Considering the additional risks of operating bio tech processes in a ball room facility 2

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BPOG
Room Classification, Closed Systems in CNC Space
ISPE Conference, Strasbourg

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Considering the additional risks of operating bio tech processes in a ball room facility 2

  1. 1. Facility Efficiency Regulatory, GMP Challenges Robin Payne (On behalf of the BPOG Room Classification / Closed Systems work stream) ‘Considering the Additional Risks of Operating BioTech Processes in a ‘Ball Room’ Facility’ BioPhorum Operations Group Thursday the 14th November 2013, 16:30-17:15
  2. 2. Objectives • Show how collaboration can move an industry forwards; • Challenge the industry to take managed risks with new technology to increase the flexibility of manufacturing facilities and hence increase access to drugs for patients. Nov 2013 ISPE Strasbourg 2
  3. 3. Content • BioPhorum Operations Group (BPOG) • Controlled Non-Classified Spaces • Flexibility • Multi-Product Application • Risk Assessment with Scenarios • The Way Forwards Nov 2013 ISPE Strasbourg 3
  4. 4. BPOG – The BioPhorum Operations Group An Exclusive Collaboration Group ‘Helping move the biopharmaceutical industry forwards.’ Constitution: 22 medium to large enterprises with global reach. The Goal: To accelerate the rate at which the biopharmaceutical industry attains a lean state by building an exclusive community of member companies, focusing on emerging industry challenges and importing and customising appropriate external best practice to deliver outstanding results. See www.biophorum.com for additional details Nov 2013 ISPE Strasbourg 4
  5. 5. Collaboration Approach / Benefits 1. Contacts and networks 2. Comparison of competence 3. Sharing experience & knowledge 4. Cooperative development of best practice & implementation approaches 5. Customer-centric standards / consistent position with regulators / influence supply base Nov 2013 ISPE Strasbourg 5
  6. 6. The Collaboration Process • Identify a Theme; • Decompose into Topics; • Develop Shared Understanding – Background – Common Language – Meaningful Deliverables • Deliver; • Review and Capture Learning Bittner, E. & Leimeister, J. M. (2013): Why Shared Understanding Matters Engineering a Collaboration Process for Shared Understanding to Improve Collaboration Effectiveness in Heterogeneous Teams. In: 46th Hawaii International Conference on System Sciences (HICSS) , Maui, Hawaii. Nov 2013 ISPE Strasbourg 6
  7. 7. CNC Space for Bulk Drug Substance Operations: The Theme Technology, with risk based approaches, can eliminate the need for clean rooms in biopharmaceutical drug substance manufacture. Nov 2013 ISPE Strasbourg 7
  8. 8. Enablers for Flexible Facilities and Manufacturing • Process design and understanding – Understand the process – Simplify the process – Make it continuous • Flexible organizations – Mindset and skills – Communication and KM • Advanced controls and testing – Automation – Data acquisition/analysis – Reduced testing • Facility design – – – – Nov 2013 Modularization Single use components Controlled Non-Classified Spaces Multi-product manufacturing ISPE Strasbourg 8
  9. 9. CNC definition and expectations Element Standard / Policy A cGMP manufacturing area designed to produce a consistent and controlled environment, but not necessarily monitored to a given environmental classification Chalk, S., et.al.; “Challenging the Cleanroom Paradigm for Biopharmaceutical Manufacturing of bulk Drug Substances,” BioPharm. Intl., August, 2011 sterilized sterilized Closed or functionally closed processes sterilized Probst, S, CLOSED-SYSTEM PROCESSING: AN ENABLING TECHNOLOGY FOR FLEXIBLE FACILITIES, IBC Flexible Facilities, 2013 Sterile tubing fuser or aseptic connector Architectural Finish Cleanable and durable surfaces Minimize particle generation Gowning Hairnet / beard covers Dedicated shoes or shoe covers, Appropriate PPE Particulates and Bioburden Not routinely monitored Air Changes, Temperature, Humidity (HVAC) Appropriate for safety, comfort and heat dissipation Air Filtration HEPA filters NOT required but filtration recommended Nov 2013 ISPE Strasbourg 9
