Int r oduct ion t o Int egr it y Tes t ing Theor y

Transcription

1 Int r oduct ion t o Int egr it y Tes t ing Theor y G. Somasundaram (Som) Associate Director Technology Management South East Asia & Oceania Singapore Somasundaram.g@merckgroup.com 16 th May 2017 Merck KGaA Darmstadt, Germany

2 Agenda 1 Why and When to Integrity Test 2 Regulatory Requirements 3 Introduction to Integrity Testing 4 Considerations for a Reliable Integrity Test

3 Sterilizing Grade Filter? Functional definition Remove microorganisms from a fluid Produce sterile fluid Limited value in defining as a pore size Define in terms of Bacterial Retention ASTM method Retains >10 7 cfu B. diminuta per cm 2 of filtration area Produce sterile filtrate Microorganisms limited to bacteria, yeast, molds, protozoa 3

4 Basic Elements of a Bacterial Retention Test ASTM F838 05

5 What is Membrane Integrity? Classification: Public

6 Why perform Integrity Testing (IT)? Check correct installation Detects system leaks due to o-rings, gaskets, faulty seals Confirms manufacturers specifications Assures the correct pore size filter Check for damages Assures integrity before sterilization Assures integrity after steaming or autoclaving Regulatory requirements Link between validation and current processing conditions GMP/Audit Requirement

7 Where & When Do We Integrity Test? WHAT DOES IT FIND? WHEN CAN YOU DO IT? Faulty housings Out-of-the box failures Before sterilization Sterilization induced failures Before use Stress (process) induced failures After use 7

8 Which Filters to Test & When Biotech Manufacturing Process Should all sterilizing grade filters (0.2um) used in the process be tested?

9 Which Filters to Test & When Biotech Manufacturing Process For final product sterilizing filters: Post-use IT: Regulatory requirement Pre-use IT: required in EU and otherwise recommended to consider as part of risk assessment Perform IT based on Risk Analysis Regulatory Requirement

10 Who defines the requirements? Among others!

11 Regulatory Requirements EU GMP: The integrity of the sterilised filter should be verified before use and should be confirmed immediately after use by an appropriate method such as a bubble point, diffusive flow or pressure hold test EU GMP Annex 1 for the manufacture of sterile medicinal products, February 2008 US FDA: Integrity testing of the filter can be performed prior to process and should be routinely performed post-use. US FDA Guideline on Sterile Drug Products Produced by Aseptic Processing, 2004 SFDA: After sterilizing filter is used, the integrity of the filter should be tested and the results recorded. The test methods could be bubble point, diffusion or pressure hold. Where sterility is claimed: IT before use is recommended, after use is required SFDA Guidelines, 2010

12 Industry Guidance PDA TR26: Where the claimed purpose of the filter is to sterilize, pre and post filtration integrity tests should be performed. Steps should be taken to ensure that the downstream side of the system remains sterile when performing a post sterilization, preuse integrity test. PDA Technical Report , pg. 34 ISO 13408: The filtration system should be designed to permit in-place integrity testing as a closed system prior to filtration. ISO 13408, 2003 PDA recommends IT pre-use and post-use. Industry guidance emphasizes that maintaining process sterility is of critical concern

13 General Types of Integrity Tests Non-Destructive: Capillary or diffusive by Manufacturers for process testing Capillary Bubble point, water intrusion Direct correlation to pore size/retention Diffusion Based Diffusion, HydroCorr, Forward Flow (same as Diffusion) Predictive of bacterial retention Sensitive check for bulk flow Destructive Bacterial Retention Actual demonstration that the filter will perform designed task Destructive and impractical for in-situ

14 Common/Regulatory accepted types of In-process Integrity Tests Hydrophilic Filters (Liquid) Hydrophobic filters (Gas & vent) Bubble point (BP) HydroCorr (Water Intrusion) Diffusion (Forward Flow) Alcohol BP Enhanced (Diffusion + BP) Alcohol Diffusion A physical integrity test is meaningful only when it can be related to specific filter retention characteristics. PDA Technical Report 26 Section 7.2 BP, Diffusion and Water Intrusion are correlated to Bacterial Retention

15 Destructive vs. Non-destructive Testing There must be a correlation between a destructive and a non-destructive integrity test Regulatory requirement FDA Aseptic Guidelines A physical integrity test is meaningful only when it can be related to specific filter retention characteristics. PDA Technical Report 26 Validation justification for the use of a test Where, LRV=log 10 [# of organisms in challenge solution/# of organisms in filter effluent] For Example, 1X10 8 cfu in challenge and 0 organisms in effluent would be reported as LRV>/= 8 > symbol means 0 in denominator of above equation

16 How Capillary forces influence IT? 16

17 Manual Bubble Point Testing Flush with water Apply air pressure Increase pressure until rapid continuous flow of bubbles is seen downstream 17

18 Setup Checks - Automatic Classification: Public

19 Physical integrity test Diffusion Upstream High Pressure Downstream Low Pressure 40psi Wet Membrane Apply pressure from validated specification Hold Pressure Gas is dissolved in liquid is held in the pores of a fully wetted membrane filter. A pressure differential will give a gas concentration gradient across the filter. Results in diffusive gas flow from upstream to downstream.

