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Durapore-Hydrophilic-Filter-Cartridges-User-Guide

1. 25 Overview OF Integrity IestiliQ 2 icut odo eia cire e ee REM Eee pue tttm deu dte nein ern oaa aAa 26 Ib cadet Mio rm 26 Non Destructive Eris E E 27 Bubble Forint Bst N E 27 ea E 28 Automatic Integrity Testing oon dias tortue ea a ae 28 Diffusion Test or Bubble Point RS ies en anea aaa a eiee ibe 29 Considerations for When to Perform Pre use Integrity Tests 31 Pre Integrity Test Wetting of Hydrophilic Durapore Cartridges and Capsules see 31 Wetting Water Quallby cdit es cete aha nM tess reed EENE 31 Wetting Set p m M 32 FRECAUT ONS E 32 WV CU EV OCC IRC ERE D C T LU UE 32 Bubble Point Testing of Hydrophilic Durapore Cartridges and Capsules ssssseseee 33 B bble Point Test Froced re iiia ee iae cuba LEER a n ss ru Eau adve ASR 33 Diffusion Integrity Testing of Hydrophilic Durapore Cartridges and Capsules eseseeeese 35 Diffusion Integrity lest Proced re u een kx De eg eene aaa iaaa 35 Additional Integrity Test Literature ssssssssssssssseseeennenennennnenennnn nnnm a aaa naai a iaaa anaiai 37 Integrity Testing Training and Certification ssssssssssssssseeeeeeeeeennnmeeee nennen nnne rnnenrr renis 37 Chapter 5 Sterile Filtration Using Hydrophilic Durapore Car
2. Slightly crack open V9 11 Ensure that all gas is purged When you can see a steady flow of water or product and no gas exiting V5 close V5 12 Open V9 fully until the feed pressure P1 is at least 40 psi NOTE Do not exceed the maximum pressure rating for the filter unit 13 Continue to maintain this pressure for at least 1 min to dissolve any residual gas within the filter and ensure membrane wetting 14 Open outlet valve s until the wetting fluid flow is approximately 1 L min per f Open V6 and crack open and throttle V7 NOTE The filtrate side pressure increases because only a small differential pressure is required to achieve 1 L min per ft Figure 5 1 Typical sterile filter cartridge and housing assembly for bubble point test 42 www millipore com Post Use Bubble Point Test SOP Part One continued 15 Rewet using the conditions specified in Table 5 1 Table 5 1 Specified Wetting Conditions Using a Fressure Tank or Peristaltic Pump Filter Type Water How Fate Wetting Volume L Required volume L L min for 5 min pressure in recirculation peristaltic pump Millidisk 10 0 5 3 1 Millidisk 20 1 0 5 2 Millidisk 30 1 5 8 2 Millidisk 40 2 0 10 3 Millipak 20 0 1 1 1 Millipak 40 0 2 1 1 Millipak 60 0 4 2 1 Millipak 100 0 5
3. using an automatic integrity tester This guide focuses on manual methods However many users use automatic testers You can apply the concepts described in this guide to either method For more information on operating automatic integrity testers refer to the user manual that came with your automatic integrity tester instrument Destructive Testing The principle of bacterial challenge testing is to subject a sterilizing membrane to bacteria under the most se vere conditions that the membrane would encounter during actual use In essence the challenge test consists of exposing the membrane to bacteria subjecting it to stringent pressure and flow conditions and analyzing the effluent for the presence or absence of the challenge organism The standard organism for challenge testing Brevundimonas diminuta ATCC 19146 is chosen for its small size and its viability in the aqueous stream In the challenge test 107 colony forming units CFU per cm of filtra tion surface area are used Challenge testing is designed to provide the membrane manufacturer with the assurance that the membrane and fabricated device meet the critical performance criteria of a sterilizing grade filter The test is performed by the filter manufacturer on a statistical sample of each lot of filters produced However this test is a destruc tive test because you cannot reuse the tested filters I WA Figure 4 1 B diminuta on Durapore membrane Hydrophilic Dur
4. 35 Table of Tables Table 1 1 Table 1 2 Table 1 8 Table 14 Table 1 5 Table 1 6 Table 1 7 Table 1 8 Table 1 9 Table 2 1 Table 3 1 Table 3 2 Table 3 3 Table 3 4 Table 3 5 Table 3 6 Table 3 7 Table 4 1 Table 4 2 Table 4 3 Table A 1 Table A 2 Hydrophilic Durapore Cartridges Materials of Construction seen 2 Hydrophilic Durapore Cartridges Nominal Device DiMensions cccceeeeeeeeeeeeeeeeeeeeeeeees 2 Hydrophilic Durapore Cartridges Nominal Effective Filtration Area cccccecceeeeeeeeeeeeeeeeeeeeeees 3 Hydrophilic Durapore Cartridges Recommended Hush Volumes Post Sterilization 4 Hydrophilic Durapore Capsules Materials of Construction ccseeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeees 5 Hydrophilic Durapore Capsules Nominal Device Dimensions ccccceeeeeeeeeeeeeeeeeeeeeeeeeeaeaea 6 Hydrophilic Durapore Capsules Nominal Effective Filtration Area ssseseeeeeeeeeeeee 8 Nominal Fold Up Volume eiut een een an 8 Hydrophilic Durapore Capsules Recommended Hush Volumes sse 9 Color Code for Hydrophilic Durapore Capsule Filter Pore Size sessssssss 13 Saturated Steam Pressure and Temperature ssssssssssssssssseeeeee nnne 16 Recommended Feed Water Quality for Pure Steam ssssssssssseee 16 Hydrophilic Durapore Cartridges Maximum Steriliza
5. 6 mm NPTM inlet and 1 4 6 mm step barb outlet 3 2 8 1 7 6 Millipak 60 MP LO6 H 1 4 6 mm Step barb inlet and outlet 10 7 6 Millipak 60 MP LO6 F 3 4 19 mm sanitary flange inlet and outlet 3 7 9 4 7 6 Millipak 100 MP L10CL 1 1 2 38 mm sanitary flange inlet and outlet 5 1 13 7 6 Millipak 100 MP L10CB 1 4 6 mm NPIM inlet and outlet 2 9 7 4 7 6 Millipak 100 MP L1 OCF 3 4 19 mm sanitary flange inlet and outlet 4 2 11 7 6 Millipak 100 MP L10CA 9 16 14 mm barb inlet and outlet 3 3 8 4 7 6 Millipak 200 MP L20CL 1 1 2 38 mm sanitary flange inlet and outlet 6 1 15 5 7 6 Millipak 200 MP L20CB 1 4 6 mm NPIM inlet and outlet 3 9 10 7 6 Millipak 200 MP L20CF 3 4 19 mm sanitary flange inlet and outlet 5 2 13 7 6 Millipak 200 MP L20CA 9 16 14 mm barb inlet and outlet 4 3 11 7 6 Millipak 200 MP L20CA 9 16 14 mm barb inlet and outlet 4 3 11 7 6 Refer to the Millipore catalogue or www millipore com for the full catalogue number of the device configuration you are interested in These abbreviated numbers are for quick reference only Measured from connection to connection Quter diameter Hydrophilic Durapore Cartridges and Capsules User Guide Table 1 6 Hydrophil
6. 60 min 1000 Capsules KVVLO1 Non Sterile Opticap 10 KVGLG1 KVVLG1 N A 1000 Capsules Non Sterile Gamma Compatible Opticap 10 KVGLS4 KVVLS4 Irradiation 500 Capsules Pre Sterilized by Gamma Opticap 4 KVG04 Autoclave at 126 C for 30 min 500 Capsules Non Sterile Opticap 4 KVGLG4 KVVLG4 N A 1000 Capsules Non Sterile Gamma Compatible Opticap 4 KVGLSI KVVLS1 Irradiation 1000 Capsules Pre Sterilized by Gamma Opticap 4 KV0304 KVO604 Autoclave at 123 C for 30 min 1000 Multimedia Capsules KV1904 Non Sterile KVSC04 KVSS04 KVSX04 Opticap 4 KVHLO 1 Autoclave at 121 C for 60 min 1000 Multimedia Capsules Non Sterile 0 45 um Refer to the Millipore catalogue or www millipore com for the full catalogue number of the device configuration you are interested in These abbreviated numbers are for quick reference only Pre test treatment conditions described in this table are not intended as a substitute for filter sterilization validation The user is responsible for conducting an on site filter sterilization validation study Recommended flush volume to meet the USP Oxidizables Test Additional Literature on Hydrophilic Durapore Cartridges and Capsules Contact Millipore to obtain the following literature for more details on available catalogue numbers E Millipore Pharmaceutical Process Separations Catalogue E Product Data Sheets E Product Applic
7. RWO6 0 5 Um Filter Membrane plus Cartridges Media Over Durapore MEC 10 30 Hydrophilic 0 22 Um on a polyester web Membrane Durapore CVSS TP3 Milligard Rgid Polypropylene Modified Spun Bonded Polypropylene Silicone 0 22 Um RWO06 0 5 Um PVDF Multimedia and RW03 0 2 Um Filter Membrane plus Cartridges Media Over Durapore MEC 10 30 Hydrophilic 0 22 Um on a polyester web Membrane Durapore CVSX TP3 Milligard Rigid Polypropylene Modified Spun Bonded Polypropylene Silicone 0 22 um RW19 1 2 Im PVDF Multimedia and RW03 0 2 Um Filter Membrane plus Cartridges Media Over Durapore MEC 10 30 Hydrophilic 0 22 Um on a polyester web Membrane Millidisk MC L Durapore Hydrophilic Polysulfone Modified PVDF n a Silicone Membrane Refer to the Millipore catalogue or www millipore com for the full catalogue number of the device configuration you are interested in These abbreviated numbers are for quick reference only Durapore Pore Sizes are as follows GL0 22 um HL 0 45 um VLO 1 um and DRO 65 um Milligard Media Nominal pore ratings are as follows RW 19 media 1 2 um RW06 media 0 5 um and RWO3 media 0 2 um Table 1 2 Hydrophilic Durapore Cartridges Nominal Device Dimensions Type Item Number Approx Nominal Approx Nominal Approx Nominal Approx Nominal abbreviated Length inch Length cm OD inch OD cm Millidisk 10 MC L10 17 8 4 8 n a n a Millidisk 20 MC L20 27 8 7 3 n
8. a n a Millidisk 30 MC L30 37 8 9 9 n a n a Millidisk 40 MC L40 47 8 12 4 n a n a Durapore 5 CV 5 5 12 7 2 7 6 9 Durapore 10 CV 1 10 25 4 2 7 6 9 Durapore 20 CV 2 20 50 8 2 7 6 9 Durapore 30 CV 3 30 76 2 2 7 6 9 Optiseal Cartridges w Durapore Membrane L LO4 4 10 2 2 3 5 7 Refer to the Millipore Catalogue or www millipore com for the full catalogue number of the device configuration you are interested in These abbreviated numbers are for quick reference only Outer diameter Table 1 3 Hydrophilic Durapore Cartridges Nominal Effective Filtration Area EFA www millipore com Type Item Number abbreviated EFA ft EFA nv Millidisk 10 MC L10 0 5 500 cm Millidisk 20 MC L20 1 1 1000 cm Millidisk 30 MC L30 1 6 1500 cm Millidisk 40 MC L40 2 2 2000 cm Durapore 5 CV L 5 3 8 0 4 m Durapore and CV L 1 CV03 1TP3 7 4 0 7 m Single Layer Milligard 10 CV06 1TP3 CV19 1TP3 Durapore and CV L 2 CV03 2TP3 14 8 1 4 m Single Layer Milligard 20 CV06 2TP3 CV19 2TP3 Durapore and CV L 3 CV03 3TP3 22 2 2 1 m Single Layer Milligard 30 CV06 3TP3 CV19 3TP3 Durapore and CVSC 1TP3 CVSS 1TP3 6 0 0 6 m Double Layer Milligard 10 CVSX 1 TP3 Durapore and CVSC 2TP3 CVSS 2TP3 12 0 1 2 m Double Layer Milligard 20 CVSX 2TP3 Durapore and CVSC 3TP3 CVSS 3TP3 18 0 1 8 m Double Layer Milligard 30 CVSX 3TP3 Optiseal Cartridges w Dur
9. filter and ensure membrane wetting 14 Open outlet valve s until WFI flow is approximately 1 L min per ft Open V6 and crack open and throttle V7 NOTE The filtrate side pressure increases because only a small differential pressure is required to achieve 1 L min per ft 15 Rewet using the conditions specified in Table 4 3 16 Perform Bubble Point Retest Repeat steps 1 through 8 If your test fails save the filter and contact Millipore Technical Service for assistance Figure 4 4 Typical sterile filter cartridge and housing assembly for bubble point test 36 www millipore com Diffusion Integrity Testing of Hydrophilic Durapore Cartridges and Capsules Diffusion Integrity Testing Procedure Before starting the procedure ensure that the proper gas type is supplied for the test air nitrogen etc 1 Allow excess water to flow out of the down stream side of the system Open V8 V3 V6 and V7 Refer to Figure 4 5 2 Set gas pressure regulator to 5 psig Hold until wetting fluid has stopped flowing from the outlet port NOTE Look for rapid continuous bubbling at this time If none occurs continue to the next step Rapid bubbling at this time may be due to insufficient wetting or improper filter installation Check the filter installation and repeat the steps listed in the previous wetting proce
