the space on the 
inlet side of the membrane filter is connected, via a line and a pressure 
control valve, to a source of gas pressure, in that a first pressure 
measuring device is provided with a bypass to said line connecting the 
pressure control valve and the space on the inlet side, and in that within 
said bypass line is a shut-off valve permitting a reference pressure 
system, capable of being insulated, to be formed between the shut-off 
valve and the pressure measuring device. 
Since the precision of the measurements is particularly subject to 
temperature variations within the measuring system, it will be preferable 
to control said shut-off valve by pneumatic means; the electric currents 
needed to control electromagnetically actuated valves have been found 
sufficient to substantially distort measuring results. 
If the shut-off valve is controlled pneumatically, it will be advisable to 
provide, for the purpose of pneumatically controlling the shut-off valve, 
an electromagnetically controlled valve connected to the source of gas 
pressure. Said electromagnetically controlled valve will be innocuous 
unless directly in contact with the reference pressure system, or the 
first system. 
So as to permit the integrity of the membrane filter and the tightness of 
the first system to be pretested, it will be appropriate to provide a 
second pressure measuring device connected with the space of the inlet 
side of the membrane filter. 
Another, independent solution of the problem to be solved is seen in the 
fact that, at the beginning of any measurement, a closed reference 
pressure system is brought up to the testing gas pressure and that, 
subsequently, any gas quantities flowing from the reference pressure 
system to said first system are measured per unit of time. 
Since the gas mass per unit of time obtained in this instance is precisely 
equal to the gas mass passing, per unit of time, through the membrane 
filter to be tested, the value measured directly indicates the rate of 
diffusion through said membrane filter; in its turn, this value provides a 
direct indication as to whether said membrane filter can be used, or not, 
for its intended purpose. The manufacturers of membrane filters quote 
maximum values for rate of diffusion. If any rate measured is greater than 
said maximum value quoted by the manufacturers, said membrane filter is 
useless. If, on the other hand, the value measured is lower than said 
level, the membrane filter is unrestrictedly suitable. 
According to the invention, a preferential embodiment of the device 
permitting the method to be performed consists in connecting, via a line 
and a pressure control valve, the first system on the inlet side of the 
membrane filter with a source of gas pressure, and by providing a 
reference pressure system connected via a gas flow measuring device with 
said first system. 
So as to provide for a state of equilibrium whenever the first system and 
said reference pressure system are brought up to the testing gas pressure, 
it may be appropriate to connect the reference pressure system with the 
first system via another line that can be closed immediately prior to the 
start of any measurement. In this case, it will be possible, when bringing 
up the reference pressure system to the testing gas pressure, for the gas 
to flow immediately from the first system into the reference pressure 
system, there being no need to have it run through the gas flow measuring 
device. 
In a laboratory environment, the rate of any pressure decline measured 
within a certain filter housing for a certain filter cartridge at a 
definite testing pressure may be used as a measure of test filter 
integrity. With testing methods as performed under normal conditions, 
additional and unavoidable feed lines at the filter housing will increase 
inlet side volumes; therefore, laboratory values for maximum admissible 
rates of pressure decline may, at best, be considered standard values. 
Knowledge about actual rates of diffusion as expressed in units of volume 
or mass is, thus, not only desirable but indispensable if integrity is to 
be tested reliably under the diffusion method of testing. 
Now, another independent solution of the problem to be solved is deemed to 
consist in a method permitting the determination of gas diffusion rates 
through membrane filters in verifying the permeability of membrane filters 
from their inlet side by first subjecting a wetted membrane filter, on its 
inlet side, in a first closed system to a first testing gas pressure and 
measuring the pressure differential per unit of time, characterized in 
that the first system is subsequently brought up to a second testing gas 
pressure, in that the overall pressure differential of the first system is 
determined during a predetermined span of measuring time, and in that, in 
addition to the pressure gradient caused by gas permeating through the 
membrane filter, an additional pressure gradient is caused to occur within 
the first system by bleeding a predetermined quantity of gas from said 
first system. 
In accordance with another preferred embodiment, the method is performed as 
described above except that, during the measuring time, a predetermined 
pressure variation of the first system is caused by bleeding off a fixed 
quantity of gas from the first system. 
With both predetermined methods, preferred procedure consists in having the 
first and second testing gas pressures equal, which considerably 
simplifies the procedure. 
