Implementing and Managing Pre-use Post-sterilization Integrity Testing (PUPSIT)
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This document summarizes a presentation given at a conference on aseptic processing. It discusses challenges implementing pre-use integrity testing (PUPSIT) of sterile filters for final product filtration and provides case studies of both successful and unsuccessful filtration setups. The presentation addresses common issues like filter sizing, complex product formulations that impact integrity testing, and assembly details. It promotes the ability to achieve PUPSIT with current single-use technology and filtration setup options.
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Implementing and Managing Pre-use Post-sterilization Integrity Testing (PUPSIT)
- 1. Merck KGaA Darmstadt, Germany Dr. Paul Beckett Technology Manager, EMEA Guillaume Lesage Technology Consultant, EMEA Joint Pharmaceutical Analysis Group (JPAG) Aseptic Processing Conference, May 9, 2019 Practical Examples of Overcoming Common Challenges Implementing and Managing PUPSIT
- 2. 01 02 03 Agenda Case studies • What went right? • What went wrong? 2 Integrity Testing • The background on the IT test itself, why it is important, and how it works Filtration Setups and Single-Use Technology • Options when it comes to designing filtration trains for final fill operations into isolators or RABS. PUPSIT • The PUPSIT debate and how PUPSIT can be achieved with current technology
- 3. Check correct installation • Detects system leaks due to o-rings, gaskets, faulty seals Confirms manufacturer’s specifications • Assures the correct pore size filter Check for damages • Assures integrity before/after sterilization Sterility assurance • Sterile filter is at the core of the aseptic process Regulatory requirements • Link between validation and current processing conditions • GMP Requirement Why Perform Integrity Testing? 3
- 4. Defect made visible by smoke Virus retention Bacteria retention Aerosol Air binary gas Freon Diffusion Current flow test for PTFE Air Diffusion Bubble point, WIT ▪ Water ▪ Low surface tension fluid Integrity Test Sensitivity Sensitivity Proprietary High sensitivity Industry Standards In development Gold standards 4
- 5. Physical Integrity Test Diffusion + Bubble point Gas Flow Bubble Point Pressure Diffusion Viscous flow Viscous flow Bubble point Pressure 5 Use the right test!
- 6. Correlation to bacteria retention Quantifying Retention Performance Graphical Summary Bubble Pt. ObservedCFU 6050403020 3000 2500 2000 1500 1000 500 0 Retentive? No Yes Measure Retention Versus Bubble Point Bubble Pt. Log(CFU) 6050403020 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Use the Relationship Log(CFU) vs. Bubble Pt. Bubble Pt. RetentionConfidence(%) 6050403020 <1 37 90 99 99.9 99.99 Determine Bubble Point with High Retention Confidence Bubble point can have a direct correlation Diffusion & other tests can have an "go - no go" correlation # of Samples Retentive Non- Retentive 2 4 6 8 10 12 14 16 18 20 22 24 2 6 Specification Diffusion rate (cc/min) 6
- 7. Supplier End-User Integrity Testing A critical element of overall sterility assurance strategy Validated sterilizing membrane Validated sterilizing filter Bacterial retention validation testing (WCC) Process Validation and Control Batch integrity test 7
- 8. 01 02 03 Agenda Case studies • What went right? • What went wrong? 8 Integrity Testing • The background on the IT test itself, why it is important, and how it works Filtration Setups and Single-Use Technology • Options when it comes to designing filtration trains for final fill operations into isolators or RABS. PUPSIT • The PUPSIT debate and how PUPSIT can be achieved with current technology
- 10. Regulatory Compliance Reference: Eudralex Volume 4 Annex I
- 11. Formulation, Filtration and Final Filling Process Overview Flush Bag or Barrier Filter Vent Bag Filter Capsule (Single/Redundant) Filtration Sterile connector Sterile disconnect Bulk Fluid Bag Or Formulation Vessel Pump Sampling Formulation Header Bag (Surge) FillingNeedle(s) Pump Filling All components can be designed in SUT Hybrid solutions are widely used (single-use and multi-use components) Sterile connector is a key component to connect the process steps Final filling step under cleanroom grade A conditions
- 12. There are a variety of final filter set-ups in use Final Sterile Filtration Options Dual filter Bioburden / Sterile Filtration Sterile – Hold - Sterile Filtration Redundant and Series Sterile Filtration • Compliance with regulatory guidance for <10 cfu/100 ml • Very low plugging risk for primary filter • Potential batch recovery if one filter fails IT • Higher hold up • Higher cost • Highest system complexity • Compliance with regulatory guidance for <10 cfu/100 ml • Very low plugging risk for primary filter • No back-up in the event of primary filter failure • Higher hold up • Higher cost • Higher system complexity Single filter Sterile Filtration • Minimum hold-up volume • Minimum flushing requirements • Ease of handling and operation • Lower filter cost • No back-up in the event of primary filter failure • Feed bioburden control • Filter plugging
- 13. Single Filter • Low value products • Very low volume products • Product can be easily reworked • Processing of bulk drug substance
- 14. Dual Filter • Products coming from open processing conditions • 10 CFU/100mL is a requirement! • Bioburden reduction filter is also sensible risk management • Only one of the filters needs formal bacterial challenge validation
- 15. Redundant Filtration • Usually has a prefilter too • Both filters are validated by bacterial challenge • Only ONE filter needs to pass testing for the batch to be released • Business risk management • Very common for reasonably sized fills of high value products
- 16. Serial Filtration • The same as redundant filtration in layout • However, both filters are validated together • BOTH filters need to pass testing to release the batch • Commonly used in applications where formulation components weaken correlation between bubble point and bacterial retention
- 17. What connects the filters to the filling line?
