Integrity Testing Sartocon Cassettes

Transcription

1 Integrity Testing Sartocon Cassettes

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3 Integrity Testing Sartocon Cassettes Background Sartorius Stedim Biotech Crossflow Cassettes are tested individually on integrity. For each cassette to the release the appropriate diffusion value is determined. From customer point of view it is helpfully to test several cassettes in the block before beginning of production. An adjustment to the available equipment must be made. 1. Introduction Cassettes can be integrity tested using gas diffusive flow (D) at 1,000 mbar test pressure (p test ); compressed air has to be used. The relatively high limit values (D max ) dictate that careful consideration must be given to the upstream volume (V N ) in which the diffusive flow is measured the stabilization time (t stab ), the test time (t test ) and the limit value when more than one cassette is installed. Note that when an automatic integrity tester is used (e.g. Sartocheck 3), D is determined from the pressure drop ( p) measured in V N according to the following equations: p = D t p 0 Equation 1 V N rearranged D = p V N Equation 2 t p 0 where: p in mbar = pressure drop measured by integrity tester D in ml/min = diffusion gas diffusive flow t test in min = test time p 0 = 1,000 mbar (absolute) atmospheric pressure V N in ml = upstream volume in which the p is being measured p test = 1,000 mbar test pressure D max = limit values of gas diffusive flow = stabilization time t stab 3

4 2. V N, t stab and t test As an example for Sartorius polyethersulfone (PESU) cassettes D max is 50 ml/min/cassette at a p test of 1,000 mbar. (Reference: Validation Guide). This high D value means that the p during testing must be within certain limits. To ensure that p test does not fall too low during testing the minimum value for V N is approx. 1 liter ( p 1 /V N, see equation 1). Additionally, t test must also be chosen to ensure the final pressure is 900 mbar (i.e. p max = 100 mbar) for testing with a Sartocheck 3. To ensure p is within limits a buffer volume is often required. This buffer volume is added to the determined V N of the holding device (see fig. 1 and ref. 1), and should be a minimum of 500 ml. The following example is valid for 1 cassette installed in a Sartocon 2+ holding device having a D value of 15 ml/min: t stab : use 2 min stabilization time to ensure pressure equilibration before testing. V N : minimum 500 ml (buffer vol) ml approx. (holding device) ml approx. (VN per cassette) = 950 ml. p: 16 mbar/min at D = 15 ml/min (see equation 1). t test: 5 min (total p 80 mbar) which is < 100 mbar. A maximum T test of 5 min will be suitable. T test must always be 2 min. Note: At V N = 450 ml (no buffer volume), p 167 mbar/5 min (> p max ). When more than 1 cassette is installed the expected total D (D total ) will be the sum (approx.) of the individual values. The t test will have to be specified after determination of V N, to ensure that the p measured is 100 mbar. Minimum t test 2 min. 4

5 For example: A system consisting of a Sartocon 2+ holding device and 2 Sartocon cassettes with a diffusion value of 15 ml/min each gives a total system diffusion (D total ) of 30ml/min, at a p test of 1,000 mbar: V N : buffer volume (minimum 500 ml) ml ml = minimum 1,100 ml. V N p t test Total p [ml] [mbar/min] [min] [mbar] 1, , t test (min) to give a total p of 100 mbar at 2 example values of V N. D total = 30 ml/min. See equation 1, page 2. Total p (mbar) = p (mbar/min) ƒ t test (min). p values rounded up (where required) to measuring accuracy of the Sartocheck 3 (±1 mbar). There will also be a p min, based on the accuracy of the integrity tester (e.g. ±1 mbar for the Sartocheck 3). Therefore, to operate within allowable test accuracy p min = 30 mbar (according to the Sartocheck 3 Validation Guide). Rearrangement of equation 1 can be used to determine the required values of V N and t test to operate within a p range of mbar. To ensure test accuracy, it is important to maintain a constant temperature (20 ± 2 C recommended). Note that the requirement for an additional buffer volume is not absolute. In large systems the feed and retentate pipework may be of sufficient volume. t stab : Recommended stabilization time. Recommended t stab for 1 to 4 cassettes: 2 min. Recommended t stab for 5 to 9 cassettes: 5 min. Recommended t stab for 10+ cassettes: 10 min. Greater cassette surface area will give greater D values. Increasing t stab will ensure pressure stabilization prior to testing. 5