10. methods for wetting membrane filters direct flow using a pressure tank or recirculation using a peristaltic pump Wetting using a pressure tank is the most efficient and preferred method Wetting using a peristaltic pump in a recirculating mode reduces the amount of water or other validated wetting fluid re quired during the wetting procedure Wetting Setup with a Pressure Tank This wetting procedure is for cartridges and capsules See Figure 4 2 The figure illustrates the cartridge wetting process However you could easily replace the cartridge housing surrounded by dashes with a cap sule filter Figure 4 2 Typical sterile filter cartridge and housing assembly for pressure tank wetting 32 www millipore com Frecautions Before starting the procedure check the following E The proper filter has been selected confirm pore size and catalogue number W Filter is installed correctly in the housing See Chapter 2 for details on proper filter installation E All valves are closed E Water or validated alternate wetting fluid can deliver at least 1 liter minute per ft of effective filter surface area at 20 psig 1 4 bar This can be supplied by using a pressure vessel or a peristaltic pump See V9 in Figure 4 2 Wetting Procedure with a Pressure Tank most efficient and preferred method Monitor and control the temperature of
11. pressure at SIP temp Code 7 tabs bent down Exceeded specification reverse hydraulic stress at SIP temp Reduce differential pressure at SIP temp Cartridge meltdown Exceeded polypropylene melting point of 168 C Check steam temp amp pressure Sleeve warping Exceeded specification SIP temperature Check steam temp amp pressure Hydrolysis Exceeded specifications for SIP cycles for polymers Replace cartridge at recommended intervals Oxidation Exceeded specifications for exposure limits for time temp in air Feplace cartridge at recommended intervals Sleeve ballooning Exceeded specification reverse stress at SIP temp Reduce differential pressure at SIP temp Brown or green color Contaminants in steam Check pH of steam amp or add pre filtration O ring distortion Exceeded specification SIP temp Check steaming conditions amp replace O rings 22 www millipore com 7 nutociasing Hydrophilic Durapore Capsules N and Cartridge Housing Assemblies Autoclaving capsules and cartridge housing assemblies has an advantage and disadvantage Bl Autoclaving advantage Uses passive steam that does not create damaging differential pressure during the process Bl Autoclaving disadvantage Once the filter is removed from the autoclave it must be installed aseptically before use 4 WARNING Do not under any circumstances SIP capsule filters See Tables 3 5 and 3 6 for the maximum conditions for autoclaving Durapore filters a
12. regularly during the sterilization phase 9 Close the steam supply valve and introduce sterile compressed gas into the system when the sterilization process completes Close V1 and slowly open V8 NOTE Make sure that the system remains under positive pressure as indicated by Pl and P2 The differen tial pressure P1 P2 should not exceed 5 psid Hydrophilic Durapore Cartridges and Capsules User Guide Post Steaming Blow Down This procedure ensures positive pressure and accelerated system cooling 21 1 Allow for steam purge from all valves Close V2 and V4 to increase the flow of gas through the system Maintain the flow to cool down the system until the temperature gauge T1 indicates approximately 30 C 2 Respectively close valves V7 V6 and V4 and V5 Keep the compressed gas flow on and the filter inlet open to maintain a positive pressure into the sterile filter system while not in use The system is now ready for integrity testing See Chapter 4 for information on integrity testing Troubleshooting the SIP Procedure If filter damage occurs check Table 3 4 to troubleshoot the probable cause of the damage The table lists probable causes and solutions for some of the problems you may encounter during the SIP procedure Table 3 4 Cartridge Filter Failure Modes from SIP Description of Failure Cause Core collapse Exceeded specification forward hydraulic stress at SIP temp Action to Prevent Reduce differential
13. solutions However some products leave residual components on the filter that affect the measured integrity test value In some cases even rigorous membrane flushing cannot remove the residual components In these cases you need to establish a product based integrity test specification Millipore s Access Services can help you establish this value To be valid the product based integrity test values must be reproducible Another option is to flush the filter with a 70 30 IPA Water reference solution Millipore sterilizing grade 0 22 um filters have a bubble point specification of 18 5 psig for a 70 30 IPA reference solution See the following procedure Part One and Part Two for details on this method Post Use Bubble Point Test SOP Part One Before starting the procedure ensure that the proper gas type is supplied for the test air nitrogen etc 1 Allow excess wetting solution to flow out of the down stream side of the system Open V8 V3 V6 and V7 Refer to Figure 5 1 2 Set gas pressure regulator to 5 psig Hold until the water has stopped flowing from the outlet port NOTE Look for rapid continuous bubbling at this time If none occurs continue to the next step Rapid bubbling at this time may be due to insufficient wetting or improper filter installation Check the filter installation and repeat the steps listed in the wetting procedure described in Chapter 4 if you see rapid bubbling 3 Increase gas pressure regulator
14. the wetting fluid and the filter system to the temperature specified for the particular diffusion or bubble point test you want to perform Tests performed at temperatures other than those recommended can affect the results of both the diffusion and the bubble point tests 1 Cleara path for the wetting fluid to enter the system and clear a path for air to exit Open V3 and V5 2 Allow the wetting fluid to enter the filter Slightly crack open V9 3 Ensure that all gas is purged When you can see a steady flow of the wetting fluid and no gas exiting V5 close V5 NOTE Trapped air can prevent the membrane from becoming fully wet this can cause improper measure ment of the diffusion rate and the bubble point test pressure 4 Increase the pressure on the feed side of the filter to a minimum of 20 psig 1 4 bar A pressure of 40 psig 2 8 bar is ideal Fully open V9 NOTE Do not exceed the maximum pressure rating for the filter unit 5 Maintain this pressure for at least 1 minute to dissolve any residual gas within the filter to ensure complete membrane wetting 6 Open outlet valve s until the wetting fluid flow is approximately 1 L min per f of effective filter surface area Open V6 and crack open and throttle V7 See Table 4 3 for wetting conditions NOTE The filtrate side pressure increases because only a small differential pressure is required to achieve 1 L min per ft 7 Shut off wetting fluid supply V9 after 5 minu
15. to the instruction manuals supplied with your automatic integrity tester for complete information on their operation You may also contact your Millipore representative for assistance with installation and opera tional qualification calibration service or training for your Millipore automatic integrity testers Hydrophilic Durapore Cartridges and Capsules User Guide Diffusion Test or Bubble Point Test Millipore recommends using a bubble point test when possible because bubble point is a function of pore size and is directly correlated to bacterial retention You can determine the bubble point manually on filters as small as a 47 mm disk and up Manual bubble point determination is typically limited to gas flow rates of up to 100 mL min Any system with a diffusional flow rate greater than 100 mL min makes a distinction between diffusional flow and bulk flow difficult Diffusion flow specifications are directly proportional to surface area Typically filters with surface area less than 2 f do not have a diffusion specification because the diffusional flow is too small to accurately measure 29 Tables 4 1 and 4 2 show the diffusion rate and bubble point specifications for Millipore cartridges and cap sules Table 4 1 Hydrophilic Durapore Cartridges Integrity Testing Specifications at 23 C Product Catalogue Integrity Test Product Specifications Test Gas Test Huid Designation Number Type Test Pr
16. type E Wetting fluid E Temperature of system room fluid and filter 28 www millipore com Diffusion Test A diffusion test involves applying a differential gas pressure below the bubble point Gas molecules migrate through the water filled pores of the membrane following Fick s Law of Diffusion The gas diffusional flow rate for a filter is proportional to the differential pressure and the total surface area of the filter At a pressure of approximately 80 of the minimum bubble point the gas which diffuses through the membrane is measured to determined filter s integrity This flow is much smaller than the bulk flow associated with bubble point Q K PI 2 Ap E Q diffusional flow K diffusivity solubility coefficient P1 P2 pressure difference across the system A membrane area p membrane porosity L effective path length Factors that affect the measurement of diffusion are the degree to which the membrane is fully wetted wetting fluid gas type and temperature NOTE The most common cause of pre use integrity test failures is insufficient wetting When performing a diffusion test you must specify the following parameters E Filter type E Filter surface area E Wetting fluid E Test gas NOTE Gases have varying diffusivities and solubilities E Temperature E Maximum acceptable flow rate E Test pressure Automatic or Manual Integrity Testing Bubble point and diffusion tests can be performed manu
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18. 3 1 Millipak 200 1 5 2 Optiseal Opticap 2 10 3 Durapore 5 3 5 18 5 Durapore 10 7 35 8 Durapore 20 14 70 12 Durapore 30 21 105 15 Hydrophilic filters wet at a minimum flow rate of approximately 1 Lpm f of effective filtration area for 5 minutes If using the recirculation method post use flush product to drain and rinse properly before recirculating 16 Continue to the next section Post Use Bubble Point Test Part Two Post Use Bubble Point Test SOP Part Two 1 Repeatsteps 2 through 6 in the previous procedure Post Use Bubble Point Test Part One 2 If the bubble point value is below the specification proceed to step 3 If the value is equal to or above the specification the filter is integral NOTE If the filter fails two integrity tests using water PDA Technical Report 26 allows the use of a lower surface tension reference fluid Millipore recommends that you use a 70 30 IPA solution with Durapore The specification for 0 22 ym Durapore is gt 18 5 psig 3 Wet the filter using 70 30 IPA solution either by static soaking cartridges only the unit for a minimum of 5 minutes or by dynamic flow capsules cartridges at a minimum flow rate of approximately 0 5 Lpm ft of effective filtration area for 5 minutes 4 Set gas pressure regulator to 5 psig Hold until the wetting fluid has stopped flowing from the outlet port NOTE Look for rapid continuous bubbling at this time If none occurs continue to the next ste
19. 4 KV LO4FH3 3 4 19 mm 6 5 16 5 Body 2 4 Body 6 1 cm sanitary flange inlet End Cap 3 7 End Cap 9 4 cm and 9 16 14 mm barb outlet Opticap 4 KV LO4FF3 3 4 19 mm 6 7 17 Body 2 4 Body 6 1 cm sanitary flange End Cap 3 7 End Cap 9 4 cm inlet and outlet Opticap 4 KV LG4HH3 9 16 14 mm 6 3 16 Body 2 4 Body 6 1 cm KV LS4HH3 barb inlet End Cap 3 7 End Cap 9 4 cm KV 04HB3 and outlet Refer to the Millipore catalogue or www millipore com for the full catalogue number of the device configuration you are interested in These abbreviated numbers are for quick reference only Measured from connection to connection Outer diameter Table 1 7 Hydrophilic Durapore Capsules Nominal Effective Filtration Area EFA www millipore com Device Item Number abbreviated EFA ft EFA n Millipak 20 MP LO2 0 1 100 cm Millipak 40 MP LO4 0 2 200 cm Millipak 60 MP LO6 0 3 300 cm Millipak 100 MP L1 0 5 500 cm Millipak 200 MP L2 1 1 0 1 m Opticap 10 Capsules Non Sterile KPHLO1 KVGLO1 KVVLO1 7 4 0 7 m Opticap 10 Capsules Non Sterile KV LG1 KV LS1 7 8 0 7 m Gamma Compatible or Pre Sterilized by Gamma Opticap 4 Capsules Non Sterile KV LO4 1 5 0 14 m Opticap 4 Capsules Non Sterile KV LG4 KV LS4 1 6 0 15 m Gamma Compatible or Pre Sterilized by Gamma Opticap 4 Multimedia Capsules KV0304 KV0604 KV1904 1 5 0 14 m
