Considering the additional risks of operating bio tech processes in a ball room facility 2
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Transcript of Considering the additional risks of operating bio tech processes in a ball room facility 2
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
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
Content
• BioPhorum Operations Group (BPOG) • Controlled Non-Classified Spaces
• Flexibility
• Multi-Product Application
• Risk Assessment with Scenarios
• The Way Forwards
Nov 2013 3 ISPE Strasbourg
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 4 ISPE Strasbourg
Collaboration Approach / Benefits
Nov 2013 ISPE Strasbourg 5
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
The Collaboration Process
• Identify a Theme;
• Decompose into Topics;
• Develop Shared Understanding
– Background
– Common Language
– Meaningful Deliverables
• Deliver;
• Review and Capture Learning
Nov 2013 ISPE Strasbourg 6
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.
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 7 ISPE Strasbourg
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 – Modularization
– Single use components
– Controlled Non-Classified Spaces
– Multi-product manufacturing
Nov 2013 8 ISPE Strasbourg
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
Closed or functionally closed processes Probst, S, CLOSED-SYSTEM PROCESSING: AN ENABLING TECHNOLOGY FOR FLEXIBLE FACILITIES, IBC Flexible Facilities, 2013
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
sterilized
sterilized
sterilized
Sterile tubing fuser or
aseptic connector
Nov 2013 9 ISPE Strasbourg
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
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
Nov 2013 10 ISPE Strasbourg
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 11 ISPE Strasbourg
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 12 ISPE Strasbourg
Closed Processing: Single-Use Systems
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
Γ-sterilized
Nov 2013 13 ISPE Strasbourg
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 14 ISPE Strasbourg
Application of CNC to Concurrent Multi-Product Design Concept
Nov 2013 15 ISPE Strasbourg
• 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
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
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
Nov 2013 16 ISPE Strasbourg
Closed Systems, Flexible Manufacturing and CNC Ballrooms
Typical Single
Use Bags /
Containers Flow Transition Spaces,
separate or combined, as appropriate to facility Flow Transition Spaces,
separate or combined, as appropriate to facility
Matls. Matls. Matls. Matls.
Common Media Prep.
Common Buffer Prep
Chromatography Line 1 Cell Culture Line 1
Final Purification Line 1
Matls.
Materials
Personnel
Equipment
Waste
Typical Bio-Reactor
SS or Single Use
Chromatography Line 2
Final Purification Line 2
Matls. Matls. Matls.
Matls. Matls.
Matls. Matls.
Cell Culture Line 2
Materials
Personnel
Equipment
Waste
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
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 cross-
contamination.
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 18 ISPE Strasbourg
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.
Nov 2013 19 ISPE Strasbourg
Risk Based Operating Principles Principles Multi-product CNC ball room
Risks Mitigation
Product
Risk
Profiles
Product cross-
contamination.
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.
Nov 2013 20 ISPE Strasbourg
Risk Based Operating Principles Principles Multi-product CNC ball room
Risks Mitigation
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 21 ISPE Strasbourg
Structured Approaches to Risk Assessment
• Standard Risk Assessment;
• Failure Mode Effects Analysis;
• Hazard and Critical Control Point Analysis.
Nov 2013 ISPE Strasbourg 22
Interacting Elements for Contamination Control
Nov 2013 23 ISPE Strasbourg
Defining terms; Closed,
Functionally Closed and Open
Verifying a System is Closed
Temporarily Open; Returning to Closed State
Unplanned Breaches;
Effective response
Viral Cross Contamination;
Risk Management
Responses to Potential Areas of Regulatory Scrutiny are being developed
Nov 2013 24 ISPE Strasbourg
Verification Risks
• Pre-Assembly: – Supplier audit; – Unit integrity testing; – Radiation and other forms of sterilisation; – Certificate of Analysis;
• Assembly: – Product design; – Cleaning and sterilisation at connections; – System integrity testing – filters; – Validated procedures;
• 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
Typical
Single Use Bags /
Containers
Flow Transition Spaces,
separate or combined, as appropriate to facility
Flow Transition Spaces, separate or combined,
as appropriate to facility
Matls. Matls. Matls.
Matls.
Common Media Prep.
Common Buffer Prep
Chromatography Line 1
Cell Culture Line 1
Final Purification
Line 1
Matls.
Materials
Personnel
Equipment
Waste
Typical
Bio-Reactor
SS or Single Use
Chromatography Line 2
Final Purification
Line 2
Matls. Matls.
Matls.
Matls. Matls.
Matls. Matls.
Cell Culture Line 2
Materials
Personnel
Equipment
Waste
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;
– Detection: • Visual; • Conductivity; • Pressure drop?
