Bioburden control: Strategies to address bioburden control in downstream processing
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The document discusses strategies for controlling bioburden in downstream processing within the life sciences sector, particularly focusing on sources of bioburden and their impact on productivity and product quality. It outlines risk assessment and mitigation techniques, case studies of bioburden excursions, and emphasizes the necessity of monitoring bioburden levels to ensure compliance and safety. A robust risk mitigation strategy is proposed, combining assessment, mitigation, and monitoring to address the challenges posed by bioburden in biopharmaceutical manufacturing.
![Monitor
How much is too much?
“Unlike non-sterile dosage forms, there are no recommended bioburden levels provided in
regulatory guidelines or compendia for the [downstream] protein purification processes of
biologic or other biopharmaceutical products, therefore, manufacturers are responsible for
setting bioburden control levels for biologic production processes.”
“The BPOG Bioburden Working Group conducted a member survey of bioburden action levels
and found that the majority of biologic processes action levels were set between 1-10
CFU/mL.”
Bain, D. “Microbial Monitoring For Biological Drug Substance Manufacturing: An Industry Perspective”
BioPhorum Operations Group. 2015.
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Bioburden control: Strategies to address bioburden control in downstream processing
- 1. Merck KGaA Darmstadt, Germany April 30, 2020 Somasundaram Gopalakrishnan Senior Technical Consultant Asia Pacific Technology Management, Process Solutions Strategies to Address Bioburden Control in Downstream Processing
- 2. Strategies to Address Bioburden Control in Downstream Processing The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada.
- 3. Objectives 1 Understand the impact of bioburden excursions 2 Recognize sources of bioburden 3 Develop strategies to mitigate risk Strategies to Address Bioburden Control in Downstream Processing
- 4. 1 Impact of uncontrolled bioburden Strategies to Address Bioburden Control in Downstream Processing
- 5. 30 Percent 1- 6Months 1-14Million Euro Percent of process deviations caused by contamination* Length of time to complete an investigation Operations cost *Sources Langer 2013, Wiebe 2014 Biologics in-process contamination Strategies to Address Bioburden Control in Downstream Processing
- 6. 30 Percent 1- 6Months 1-14Million Euro *Sources Langer 2013, Wiebe 2014 Biologics in-process contamination Impact Productivity losses Material replacement costs Batch loss Interruption of product supply Delay in clinical development Strategies to Address Bioburden Control in Downstream Processing
- 7. 2 Sources of bioburden Strategies to Address Bioburden Control in Downstream Processing
- 8. Microbial Byproducts Endotoxin Exotoxin Lipopeptides Flagellin DNA Extracellular proteases Bioburden Bacteria Fungi Mycoplasma Virus TSE Agents What? Downstream bioburden and byproducts Scope Strategies to Address Bioburden Control in Downstream Processing
- 9. Facility & Environment Equipment Processes Materials Utilities Personnel Each source contributes to the process bioburden profile Sources of bioburden Origin? Staphylococcus Bacillus Non-fermenting Gram Negative rods Aspergillus Source: Public domain CDC/ Robert Simmons Strategies to Address Bioburden Control in Downstream Processing
- 10. Downstream Where? Risk profile and control strategies differ throughout the process Secondary Clarification Chromatography Protein A Final FillingFinal Sterile Filtration Concentration & Formulation Bulk Storage and Transport Viral Inactivation Chromatography CEX Virus Filtration Clearance Ultrafiltration / Diafiltration Bioreactor Primary Clarification MCB WCB Seed Train Raw Materials Filtration Bioburden Reduction Bioburden Reduction Chromatography AEX Bioburden Reduction Bioburden Reduction Final Fill Risk Areas Upstream Downstream Strategies to Address Bioburden Control in Downstream Processing
- 11. Case Study Bioburden excursions in the Protein A Pool Chrom Protein A Bulk Storage and Transport Viral Inactivation Chrom CEX Virus Filtration Clearance Ultrafiltration Diafiltration Bioburden Reduction Bioburden Reduction Chrom AEX Bioburden Reduction Bioburden Reduction Situation • Spore-forming bioburden alert-level excursions in the Protein A pool over several campaigns Root Cause • Failure to recognize a trend in the pattern of excursions • Sanitization solution was not sporicidal • Sub-optimal sanitization process Corrective and Preventative Actions • Scale down studies with a new sanitizer and optimization of sanitization conditions • Process scale verification Strategies to Address Bioburden Control in Downstream Processing