20 Physical integrity test Diffusion Upstream High Pressure 40psi Hold Pressure Gas Flow Out of specification Bad Filter Good Filter Within specification Pressure Downstrea m Low Pressure For this test, you are measuring that gas flow at the prescribed test pressure meets validated specifications.

21 Upstream High Pressure Downstrea m Low Pressure Classification: Public Physical integrity test Bubble Point 30psi 40psi 50psi Gradually raise pressure Wet Membrane Water held in by capillary forces Sufficient pressure will over come the capillary forces to evacuate the liquid from the filter. Bubble point is the transition point from diffusive to bulk flow, where liquid gets evacuated from the largest pores. For this test, you are seeking to identify this transition point which must align with validated filter specifications.

22 Physical integrity test Bubble Point Bubble point is the transition point from diffusive to bulk flow, where liquid gets evacuated from the largest pores. Upstream High Pressure For this test, you are seeking to identify this transition point which must align with validated filter specifications. Downstrea m Low Pressure Gas Flow Out of specification Bad Filter Within specification Good Filter Durapore CVGL: 50psid Pressure

23 Hydrocorr/Water Intrusion Test for Hydrophobic Filters bar Install dry cartridge Fill upstream w/ water Hydrophobic polymers repel water Water Intrusion Pressure is the minimum pressure necessary to force water into the largest pores of a hydrophobic (water resistant) membrane. Apply pressure Hold pressure P atm Pressure causes pleats to compact - resulting in apparent water flow Measure pressure decay

24 Hydrocorr/Water Intrusion Test for Hydrophobic Filters bar Hydrophobic polymers repel water Water Intrusion Pressure is the minimum pressure necessary to force water into the largest pores of a hydrophobic (water resistant) membrane. Water Flow ml/min Bad Filter Out of Specification P atm Measure pressure decay minutes Aervent : 0.75 ml/min for 10 Good Filter Within Specification Time

25 What can Affect the Integrity Test Bubble Point Wetting along and through the device Pore shape Wetting solution What is on the pore Pore diameter Temperature Diffusion Wetting along and through the device Wetting solution What is on the pore Test gas Temperature Differential pressure Porosity Area Wetted thickness 25

26 What is the Best Integrity Test? The one that Gives the greatest sensitivity/reliability Gives the best accuracy Can be done in the test environment Uses specifications provided by the manufacturer Can be done with the test equipment available Fits in with the company philosophy Sometimes it is diffusion, sometimes it is bubble point, sometimes is it both All non destructive integrity tests measure or detect gas flow 26

27 Manual vs Automated Integrity Testing Manual Automated Advantages Simple equipment Direct measurement or observation of gas flow Fast Disadvantages Nearly impossible to perform aseptically Operator Subjectivity Advantages No downstream interventions Facilitates post-sip testing without risking downstream contamination Repeatable, can be validated Eliminates Operator subjectivity Enhanced record keeping Hard Copy Printout enabling Troubleshooting Disadvantages False Failures

28 Consider at ions f or a Reliable Int egr it y Test

29 Considerations for a Reliable Integrity Test

30 Test Selection Hydrophilic Filters (Liquid) Bubble point (BP) Hydrophobic filters (Gas & vent) HydroCorr (Water Intrusion) Diffusion (Forward Flow) Alcohol BP Enhanced (Diffusion + BP) Alcohol Diffusion Test Selection FTET What needs to be considered in selecting the right test?

31 Selecting the right test depends on the properties of the filter and your process Filter Characteristics Hydrophobic or hydrophilic Membrane area Pore size >0.45 to 0.1µm Pore structure Test Selection Process Characteristics Test method Manual v. Automated Environment Temperature stability FTET Your supplier should help to recommend the best test for your process.

32 Certified Operator: Critical Link to Sterility assurance Program information Operator and lot info Test Specifications Upstream volume Diffusion Bubble point Summary FTET Trained Operato r Operators trained to interpret the test results is critical to verify the validity of the integrity test.