20. HL TP 121 C 30 minutes 10 times max Multimedia Cartridges Durapore 0 22 um CVO03 TP3 CVSC TP3 123 C 30 minutes 6 times max Multimedia Cartridges CV06 TP3 CVSS TP3 CV19 TP3 CVSX TP3 Millidisk Cartridges MC L 135 C 60 minutes 5 times max Optiseal Charged Durapore Cartridges LCGLO4 135 C 30 minutes 10 times max Optiseal Cartridges w Durapore Membrane LAGLO4 LAVLO4 LAHLO4PP 135 C 30 minutes 30 times max Optiseal Multimedia Cartridges LAHLO4 TP 121 C 30 minutes 10 times max w Durapore Membrane These are the maximum conditions Durapore cartridges have been validated to withstand Select the time and temperature appropriate to validate the proper sterilization of the device and housing The recommendations in this table are not intended as a substitute for filter sterilization validation The user is responsible for on site filter sterilization validation studies 18 www millipore com SIP System Design Overview Figure 3 1 is a schematic of the filter assembly or target unit to steam in place This schematic includes the filter the filter housing valves pressure and or temperature gauges Figure 3 1 Typical sterile filter cartridge and housing assembly for SIP SIP System Design Considerations Consider the following when designing an SIP system Bl Air Removal The ideal air removal system allows steam
21. Lenntech info lenntech com Tel 431 152 610 900 www lenntech com Fax 431 152 616 289 MILLIPORE Hydrophilic DURAPO RE Cartridges and Capsules User Guide HOW TO USE THIS GUIDE The Hydrophilic Durapore Cartridges and Capsules User Guide is a reference that operators should find helpful at all stages of product use This document contains details on supporting background guidelines standard operating procedures and provides references for users to access additional information The information is provided in chronological order physical description handling and installation sterilization pre use integrity testing sterile filtration and post use integrity testing Each section begins with supporting background information to help users understand the reasoning behind the recommendations and standard operating procedures SOPs If users ever encounter problems this guide provides information on how to identify and solve them The guide is designed this way to encourage the user to read the background information before using the filter It also helps users avoid common pitfalls and make their filter using experience predictable and problem free The recommendations and SOPs follow the back ground information so users can successfully complete any of the filter processes Contact Millipore Technical Service at 1 800 MILLIPORE 1 800 645 5476 if you have any questions or re quire further information Table of Contents Chapte
22. Non Sterile Opticap 4 Multimedia Capsules KVSC04 KVSS04 KVSX04 1 2 0 11m Non Sterile Refer to the Millipore catalogue or www millipore com for the full catalogue number of the device configuration you are interested in These abbreviated numbers are for quick reference only Table 1 8 Nominal Hold Up Volume Product Designation Item Number abbreviated Upstream Volume Hold Up Volume nominal Exceeding Bubble Point Millipak 20 MPGLO2 30 mL 1 mL Millipak 40 MPGLO04 40 mL 2 mL Millipak 60 MPGLO6 50 mL 2 mL Millipak 100 MPGL10 70 mL 3 mL Millipak 200 MPGL20 110 mL 7 mL Durapore 10 Cartridge CVGL 3000 mL 90 mL 4 Opticap KVGL04 140 mL 20 mL 10 Opticap KVGLO1 640 mL 90 mL Refer to the Millipore catalogue or www millipore com for the full catalogue number of the device configuration you are interested in These abbreviated numbers are for quick reference only Hydrophilic Durapore Cartridges and Capsules User Guide 9 Table 1 9 Hydrophilic Durapore Capsules Recommended Flush Volumes Post Sterilization Device Item Number Worst Case Recommended abbreviated Pre Test Treatment Aush Volume mL Millipak MP LO MP L1 Autoclave at 123 C for 90 min 200 Non Sterile MP L2 Capsules Millipak MP L G MP L G Irradiation 200 Pre Sterilized by Gamma Capsules Opticap 10 KPHLO1 KVGLO1 Autoclave at 126 C for
23. O rings Polypropylene Multimedia 0 2 um Filter Media Over MEC on a in Vent Durapore Hydrophilic polyester web Ports 0 22 um Membrane Refer to the Millipore catalogue or www millipore com for the full catalogue number of the device configuration you are interested in These abbreviated numbers are for quick reference only Durapore Pore Sizes are as follows GL0 22 um HL 0 45 um VLO 1 um and DRO 65 um Milligard Media Nominal pore ratings are as follows RW 19 media 1 2 um RW06 media 0 5 um and RW03 media 0 2 um Table 1 6 Hydrophilic Durapore Capsules Nominal Device Dimensions Type Millipak 20 Item Number abbreviated MP LO2 H 1 4 6 mm step barb inlet and outlet Configuration Approx Nominal Length inch 4 Approx Nominal Length cm 10 Approx Nominal OD inch 3 www millipore com Approx Nominal OD cm 7 6 Millipak 20 MP L02 F 3 4 19 mm sanitary flange inlet and outlet 3 3 8 4 7 6 Millipak 40 MP L04 K 1 4 6 mm NPTM inlet and 1 4 6 mm step barb outlet 3 6 9 1 7 6 Millipak 40 MP L04 H 1 4 6 mm Step barb inlet and outlet 10 7 6 Millipak 40 MP LO4 F 3 4 19 mm sanitary flange inlet and outlet 3 5 8 9 7 6 Millipak 60 MP LO6CL 1 1 2 38 mm sanitary flange Inlet 1 4 6 mm step barb outlet 3 6 9 1 7 6 Millipak 60 MPSLO6CB 1 4
24. ad to less moist heat contact and lower sterilization temperatures of the target unit Condensate resistance to heat transfer is 70 times greater than that of stainless steel Air resis tance to heat transfer is 25 times greater than that of water Accumulated condensate can be acceler ated by flowing steam producing what is known as a water hammer Removing condensation prevents a water hammer from forming and damaging the filter 4 Introduce steam progressively and heat up the filter Slowly open V3 5 Partially close bleed valves V2 V4 and V5 so that you can see a 6 inch wisp of steam and a continuous drip of condensate exiting 6 Establish a steady flow of steam and allow for condensate drainage and air removal from the filter housing Fully open V6 then crack open V7 NOTE Control the pressure drop across the filter P1 P2 The differential pressure across the filter P1 P2 should not exceed 5 psid Only a small flow of steam is required to heat up the assembly because steam can effectively transfer a large amount of heat approximately 1000 BTU b 7 Ensure that all air and condensate are effectively removed Keep V2 V4 V5 and V7 cracked open so that you can see a 6 inch wisp of steam and a continuous drip of water exiting 8 Start timing the sterilization cycle when the pressure gauge P3 reaches the validated pressure or the temperature gauge T1 reaches the validated temperature Record both temperature and pressure
25. ally or with an automatic integrity tester A manual test requires minimal equipment and is easy to perform However its use as a post sterilization pre use integ rity test is limited because manual tests require aseptic manipulations downstream of the filter In contrast to manual methods automatic integrity testers rely upon upstream measurements for the determina tion of filter integrity Connection and operation of these instruments does not compromise downstream steril ity These instruments eliminate operator subjectivity provide a hard copy of the data and may provide data storage However automatic integrity testers are very sensitive to small leaks and small temperature variations and require appropriate installation and operational qualification Users performing any integrity test should be qualified and certified If an automatic integrity test is the user s preferred method that user should be trained in performing manual integrity test methods so that these methods can be used as a back up should an automatic integrity tester become unavailable The following sections describe manual methods for integrity testing NOTE Millipore offers two models of automatic integrity testers the Integritest II series and the Integritest Exacta series instruments Each instrument has specific features and uses different features and methods to determine filter integrity The operation of these instruments is outside the scope of this guide Refer
26. apore Cartridges and Capsules User Guide 27 Non Destructive Testing A non destructive physical integrity test is used in place of a destructive test because a destructive test leaves the filter unfit for use The stringent requirements of the pharmaceutical industry dictate that non destructive tests for filter integrity be used on each application For the integrity test to be meaningful it must be corre lated with bacterial retention tests Two common non destructive integrity tests are bubble point test and diffusion test The bubble point integrity test has a direct correlation to bacterial retention while diffusion testing has an indirect correlation Bubble Point Test The bubble point test is based on the fact that liquid is held in the pores of the filter by surface tension and capillary forces Bubble point is the pressure where gas displaces liquid from the largest set of filter pores and flows rapidly bulk flow through the filter The theoretical equation describing bubble point is P 4kcos 0 6 d P bubble point pressure d pore diameter k shape correction factor 0 liquid solid contact angle o surface tension Other factors that affect bubble point measurements are membrane structure temperature wetting fluid and degree of wetting NOTE The most common cause of pre use integrity test failures is insufficient wetting When performing a bubble point test you must specify the following parameters B Filter
27. apore Membrane L L04 1 9 0 2 m Table 1 4 Hydrophilic Durapore Cartridges Recommended Hush Volumes Post Sterilization Device Item Number Worst Case Recommended Hush abbreviated Pre Test Volume mL Treatment Charged Durapore Cartridges CCGL Autoclave at 126 C for 30 minutes 1000 per 10 Durapore 5 Cartridges CV L 5 Autoclave at 126 C for 60 minutes 500 Durapore Cartridges CVDR PP CVHL PP Autoclave at 126 C for 60 minutes 1000 per 10 CVGL CVVL Durapore CVDR TP CVHL TP CV19 Autoclave at 121 C for 60 minutes 1000 per 10 Multimedia CV03 CV06 CVSC Cartridges CVSS CVSX Millidisk Cartridges MC L Autoclave at 126 C for 60 minutes 200 per device Optiseal Charged LCGLO4 Autoclave at 126 C for 30 minutes 500 Durapore Cartridges Optiseal Cartridges LAGLO4 LAVLO4 Autoclave at 126 C for 30 minutes 500 w Durapore Membrane Optiseal Multimedia LAHL TP Autoclave at 121 C for 30 minutes 500 Cartridges w Durapore Membrane Refer to the Millipore catalogue or www millipore com for the full catalogue number of the device configuration you are interested in These abbreviated numbers are for quick reference only Recommended flush volume to meet USP oxidizables test KKK ization validation study is the responsibility of the user Pre test treatment conditions described are not intended as a substitute fo
28. ation Notes E Millipore Validation Guides E Millipore Validation Services Or visit our web site at www millipore com Chapter 2 Installation of Hydrophilic Durapore Cartridges and Capsules Introduction This chapter provides information on Wi Filter inspection E Filter box contents Bi Guidelines for filter installation including suggestions for the proper handling of cartridges and capsules Wi Filter shelf life and storage conditions 12 www millipore com Inspecting the Filter When you receive a new box of filters visually inspect them to ensure that they were not damaged during shipping The outer box should be intact and in good condition The outer bags within the box that protect the filters should also be intact If necessary call Millipore Technical Service to report any damage In the U S call 1 800 MILLIPORE 1 800 645 5476 Outside the U S see your Millipore catalogue for the phone number of the Millipore office nearest you Or contact Millipore Technical Service by e mail at tech service amp millipore com Unpacking the Box Your box of Durapore filters should include Bl Certificate of Quality The Certificate of Quality provides detailed product properties and performance data It is product specific and typically lists lot release criteria product audit criteria and in process testing Bl Wetting Instructions The Wetting Instructions provide helpful procedural information on how to completely wet the f