- 12. Case Study Bioburden action-level excursions in the UF/DF step Chrom Protein A Bulk Storage and Transport Viral Inactivation Chrom CEX Virus Filtration Clearance Ultrafiltration Diafiltration Bioburden Reduction Bioburden Reduction Chrom AEX Bioburden Reduction Bioburden Reduction Situation • Bioburden and endotoxin exceeded action levels in multiple batches • Intensive investigation of the process and support areas Root Cause • Bioburden formation in the TFF cassettes due to inadequate cleaning and storage processes Corrective and Preventative Actions • Improve cleaning and storage processes • Sterilization or sanitization of buffer tanks • Assessment of the water for injection (WFI) system and transfer lines • Introduction of bioburden reducing filters • Validation of hold times and storage conditions • Revision of bioburden limits based on process capability Buffer, Sanitizer, and Storage Solutions Operations WFI Operation Suvarna K. et. al. “Case Studies of Microbial Contamination in Biologic Product”, American Pharmaceutical Review 14(1) January/February 2011. Strategies to Address Bioburden Control in Downstream Processing
- 13. Case Study Sporadic bioburden action-level excursions Chrom Protein A Bulk Storage and Transport Viral Inactivation Chrom CEX Virus Filtration Clearance Ultrafiltration Diafiltration Bioburden Reduction Bioburden Reduction Chrom AEX Bioburden Reduction Bioburden Reduction Situation • Sporadic mixed bioburden excursions at multiple points in the downstream process Root Cause • Aseptic connections of equipment and sampling devices Corrective and Preventative Actions • Short term: • Retrained operators in aseptic techniques • Long term: • Reduced the number of aseptic connections • Implemented sterile to sterile connectors and steam to sterile connectors. • Introduced a facility-wide sterile sampling system Strategies to Address Bioburden Control in Downstream Processing
- 14. Case Study Bulk solution contamination with Bacillus species Chrom Protein A Bulk Storage and Transport Viral Inactivation Chrom CEX Virus Filtration Clearance Ultrafiltration Diafiltration Bioburden Reduction Bioburden Reduction Chrom AEX Bioburden Reduction Bioburden Reduction Situation • Prefiltration bioburden load was 20 x the specification • Bacillus species suggested a steam-in-place issue Root Cause • Equipment design: improper pipe slope resulted in cold spots that were insufficiently sterilized Corrective and Preventative Actions • Discard (scrap) the batch • Redesign piping • Requalify SIP (steam-in-place) cycle • New processes will use single-use storage systems Strategies to Address Bioburden Control in Downstream Processing
- 15. Many routes for microbial ingress Downstream bioburden excursions are often the result of Improper cleaning, storage, or sanitization Suboptimal system design Aseptic connections Sampling Lapses in aseptic technique Intensive risk assessments could have prevented many of these contaminations or excursions Key Points Sources of bioburden Strategies to Address Bioburden Control in Downstream Processing
- 16. 3 Mitigation Strategies Strategies to Address Bioburden Control in Downstream Processing
- 17. Assess Mitigate Monitor Risk Mitigation Strategies Strategies to Address Bioburden Control in Downstream Processing
- 18. The risk profile varies from upstream to final fill Risk Hammock Upstream Downstream Finish and Fill Operations Risk High Low Aseptic AsepticBioburden Controlled “The level of effort, formality and documentation of the quality risk management process should align with the level of risk” (ICH Q9A) Strategies to Address Bioburden Control in Downstream Processing
- 19. Assess Mitigate Monitor Assess Risk Assess extent of risk, ability to detect, and frequency of occurrence Strategies to Address Bioburden Control in Downstream Processing
- 20. Microbiological Profile Get to know the bioburden in your neighborhood Who are we? How many of us? Will we cause you trouble? Where are we from? Strategies to Address Bioburden Control in Downstream Processing
- 21. Focus Objective Fault Tree Analysis FMEA HACCP Statistical Methods Ishekawa (Fish Bone) Risk Assessment Risk Identification Risk Analysis Risk Evaluation X Risk Control Risk Reduction X X Risk Acceptance X X Risk Review X Risk Communication X X Characterize Process Risk Multiple tools are available Adapted from Roenninger S., Hertlein M. “Which Risk assessment fits best?” Logfile No 15 November 2011 1-4 Maas & Peither AG GMP Publishing Very suitable Limited suitability X Not suitable Strategies to Address Bioburden Control in Downstream Processing