  10. 10. Controlled Non-Classified (CNC) DS Manufacturing Benefits • Lower Operating Costs – Gowning/transitions – Environmental Monitoring – Energy • Lower Construction Costs – HVAC equipment and ducting – Personnel and material airlocks • Faster construction and qualification – Delay capital investment Nov 2013 Considerations • High degree of assurance that process equipment is closed • Defining risk based and effective design and operating principles • Facility organization to manage the interface between manufacturing and external environments • Managing planned and unplanned system breaches • Assurance of environmental control ISPE Strasbourg 10
  11. 11. Functionally Closed Processing • System Closure established and maintained during processing • Limited environmental exposure (or none) between processing; pre-use sanitization • Consideration for system impact on environment during “open” status Nov 2013 ISPE Strasbourg 11
  12. 12. Closed Processing: Stainless Steel Systems • More complex design • Vessel and transfer line can be steamed and sanitized without opening • Integrity testing possible • Precedent for CNC manufacturing • Facility segregation may not be necessary May not be flexible! Nov 2013 ISPE Strasbourg 12
  13. 13. Closed Processing: Single-Use Systems Γ-sterilized Γ-sterilized Γ-sterilized Γ-sterilized Sterile tubing fuser or aseptic connector • Design complexity borne by the vendor, not the end user. • Possibility of leaks (integrity test may not be possible) • Bag seams • Tubing engagements • Peristaltic pump tubing wear or misalignment Nov 2013 ISPE Strasbourg 13
  14. 14. Functionally Closed Systems: Burden of Proof NEED PROOF! Functionally-Closed Connection in CNC ≥ Open Connection in Grade C What could be in a CNC environment? • Bacteria, mold, virus • Cell culture material (from spill) • In-Process API from another process Sanitization measures need to be validated Nov 2013 ISPE Strasbourg 14
  15. 15. Application of CNC to Concurrent Multi-Product Design Concept • Concurrent multi-product process: A facility where different products of the same or different class are manufactured at the same time in parallel. – More challenging than a ‘campaign’ scenario where production has been sequenced to allow temporal segregation with effective cleaning and changeover. • Application of Quality and Scientific Risk Management approaches – Special considerations for product class, product compatibility and requirement for product containment • Assumptions – – – – Shared media/buffer prep, bioreactor, harvest and purification process operations Extensive use of single use components Product specific validated cleaning for product contact equipment/parts Enhanced controls for some operations (inoc. prep, column packing, final DS filtration) – Compatible products requiring no special handling Nov 2013 ISPE Strasbourg 15
  16. 16. Controlled Non-Classified (CNC) plus Multi-Product Manufacturing Benefits • Lower Operating Costs – Gowning/transitions – Environmental Monitoring – Energy – Capacity Utilization • Lower Construction Costs – HVAC equipment and ducting – Personnel and material airlocks • Faster construction and qualification – Delay capital investment Nov 2013 Considerations • Defining risk based and effective design and operating principles • The additional complexity of procedural controls and flow-path management without physical or temporal segregation • Facility organization to manage the interface between manufacturing and external environments • Managing planned and unplanned system breaches – Risk cross contamination • Contamination detection and lot disposition • Assurance of environmental control ISPE Strasbourg 16
  17. 17. Closed Systems, Flexible Manufacturing and CNC Ballrooms Typical Bio-Reactor SS or Single Use Chromatography Line 1 Cell Culture Line 1 Typical Single Use Bags / Container s Matls. Matls. Matls. Final Purification Line 1 Matls. Flow Transition Spaces, separate or combined, as appropriate to facility Matls. Flow Transition Spaces, separate or combined, as appropriate to facility Materials Materials Personnel Personnel Equipmen t Common Media Prep. Waste Matls. Equipmen t Common Buffer Prep Matls. Waste Matls. Matls. Matls. Matls. Cell Culture Line 2 Chromatography Line 2 Matls. Final Purification Line 2 New Challenges to the Cleanroom Paradigm for Multi-Product Facilities - Additional challenges to the new cleanroom paradigm from concurrent multiproduct manufacturing of bulk drug substances in a controlled non-classified (CNC) ballroom environment. May 1, 2013, By: Simon Chalk, Scott Probst, Ken Green, Russell Moser, Frank Urbanski, Matthew Zicaro, Paul Smock, Larry Pranzo, Liz Dooley, Phil McDuff BioPharm International pp. 38-47