29. d Rigid Polypropylene Modified Spun Bonded Polypropylene Silicone 0 45 Um LAHLO4TP RWO06 0 5 Um PVDF Multimedia Filter Media Membrane plus Cartridges Over Durapore Hydrophilic MEC 10 30 and 0 45 Um on a polyester web Optiseal Multimedia Cartridges Membrane w Durapore membrane Durapore CVO03 TP3 Milligard Rigid Polypropylene Modified Spun Bonded Polypropylene Silicone 0 22 Um RW03 0 2 Um PVDF Multimedia Filter Media Membrane plus Cartridges Over Durapore Hydrophilic MEC 10 30 0 22 Um on a polyester web Membrane Durapore CVO06 TP3 Milligard Rigid Polypropylene Modified Spun Bonded Polypropylene Silicone 0 22 Um RW06 0 5 Um PVDF Multimedia Filter Media Membrane plus Cartridges Over Durapore Hydrophilic MEC 10 30 0 22 Um on a polyester web Membrane Hydrophilic Durapore Cartridges and Capsules User Guide 3 Table 1 1 Hydrophilic Durapore Cartridges Materials of Construction continued Device Item Number Membrane Materials Materials Membrane Materials Support Materials abbreviated Cage Core or Disk Filter Web O ring Durapore CV19 TP3 Milligard Rigid Polypropylene Modified Spun Bonded Polypropylene Silicone 0 22 um RW19 1 2 Im PVDF Multimedia Filter Media Membrane plus Cartridges Over Durapore Hydrophilic MEC 10 30 0 22 Um on a polyester web Membrane Durapore CVSC TP3 Milligard Rigid Polypropylene Modified Spun Bonded Polypropylene Silicone 0 22 um RW19 1 2 Um PVDF Multimedia and
30. densate Table 3 2 Recommended Feed Water Quality for Pure Steam Conductivity Silica Amine Chlorine Bacterial Endotoxins not to exceed not to exceed below below not more than 5 microsiemens uS cm 1 ppm 100 ppm 100 ppm 0 25 EU mL EU Endotoxin Units PPM Parts Per Million Hydrophilic Durapore Cartridges and Capsules User Guide 17 N Steaming In Place of Hydrophilic Durapore Cartridges Steaming In Place SIP has the following advantage and disadvantage Bl SIP advantage Reduces the number of manipulations and aseptic connections that might compromise the sterility of the downstream equipment E SIP disadvantage Uses flowing steam accidental differential pressure at high temperature that can damage a cartridge A WARNING Do not under any circumstances SIP capsule filters see the Autoclaving Hydrophilic Durapore section in this chapter for details Table 3 3 lists the maximum SIP conditions for Durapore cartridges and the number of SIP cycles that the car tridges can withstand Table 3 3 Hydrophilic Durapore Cartridges Maximum Sterilization Cycles SIP Device Item Number abbreviated In Line Steam Charged Durapore Cartridges CCGL 135 C 30 minutes 10 times max Durapore 5 Cartridges CV L 5 135 C 30 minutes 30 times max Durapore Cartridges CVDR PP CVHL PP CVGL 135 C 30 minutes 30 times max CVVL Durapore 0 45 um and 0 65 um CVDR TP CV
31. dure if you see rapid bubbling 3 Increase gas pressure regulator to diffusion test pressure specification See Tables 4 1 and 4 2 for details 4 Allow the system to equilibrate for 5 minutes 5 Measure the diffusion flow rate with a flow meter or a water filled inverted graduated cylinder See Figure 4 5 6 Hold the open end of tubing attached to system outlet under the graduated cylinder The gas diffusing through the filter displaces the wetting fluid in the graduate Time for 1 minute You can read the diffusion rate in cc min directly from the cylinder 7 Do one of the following E If the diffusional flow rate is greater than the specification a failing diffusion rate proceed to step 8 B If the value is equal to or below the specification a passing diffusion rate proceed with the sterile filtration process in Chapter 5 NOTE To ensure that the integrity test failure is not due to insufficient wetting prepare to rewet the system at higher pressure and increased contact time Figure 4 5 Typical sterile filter cartridge and housing assembly for diffusion test Hydrophilic Durapore Cartridges and Capsules User Guide 37 Diffusion Integrity Testing Procedure continued 8 Check the following Wi All connections and valves for potential leaks Wi Ensure the
32. e 40 www millipore com Guidelines for Sterile Filtering and Post Use Integrity Testing Once you reach this chapter on hydrophilic Durapore use you should have already inspected the filter out of the box installed it for use sterilized it cooled it under positive pressure wetted it for integrity testing post sterilization integrity tested it drained it and are now ready to use it The previous chapters in this manual define the basic guidelines for use When you begin your filtration slowly wet the filter at low pressure and purge all air This ensures that all of the effective membrane area is used and that the membrane is fully wet ted prior to the post use integrity test NOTE Wetting the membrane completely before the start of the integrity test is critical to properly measuring the diffusion rate and the bubble point pressure because trapped air can prevent the membrane from becoming fully wet See Chapter 4 Pre Use Integrity Testing of Hydrophilic Durapore Cartridges and Capsules for details Post Altration Integrity Testing of Cartridges and Capsules There are two types of post use integrity testing water based and product based The choice depends on the nature of the product you want to filter If all of the product components can be effectively flushed from the filter then use a water based integrity specification Some typical fluids used for flushing include B WFI E Hot WFI 80 C Bi Alcohol or alcohol water
33. e available heat than air at the same temperature Saturated steam has a unique temperature at each pressure for example 15 psig at 121 C See Table 3 1 for details Table 3 1 Saturated Steam Pressure and Temperature Saturated Steam Pressure psig Saturated Steam Temperature C 15 121 21 126 31 135 46 145 Steam sterilization is the most studied method of sterilization and is predictable and reproducible under de fined operating conditions Steam sterilization processes are characterized by measuring their microorganism kill efficiency Bacillus stearothermophilus spores are used as the challenge organism because they are particu larly resistant to moist heat and represent the worst case scenario This section describes how to sterilize Millipore cartridges and capsules without damaging the filters and com promising filter integrity The steaming and autoclave cycle conditions mentioned in the SOPs and the guide lines are based on the thermal and hydraulic stress resistance of the filters These recommendations are not intended as a substitute for filter sterilization validation You must still perform on site validation tests Steam Requirements Whether you use Steam in Place SIP or autoclaving you should supply pure steam Pure steam is uncondensed WFI Water For Injection It is free of pyrogens chemicals particles and microorganisms and must be supplied dry saturated and free of non condensable gases and con
34. ed horizontally or upside down condensate accumulates in the core The filter can be autoclaved while attached to the piece of process equipment Or place the filter in a basket or loose in the autoclave chamber NOTE Ensure that the openings are covered with suitable barrier paper or place the entire filter in an auto clave bag Troubleshooting the Autoclaving Procedure If filter damage occurs check Table 3 7 to troubleshoot the probable cause of the filter damage The table lists probable causes and possible solutions for some of the problems you may encounter during autoclaving Table 3 7 Cartridge Filter Failure Modes from Autoclaving Description of Failure Cause Action to Prevent Loss of capsule roundness Capping off of inlet and outlet connections Ensure inlet amp outlet connections are open and unobstructed or joining the inlet and outlet tubing Do not join inlet and outlet connections or crimping any inlet or outlet tubing Ensure that inlet amp outlet tubing is not crimped Distortion of fittings Supporting excessive weight Do not use connections to support excessive weight Distortion of vents Vents used to support weight of capsule Do not use filter vents to support the weight of the capsule during autoclaving Additional Steam Sterilization literature Contact Millipore to obtain the following literature for more details on Steam Sterilization Wi Technical Brief Principles of Moist Heat Sterilization Lit N
35. efinition of a Cartridge and a Capsule NJ Y A cartridge is a filter used in a stainless steel housing A A capsule is a filter in a self contained disposable plastic housing N Hydrophilic Durapore Cartridges This section outlines the materials of construction nominal device dimensions nominal effective filter area recommended flush volumes post sterilization and maximum oxidizable substances of the hydrophilic Du rapore cartridge Table 1 1 Hydrophilic Durapore Cartridges Materials of Construction Device Item Number Membrane Materials Materials Membrane Materials Support Materials abbreviated Cage Core or Disk Filter Web O rings Durapore CVGL Durapore Rigid Polypropylene Modified Spun Bonded Polypropylene Silicone Cartridges CVDR PP Hydrophilic Polyvinylidene 5 30 and CVHL PP Membrane fluoride PVDF Optiseal CVVL Durapore LAGLO4 Cartridges LAHLO4PP LAVLOA Charged CCGL Durapore Rgid Polypropylene Modified Spun Bonded Polypropylene Silicone Durapore LCGL Hydrophilic PVDF Cartridges Membrane with positive and Optiseal with positive charge Charged Durapore charge Cartridges Durapore CVDR TP Milligard Rigid Polypropylene Modified Spun Bonded Polypropylene Silicone 0 65 Um RW19 1 2 Um PVDF Multimedia Filter Media Membrane plus Mixed Cartridges Over Durapore Hydrophilic Esters of Cellulose MEC 0 65 Um on a polyester web Membrane Durapore CVHL TP Milligar
36. essure Durapore CVGL Bubble Point gt 50 0 psig 3450 barg Air Waiter 0 22 um 0 22 um gt 18 5 psig 1280 mbar Nitrogen 70 30 IPA Water 5 to 30 CV19 Cartridges CV06 Diffusion 5 6 6 cc min CV03 10 lt 13 3 cc min Air Water with single 20 26 6 cc min 40 psig 2760 mbar Milligard layer 30 lt 39 9 cc min Durapore Bubble Point gt 50 0 psig 3450 barg Air Water 0 22 um CVSC 10 to 30 CVSS Diffusion 10 lt 10 8 cc min Air Cartridges CVSX 20 21 6 cc min 40 psig 2800 mbar Water with Double with double 30 lt 32 4 cc min Milligard Layer Milligard layer Charged Bubble Point gt 40 psig 2760 mbar Air Water Durapore CCGL 0 22 um 0 22 um Diffusion 10 lt 10 cc min Air 10 to 30 20 lt 20 cc min 30 psig 2070 mbar Water Cartridges 30 lt 30 cc min Durapore Bubble Point 2 70 psig 4830 mbar Air Water 0 1 um CVVL 5 to 30 0 1 um Diffusion 5 10 cc min Cartridges 10 20 cc min Air Water 20 40 cc min 56 psig 3860 mbar 30 60 cc min Durapore Bubble Point gt 28 psig 1930 mbar Air Water 0 45 um CVHL 10 to 30 0 45 um Diffusion 10 lt 15 cc min Air Cartridges 20 30 cc min 22 0 psig 1520 mbar Water 30 lt 45 cc min Bubble Point gt 14 psig 970 mbar Air Water 0 65 um CVDR 10 to 30 0 65 um Diffusion 10 lt 8cc min Air Cartridges 20 lt 16cc min 9 0 psig 620 mbar Water 30 lt 24 cc min Opti