A device permitting the method to be performed is characterized in that the 
space on the inlet side of the membrane filter is connected, via the line 
and pressure control valve, with a source of gas pressure, in that a first 
pressure measuring device is provided within the bypass line of the line 
between pressure control valve and the space on the inlet side, in that a 
shut-off valve is provided within the bypass line for the purpose of 
forming, within the shut-off valve and the pressure measuring device, a 
reference pressure system, capable of being closed, and in that, together 
with the space on the inlet side of the membrane filter, a gas draining 
valve and a gas flow measuring device downstream from said gas draining 
valve are provided.

FIG. 1 shows a prior art arrangement permitting both initial tesing of 
membrane filter permeability and subsequent filtration. Within housing 10, 
there is a rod-shaped membrane filter 11 (membrane filter cartridge). The 
exterior of said cartridge constitutes the inlet side of the membrane 
filter and is surrounded by space 12 through which the medium to be 
filtered, for instance a liquid, is introduced. Interior 13 of the 
cartridge constitutes the outlet side of membrane filter 11. Within said 
interior, the filtered medium collects and is drained through bottom end 
14 of said cartridge, via line 15 and drain valve 16 within said line. 
Moreover, pressure measuring device P.sub.2 is located within line 15, 
which device, if connected to pressure measuring device P.sub.1 located on 
the inlet side of said membrane filter and connected with space 12 permits 
the measurement of the pressure differential prevailing between inlet and 
outlet sides of membrane filter 11. Furthermore, line 15 comprises valve 
17 located within drain sleeve 18. Said sleeve may be connected to hose 19 
the free end of which may be introduced into an upended graduated 
cylinder, 20, located within beaker, 21, filled with liquid. 
On the inlet side of membrane filter 11, there is inlet valve 22, connected 
with space 12 which permits the introduction of the medium to be filtered. 
Another valve, 23, is connected with space 12; through said valve 23, a 
pressurized gas may be introduced, which gas will permit space 12 to be 
brought up to a predetermined pressure for the purpose of performing 
integrity testing as well as filtration. Finally, space 12 comprises 
another valve, 24, for venting space 12 to atmospheric pressure. 
With the so-called gas diffusion testing method, membrane filter 11 is 
impregnated first; thereupon, space 12, i.e., the inlet side of membrane 
filter 11, is brought up to a predetermined level of pressure by 
introducing a gas, e.g. nitrogen, subject to a predetermined level of 
pressure. Next, the pressure differential across the membrane filter and 
the quantity of gas having passed, per unit of time, through membrane 
filter 11 and now collected within graduated cylinder 20, are determined 
by reading off pressure measuring devices P.sub.1 and P.sub.2. This 
measurement permits some conclusions as to the permeability of the 
membrane filter. Finally, by continuously increasing the pressure acting 
upon space 12 on the inlet side, the so-called visual bubble point will be 
determined, which point is reached whenever the velocity of gas bubble 
production increases significantly at the outlet side, i.e., at the end of 
hose 19. If the measurements so performed indicate that membrane filter 11 
is acceptably permeable, valves 17, 23 and 24 are closed and filtration 
proper can start. 
For improved understanding of the term "visual bubble point," reference is 
made to FIG. 2, where test gas pressure p, as applied to the inlet side of 
the membrane filter to be tested, is plotted on the abscissa while rate of 
gas flow J, i.e., the quantity of gas per unit of time diffusing or 
flowing through the membrane filter at pressure p is plotted on the 
ordinate. At lower pressures, J and p are proportional to each other. In 
area 26, gas moves through the membrane filter only by diffusion. Whenever 
pressure p increases beyond point p.sub.1, there will be a deviation from 
the proportional behavior described above; if pressure p is increased even 
more, the rate of gas flow permeating the membrane filter, i.e., quantity 
J, will increase substantially. In area 27, the major part of gas flow J 
is due, in addition to a certain part applicable to diffusion, to ducts 
having formed through the membrane filter. Thus, the visual bubble point, 
as determined in a purely subjective manner according to the amount of the 
gas flow passing through the membrane filter, is located somewhere within 
the transitional range between areas 26 and 27; however, with reference to 
point p.sub.1 (the true bubble point of the membrane), it will be 
displaced towards higher pressure values: in FIG. 2, the visual bubble 
point is marked by the abbreviation B.P. 