  18. 18. Risk Based Operating Principles Principles Multi-product CNC ball room Risks Mitigation Process Definition Process not capable to meet quality specs. Equipment or process step not closed or reliable. Ability to inactivation/removal of endogenous agents. Robust controls for endogenous and adventitious agents. Application of QRM principles for control philosophies. Selection of closed and reliable process technologies. Application of localized classified environment. Product Risk Profiles Product crosscontamination. Operator exposure. Procedures to manage breaches and temporary openings. Appropriate cleaning and changeover for designated products. Rapid analytical detection for potential contaminants. Robust tracking, monitoring & disposition of product batches/lots. Product & material environmental health & safety assessment. Operational philosophies Inadequate controls. Operational systems overly complex. Delay to facility/product approval. Facility not fully optimized for throughput. Detailed ops and procedural controls for CNC ballroom. Minimize manual handling via automation. Staffing resources to perform all aspects of DS processing. Solicit external regulatory feedback on design and operation. Alignment of internal Quality and Regulatory activities. Review scheduling, cleaning, changeover and maintenance programs. Nov 2013 ISPE Strasbourg 18
  19. 19. Risk Based Operating Principles Principles Multi-product CNC ball room Risks Process Definition Process not capable to meet quality specs. Equipment or process step not closed or reliable. Mitigation Ability to inactivation/removal of endogenous agents. Robust controls for endogenous and adventitious agents. Application of QRM principles for control philosophies. Selection of closed and reliable process technologies. Application of localized classified environment. Nov 2013 ISPE Strasbourg 19
  20. 20. Risk Based Operating Principles Principles Multi-product CNC ball room Risks Product Risk Profiles Mitigation Product crosscontamination. Procedures to manage breaches and temporary openings. Operator exposure. Appropriate cleaning and changeover for designated products. Rapid analytical detection for potential contaminants. Robust tracking, monitoring & disposition of product batches/lots. Product & material environmental health & safety assessment. Nov 2013 ISPE Strasbourg 20
  21. 21. Risk Based Operating Principles Principles Multi-product CNC ball room Risks Operational philosophies Mitigation Detailed ops and procedural controls for CNC ballroom. Inadequate controls. Operational systems overly complex. Delay to facility/product approval. Facility not fully optimized for throughput. Minimize manual handling via automation. Staffing resources to perform all aspects of DS processing. Solicit external regulatory feedback on design and operation. Alignment of internal Quality and Regulatory activities. Review scheduling, cleaning, changeover and maintenance programs. Nov 2013 ISPE Strasbourg 21
  22. 22. Structured Approaches to Risk Assessment • Standard Risk Assessment; • Failure Mode Effects Analysis; • Hazard and Critical Control Point Analysis. Nov 2013 ISPE Strasbourg 22
  23. 23. Interacting Elements for Contamination Control Nov 2013 ISPE Strasbourg 23
  24. 24. Responses to Potential Areas of Regulatory Scrutiny are being developed Defining terms; Closed, Functionally Closed and Open Nov 2013 Verifying a System is Closed Temporarily Open; Returning to Closed State ISPE Strasbourg Unplanned Breaches; Effective response Viral Cross Contamination; Risk Management 24