37. ev A 05 99 W Reprint from Pharmaceutical Technology September 1989 Principles of Integrity Testing Hydrophilic Microporous Membrane Filters Part I Lit No TB036 E Reprint from Pharmaceutical Technology September 1989 Principles of Integrity Testing Hydrophilic Microporous Membrane Filters Part II Lit No TB036 Integrity Testing Training and Certification Operators who need to perform integrity tests need proper training Millipore offers a course that teaches the current theories and methods for filter integrity testing This course allows operators to meet CGMP training requirements Some of the key points covered in this course are E Perform and master bubble point diffusion and automatic integrity testing methods W Run integrity tests on hydrophobic and hydrophilic filter devices E Practice manual and automatic test methods and techniques E Reinforce all the classroom material through comprehensive laboratory sessions Wi learn methods from Millipore integrity testing and process filtration experts E Attend classes that allow limited class sizes to ensure individual attention Contact your Millipore Application Specialist for more information Chapter 5 Guidelines for Sterile Filtering and Post Use Integrity Testing Introduction This chapter provides information on properly performing Bi Sterile filtration of your process fluid E A post filtration integrity test to release the sterile filtered product for us
38. fete esee Sup aaa Taa Ea rues a Dea tene Ru des 16 Steaming in Place of Hydrophilic Durapore Cartridges ssssssssseeeeeeeeneeeen nnn 17 SIP System Design Overview an a ecke nee 17 SIP System Design Considerations sssssnsssssnnnnnnnnnnnnnnennnnnnnnnnnnnnnnnnnnnnnennnnnnnnnnnnnnnnnnnnann 18 SIP Standard Operating Procedure scorrerie iina a Eiaa ss ssh nnns anaa aiias 19 g ze l e me ET 19 Post Integrity Test Bow DOWN sssini a aai naa Aae Eiaeai a Eaa 19 FANG SSSA se oae cu ea aiaee E aAA EEE EAA AA bens do AN Ed aaaeei Eaa eE SEA dad 20 Fos Steaming Blow DOWN T 21 Troubleshooting the SIP Procedure sssssssnsssennnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 21 Autoclaving Hydrophilic Durapore Capsules and Cartridges Housing Assemblies sseeesssss 22 Autoclave Standard Operating Procedure 2244244444444nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 23 Alter Preparation te EN INURERLEPEEENUDENESTERLEFEEFEEPPPSUESEEETERSUHERSELENSERSTUERENEERTEHTIERELFFFPORSEEERSE UFHFHEREEERER 23 Autoclave LOGGING eT 24 Troubleshooting the Autoclaving Procedure 4444444444444H HH nn nenn OERE RE RERA 24 Additional Steam Sterilization literatu sire aaa aa anaa a EE EEEE aE 24 Chapter 4 Pre Use Integrity Testing of Hydrophilic Durapore Cartridges and Cap sules uoreli eife
39. filter is installed properly E Ensure the temperature is stable and within temperature specification Bi Close all valves 9 Cleara path for wetting fluid to enter and clear a path for air to exit 10 Allow the wetting fluid to enter the filter Slightly crack open V9 11 Ensure that all gas is purged When you can see a steady flow of water and no gas exiting V5 close V5 12 Increase the pressure on the feed side of the filter to at least 20 psi A pressure of 40 psi is ideal Fully open V9 NOTE Do not exceed the maximum pressure rating for the filter unit 13 Continue to maintain this pressure for at least 1 min to dissolve any residual gas within the filter and ensure membrane wetting 14 Open outlet valve s until wetting fluid flow is approximately 1 L min per f Open V6 and crack open and throttle V7 NOTE The filtrate side pressure increases because only a small differential pressure is required to achieve 1 L min per f 15 Rewet using the conditions specified in Table 4 3 16 Repeat steps 1 through 8 If your test fails save the filter and contact Millipore Technical Service for assis tance 38 www millipore com Additional Integrity Testing Literature Contact Millipore to obtain the following literature for more details on Integrity Testing E Technical Note Integrity Testing of Sterilizing Membrane Filters Lit No TN012 Rev 06 91 E Technical Brief Filter Integrity Test Methods Lit No TB039 R
40. ic Durapore Capsules Nominal Device Dimensions continued Type Item Number Configuration Approx Nominal Approx Nominal Approx Nominal Approx Nominal abbreviated Length inch Length cm OD inch OD cm Opticap 10 KV LG1TH1 1 1 2 38 mm N A N A Body 3 3 Body 8 4 cm KV LS1TH1 sanitary flange inlet End Cap 4 5 End Cap 11 cm and 9 16 14 mm barb outlet Opticap 10 KV LG1FH1 3 4 19 mm N A N A Body 3 3 Body 8 4 cm KV LS1FH1 sanitary flange inlet End Cap 4 5 End Cap 11 cm and 9 16 14 mm barb outlet Opticap 10 KV LG1TT1 1 1 2 38 mm 13 7 35 Body 3 3 Body 8 4 cm KV LS1TT1 sanitary flange inlet End Cap 4 5 End Cap 11 cm KV LO1TC1 and outlet KP LO1TC1 Opticap 10 KV LG1FF1 3 4 19 mm 13 7 35 Body 3 3 Body 8 4 cm KV LS1 FF1 sanitary flange End Cap 4 5 End Cap 11 cm inlet and outlet Opticap 10 KV LG1HH1 9 16 14 mm 13 3 34 Body 3 3 Body 8 4 cm KV LS1HH1 barb inlet and outlet End Cap 4 5 End Cap 11 cm KV LO1HB1 KP L01 HB1 Opticap 4 KV LG4TH3 1 1 2 38 mm 6 5 16 5 Body 2 4 Body 6 1 cm KV LS4TH3 sanitary flange inlet End Cap 3 7 End Cap 9 4 cm and 9 16 14 mm barb outlet Opticap 4 KV LG4TT3 1 1 2 38 mm 6 7 17 Body 2 4 Body 6 1 cm KV LSATT3 sanitary flange End Cap 3 7 End Cap 9 4 cm KV LO4TC3 inlet and outlet Opticap 4 KV LO4NP3 1 4 6 mm NPM 5 9 15 Body 2 4 Body 6 1 cm inlet and outlet End Cap 3 7 End Cap 9 4 cm Opticap
41. ilic Durapore Cartridges and Capsules User Guide 23 Table 3 6 Hydrophilic Durapore Capsules Maximum Sterilization Cycles Autoclaving Device Item Number abbreviated In Line Steam Autoclave Millipak Capsules Non Sterile MP LO MP L1 MP L2 Not Recommended 123 C 90 minutes 3 times max Pre Sterilized by Gamma MP L G Not Recommended 123 C 90 minutes 3 times max Opticap 10 Capsules Non Sterile KPHLO1 KVGLO1 KVVLO1 Not Recommended 126 C 60 minutes 3 times max Non Sterile KVGLG1 KVVLG1 Not Recommended Capable of 45 kilogram gamma Gamma Compatible single dose or 123 C 60 minutes 3 times max Pre Sterilized by Gamma KVGLS4 KVVLS4 Not Recommended 123 C 60 minutes 3 times max Opticap 4 Capsules Non Sterile KVG 04 Not Recommended 126 C 60 minutes 3 times max Non Sterile KVGLG4 KVVLG4 Not Recommended Capable of 45 kilogray gamma Gamma Compatible single dose or 123 C 60 minutes 3 times max Pre Sterilized by Gamma KVGLS1 KVVLS1 Not Recommended 123 C 60 minutes 3 times max Opticap 4 Multimedia Capsules Non Sterile KV0304 KV0604 KV1904 Not Recommended 123 C 60 minutes 3 times max KVSC04 KVSS04 KVSX04 Non Sterile 0 45 um KVHLO 1 Not Recommended 121 C 60 minutes 10 times max These are the maximum conditions Durapore capsules have been validated to withstand Select the time and temperature appr
42. ilter to ensure optimum performance Bl Change Notification If a minor change is made to the product or packaging you may find a change notification statement in the box in accordance with Millipore s Change Notification policy Installing the Filter Before using the filter verify the pore size and the catalogue number AS N Pore Size Verification Cartridges For cartridges the catalog number lot number and pore size are located on top of the cartridge as shown The appearance of the cartridge is the same regardless of pore size Catalog No Prefix X Dem Sm Lot Number Figure 2 1 Durapore cartridge filter catalog number pore size and lot number location Hydrophilic Durapore Cartridges and Capsules User Guide 13 Usage Guidelines for Cartridges It is very important that you install the filter in the housing correctly The cartridges are shipped double bagged Carefully tear open the outer bag then carefully tear open the inner bag Use the inner bag as a glove to avoid touching the cartridge with ungloved hands as you install it into the housing To ease installa tion of the cartridge into the housing wet the O rings with sterile water and gently slide the cartridge into place For a Code 7 cartridge after the O rings are in the socket twist the cartridge slightly to lock it in place When installing the cartridge avoid pinching the O rings or bending the tabs on the Code 7 cartridge A pre use integrity tes
43. ly in the housing See Chapter 2 for details on proper filter installation E All valves are closed Wetting Procedure with a Peristaltic Pump Monitor and control the temperature of the wetting fluid and the filter system to the temperature specified for the particular diffusion or bubble point test you want to perform Tests performed at temperatures other than those recommended can affect the results of both the diffusion and the bubble point tests 1 Ensure that all valves are closed Set the peristaltic pump at the correct setting and start the pump Open the vent valve V2 Gradually open the feed side valve V1 gm e w m Ensure that all gas is purged When you can see a steady flow of the wetting fluid and no gas exiting V2 close V2 NOTE Trapped air can prevent the membrane from becoming fully wet this can cause improper measure ment of the diffusion rate and the bubble point test pressure 6 Stop the pump and continue to maintain pressure at least 1 minute to dissolve any residual gas within the filter to ensure complete membrane wetting 7 Restart the pump and open the filtrate side valve V3 8 Adjust the peristaltic pump until the differential pressure P1 P2 is approximately 3 psig 200 mbar 9 Recirculate the wetting fluid through the filter at approximately 1 L min per ft2 of effective filter surface area See Table 4 3 for the recommended flow rate and minimum volume of wetting fluid necessary to wet the fil
44. mbrane Optiseal Multimedia Cartridges w Durapore Membrane LAHL TP Autoclave at 126 C for 30 minutes 15 Refer to the Millipore catalogue or www millipore com for the full catalogue number of the device configuration you are interested in These abbreviated numbers are for quick reference only Pre test treatment conditions described in this table are not intended as a substitute for filter sterilization validation The user is responsible for conducting an on site filter sterilization validation study Hydrophilic Durapore Cartridges and Capsules User Guide Table A 2 Hydrophilic Durapore Capsules Maximum Extractables 47 Device Item Number Extractables Gravimetric abbreviated Pre Test Treatment Extractables less than or equal to mg unit Millipak 60 MP L06 Autoclave at 123 C for 90 min 2 0 Non Sterile Capsules Millipak 100 MP L1 Autoclave at 123 C for 90 min 2 5 Non Sterile Capsules Millipak 200 MP L2 Autoclave at 123 C for 90 min 5 0 Non Sterile Capsules Millipak 20 Pre Sterilized MP L G Irradiation 1 0 mg by Gamma Capsules after a 200 mL Hush Millipak 40 Pre Sterilized MP L G Irradiation 1 5 mg by Gamma Capsules after a 200 mL Hush Millipak 60 Pre Sterilized MP L G Irradiation 2 0 mg by Gamma Capsules after a 200 mL Hush Millipak 100 Pre Sterilized MP LG Irradiation 2 5 mg by Gamma Capsules after a 200 mL Hush Milli
45. nation Number Type Pressure Opticap Non Sterile Bubble Point gt 50 0 psig 3450 mbar Air Waiter 0 22 um KVGLO gt 18 5 psig 1280 mbar Nitrogen 70 30 IPA Water 4 to 10 0 22 um Capsules Diffusion for lt 13 3 cc min Air Water 10 Capsule 40 psig 2760 mbar Opticap Gamma Stable Bubble Point gt 50 0 psig 3450 mbar Air Water 0 22 um KVGLG gt 18 5 psig 1280 mbar Nitrogen 70 30 IPA Water 4 to 10 Gamma Sterilized Capsules KVGLS Diffusion for 14 0 cc min Air Water 10 Capsule 40 psig 2760 mbar Opticap Non Sterile Bubble Point gt 70 0 psig 4828 mbar Air Water 0 1 um KVVLO 4 to 10 0 1 um Diffusion for lt 20 cc min Air Water Capsules 10 Capsule 56 psig 8862 mbar Opticap Gamma Stable Bubble Point gt 70 0 psig 4828 mbar Air Waiter 0 1 um KVVLG 4 to 10 Gamma Sterilized Diffusion for lt 21 1 cc min Air Water Capsules KVVLS 10 Capsule 40 psig 2760 mbar Millipak MPGL 0 22 um Bubble Point gt 50 0 psig 3450 mbar Air Water Stacked Disk gt 18 5 psig 1280 mbar Nitrogen 70 30 IPA Water Capsules MPVL 0 1 um Bubble Point gt 70 0 psig 4800 mbar Air Water MPHL 0 45 um Bubble Point gt 26 0 psig 1800 mbar Air Water MPSL 5 0 um Bubble Point 22 0 psig 140 mbar Air Water Diffusion tests are not recommended for devices less than 2 f Test pressure specified for the Diffusion Test NOTE The specifications supplied in this document are for refere