Now, this invention tries to find a sensitive method of measuring pressure 
p.sub.1 in FIG. 2 without having to perform any measurement on the outlet 
side of any membrane filter as represented by cartridge 11 in FIG. 1. With 
a view towards finding a suiable testing method, the following matters 
were considered, among others, and finally led to the desired object of a 
suitable testing method: 
Hereinafter, the following designation shall mean: 
p.sub.test =testing pressure 
V.sub.up =closed testing volume within the filter housing, on the inlet 
side of the membrane filter 
V.sub.0 =volume within the filter housing, on the inlet side of the 
membrane filter, as normalized to atmospheric pressure 
p.sub.atm =atmospheric pressure 
V.sub.D =volume diffused over time t 
p.sub.t =pressure prevailing on the inlet side of the membrane filter 
subsequent to time t 
Assuming that temperatures will remain constant during any one measurement, 
the following equations can be set up: 
##EQU1## 
If equation (3) 
##EQU2## 
as applicable to the initial state at the beginning of a measurement, is 
substituted into equation (2), the following is obtained: 
##EQU3## 
By further substituted 
EQU .DELTA.p=p.sub.test -p.sub.t (5) 
into equation (4) the following is obtained: 
##EQU4## 
This means that the pressure decline for initial testing pressures will be 
proportional to the volume diffused corresponding to the region of 
diffused flow, 26 in FIG. 2, always assuming that atmospheric pressure 
will remain constant during any individual measurement; this will normally 
be true since variations may be expected not to exceed .+-.3%. Moreover, 
the above result means that any pressure decline will be inversely 
proportional to the volume existing on the inlet side of the membrane 
filter within the filter housing, i.e., the sensitivity of any measurement 
so performed will increaase as the volume of the filter housing on the 
inlet side of the membrane filter decreases. More particularly, equation 
(6) shows that pressure decline .DELTA.p is directly proportional to gas 
diffusion volumes so that there is a linear relationship between pressure 
decline and said volume which, in its turn, is a linear function of time 
(for at least 15 minutes). Whenever volume V.sub.up is known, the pressure 
variation corresponding to any given volume of gas diffusion can be 
calculated directly. 
If maximum pore size for a membrane filter is to be computed precisely, it 
is important to determine, in accordance with FIG. 2, that pressure p at 
which its purely diffusion-type flow becomes a combination of diffusion 
and ducting through the membrane filter. In FIG. 2, by way of example, 
this occurs at point p.sub.1. Whenever said pressure has been determined, 
it will be possible to determine--even though no details are to be given 
here--maximum pore size for the membrane filter as a function of 
thickness, surface, and certain structural assumptions. Manufacturers of 
membrane filters available for sale, quote pressures at which pressure 
diffusion-type flow changes into a combination of diffusion and duct-type 
flow. This manufacturer's estimate provides a basis for checking, prior to 
using the filter, whether the integrity of the filter is unimpaired and 
whether pore size is in accordance with requirements. If measurements are 
obtained which are lower than the pressures quoted by the manufacturer, 
then the filter is probably damaged. 
Below, the preferential method of determining pressure p.sub.1 according to 
FIG. 2 is to be explained on the basis of a preferential embodiment of a 
measuring device as shown in FIG. 3. At point 30, line 31 may be connected 
with a source of gas pressure, not shown, e.g. a reservoir containing 
nitrogen at a pressure of 7 bars. Via needle valve 32 and a first 
electromagnetic valve, 33, line 31 is connected with line 34 which 
functions as a common manifold for the connecting lines seen in FIG. 3. At 
point 35, line or manifold 34 may be connected, e.g. with valve 24 of FIG. 
1, for link-up to system 10. Line 34 is connected with venting valve 36. 
Moreover, line 34 is connected with a first pressure measuring device, 37, 
permitting the determination of absolute pressure p prevailing within line 
34. In bypass line 38 of line 34, a second pressure measuring device, 40, 
and pneumatically controllable valve 41 are arranged in series. At points 
43 and 44, bypass line 38 ties into line 34. The second pressure measuring 
device, 40, is used to measure the pressure differential between the 
pressure prevailing in line 34 and within that section of line 38 located 
between the second pressure measuring device, 40, and pneumatically 
controllable valve 41. As will be explained in detail below, this section 
of said line forms reference pressure system 45. 
Another electromagnetically controllable valve, 46, is provided to permit 
controlling pneumatically controllable valve 41; via connection 47, valve 
46 ties into line 31 while being connected, moreover, with line 48. Line 
48 leads to change-over 49 of pneumatically controllable valve 41; 
moreover, there is an arrangement, not shown in detail, such that, 
whenever the pressure prevailing in line 48 is above atmospheric pressure, 
change-over switch 49 will move from its position shown in FIG. 3, which 
position connects lines 38 and 34, into the position shown in broken 
lines, which position interrupts the connection line 34 and reference 
pressure system 45, and in which both reference pressure system 45 and the 
connection linking line 34 to the pneumatically controllable valve 41 will 
be closed. The end of the line corresponding to the broken-line position 
of valve 41 is represented by cut-off line section 50. 