- 22. What parts of the process could introduce bioburden? (Hu)Man Mother Nature Material MethodMachine Hygiene Training Air Handling Water Sanitizers Disinfectants Buffers Chromatography Gaskets Water System Storage Buffer Load cells Mixer Mixing Compounding Hold Time Room Cleaning Transfer Transfer Testing Sampling Weighing Measurement Calibration Microscopy Humidity Tubing / Piping Filters Resin Tanks Pump Transfer Panel Steam Generator Aseptic Technique Clean room Filtration Pump Air compressor Pressure Flow Rate Time Temperature Enumeration Insects Animals i.e. Rodents Microorganisms Mass Columns Experience ChromatogramData Acquisition Packing Installing Bioburden profile Strategies to Address Bioburden Control in Downstream Processing
- 23. CMC Biotech Working Group: A-Mab: A case Study in Bioprocess Development Score • Probability of occurrence • Severity • Ability to detect • Criticality Prioritize How can I put the risks into perspective? Strategies to Address Bioburden Control in Downstream Processing
- 24. Key Points Characterize the microbial profile of the process Utilize a combination of assessment tools A cross-functional team is crucial to the process Your bioburden risk mitigation strategy should address Patient safety Drug supply Business risk Assess Risks Strategies to Address Bioburden Control in Downstream Processing
- 25. Assess Mitigate Monitor Mitigation Considerations Eliminate source or reduce likelihood of occurrence Strategies to Address Bioburden Control in Downstream Processing
- 26. Bioburden profile What microorganisms are present? How many? Variation over time? Toxin producing? Spore formers? Material Origin Material consistency Supplier transparency Quality management system Quality philosophy Material Characteristics Growth Promoting Bacteriostatic Bactericidal Risk Mitigation Material Considerations Mitigate Strategies to Address Bioburden Control in Downstream Processing
- 27. Risk Cell disruption results in byproducts Sanitizer Modes of Action Bacterial spores • Spore coat penetration Vegetative bacteria • Cell wall and cytoplasmic disruption Fungi • Cell wall and cytoplasmic disruption Virus • Capsid and nucleic acid damage Risk Mitigation Sanitization and Storage Modes of action of sanitizers Reduce bioburden load Material selection Containment • Single-use • Closed sampling • Pre-packed columns Removal • Filtration Mitigate Strategies to Address Bioburden Control in Downstream Processing
- 28. Prevent Contamination by Containment Implement Single-use Systems and Closed Sampling Eliminate bioburden contribution Prevent microbial ingress Minimize process validation Mitigate Strategies to Address Bioburden Control in Downstream Processing
- 29. Upstream Process Bioreactor protection Drug supply continuity Business risk mitigation Downstream Process Bioburden Reduction Assure drug substance purity Final Fill Regulatory requirements Drug product sterility assurance Assure patient safety What is your objective? Risk-based filter selection What filtration option is best for my process? Strategies to Address Bioburden Control in Downstream Processing
- 30. Goal: Minimize in-process bioburden • No requirement to validate sterility • Reduce bioburden proliferation • With other controls, bioburden reduction filters may provide sufficient process safety • Prefiltration can increase filter capacity and improve efficiency Bioburden reduction filters (0.45 or 0.2 m) • May be sufficient for intermediate processing steps • May be used as prefilters upstream of sterilizing- grade filters • Manufacturers may validate bacterial reduction, but not sterilizing performance Sterilizing-grade rated filters (0.2 m) Manufacturers must validate bacterial removal Traditionally used for intermediate processing steps Downstream Filtration Minimize Bioburden What filtration option is best for my downstream process? Strategies to Address Bioburden Control in Downstream Processing
- 31. Mitigate Risks Key Points A downstream bioburden control risk mitigation strategy addresses drug supply continuity, business risk, and patient safety The act of sanitization, while effective, can release microbial byproducts into the process Single-use systems prevent microbial ingress and reduce bioburden contribution Closed sterile sampling prevents false-positive tests Filtration choice is dependent upon risk assessment, capacity, and cost per liter Mitigate Strategies to Address Bioburden Control in Downstream Processing