46. nce purposes only Always refer to the certificate of quality for the lot of product in use for current information Hydrophilic Durapore Cartridges and Capsules User Guide 31 Considerations for W hen to Perform Pre use Integrity Tests There are two options for pre use integrity testing pre and post sterilization Either option is a good practice for a number of reasons E Prevents batch processing with a non integral filter E Alerts operator to a problem E Ensures proper installation Wi Verifies unit was not damaged during shipping In addition post sterilization integrity tests check for damage during the sterilization process However you must maintain system sterility during filter wetting and integrity testing steps You may find an automatic integ rity tester very useful in post sterilization integrity testing PreIntegrity Test Wetting of Hydrophilic Durapore Cartridges and Capsules You must wet the membrane completely before starting the test Complete wetting is critical to properly mea sure the diffusion rate and the bubble point pressure Wetting Water Quality The water used for wetting prior to integrity testing should be reverse osmosis RO deionized DI or USP Water for Injection WFI at ambient temperature impurities can affect the integrity test results An alternative wetting fluid may be necessary in some cases Alternative wetting fluids must be validated prior to using W etting Methods There are two
47. nd the number of auto clave cycles that the cartridges can withstand Table 3 5 Hydrophilic Durapore Cartridges Maximum Sterilization Cycles Autoclaving Device Item Number abbreviated Autoclave Charged Durapore Cartridges CCGL 126 C 30 minutes 10 times max Durapore 5 Cartridges CV L 5 126 C 60 minutes 30 times max Durapore Cartridges CVDR PP CVHL PP 126 C 60 minutes 30 times max CVGL CVVL Durapore 0 45 um and 0 65 um CVDR TP CVHL TP 121 C 60 minutes 10 times max Multimedia Cartridges Durapore Cartridges 0 22 um CV03 TP3 CVSC TP3 123 C 30 minutes 6 times max Multimedia Cartridges CVO06 TP3 CVSS TP3 CV19 TP3 CVSX TP3 Millidisk Cartridges MC L 126 C 60 minutes 5 times max Optiseal Charged Durapore Cartridges LCGLO4 126 C 30 minutes 10 times max Optiseal Cartridges LAGLO4 LAVLO4 LAHLO4PP 126 C 30 minutes 10 times max w Durapore membrane Optiseal Multimedia Cartridges LAHLO4 TP 12 C 30 minutes 10 times max w Durapore membrane These are the maximum conditions Durapore cartridges have been validated to withstand Select the time and temperature appropriate to validate the proper sterilization of the device and housing The recommendations in this table are not intended as a substitute for filter sterilization validation The user is responsible for an on site filter sterilization validation study Hydroph
48. o ETO10ENOO Rev 09 00 E Reprint from Genetic Engineering News Cartridge Filter Steaming in Place Allows Single Unit Downstream Sterilization September 1 1997 Technical Brief General Principles of Steam In Place Lit No TB059 Copyright 4 91 Technical Brief Principals of Steam In Place Lit No ETO11ENOO Rev A 08 00 Technical Brief Millipore Steam Sterilization amp Integrity Testing Procedures Lit No ETO15ENOO Rev 09 00 Technical Brief Opticap Disposable Capsule Filters Autoclave Guidelines Lit No TB072 Chapter 4 Pre Use Integrity Testing of Hydrophilic Durapore Cartridges and Capsules Introduction This chapter describes how to properly integrity test hydrophilic Durapore cartridges and capsules Integrity tests provide assurance that a sterile filter will perform as intended prior to performing the entire filtration process This chapter includes E Background on integrity testing il General guidelines and Standard Operating Procedures SOP for membrane wetting E General guidelines and Standard Operating Procedures for bubble point integrity testing il General guidelines and Standard Operating Procedures for diffusion integrity testing Bl Comparison of using bubble point integrity test versus diffusion integrity test 26 www millipore com Overview of Integrity Testing The integrity test of sterilizing grade filters is a generally accepted requirement in critical process filtration ap plications particularl
49. opriate to validate the proper sterilization of the device Autoclave Standard Operating Procedure The procedure for autoclaving Durapore filters consists of two stages 1 Filter preparation pre autoclave loading 2 Autoclave loading Filter Preparation This section includes guidelines for vent positions inlet and outlet openings tubing and clamp and fitting attachments Millipore recommends performing an integrity test pre and post filtration See Chapter 4 for details on filter integrity testing If you decide to perform a pre sterilization integrity test the membrane in the capsule will be wet Unlike Steam In Place however you can autoclave filters wet or dry as long as they are autoclaved using the same conditions used for filter sterilization validation 1 Open filter vents and make sure that they remain open throughout the entire sterilization cycle The vents provide proper air displacement and condensate removal only when open and unobstructed NOTE Trapped air or condensate acts as a barrier to heat transfer and inhibits effective steam penetration These conditions can lead to less moist heat contact and lower sterilization temperatures of the target unit Condensate resistance to heat transfer is 70 times greater than that of stainless steel Air resis tance to heat transfer is 25 times greater than that of water 2 Ensure that the filter inlet and outlet openings are open and unobstructed to allow maximum air di
50. ores eliminates the possibility of exceeding the maximum differential pressure specification of 5 psid when steam ing If you choose not to perform a pre sterilization integrity test the filter will be dry out of the box Skip this section and see Filter Steaming in this chapter 1 Clear a path for the compressed gas flow through the filter to drain Open V3 V6 and V7 Refer to Figure 3 1 2 Set compressed gas pressure to 5 psi Start compressed gas flow into the filter Open V8 Slowly increase pressure to 10 psi above the bubble point of the installed membrane cartridge 3 Allow gas to flow for 5 minutes to force all water out of the pores and dry the filter NOTE As the filter dries the air flow rate will increase and the differential pressure decreases 4 Shut off the gas supply and close all valves V8 V3 V6 and V7 after 5 minutes 20 www millipore com Filter Steaming Perform this procedure on a dry filter to prevent damaging it and compromising its integrity 1 Check that steam supply and compressed gas pressures are set up at the values determined during the validation process for steam sterilization of the specific system being used 2 Purge the steam line until all condensate is gone Open V1 and V2 3 Allow for subsequent air and condensate removal Fully open V4 and V5 NOTE Trapped air or condensate acts as a barrier to heat transfer and inhibits effective steam penetration These conditions can le
51. p Rapid bubbling at this time may be due to insufficient wetting or improper filter installation Check the filter installation and repeat the steps listed in the wetting procedure described in Chapter 4 if you see rapid bubbling 5 Increase gas pressure regulator to 8076 of the bubble point specification for 70 30 isopropyl alcohol 6 Allow the system to equilibrate for 5 minutes 7 Increase the pressure in 1 psi increments waiting 10 seconds between increases to allow the system to stabilize 8 Record the pressure as the bubble point pressure when the slow steady flow of bubbles diffusion only increases at the outlet of the filter to rapid bubbling bulk flow If the bubble point value is still below the specification save the filter and contact Millipore Technical Service for assistance Hydrophilic Durapore Cartridges and Capsules User Guide 43 Post Use Diffusion Test The post use diffusion test is identical to the pre use diffusion test defined in Chapter 4 If filter is wet with a liquid other than water a product diffusion test should be determined Millipore Access Services can determine a product based diffusional flow rate specification Troubleshooting This section highlights common pitfalls of integrity testing Symptom Possible cause Corrective action Marginal bubble point or diffusion Product remaining on 1 Review flushing technique failure filter product suppression 2 Perform alcohol referee test Temperature va
52. pak 200 Pre Sterilized MP L G Irradiation 5 0 mg by Gamma Capsules after a 200 mL Hush Opticap 10 Capsules KPHLO1 KVGLO1 Autoclave at 126 C for 60 min 25 Non Sterile KVVLO1 Opticap 10 Capsules KVGLG1 KVVLG1 N A 25 Non Sterile Gamma Compatible Opticap 10 Capsules KVGLS4 KVVLS4 Irradiation 10 mg Pre Sterilized by Gamma after a 500 mL Hush Opticap 4 Capsules KVG04 Autoclave at 126 C for 30 min 10 Non Sterile Opticap 4 Capsules KVGLG4 KVVLG4 N A 10 Non Sterile Gamma Compatible Opticap 4 Capsules KVGLS1 KVVLS1 Irradiation 25 mg Pre Sterilized by Gamma after a 1000 mL Hush Opticap 4 Multimedia KV0304 KV0604 Autoclave at 123 C for 30 min 15 Capsules Non Sterile KV1904 Opticap 4 Multimedia KVSCO4 KVSSO4 Autoclave at 123 C for 30 min 20 Capsules Non Sterile KVSX04 Opticap 4 Multimedia KVHLO1 Autoclave at 121 C for 30 min 15 0 45 um Capsules Non Sterile Refer to the Millipore catalogue or www millipore com for the full catalogue number of the device configuration you are interested in These abbreviated numbers are for quick reference only Pre test treatment conditions described in this table are not intended as a substitute for filter sterilization validation The user is responsible for conducting an on site filter sterilization validation study Lenntech info lenntech com Tel 431 152 610 900 www lenntech com Fax 3
53. pore CCGL 1 Autoclave at 126 C for 30 minutes 20 10 Cartridges Charged Durapore CCGL 2 Autoclave at 126 C for 30 minutes 40 20 Cartridges Charged Durapore CCGL 3 Autoclave at 126 C for 30 minutes 60 30 Cartridges Durapore 5 Cartridges CV L 5 Autoclave at 126 C for 60 minutes 10 Durapore 10 Cartridges CVDR 1PP CVHL 1PP Autoclave at 126 C for 60 minutes 20 CVGL 1 CVVL 1 Durapore 20 Cartridges CVDR 2PP CVHL 2PP Autoclave at 126 C for 60 minutes 40 CVGL2 CVVL 2 Durapore 30 Cartridges CVDR 3PP CVHL 3PP Autoclave at 126 C for 60 minutes 60 CVGL 3 CVVL 3 Durapore Multimedia CVDR 1TP CVHL 1TP Autoclave at 126 C for 60 minutes 45 Cartridges 10 CV19 TP3 CVO6 TP3 CV03 TP3 Durapore Multimedia CVDR2TP CVHL 2TP Autoclave at 126 C for 60 minutes 90 Cartridges 20 CV19 TP3 CV06 TP3 CV03 TP3 Durapore Multimedia CVDR3TP CVHL 3TP Autoclave at 126 C for 60 minutes 135 Cartridges 30 CV19 TP3 CV06 TP3 CV03 TP3 Millidisk 10 Cartridges MC L10 Autoclave at 126 C for 60 minutes 2 5 Millidisk 20 Cartridges MC L20 Autoclave at 126 C for 60 minutes 5 0 Millidisk 30 Cartridges MC L30 Autoclave at 126 C for 60 minutes 7 5 Millidisk 40 Cartridges MC L40 Autoclave at 126 C for 60 minutes 10 Optiseal Charged LCGLO4 Autoclave at 126 C for 30 minutes 15 Durapore Cartridges Optiseal Cartridges LAGLO4 LAVLO4 Autoclave at 126 C for 30 minutes 10 w Durapore Me
54. r 1 Description of Hydrophilic Durapore Cartridges and Capsules Inifero Uei o y T 1 Definition of a Cartridge and a Capsule nennen nennen nnns nennen nennen nennen 2 Hydrophilic Durapore Cartridges en n en imet chan nete tex a n esa cna RARE E Una Du M Res DEEP ar Einen 2 Hydrophilie Durapore Capsules iii 22 22 2 0 1 a ein 5 Additional Literature on Hydrophilic Durapore Cartridges and Capsules ssss 9 Chapter 2 Installation of Hydrophilic Durapore Cartridges and Capsules IMMOG UCU ON pes cee RAR 11 Inspecting the MCT nannte een ie eiaa eaa 12 Unpacking TNE dem e EE 12 Installing the Alten rs E hie dete i ee Le TEs 12 Pore Size Verification Cartridges sssssssssssssseeeesssseeeeene nennen nnne nnn nnn nnne nent nnne nnns nsns 12 Usage Guidelines for Cartridg eSis enian de aana eiia a ia E aa aa O oada EEE 13 Pore Size Verification Capsules ssssssssssseessssseee eene nn iea iaa iea EAA ENa Eaa ina Saaai 13 Usage Guidelines for Millipak Opticap Capsule Filters ssssesee 13 HOPING TE ANGE e ID T LEITET 14 Chapter 3 Steam Sterilization of Hydrophilic Durapore Cartridges and Capsules Jau ero Sei o y RR ICE 15 Overview of Steam Sterilization siros eninin ann cce eases teeter A a A nn sn snnt Eaa nnn nnns nena 16 Seam Peguir ements assisia d i et pee a aaa