In its deactivated position, as shown, electromagnetically controllable 
valve 46 establishes a connection between line 48 and line 51 which line 
51 opens out into the atmosphere. In its activated position, shown as a 
broken line, valve 46 connects lines 31 and 48 via connection 47. 
It is position shown in FIG. 3, first electromagnetic valve 33 connects 
line 31 and closed end 52 of valve 33 via pressure reducing valve 32. In 
said valve position, line 34 is likewise closed at point 53. In the 
activated state of the first electromagnetic valve, 33, change-over switch 
54 will be in the position shown in broken lines. In this position, needle 
valve 32 is directly connected with line 34. 
Venting valve 36 is likewise shown in the position with its solenoid 
deactivated. In said position, line 34 is connected, via change-over 
switch 55, with outlet 56, which outlet is open to atmospheric air. Upon 
activation of venting valve 36, change-over switch 55 is thrown into the 
position shown in broken lines, in which position line 34 is connected 
with closed end 57. 
In FIG. 3, all of valves 33, 36, 41 and 46 are shown deactivated. 
In order to test a membrane filter already built in, e.g. into housing 10 
according to FIG. 1, the test measuring device globally designated 60 is 
placed next to valve 24 at point 35 and tightly connected with said valve. 
Thereupon, valve 36 will be activated, causing it to close. Next, valve 33 
will be activated so that needle valve 32 and line 34 are connected. Next, 
the pressure within line 34 is adjusted to a predetermined testing gas 
pressure. Said testing gas pressure will be measured by way of the first 
pressure measuring device, 37. Whenever the pressure erroneously increases 
beyond the maximum admissible pressure of approx. 7 bars, pressure 
measuring device 37 will automatically transmit a signal to venting valve 
36, causing it to be deactivated. Upon such deactivation, line 34 will 
open out to the atmosphere so that any excess pressure can be reduced and 
even further gas supplies cannot cause excess pressure to build up within 
the system. Rather, all the gas is vented directly to the atmosphere. 
As soon as the predetermined testing gas pressure has been reached, valve 
33 will be deactivated so that line 34 is closed at point 53. Thus, 
deactivation of valve 33 forms a closed system existing within line 34 and 
space 12 (of FIG. 1) on the inlet side of membrane filter 11. From this 
moment in time, the pressure decline within said closed system is measured 
as a function of time. A rapid pressure decline may mean either that the 
system itself has a leak or that the membrane filter is defective. This 
measurement may be deemed a preliminary one intended to guarantee that 
there are no major leaks. During this measurement, there is no need for 
pressure measuring device 40. Since the pressures prevailing on either 
side of said measuring device are equal, it may not be damaged. As soon as 
the system has been found to be tight, the first test on membrane filter 
permeability can be run. To do so, valve 33 as activated and line 34 and 
the system connected therewith are brought up to a first testing gas 
pressure, if possible to a value below p.sub.1 according to FIG. 2. 
Thereupon, valve 33 is deactivated. Since reference pressure system 45 and 
line 34 are connected via valve 41, the testing gas pressure prevailing in 
reference system 45 at that moment in time will be at the same level as 
the one within line 34. Next, valve 46 is activated so that line 48 is 
separated from the atmosphere and is connected with line 31, which is 
subject to approx. 7 bars of increased pressure. This will cause 
change-over switch 49 of pneumatically controllable valve 41 to move over 
into the position shown by broken lines in FIG. 3, which isolates 
reference pressure system 45. As from this moment in time, pressure 
measuring device 40 will be used to measure the pressure decline occurring 
between the pressure prevailing within line 34 and the one in reference 
pressure system 45. According to equation (6), said pressure differential 
.DELTA.p is proportional to gas diffusion volume V.sub.D permeating 
through the membrane filter. The value of .DELTA.p per t, i.e. the 
pressure differential per unit of time, is directly proportional to the 
value of J in accordance with FIG. 2. In order to be sure a constant value 
has been obtained, the measurement is continued over four to five minutes. 