- 32. Assess Mitigate Monitor Mitigation Strategy: Monitor Monitor trends Strategies to Address Bioburden Control in Downstream Processing
- 33. Downstream Monitoring What do I test for? Where? Why? Chromatography Protein A Bulk Storage and Transport Viral Inactivation Chromatography CEX Virus Filtration Clearance Ultrafiltration / Diafiltration Bioburden Reduction Bioburden Reduction Chromatography AEX Bioburden Reduction Bioburden Reduction Bioburden Virus Mycoplasma Endotoxin V M B E B E B E B E V E V E B E B E M Monitor Strategies to Address Bioburden Control in Downstream Processing
- 34. Monitor How much is too much? “Unlike non-sterile dosage forms, there are no recommended bioburden levels provided in regulatory guidelines or compendia for the [downstream] protein purification processes of biologic or other biopharmaceutical products, therefore, manufacturers are responsible for setting bioburden control levels for biologic production processes.” “The BPOG Bioburden Working Group conducted a member survey of bioburden action levels and found that the majority of biologic processes action levels were set between 1-10 CFU/mL.” Bain, D. “Microbial Monitoring For Biological Drug Substance Manufacturing: An Industry Perspective” BioPhorum Operations Group. 2015. Strategies to Address Bioburden Control in Downstream Processing
- 35. Downstream processing is considered a low-bioburden controlled process Bioburden monitoring is a supporting tool in a risk mitigation strategy Appropriately set action and alert levels coupled with data trending permit timely responses Key Points Mitigation Strategy Monitor Strategies to Address Bioburden Control in Downstream Processing
- 36. Summary Strategies to Address Bioburden Control in Downstream Processing
- 37. Strategies to address bioburden control in downstream processing Final Points Bioburden excursions present real and under-appreciated risks For every publically disclosed contamination event, there are countless others Implications of bioburden excursions can be significant Investigational and decontamination costs, production downtime, lost revenues due to drug stock-out, regulatory fines, loss of consumer confidence Multiple approaches are needed to provide the required control Low bioburden processes require as much attention as sterile processes. A robust risk mitigation strategy uses a three-pronged approach of Risk assessment Mitigation Monitoring Strategies to Address Bioburden Control in Downstream Processing
- 38. Langer, E. “Biopharm Shows Signs of Maturity”. Pharmaceutical Manufacturing, in: Biopharmaceutical manufacturing Excellence Within a Rapidly Changing Landscape, pp 20-25, 2013. Link Wiebe, M. “Update on the CAACB Virus Contamination Project”. presented at 2014 PDA/FDA Virus & TSE Safety Conference 2014. von Wintzingerode, V. “Biologics Production: Impact of Bioburden Contaminations of Non-Sterile Process Intermediates on Patient Safety and Product Quality”. American Pharmaceutical Review. 20(3). April 2017. Link Suvarna K. et. al. “Case Studies of Microbial Contamination in Biologic Product”, American Pharmaceutical Review 14(1) January/February 2011. Link K. Suvarna “Case Studies of Microbial Contamination in Biologic Product” presented at PDA 5th Annual Global Conference on Pharmaceutical Microbiology, October 2010. Roenninger S., Hertlein M. “Which Risk assessment fits best?” Logfile No 15 November 2011 1-4 Maas & Peither AG GMP Publishing. Oliver J. “3D risk assessment model”, Journal of Validation Technology, Autumn 2008, page 70-76. Link Bain, D. “Microbial Monitoring For Biological Drug Substance Manufacturing: An Industry Perspective” BioPhorum Operations Group. 2015. Link CMC Biotech Working Group: A-Mab: A case Study in Bioprocess Development. Link PDA, “Technical Report No. 69 Bioburden and Biofilm Management in Pharmaceutical Manufacturing Operations. Parenteral Drug Association. 2015. Strategies to address bioburden control in downstream processing Recommended Reading Strategies to Address Bioburden Control in Downstream Processing
- 39. Acknowledgments • Kerry Roche Lentine, Director, Technology Management, Global Growth Programs Strategies to Address Bioburden Control in Downstream Processing
- 40. Somasundaram G. © 2020 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved. The vibrant M is 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. Senior Technical Consultant [email protected]