33 Robust Wetting Procedurec BP and Diffusion require a fully wet filter Bulk gas flow through dry pores results in false failures Most common reason for improper wetting is flow rate and pressure are not defined or controlled Robust wetting procedure design should be based on - Manufacturers recommendation Understanding membrane wetting characteristics Process capability, control and monitoring 1 LPM/ft 2 (0.1 m 2 ) filter area for 5 minutes Wetting Instructions P35515

34 Stable Temperature Environment Manufacturers Specifications are typically established at ambient temperature (~23 C) If operating outside of ambient temperature, a ratio should be established during validation and applied to test specification E.g.: Cold room operation or heat jacketed housing FTET Stable Environment Correction Factor (Relative to 23 C) Effect of Temperature on Diffusional Flowrate Temperature (C) There is no significant impact on diffusive flow or BP over normal ambient temperature range

35 Stable Temperature Environment When using Automatic Testers, temperature changes during a test leads to additional upstream pressure gain or loss Test Error Ideal Gas Law - PV = nrt As Temperature increases Pressure increases As Temperature decreases Pressure decreases Trained Operator can identify the Temperature effect by reviewing the flow curve Even a change of 1 o C DURING the test can lead to false failure because the pressure change WILL NOT be solely due to gas flow Air Flow ml/min Common reasons for temperature changes Inadequate stabilization After steaming or wetting with hot WFI Environmental changes during testing Near autoclave, HVAC outlets, Cold room door, Near a window Diffusion flow Out of Specification Flow at Unstable Temp False Failure Durapore : 13.3 ml/min for 10 Flow at Stable Temp Within Specification FTET Stable Environment Test has to be repeated per retest SOP after establishing stable test conditions Time min

36 Validated Equipment Design Specification and Qualification Installation Qualification Operational Qualification Process Validation FTET Validated Equipment Change Control Regulatory agencies require instrument validation to ensure reliable and predictable performance Establish and provide documentary evidence that: DQ: Instrument Change is designed Control in accordance with the requirements of GMP. (Supplier) Changes to instrument initiates the design IQ: Instrument process at has the been supplier. URS built and It installed should follow in compliance the same Functional with qualification their Specification design specifications. (Supplier) Design Specification process steps DQ, IQ, OQ, PQ. OQ: The supporting utilities and the Acceptance Test instrument operate in accordance with Module Test their design specifications. (Supplier) Component Construction Integration Tests Systems Acceptance Test PQ: Regulatory A specific process requirements will consistently are produce established a product via meeting DQ, Validation IQ, its OQ Summary predetermined and PQ. Suppliers specifications typically and quality attributes. offer protocols (End User and with execution Supplier Assistance)

37 Fluid properties affecting IT results Feed stream components can impact surface tension and/or gas diffusion rate impacting IT results as compared to suppliers ( typically water based) specifications This must be controlled or validated. Common causes for alteration: Contaminants: New silicone tubing, residual cleaning agent, etc Identify and eliminate Residual Product: Develop product based integrity test specification or post use flush procedure FTET Consistent Test Fluids Application Note AN1505EN00 During filter validation, your supplier can help to establish product specific integrity test

38 Troubleshooting SOP with Decision tree SOP should Be based IT physical principles and ability to interpret test results Minimize re-tests & improve overall test efficiency Link to the validated process parameters SOP should address the following Is the filter integral? If it is a false failure, why did it fail? Leaks or temperature changes Poor wetting Surface tension suppression PDA Journal of Pharmaceutical Science and Technology, Vol. 62, No. S-5, 2008

39 Pr oduct S pe c if ic Integrity T e s t ing

40 Product-Wetted versus Water-Wetted Integrity Testing Classification: Public Filter manufacturers recommended test values are for specified fluid(s) and conditions. Testing with non-specified fluid(s) conditions requires establishing product/process specific test parameters Testing includes examining the effect of fluid AND process variables on integrity test results and the reproducibility of these values PDA Tech Report 26 Sec

41 Product Specific Test Principles Compare water to product on the same filters Variables that could effect bubble point include: surface tension contact time/volume membrane lots temperature Bubble point should test multiple filter lots Diffusion can be multiple trials on one filter Product based specifications should be based on experimental results, rather than calculations 41

42 Summary Classification: Public IT is a critical component of Sterility Assurance and is a regulatory requirement The choice of an integrity test depends on the size and type of the filter and your risk mitigation strategy. Good process design will deliver reliable IT operation. Validated, automatic integrity testers improve process efficiency. We are here to help.

43 Thank You 43