- 18. Increase filling productivity – reduce time to market Why Single-Use Technology in Aseptic Processing? Reduced risk of cross contamination Avoids aseptic assembly Validated sterilization process Minimize capital investment (no CIP/SIP) Outsource sterilization & assembly Reduce labor and on-going validation burden Achieves high flexibility (multi purpose line) Facilitates contract manufacturing Fast small scale clinical manufacturing Process Security Enhanced Economics Speed-to-market 1 2 3 Mobius® single-use assembly installed in Groninger FlexPro
- 19. Ability to interface with an isolator while maintaining sterility Isolator Interface with Getinge DPTE® Beta Bag Sterile transfer of fill lines and needles
- 20. Easier handling of filter placed in grade C Sterile Filter Placement Grade C Grade A (RABS/ isolator) Bulk Product Peristaltic Pump Sterile Filter Header Bag Peristaltic Pump Filling Needle Grade C Grade A (RABS/isolator) Bulk Product Peristaltic Pump Sterile Filter Header Bag Peristaltic Pump Filling Needle Filter in Grade A / ISO 5 / Class 100 Low risk to fluid path contamination Open vents, connections Sterile environment risk from vented liquid Handling challenges Large number of components to transfer Pre-use integrity testing challenge Filter in Grade C / ISO 7 / Class 10,000 Easier manipulations Installation, flushing, integrity testing, venting, pump tubing adjustment Potential to replace filter if integrity fails More potential points for ingress Demonstration of assembly integrity more critical
- 21. 01 02 03 Agenda Case studies • What went right? • What went wrong? 21 Integrity Testing • The background on the IT test itself, why it is important, and how it works Filtration Setups and Single-Use Technology • Options when it comes to designing filtration trains for final fill operations into isolators or RABS. PUPSIT • The PUPSIT debate and how PUPSIT can be achieved with current technology
- 22. 22 The Debate - PUPSIT
- 23. 23 The Guidance (As It Stands)
- 24. PUPSIT in the most complex assembly 24 Primary Product Filter Product Inlet Redundant Product Filter SPG Gas Filter Barrier Filter Flush/Air Inlet Vent Collection Bags Product Outlet
- 25. 25 25 PUPSIT is more than possible with single-use assemblies
- 26. Millipak® and Millidisk® Barrier Filters Liquid Wetting and flushing fluids evacuate to drain Gas Air from integrity test and blow down can vent from same filter One disk pair 3 Hydrophilic membranes 1 Hydrophobic membrane
- 27. Redundant Filtration – Enable a Valid Test Pre-use F1 F2 P2 P1 Post-use F1 F2 P2 P1 optional 27
- 28. Case studies
- 29. Get the Filter Sizing Right Small volume fill 10L BDS of a biologic Processed through a 10” PVDF 0.22um No flushing – E&L Hold up concerns BDS 10L Durapore® membrane 0.22um 10” Isolator boundaryIT Durapore® membrane 0.45um 10”
- 30. Tricky products Viral vectors are booming 25L of lentiviral vector 60% yield loss Closed system design 0.45um/0.45um BDS 25L Durapore® membrane 0.22um Millipak® filter 200 Isolator boundaryIT Durapore® membrane 0.45um/0.22um Millipak® filter 200
- 31. Policy is Inside the Isolator Checking the dimensions Actually from CCM filtration Expensive hardware for storage Capsule would not fit through the port Same concerns with too much tubing – integrity tester inside the isolator BDS Millipore® Express SHR XL300 0.1um Isolator boundaryIT Millipore® Express SHC XL300 0.5/0.2um
- 32. Devil is the Detail Difference between aseptic and sterile Assemblies can be very big, too big to ship They need to be connected, sometimes this connection needs to take place in the isolator Ensure this connector is up to standard Transfer connector to outside the isolator BDS Durapore® membrane 0.22um Millipak® filter 200 Isolator boundaryIT Durapore® membrane 0.45um/0.22um Millipak® filter 200 Aseptic connector
- 33. Plan your visit today. EMDMillipore.com/mlab
- 34. The vibrant M, Durapore, M Lab, Millidisk, Millipak, Millipore, and Mobius are trademarks of Merck KGaA, Darmstadt, Germany or its affiliates. All other trademarks are the property of their respective owners. Detailed information on trademarks is available via publicly accessible resources. © 2020 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.