Values obtained via pressure measuring device 40 may be recorded by means 
of a recorder, or stored in a magnetic memory. At the end of such 
measurement, valve 46 is deactivated once more, which likewise deactivates 
valve 41 by connecting line 34 with reference pressure system 45 so that 
the pressures prevailing on the two sides of pressure measuring device 40 
are equalized. Thereupon, venting valve 36 may be actuated; however, this 
is unnecessary if, by way of example, the system is to be brought up, for 
the next measurement, to a pressure higher than the one for the first 
measurement. Thereupon, a second measurement can be made according to the 
same procedure as the one described above, except that the system 
consisting of line 34 and space 12 is now brought up to a pressure p 
greater than the value of the first measurement. Other measurements may 
follow, provided their initial p value is greater than the preceding one. 
As long as the measuring system is operated within the range characterized 
by diffusion and designated 26 in FIG. 2, the values obtained ought to 
result in a linear function, i.e. they have to form a straight line when 
plotted as in FIG. 2. Whenever the value for J obtained for the most 
recent value of p in a series of increasing pressures deviates from said 
straight line, such deviation indicates that during the previous 
measurement, the point was passed which separates the region where the gas 
flows through the membrane only by diffusion from the region where gas 
flows through the membrane by diffusion and ducting. The value of p 
previously obtained may then be used either to directly compute the size 
of membrane filter pores or to check, based on the data quoted by the 
manufacturers, whether the membrane filter being tested meets pore size 
requirements. 
Subsequent to this measurement, venting valve 36 can be deactivated so that 
the entire system will once more be under atmospheric pressure. Another 
advantage of the system shown in FIG. 3 consists in the fact that no power 
failure will damage the system. In such event, no overpressure can build 
up within the system since said venting valve will be open to the 
atmosphere. 
Pressure measuring devices 37 and 40 may be conventional instruments, if 
possible providing an electrical output signal which may be used to record 
the pressure obtained directly by way of a recorder, to drive a digital or 
analog display, or which can be directly transmitted to a suitable 
computer. 
Another substantial advantage of the system shown in FIG. 3 consists in the 
fact that reference pressure system 45, line 34, and space 12 may directly 
be brought up to the same testing gas pressure at a single stroke, i.e., 
by activating vave 33. On the one hand, this expedites measuring 
procedures while, on the other hand, it is guaranteed that testing gas 
pressures both in the measuring system and in the reference pressure 
system were at the same level at the beginning of any measurement. The 
preceding procedure notwithstanding, the method could be applied so as to 
bring the reference pressure system up to the testing gas pressure 
irrespective of line 34. In this case, it would not be necessary to 
separate the reference pressure system from the source of gas pressure if 
it can be guaranteed that the source of gas pressure will reliably remain 
at testing gas pressure during the entire measurement. However, it will be 
preferable to isolate the reference pressure system whenever the testing 
gas pressure has been reached. 
The essential advantage of the method described above consists in the fact 
that measurements can be made on the inlet side of the membrane filters so 
that the measuring procedure per se will not contaminate a sterile filter. 
Moreover, there is the possibility of determining, to an extremely high 
degree of precision, the pressure at which the transition from purely gas 
diffusion flow to a combination of diffusion and duct-type flow through 
the membrane filter occurs. This permits the maximum size of membrane 
filter pores to be determined in an extremely precise manner. 
By another embodiment of the invention, ways and means were sought of 
directly determining, if at all possible, the value for the rate of 
diffusion through cartridge 11, since this value may be compared directly 
to the one provided by the manufacturer of such membrane filter and will 
provide a simple means of determining whether said filter is defective or 
in working order. Thus, the aim is to measure quantity J indicating the 
volume of gas having diffused through the membrane filter per unit of 
time. Measuring quantity J is difficult because no measurements may be 
made, for sterility's sake, on the outlet side of the membrane filter. So 
as to permit quantity J to be measured, the following preferential 
embodiment of a measuring device is proposed in accordance with the 
invention. 
FIG. 4 shows a measurng device similar to the one used in FIG. 3. Identical 
references mean functionally identical components, so there is no need to 
discuss them in detail. Said measuring arrangement is distinguished from 
the arrangement shown in FIG. 3 in that pressure measuring device 40 in 
bypass 38 of line 34, which functions as a common manifold for the 
connecting lines seen in FIG. 4, has been replaced by gas flow metering 
device 68 connected in series to reference pressure system 65 in the form 
of a pressure vessel and inserted between line 38 and pneumatically 
controllable valve 41. The function of gas flow metering device 68 is to 
measure the gas flowing from reference pressure system 65 into line or 
manifold 34. 