6 3. Equipment Required Any suitable automatic integrity tester can be used. The equipment list below describes requirements for a Sartocheck 3: 3.1 Cassettes installed in a suitable holding device. 3.2 Valves or blanks to shut off feed and retentate lines (see fig. 1). It will often be necessary to dismantle pipework. 3.3 Attachment for connection of integrity tester to system (e.g. sanitary flange to RBE 3 male Staubli). 3.4 Automatic integrity testing device (e.g. Sartocheck 3). 3.5 Compressed instrument grade air (regulated bar). 3.6 Appropriate sized buffer volume (see section 2). The total upstream volume required must be calculated using equation 1. Sartocheck 3 V 2 P 2 Retentate Line P 1 P 3 Buffer volume V 1 Feed line Holding Device V 3 Permeate line Fig. 1. Equipment set up for integrity testing crossflow filter cassettes. 6

7 Cassette Block-Testing 4. Limit value when more than one cassette is installed It is possible that high diffusion from a failing cassette will be masked by the other cassettes when more than 2-3 units are installed as a set. In this situation the D total will be within the limit value ( 50 ml/min ƒ number of cassettes). For example, 10 cassettes giving D values of < 15 ml/min for 9 integral cassettes and 115 ml/min for a failed 10 th unit will give a D total of 179 ml/min. On first examination this gives a pass result: Example List for release results (PESU Cassettes): # Cassettes Diff. Results Diff. Spec. Comments [ml/min] [ml/min] released released released released released released failed released released released Total D total (179 ml/min) D max (500 ml/min) However, the fail cassette has been masked by the other 9 units. The procedure given in the next section has been designed to detect a failing cassette within an installed set. 7

8 5. Method for Testing a New Set of Cassettes 5.1 The new cassettes should be first flushed (purified water) and cleaned (e.g. 1 M NaOH) using the method that will be used after processing product. 5.2 Individual cassettes should be integrity tested after installation into the holding device at the recommended torque. For Sartorius cassettes this information can be found in ref. 1. Refer to fig. 1 for system set up. Isolate the holding device from the system (close appropriate valves) and attach the integrity tester to the retentate port. The feed port will be valved closed (V 1 ), and the permeate line must be open to atmosphere to prevent testing of a closed system (V 3 open). Attachment to the retentate port (V 2 open), which is invariably higher than the feed port, will prevent the possibility of entrained water within the cassettes contaminating the internal pneumatics of the integrity tester. Typical programming using a Sartocheck 3 integrity tester is: Diffusion Test Test pressure (p test ): 1,000 mbar Stab. Time (t stab ): 1 to 4 cassettes: 2 min 5 to 9 cassettes: 5 min 10+ cassettes: 10 min Test Time (t test ): Determined in section 2. Diff. max. (D max ): Refer to vendor s guide. This should demonstrate that all individual cassettes are integral. 5.3 Integrity test cassettes as a set. The programming details will be similar to that in step 5.2 (individual cassette), except that the value for D max entered at this stage should be the individual limit value ƒ number of cassettes. For example 50 ƒ 10 = 500 ml/min for 10 PESU cassettes. The value found is D total, and should be approx. the sum of the individual values found in step 5.2. (see example list). Prepared by Dr. Geoff Dunn, Revision 06 Review by Pahl, Meyeroltmanns, Baumfalk, Confirmed by B. Semrock, F. Weckmann,

9 5.4 The cassette with the highest diffusion value is used to determine the D max value for the set of cassettes: i) Determine D max D for this cassette, where D is the value found in 5.2 (e.g * = 33 ml/min). (* Cassette # 3 see example list ) ii) Add this value to D total, determined in 5.3 (e.g = 215 ml/min). (see example list) iii) This is the D max value for the set of cassettes. If during subsequent testing D total, becomes >215 ml/min (this example), this indicates that a cassette is failing and this failure will not be masked. The cassettes will have to be tested individually to identify this unit for further analysis and or replacement. Notes 1. High diffusion rates can be caused by: I) damaged filter membrane, II) cassette(s) not properly installed (e.g. incorrect torque), III) contamination with cleaning sanitization chemicals, IV) temperature too high (> 22 C), V) insufficient wetting, VI) general system leaks. Only point I) is based on a failing cassette(s); all other points are false fails. Points II) to VI) should be checked first. Always check the performance of the system by testing the quality of the permeate. Reference Directions for Use Sartocon Cassettes and Sartocon Slice Cassettes; (Order No.: ). This is the A5 size booklet included with each cassette. The 3 year shelf life of each cassette before first use means that different versions of this document will be supplied. Depending on the version supplied, the figure showing the installation of the buffer volume is on page 14, 15 or 16 in the section Checking the Functionality of the Filter Cassettes. Integrity test figures are given on page 30 in the section Specifications. This information is also given in the current Validation Guide (Validation Guide Sartocon Cassettes, Order No.: ) as follows: Buffer volume: Section 2.8 Checking the Integrity of the Filter Cassettes, pages Integrity test figures: Section 2.17 Specifications, pages

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