55. r filter sterilization validation Conducting an on site filter steril Hydrophilic Durapore Cartridges and Capsules User Guide 5 7 Hydrophilic Durapore Capsules This section lists the materials of construction nominal device dimensions nominal effective filter area nomi nal hold up volume and recommended flushes post sterilization of the hydrophilic Durapore capsule Table 1 5 Hydrophilic Durapore Capsules Materials of Construction Device Item Number Membrane Materials Materials Materials Materials Materials abbreviated Cage Core Membrane Filter Support Web O rings Capsule or Disk Housing Millipak Capsules MP L Durapore Hydrophilic Polycarbonate Modified PVDF va va Polycarbonate Membrane Opticap 4 and 10 KPHLO1 Durapore Hydrophilic Rigid Modified PVDF Spun Bonded Silicone Rigid Capsules Non Sterile KVGLO1 Membrane Polypropylene Polypropylene O rings Polypropylene KVVLO1 in Vent KVGLO4 Ports KVVLO4 Opticap 4 and 10 KVGLG1 Durapore Hydrophilic Gamma Modified PVDF Gamma Stable Silicone Gamma Stable Capsules Non Sterile KVVLG1 Membrane Stable Rigid Spun Bonded O rings Rgid Gamma Compatible or KVGLS1 Polypropylene Polypropylene in Vent Polypropylene Pre Sterilized by KVVLS1 Ports Gamma Opticap 4 and 10 KV03 Milligard RWOS Rigid Modified PVDF Spun Bonded Silicone Rigid Capsules 0 2 um Filter Media Polypropylene Membrane plus Polypropylene O rings Pol
56. riations Check fluid and environment temperature Insufficient wetting Rewet at higher pressure Specifications Review test specification and verify installed filter is correct Gross Leak failure System leaks Check system connection valves and filter installation Non integral filter Inspect replace filter Insufficient wetting Rewet at higher pressure If your tests continue to fail save the filter and contact Millipore Technical Service for assistance Additional Literature on Sterile Filtration and Fost Use Integrity Testing Contact Millipore for the following literature for more details on Sterile Filtration and Post Filtration Integrity Testing E Applications Note Establishing Product Specific Bubble Point Specifications For sterilizing Grade 0 22 um Durapore Filters E PDA Journal of Pharmaceutical Science and Technology Technical Report No 26 Sterilizing Filtration of Liquids 1998 Appendix A Maximum Extractables of Hydrophilic Durapore Cartridges and Capsules Introduction This appendix provides table information on maximum extractables for hydrophilic Durapore cartridges and cap sules It includes details on E Gravimetric extractables 46 Table A 1 Hydrophilic Durapore Cartridges Maximum Extractables www millipore com Device Item Number Extractables Gravimetric abbreviated Pre Test Extractables Treatment less than or Equal to mg unit Charged Dura
57. ridges and Capsules User Guide 35 Bubble Point Testing of Hydrophilic Durapore Cartridges and Capsules continued 7 Do one of the following B If the bubble point value is below the specification a failing bubble point close V8 allow pressure P1 to decay to zero and proceed to step 8 E If the value is equal to or above the specification a passing bubble point proceed with the sterile filtration process in Chapter 5 NOTE To ensure that the integrity test failure is not due to insufficient wetting prepare to rewet the system at higher pressure and increase contact time 8 Check the following if the bubble point value is below the specification Wi All connections and valves for potential leaks E Ensure the filter is installed properly E Ensure the temperature is stable and within temperature specification E Close all valves 9 Rewet filter in preparation for re test as follows Clear a path for wetting fluid to enter and clear a path for air to exit 10 Allow the wetting fluid to enter the filter Slightly crack open V9 11 Ensure that all gas is purged When you can see a steady flow of water and no gas exiting V5 close V5 12 Increase the pressure on the feed side of the filter to at least 20 psi A pressure of 40 psi is ideal Fully open V9 NOTE Do not exceed the maximum pressure rating for the filter unit 13 Continue to maintain this pressure for at least 1 min to dissolve any residual gas within the
58. rophilic Durapore Cartridges and Capsules Introduction This chapter describes how to properly steam sterilize hydrophilic Durapore cartridges and capsules including E Background information on steam sterilization il General guidelines and Standard Operating Procedures SOPs for Steam In Place SIP ll General guidelines and Standard Operating Procedures SOPs for autoclaving CAUTION Fead this chapter carefully since improper steam sterilization can often damaged filters 16 www millipore com Overview of Steam Sterilization The simplest definition of sterility is the complete absence of life as seen through growth or reproduction Something can be proven sterile by conducting tests to show that nothing grows in or on it Drug manufactur ers go to great lengths to validate the sterility of their parenteral products Sterility of parenteral products is critical because the presence of viable microorganisms or their by products endotoxins is detrimental The most common sterilization method is steam under pressure This method of sterilization is done in situ Steam In Place or in an autoclave In either case moist heat water saturated steam under pressure is used The moist hot environment is an effective method of sterilization because the moist heat irreversibly denatures vital enzymes that result in the death of microorganisms Moisture contributes a great deal to the process Satu rated steam at 121 C supplies seven times mor
59. seal Bubble Point gt 50 0 psig 3450 mbar Air Water 0 22 um LAGL gt 18 5 psig 1280 mbar Nitrogen 70 30 IPA Water Cartridges 0 22 um Diffusion lt 5 0 cc min Air Water 40 psig 2800 mbar 30 www millipore com Table 4 1 Hydrophilic Durapore Cartridges Integrity Testing Specifications continued Product Catalogue Integrity Test Product Specifications Test Gas Test Huid Designation Number Type Test Pressure Charged Bubble Point gt 40 psig 2759 mbar Air Water Optiseal LOGL 0 22 um 0 22 um Diffusion 4 0 cc min Air Water Cartridges 30 psig 2069 mbar Optiseal Bubble Point gt 70 0 psig 4800 mbar Air Water 0 1 um LAVL Cartridges 0 1 um Diffusion 7 0 cc min Air Water 56 psig 3900 mbar Optiseal Bubble Point gt 28 psig 1931 mbar Air Water 0 45 um LAHL Cartridges 0 45 um Diffusion 4 0 cc min Air Water 22 psig 1517 mbar Millidisk MCGL 0 22 um Bubble Point gt 50 0 psig 3450 mbar Air Water Stacked Disk gt 18 5 psig 1280 mbar Nitrogen 70 30 IPA Water Cartridges MOVL 0 1 um Bubble Point gt 70 0 psig 4830 mbar Air Water MCHL 0 45 um Bubble Point gt 26 0 psig 1800 mbar Air Water MCSI 5 0M um Bubble Point gt 2 0 psig 140 mbar Air Water Table 4 2 Hydrophilic Durapore Capsules Integrity Testing Specifications at 23 C Product Catalogue Integrity Test Product Specifications Test Gas Test Huid Desig
60. splace ment and steam flow 3 Ensure that any tubing attached to the filter is open and unobstructed to provide for adequate steam flow NOTE The tubing should be of the largest possible inner diameter should not exceed 4 feet in length should not be crimped bent or U shaped If tubing is present on both inlet and outlet it should not be connected in a continuous loop 24 www millipore com Filter Preparation continued 4 Ensure that all open vents open inlets and open outlets are covered with suitable barrier paper Alterna tively place the filter in an autoclave bag 5 If using sanitary clamps with capsule filters do not overtighten the clamps Overtightening can distort the fittings Use three piece sanitary clamps if necessary NOTE Three piece sanitary clamps are preferred over two piece clamps since they provide more uniform stress distribution 6 If you attached stainless steel parts do not allow capsule fittings to support the weight of these attachments Use separate support structures to eliminate stress on the capsule fittings NOTE The weight of unsupported attachments coupled with the loss of the fitting s rigidity at the autoclave temperatures can deform and damage the capsule Autoclave Loading Place the filter into the autoclave as follows The ideal filter orientation is in the upright or normal operating position direction of flow with the core out let facing downward If the filters are orient
61. t can confirm that you installed the filter in the housing correctly See Chapter 4 for details on filter integrity testing NOTE Do not touch a cartridge with ungloved hands since dirt and oils from your skin can affect the perfor mance of the filter Wi Pore Size Verification Capsules Millipak and Opticap filters have color coded labels that list the catalogue number lot number and pore size The Millipak label is located at the top of the inlet side of the filter The Opticap label is located along the length of the Opticap housing Table 2 1 Color Code for Hydrophilic Durapore Capsule Filter Pore Size Color Pore Size Orange 0 1 um Yellow 0 22 um Red 0 45 um 14 www millipore com Usage Guidelines for Millipak Opticap Capsule Filters E Avoid dropping these filters If a Millipak or Opticap filter accidentally drops on the floor perform a pre use integrity test to ensure that the filter was not damaged See Section 4 on filter integrity testing E Use sterile technique Certain Millipak and Opticap filters are shipped in a pre sterile configuration To prevent accidentally contaminating the filter handle the outside of the housing only Do not touch any of the inlet or outlet fittings of a capsule with ungloved hands E Orient Millipak and Opticap filters vertically The inlet can be at the top or bottom For Millipak and Opticap filters it is strongly recommended that flow be in the forward direction inle
62. t to outlet because the filter is structurally stronger in the forward flow direction NOTE Millipak filters The inlet side of the housing is clear the outlet side is opaque Opticap filters An arrow indicates direction of flow Product Inlet Identification Label Identification Label Outlet Millipak Figure 2 2 Capsule filter catalogue number pore size and lot number location E For Millipak Opticap Filters with Hosebarb Connections Use tubing clamps to secure the tubing to the hosebarb connections this prevents the tubing from slipping off the hosebarb accidentally when under pressure E For Millipak Opticap Filters with Sanitary Flanges Do not overtighten the sanitary flange Finger tight is sufficient Overtightening can result in cracking the fitting Use caution when connecting a plastic Millipak Opticap fitting to a stainless steel fitting Storing the Filter Millipore assigns an expiration date only to sterile Millipak and Opticap filters two years from the date of manufacturing for Millipak filters three years from the date of manufacturing for Opticap filters Millipore recommends that you store filters in their original packaging away from direct sunlight and at room tempera ture We also recommend that you integrity test all Durapore filters before use to ensure there was no damage during shipping or storage See Chapter 4 on filter integrity testing Chapter 3 Steam Sterilization of Hyd