In order to test a membrane filter already built in, e.g. into housing 10 
according to FIG. 1, the test measuring device globally designated 60 is 
placed next to valve 24 at point 35 and tightly connected with said valve. 
Thereupon, valve 36 will be activated, causing it to close. Next, valve 33 
will be activated so that needle valve 32 and line 34 are connected. Next, 
the pressure within line 34 is adjusted to a predetermined testing gas 
pressure. Said testing gas pressure will be measured by way of the first 
pressure measuring device, 37. Whenever the pressure erroneously increases 
beyond the maximum admissible pressure of approx. 7 bars, pressure 
measuring device 37 will automatically transmit a signal to venting valve 
36, causing it to be deactivated. Upon such deactivation, line 34 will 
open out to the atmosphere so that any excess pressure can be reduced and 
even further gas supplies cannot cause excess pressure to build up within 
the system. Rather, all the gas is vented directly to the atmosphere. 
As soon as the predetermined testing gas pressure has been reached, valve 
33 will be deactivated so that line 34 is closed at point 53. Thus, 
deactivation of valve 33 forms a closed system existing within line 34 and 
space 12 of FIG. 1 on the inlet side of membrane filter 11. From this 
moment in time, the pressure decline within said closed system is measured 
as a function of time. A rapid pressure decline may mean either that the 
system itself has a leak or that the membrane filter is defective. This 
measurement may be deemed a preliminary one intended to guarantee that 
there is no need for flow metering device 68. As soon as the system has 
been found to be tight, the first test on membrane filter permeability can 
be run. To do so, valve 33 is activated and line 34 and the system 
connected therewith are brought up to a first testing gas pressure 
amounting to approx. 80% of the so-called bubble-point pressure. 
Thereupon, valve 33 is deactivated. Since reference pressure system 65 and 
line 34 are connected via valve 41, the testing gas pressure prevailing in 
reference system 65 at that moment in time will be at the same level as 
the one within line 34. Next, valve 46 is activated so that line 48 is 
separated from the atmosphere and is connected with line 31, which is 
subject to approx. 7 bars of increased pressure. This will cause 
change-over switch 49 of pneumatically controllable valve 41 to move over 
into the position shown by broken lines in FIG. 4, which isolates 
reference pressure system 65. From this moment in time, the gas flow is 
measured through flow metering device 68 of line 38. In order to be sure a 
constant value has been obtained, the measurement is continued over 4 to 5 
minutes. Values obtained via flow metering device 68 may be recorded by 
means of a recorder, or stored in a magnetic memory. At the end of such 
measurement, valve 46 is deactivated once more, which likewise deactivates 
valve 41 by connecting line 34 with reference pressure system 65 so that 
the pressure prevailing on the two sides of flow metering device 68 are 
equalized. Thereupon, venting valve 36 may be actuated; however, this is 
unnecessary if, by way of example, the system is to be brought up, for the 
next measurement, to a pressure higher than the one for the first 
measurement. Thereupon, a second measurement can be made according to the 
same procedure as the one described above, except that the system 
consisting of line 34 and space 12 is now brought up to a pressure p 
greater than to the value of the first measurement. Other measurements may 
follow, provided their initial p value is greater than the preceding one. 
As long as the measuring system is operated within the range characterized 
by diffusion, designated 26 in FIG. 2, values obtained ought to result in 
a linear function, i.e., the quality of volumetric gas flow measured per 
unit of time ought to be directly proportional to the testing gas 
pressure. 
Subsequent to this measurement, venting valve 36 can be deactivated so that 
the entire system will once more be under atmospheric pressure. Another 
advantage of the system shown in FIG. 4 consists in the fact that no power 
failure will damage the system. In such event, no over-pressure can build 
up within the system since said venting valve will be open to the 
atmosphere. 
Another substantial advantage of the system shown in FIG. 4 consists in the 
fact that the reference pressure system 65, line 34 and space 12 may 
directly be brought up to the same testing gas pressure at a single 
stroke, i.e., by activating valve 33 via change-over valve 41. On the one 
hand, this expedites the measuring procedure while, on the other hand, it 
guarantees that testing gas pressures both in the measuring system and in 
the reference pressure system were at the same level at the beginning of 
any measurement. The preceding procedure notwithstanding, the method could 
be applied so as to bring the reference pressure system up to the testing 
gas pressure irrespective of line 34. In this case, it would not be 
necessary to separate the reference pressure system from the source of gas 
pressure if it can be guaranteed that the source of gas pressure will 
reliably remain at the testing gas pressure during the entire measurement. 