  25. 25. Verification Risks Typical Bio-Reactor SS or Single Use Chromatography Line 1 Final Purification Line 1 Cell Culture Line 1 • Pre-Assembly: – – – – Typical Single Use Bags / Containers Supplier audit; Unit integrity testing; Radiation and other forms of sterilisation; Certificate of Analysis; Matls. Matls. Matls. Materials Materials Personnel Personnel Equipment Equipment Common Media Prep. Common Buffer Prep Waste Waste Matls. Matls. Matls. Matls. Matls. Matls. Matls. • Assembly: – – – – Flow Transition Spaces, separate or combined, as appropriate to facility Matls. Matls. Flow Transition Spaces, separate or combined, as appropriate to facility Product design; Cleaning and sterilisation at connections; System integrity testing – filters; Validated procedures; Final Purification Line 2 Cell Culture Line 2 Chromatography Line 2 • In Production: – Raw materials – culture media – additional treatments; – Measures and sampling – temperature, O2/CO2; – More possible? Pressure changes, rheometry, turbidity, UV, pH – rapid sample analysis Nov 2013 ISPE Strasbourg 25
  26. 26. Breach Risks - Upstream • Significant loss from single use reactor bag: – Causes: • Flaws in manufacture; • Flaws introduced in assembling the system; • Flaws introduced in running the system; Typical Bio-Reactor SS or Single Use – Detection: Chromatography Line 1 Final Purification Line 1 Cell Culture Line 1 • Visual; • Conductivity; • Pressure drop? Typical Single Use Bags / Containers Flow Transition Spaces, separate or combined, as appropriate to facility Matls. Matls. Matls. Matls. Matls. Flow Transition Spaces, separate or combined, as appropriate to facility Materials Materials Personnel Personnel – Mitigation: Equipment Equipment Common Media Prep. Common Buffer Prep Waste Waste • Validated spill procedure; • Include sample taking; • Investigation; Matls. Matls. Matls. Matls. Matls. Matls. Matls. Final Purification Line 2 Cell Culture Line 2 Chromatography Line 2 – Outcome for Directly Affected Product – Outcome for Adjacent Product Nov 2013 ISPE Strasbourg 26
  27. 27. Breach Risks - Upstream • Significant loss from single use reactor bag: – Causes: • Flaws in manufacture; Inspection – all or sample • Flaws introduced in assembling the system; Validated Procedures - Helium • Flaws introduced in running the system; Validated operations + Detection – Detection: • Visual; • Conductivity; • Pressure drop? Typical Bio-Reactor SS or Single Use Chromatography Line 1 – Mitigation: Final Purification Line 1 Cell Culture Line 1 Typical Single Use Bags / Containers • Validated spill procedure; • Include sample taking; • Investigation; Flow Transition Spaces, separate or combined, as appropriate to facility Matls. Matls. Matls. Matls. Matls. Flow Transition Spaces, separate or combined, as appropriate to facility Materials Materials Personnel Personnel Equipment – Outcome for Directly Affected Product – Outcome for Adjacent Product Equipment Common Media Prep. Common Buffer Prep Waste Waste Matls. Matls. Matls. Matls. Matls. Matls. Matls. Final Purification Line 2 Cell Culture Line 2 Chromatography Line 2 Nov 2013 ISPE Strasbourg 27
  28. 28. Breach Risks - Upstream • Significant loss from single use reactor bag: – Causes: • Flaws in manufacture; • Flaws introduced in assembling the system; • Flaws introduced in running the system; Typical Bio-Reactor SS or Single Use – Detection: Chromatography Line 1 Final Purification Line 1 Cell Culture Line 1 • Visual; Operator presence - webcams • Conductivity; Bunded pans + sensors • Pressure drop? Contact pressure sensors – Mitigation: Typical Single Use Bags / Containers Flow Transition Spaces, separate or combined, as appropriate to facility Matls. Matls. Matls. Matls. Matls. Flow Transition Spaces, separate or combined, as appropriate to facility Materials Materials Personnel Personnel Equipment Equipment Common Media Prep. Common Buffer Prep Waste Waste • Validated spill procedure; • Include sample taking; • Investigation; Matls. Matls. Matls. Matls. Matls. Matls. Matls. Final Purification Line 2 Cell Culture Line 2 Chromatography Line 2 – Outcome for Directly Affected Product – Outcome for Adjacent Product Nov 2013 ISPE Strasbourg 28