63. ter in recirculation mode 10 Shut off the pump after 5 minutes of recirculation Allow the feed side pressure to decay to zero psig then close all valves You may now perform an integrity test on the filter Bubble Point Testing of Hydrophilic Durapore Cartridges and Capsules Manual Method Before starting the procedure ensure that the proper gas type is supplied for the test air nitrogen etc 1 Allow excess wetting fluid to flow out of the down stream side of the system Open V8 V3 V6 and V7 Refer to Figure 4 4 2 Set gas pressure regulator to 5 psig Hold until the water has stopped flowing from the outlet port NOTE Look for rapid continuous bubbling at test apparatus attached to Valve 7 at this time If none occurs continue to the next step Rapid bubbling at this time may be due to insufficient wetting or improper filter installation Check the filter installation and repeat the steps listed in the previous wetting procedure if you see rapid bubbling 3 Increase gas pressure regulator to 80 of the bubble point test pressure specification See Tables 4 1 and 4 2 for details 4 Allow the system to equilibrate for 5 minutes 5 Increase the pressure in 1 psi increments Wait 10 seconds in between increases to allow the system to stabilize 6 Record the pressure as the bubble point pressure when the slow steady flow of bubbles increases at the outlet of the filter to rapid bubbling Hydrophilic Durapore Cart
64. tes Allow the feed side pressure to decay to zero psig then close all valves You may now perform an integrity test on the filter Hydrophilic Durapore Cartridges and Capsules User Guide 33 Table 4 3 Specified Wetting Conditions Using a Pressure Tank or Peristaltic Pump Filter Type Water How Rate Wetting Volume L Required volume L L min for 5 min pressure in recirculation peristaltic pump Millidisk 10 0 5 3 1 Millidisk 20 1 0 5 2 Millidisk 30 1 5 8 2 Millidisk 40 2 0 10 3 Millipak 20 0 1 1 1 Millipak 40 0 2 1 1 Millipak 60 0 4 2 1 Millipak 100 0 5 3 1 Millipak 200 1 5 2 Optiseal Opticap 2 10 3 Durapore 5 3 5 18 5 Durapore 10 7 35 8 Durapore 20 14 70 12 Durapore 30 21 105 15 Hydrophilic filters wet at a minimum flow rate of approximately 1 Lom f of effective filtration area for 5 minutes Wetting Setup with a Peristaltic Pump This wetting procedure is for cartridges and capsules See Figure 4 3 The figure illustrates the cartridge wet ting process However you could easily replace the cartridge housing with a capsule filter Figure 4 3 Typical sterile filter cartridge and housing assembly for recirculation wetting using a peristaltic pump 34 www millipore com Precautions Before starting the procedure check the following E The proper filter has been selected confirm pore size and catalogue number W Filter is installed correct
65. tion Cycles SIP sssssusse 17 Cartridge Filter Failure Modes from SIP 444444sssssnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 21 Hydrophilic Durapore Cartridges Maximum Sterilization Cycles Autoclaving 22 Hydrophilic Durapore Capsules Maximum Sterilization Cycles Autoclaving 23 Cartridge Filter Failure Modes from Autoclaving ssssssseeeenenneneene 24 Hydrophilic Durapore Cartridges Integrity Testing Specifications sssssssssssss 29 Hydrophilic Durapore Capsules Integrity Testing Specifications seseesssessssss 30 Specified Wetting Conditions Using a Pressure Tank or Peristaltic Pump nenn 34 Hydrophilic Durapore Cartridges Maximum Extractables cccseeeeseeeeeeeeeeeeeeeeeeeeeeeeeeeeees 46 Hydrophilic Durapore Capsules Maximum Extractables cccseeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeees 47 Chapter 1 Description of Hydrophilic Durapore Cartridges and Capsules Introduction This chapter provides information on the physical characteristics of hydrophilic Durapore cartridges and capsules The physical characteristics of the filters include E Materials of construction E Nominal device dimensions E Nominal effective filter area E Maximum extractables E Maximum oxidizable substances 2 www millipore com D
66. to 80 of the bubble point specification If you are using a product based bubble point test the product specific bubble point is the bubble point specification Hydrophilic Durapore Cartridges and Capsules User Guide 41 Post Use Bubble Point Test SOP Part One continued 4 Allow the system to equilibrate for 5 minutes 5 Increase the pressure in 1 psi increments waiting 10 seconds between increases to allow the system to stabilize 6 Record the pressure bubble point pressure when the slow steady flow of bubbles increases at the outlet of the filter to rapid bubbling 7 Proceed to step 8 if the bubble point value is below the specification If the value is equal to or above the specification the filter is integral NOTE To ensure that the integrity test failure is not due to insufficient wetting prepare to rewet the system at higher pressure and increased contact time 8 Check the following E All connections and valves for potential leaks E Ensure filter is installed properly E Ensure temperature is stable and within temperature specification E Close all valves NOTE If you are using a product based bubble point test skip the remaining steps in this procedure Instead see step 8 in the next part of this procedure Post use Bubble Point Test SOP Part Two 9 Clear a path for the wetting fluid to enter and clear a path for air to exit Open V3 and V5 10 Allow the wetting fluid to slowly fill the feed side of housing
67. to enter at the high points and air to flush out at the low points of the system This setup is ideal because air molecular weight 29 g mol is heavier than steam molecular weight 18 g mol and naturally tends to sink to the low points But this setup is not always practical Fortu nately the steam flow rates used are sufficient to force all the air out of the system even when steam enters at a low point Minimize dead legs section of pipe where the length is six times the diameter If a dead leg exists install an air vent to prevent air from being trapped in this part of the system during steaming E Condensate Removal Install drain valves or steam traps every 100 ft of steam piping upstream of control valves and normally closed isolation valves on the upstream side of the filter housing and at the bottom of any vertical risers Angle horizontal sections of pipe downward to prevent condensate collection 1 120 or 1 inch every 10 ft Use air breaks on the condensate drains to prevent siphoning of condensate during system cooling Bl Temperature Gauge Placement Position a monitoring temperature gauge at the slowest heating or coldest spot in the system generally the farthest drain point from the steam source During validation the coldest spots in the system are determined by means of thorough coverage of the system with thermocouples Hydrophilic Durapore Cartridges and Capsules User Guide 19 SIP Standard Operating Procedure The proced
68. tridges and Capsules NFM OC IGT OM E cr 39 Guidelines for Sterile Filtering Your Product Using Cartridges and Capsules esssesss 40 Post Filtration Integrity Testing of Cartridges and Capsules sssssesessessssss nnns 40 Post Use Bubble Point Test SOP Part One essen nennen nennen nenne nennen 40 Post Use Bubble Point Test SOP Part Two essen nnn nenne enne nennen senes nns 42 Post Use Diffusion lest SO P CD 43 MOUDIESNOOTING MEE E 43 Additional Literature on Sterile Filtration and Post Use Integrity Testing sessseee 43 Appendix A Maximum Extractables of Hydrophilic Durapore Cartridges and Capsules IMirOAUEH GIN cs ans sea EEEE E A nen en Ta nenn nee een en ee 45 Table of Figures Figure 2 1 Figure 3 1 Figure 4 1 Figure 4 2 Figure 4 3 Figure 4 4 Durapore cartridge filter catalog number pore size and lot number location 12 Typical sterile filter cartridge and housing assembly for SIP sseessssssseeee 17 B diminuta on Durapore membrane nssssssssssnnnssnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnrn nn 26 Typical sterile filter cartridge and housing assembly for wetting eese 31 Typical sterile filter cartridge and housing assembly for bubble point test 33 Typical sterile filter cartridge and housing assembly for diffusion test een
69. ure for performing SIP consists of the following stages 1 Postintegrity test blow down only necessary if you performed an integrity test or filter flushing before steaming 2 Steaming 3 Post steaming blow down Precautions Before starting the procedure check the following E The proper filter pore size catalogue number has been selected and the filter is installed in the housing correctly See Chapter 2 for proper filter installation E All valves are closed and tubing is attached to bleed valves and directed to condensate drain E People participating in the steaming process are appropriately trained and wearing protective glasses and heat resistant gloves A WARNINGS Avoid unprotected contact with steam or hot stainless steel surfaces to prevent bodily injury And do not under any circumstances SIP capsule filters see the Autoclaving Hydrophilic Durapore section in this chapter for details If you did not perform a pre sterilization integrity test or flush the filter and the filter is dry skip the following section Instead see Filter Steaming in this chapter Post Integrity Test Blow Down Millipore recommends performing an integrity test pre and post filtration See Chapter 4 for details on filter integrity testing If you decide to integrity test or flush prior to steam sterilization the membrane in the car tridge will be wet Blowing down the cartridge with clean air or nitrogen to remove water from the p
70. y in the pharmaceutical industry FDA regulations of large volume parentals LVP and small volume parentals SVP place an obligation on the user to test the integrity of these filters Section 7 5 of the PDA Technical Report No 26 states that It is generally regarded as a cGMP requirement that filter or filter systems routinely be integrity tested both prior to and after use The FDA also requires corresponding documentation on integrity testing to be included with batch product records There are also sound economic reasons for integrity testing sterilizing filters before use and after the batch has been filtered The ability to monitor filter integrity before use prevents batch processing with a non integral filter A post use integrity test verifies that the filter performed as specified This allows rapid repro cessing and avoids waiting for the results of product sterility testing Therefore it is important that the user understand the principles and procedures of non destructive integrity testing There are two categories of integrity testing the destructive and non destructive methods Destructive integrity test methods leave the tested filter unfit for further use Non destructive integrity test methods allow the contin ued use of the filter after testing The bacterial challenge test is an example of a destructive test Non destructive methods include bubble point and diffusion You can perform non destructive integrity tests manually or by
71. ypropylene Non Sterile Multimedia Over Durapore Hydrophilic MEC ona in Vent 0 22 Um Membrane polyester web Ports Opticap 4 and 10 KVO6 Milligard RW06 Rigid Modified PVDF Spun Bonded Silicone Rigid Capsules Non Sterile 0 5 um Filter Media Polypropylene Membrane plus Polypropylene O rings Polypropylene Multimedia Over Durapore MEC on a in Vent Hydrophilic 0 22 um polyester web Ports Membrane Opticap 4 and 10 KV19 Milligard RW 19 Rigid Modified PVDF Spun Bonded Silicone Rigid Capsules Non Sterile 1 2 um Filter Media Polypropylene Membrane plus Polypropylene O rings Polypropylene Multimedia Over Durapore MECona in Vent Hydrophilic 0 22 um polyester web Ports Membrane Opticap 4 and 10 KVSC Milligard RW19 Rigid Modified PVDF Spun Bonded Silicone Rigid Capsules Non Sterile 1 2 um and RW06 Polypropylene Membrane plus Polypropylene O rings Polypropylene Multimedia 0 5 um Filter Media MEC ona in Vent Over Durapore polyester web Ports Hydrophilic 0 22 um Membrane Opticap 4 and 10 KVSS Milligard RW06 Rigid Modified PVDF Spun Bonded Silicone Rigid Capsules Non Sterile 0 5 um and RWO3 Polypropylene Membrane plus Polypropylene O rings Polypropylene Multimedia 0 2 um Filter Media Over MEC on a in Vent Durapore Hydrophilic polyester web Ports 0 22 um Membrane Opticap 4 and 10 KVSx Milligard RW 19 Rigid Modified PVDF Spun Bonded Silicone Rigid Capsules Non Sterile 1 2 um and RW03 Polypropylene Membrane plus Polypropylene

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