However, it will be preferable to isolate the reference pressure system 
whenever the testing gas pressure has been reached. Of course, it is not 
really necessary to connect reference pressure system 65, via line 45 and 
valve 41, with line 34. Properly speaking, it would be enough to link 
reference pressure system 65 via line 38 and flow metering device 68. 
However, since the flow metering device might cause certain bottlenecks, 
particularly as regards reverse flows, which bottlenecks might increase 
the time needed for the reference pressure system to be brought up to 
testing gas pressures, the system shown in FIG. 4 is preferred. 
The manufacturers of membrane filters invariably quote a value for maximum 
rate of gas diffusion through the membrane filter, e.g. 10 ml per minute 
at a testing pressure of p.sub.test =2.5 bars, in order to provide 
membrane filter users with a reference point for testing the filter, prior 
to using it, so as to tell whether it is subject to any defects, or may be 
used unrestrictedly. Anyone wanting to test, prior to filtration, the 
integrity and suitability for its intended use of any such membrane filter 
is faced with the problem of performing this test exclusively on the inlet 
side of the membrane filter and to determine, if at all possible, the rate 
of gas diffusion through the membrane filter in order to obtain a value 
which can be compared directly with manufacturer's data as to maximum 
speed of gas diffusion. 
Below, another method of verifying said values is described. From equation 
(6) it can be seen that pressure variation over time is proportional to 
rate (J) of gas diffusion. Hitherto, it has been impossible to obtain an 
absolute value for said rate of gas diffusion since the formula set forth 
above shows that the volume (V.sub.up) present on the inlet side of the 
membrane filter has to be taken into account in this measurement, and 
since it had hitherto been impossible to determine said value without 
complicated apparatus. 
It is now possible to directly determine the rate of gas diffusion 
according to the following method, which is to be explained 
diagrammatically in FIG. 6. In said diagram, pressure is plotted 
descendingly along the ordinate. Time is plotted along the abscissa. At 
moment in time A, the system is brought up to testing gas pressure T on 
the inlet side of the membrane filter. During period (AB), a pressure 
decline amounting to (TG) occurs. Since said pressure decline occurs as a 
linear function of time, the rate of pressure decline (p') may be 
determined by dividing TG by AB. Subsequent to determining rate p' of 
pressure decline, testing pressure is brought up to T at moment in time B. 
Subsequent to an arbitrary lapse of time, BC, during which another 
pressure loss, TF, occurs, a known volume V of gas will be drained from 
the system on the inlet side of the membrane filter over period of time 
CD, of arbitrary duration. In addition to the loss of pressure due to 
diffusion, there will be another pressure decline, FH. At an arbitrary 
moment in time, E, the measuring procedure is stopped after determination 
of TI, the amount of pressure lost over period BE. 
If rate p' of pressure decline over period AB, loss TI of pressure and 
calibration time BE are known, the pressure decline per unit of volume can 
be determined as follows: 
##EQU5## 
By substituting the value obtained in equation (7) into equation (8), the 
following is obtained: 
##EQU6## 
If standard conditions, i.e., a temperature of 20.degree. C. and a pressure 
of 1,013 mbar are to be applied to the above equation, factors p.sub.atm 
and T as well as a constant amounting to 3.457 have to be introduced into 
equation (9), the applicable unit being pressure divided by temperature; 
T corresponds to the absolute temperature in degrees Kelvin (K.), and 
p.sub.atm corresponds to the air pressure expressed in mbar. 
As regards speed of gas diffusion, the following expression results 
##EQU7## 
The testing method is applied by means of a system as described in FIGS. 1 
and 5. Measuring procedure is shown diagrammatically in FIG. 6. 
In order to determine the rate of gas diffusion and to test the integrity 
of a membrane filter already built in, e.g. into housing 10 according to 
FIG. 1, the test measuring device globally designated 60 is placed next to 
valve 24 at point 35 and tightly connected with said valve. At this moment 
in time, control valve 62 is closed. Thereupon, valve 36 will be 
activated, causing it to close. Next, valve 33 will be activated so that 
needle valve 32 and line 34, which functions as a common manifold for the 
connecting lines seen in FIG. 5, are connected. Next, the pressure within 
line 34 is adjusted to a predetermined testing gas pressure. Said testing 
gas pressure will be measured by way of the first pressure measuring 
device, 37. Whenever the pressure erroneously increases beyond the maximum 
admissible pressure of approx. 7 bars, pressure measuring device 37 will 
automatically transmit a signal to venting valve 36, causing it to be 
deactivated. Upon such deactivation, line or manifold 34 will open out to 
the atmosphere so that any excess pressure can be reduced and even further 
gas supplies cannot cause excess pressure to build up within the system. 