  29. 29. Breach Risks - Upstream • Significant loss from single use reactor bag... • What about Ingress? – Causes as above... – Egress reduces risk; – Detection more challenging: • Can one MAB be picked out? • Endotoxins? • Elements of the media? Typical Bio-Reactor SS or Single Use Chromatography Line 1 Final Purification Line 1 Cell Culture Line 1 Typical Single Use Bags / Containers Flow Transition Spaces, separate or combined, as appropriate to facility Matls. Matls. Matls. Matls. Matls. Flow Transition Spaces, separate or combined, as appropriate to facility Materials Materials Personnel Personnel Equipment Equipment Common Media Prep. Common Buffer Prep Waste – Chemical ‘sniffing’. Waste Matls. Matls. Matls. Matls. Matls. Matls. Matls. Final Purification Line 2 Cell Culture Line 2 Chromatography Line 2 Nov 2013 ISPE Strasbourg 29
  30. 30. Upstream Downstream CrossContamination Risk • The usual reason (excuse) for segregation: – Causes: • Human error!??? – Detection: • Supervision; Typical Bio-Reactor SS or Single Use Chromatography Line 1 – Mitigations: Typical Single Use Bags / Containers Flow Transition Spaces, separate or combined, as appropriate to facility Matls. Matls. Matls. Matls. Matls. Flow Transition Spaces, separate or combined, as appropriate to facility • Scheduling • Focus on Human Performance; • Poke Yoke: – Change parts - barcoding; – Procedures; – Truly effective training. Nov 2013 Final Purification Line 1 Cell Culture Line 1 ISPE Strasbourg Materials Materials Personnel Personnel Equipment Equipment Common Media Prep. Common Buffer Prep Waste Waste Matls. Matls. Matls. Matls. Matls. Matls. Matls. Final Purification Line 2 Cell Culture Line 2 Chromatography Line 2 30
  31. 31. Breach Risks - Downstream • Perforation of tubing within a peristaltic pump: Typical Bio-Reactor SS or Single Use Chromatography Line 1 – Similar causes – Less impact – More likely to be detected visually – Or by pressure drop – Easier to clear up Nov 2013 ISPE Strasbourg Final Purification Line 1 Cell Culture Line 1 Typical Single Use Bags / Containers Flow Transition Spaces, separate or combined, as appropriate to facility Matls. Matls. Matls. Matls. Matls. Flow Transition Spaces, separate or combined, as appropriate to facility Materials Materials Personnel Personnel Equipment Equipment Common Media Prep. Common Buffer Prep Waste Waste Matls. Matls. Matls. Matls. Matls. Matls. Matls. Final Purification Line 2 Cell Culture Line 2 Chromatography Line 2 31
  32. 32. Sanitisation • Recovery from Breach: – Speed of the essence to prevent dry out; – Personal Protective Equipment; – Heat to 121 oC; – Alter pH (NaOH aq); – Aerosol detection; – Sampling; Nov 2013 ISPE Strasbourg 32
  33. 33. In Conclusion The leading Biopharm companies via BPOG are collaborating to define appropriate area classification for multi-product ballroom operations by; • Developing common definitions and sharing best practices – Application of Quality and Scientific Risk Management approaches – Considerations for closed processes utilizing technical and procedural advances – Guidance for Industry* • Influence the environment – A work in progress – Internal Quality and Regulatory – External Regulatory authorities • FDA Meeting Highlights • New work streams to expand the concepts * Chalk, S., et.al.; “Challenging the Cleanroom Paradigm for Biopharmaceutical Manufacturing of bulk Drug Substances,” BioPharm. Intl., August, 2011 *Chalk, S., et.al.; “New Challenges to the Cleanroom Paradigm for Multi-Product Facilities”, BioPharm Intl., May 2013 Nov 2013 ISPE Strasbourg 33
  34. 34. Going Forwards – What If? • • • • • • Compliant; Low capital cost; Low running cost; Reliable; In country; Orphan drug manufacture. Nov 2013 ISPE Strasbourg 34
  35. 35. Acknowledgements • Co-Authors • Reviewers/Collaborators – Simon Chalk, BioPhorum Operations Group – Scott Probst, Bayer Technology Services – Ken Green, Pfizer Manufacturing Services – Russell Moser, Janssen Biopharmaceuticals – Frank Urbanski, Pfizer Global Engineering – Matthew Zicaro, HVAC Engineer – Larry Pranzo, Merck Global Engineering – Liz Dooley, Janssen Supply Chain – Phil McDuff, Biogen Idec Engineering Nov 2013 – Marc Pelletier, CRB Engineers – Steve Buchholz, Gallus Biopharmaceuticals – Martyn Becker, GSK – Joe Rogalewicz, GSK – Beth Junker, Merck – Teresa Feeser, BMS ISPE Strasbourg 35
  36. 36. Thank you for Listening • Any Questions? • Robin Payne - robin@biophorum.com • www.biophorum.com Nov 2013 ISPE Strasbourg 36

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