Rather, all the gas is vented directly to the atmosphere. 
As soon as the predetermined testing gas pressure has been reached, valve 
33 will be deactivated so that line 34 is closed at point 53. Thus, 
deactivation of valve 33 forms a closed system existing within line 34 and 
space 12 (of FIG. 1) on the inlet side of membrane filter 11. From this 
moment in time, the pressure decline within said closed system is measured 
as a function of time. A rapid pressure decline may mean either that the 
system itself has a leak or that the membrane filter is defective. This 
measurement may be deemed a preliminary one intended to guarantee that 
there are no major leaks. During this measurement, there is no need for 
pressure measuring device 40. Since the pressure prevailing on either side 
of said measuring device are equal, it may not be damaged. As soon as the 
system has been found to be tight, the first test on membrane filter 
permeability can be run. To do so, valve 33 is activated and line 34 and 
the system connected therewith are brought up to a first testing gas 
pressure. Thereupon, valve 33 is deactivated. Since reference pressure 
system 45 and line 34 are connected via valve 41, the testing gas pressure 
prevailing in reference system 45 at that moment in time will be at the 
same level as the one within line 34. Next, valve 46 is activated so that 
line 48 is separated from the atmosphere and is connected with line 31, 
which is subject to approx. 7 bars of increased pressure. This will cause 
change-over switch 49 of pneumatically controllable valve 41 to move over 
into the position shown by broken lines in FIG. 5, which isolates 
reference pressure system 45. From this moment in time, pressure measuring 
device 40 will be used to measure the pressure decline occurring between 
the pressure prevailing within line 34 and the one in reference pressure 
system 45. In the process, .DELTA.p per t, i.e., the pressure differential 
per unit of time, or the pressure differential TG per AB, is measured. In 
order to obtain a high enough degree of precision, the measurement is 
continued over 4 to 5 minutes. Values obtained via pressure measuring 
device 40 may be recorded by means of a recorder, or stored in a magnetic 
memory. At the end of such measurement, valve 46 is deactivated once more, 
which likewise deactivates valve 41 by connecting line 34 with reference 
pressure system 45 so that the pressure prevailing on the two sides of 
pressure measuring device 40 are equalized. Thereupon, venting valve 36 
may be actuated; however, this may be unnecessary since the system would 
be brought up again, e.g. if measurements go on, to some testing gas 
pressure. By means of line 34 and reference pressure system 45, the system 
is subsequently brought up to its test pressure, preferably the initial 
one; according to the diagram in FIG. 6 this ought to be achieved by 
moment in time B. Subsequent to the end of any pressure decline 
measurement, some period of time may obviously lapse until the system is 
back to testing gas pressure T. Time, corresponding to BE, will begin 
running and will be measured as soon as the measurement is initiated. 
After an arbitrary period of time, e.g. BC, subsequent to the initiation 
of said second measurement, control valve 62 is opened at moment in time 
C, and, simultaneously, a predetermined volume of gas, V, measured by 
means of a suitable measuring device, will be drained from line 34. 
Thereupon, control valve 62 is closed again. By draining the volume of gas 
from line 34, an additional decline of system pressure, of quantity FH, is 
caused to occur. Said decline will be added to the one amounting to TF to 
which the system is subject due to gas diffusion through the membrane 
filter at moment in time C. At moment in time D, i.e., when control valve 
62 is closed, an overall pressure of H prevails within the system. During 
period of time DE, said pressure will be reduced by pressure differential 
HI. Said reduction is entirely due to the diffusion of gas through the 
membrane filter. At moment in time E, this second measurement is 
terminated; period BE and overall pressure decline TI can now be 
determined. Thereupon, the system may be returned, as discussed above, to 
its initial state, i.e., to atmospheric pressure. Upon determination of 
the values applicable to the rate of pressure decline p' due to diffusion, 
to predetermined volume V drained from the system via control valve 62, to 
period of time BE corresponding to the duration of the second measurement, 
and to the total decline TI in pressure during said second measurement, 
equation (11) may be used to unequivocally determine the rate of 
diffusion. Every such quantity may be recorded automatically and 
transmitted to a suitable data processor for automatic determination of J.