– Mitigation: • Validated spill procedure; • Include sample taking; • Investigation;
– Outcome for Directly Affected Product – Outcome for Adjacent Product
Nov 2013 ISPE Strasbourg 26
Typical
Single Use Bags /
Containers
Flow Transition Spaces,
separate or combined, as appropriate to facility
Flow Transition Spaces,
separate or combined,
as appropriate to facility
Matls. Matls. Matls.
Matls.
Common
Media Prep. Common Buffer Prep
Chromatography Line 1
Cell Culture Line 1
Final Purification
Line 1
Matls.
Materials
Personnel
Equipment
Waste
Typical
Bio-Reactor SS or Single Use
Chromatography Line 2
Final Purification Line 2
Matls. Matls.
Matls.
Matls. Matls.
Matls. Matls.
Cell Culture Line 2
Materials
Personnel
Equipment
Waste
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?
– Mitigation: • Validated spill procedure; • Include sample taking; • Investigation;
– Outcome for Directly Affected Product – Outcome for Adjacent Product
Nov 2013 ISPE Strasbourg 27
Typical Single Use
Bags /
Containers
Flow Transition Spaces,
separate or combined,
as appropriate to facility
Flow Transition Spaces,
separate or combined, as appropriate to facility
Matls. Matls. Matls.
Matls.
Common Media Prep.
Common Buffer Prep
Chromatography Line 1
Cell Culture Line 1
Final Purification Line 1
Matls.
Materials
Personnel
Equipment
Waste
Typical
Bio-Reactor
SS or Single Use
Chromatography Line 2
Final Purification
Line 2
Matls. Matls.
Matls.
Matls. Matls.
Matls. Matls.
Cell Culture Line 2
Materials
Personnel
Equipment
Waste
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;
– Detection: • Visual; Operator presence - webcams • Conductivity; Bunded pans + sensors • Pressure drop? Contact pressure sensors
– Mitigation: • Validated spill procedure; • Include sample taking; • Investigation;
– Outcome for Directly Affected Product – Outcome for Adjacent Product
Nov 2013 ISPE Strasbourg 28
Typical
Single Use Bags /
Containers
Flow Transition Spaces,
separate or combined, as appropriate to facility
Flow Transition Spaces,
separate or combined,
as appropriate to facility
Matls. Matls. Matls.
Matls.
Common
Media Prep. Common Buffer Prep
Chromatography Line 1
Cell Culture Line 1
Final Purification
Line 1
Matls.
Materials
Personnel
Equipment
Waste
Typical
Bio-Reactor SS or Single Use
Chromatography Line 2
Final Purification Line 2
Matls. Matls.
Matls.
Matls. Matls.
Matls. Matls.
Cell Culture Line 2
Materials
Personnel
Equipment
Waste
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?
– Chemical ‘sniffing’.
Nov 2013 ISPE Strasbourg 29
Typical
Single Use
Bags / Containers
Flow Transition Spaces, separate or combined,
as appropriate to facility
Flow Transition Spaces, separate or combined,
as appropriate to facility
Matls. Matls. Matls.
Matls.
Common
Media Prep. Common Buffer Prep
Chromatography Line 1
Cell Culture Line 1
Final Purification
Line 1
Matls.
Materials
Personnel
Equipment
Waste
Typical
Bio-Reactor
SS or Single Use
Chromatography Line 2
Final Purification Line 2
Matls. Matls.
Matls.
Matls. Matls.
Matls. Matls.
Cell Culture Line 2
Materials
Personnel
Equipment
Waste
Upstream Downstream Cross-Contamination Risk
• The usual reason (excuse) for segregation: – Causes:
• Human error!???
– Detection: • Supervision;
– Mitigations: • Scheduling • Focus on Human Performance; • Poke Yoke:
– Change parts - barcoding; – Procedures; – Truly effective training.
Nov 2013 ISPE Strasbourg 30
Typical
Single Use Bags /
Containers
Flow Transition Spaces,
separate or combined, as appropriate to facility
Flow Transition Spaces, separate or combined,
as appropriate to facility
Matls. Matls. Matls.
Matls.
Common Media Prep.
Common Buffer Prep
Chromatography Line 1
Cell Culture Line 1
Final Purification
Line 1
Matls.
Materials
Personnel
Equipment
Waste
Typical
Bio-Reactor
SS or Single Use
Chromatography Line 2
Final Purification
Line 2
Matls. Matls.
Matls.
Matls. Matls.
Matls. Matls.
Cell Culture Line 2
Materials
Personnel
Equipment
Waste
Breach Risks - Downstream
• Perforation of tubing within a peristaltic pump:
– Similar causes
– Less impact
– More likely to be detected
visually
– Or by pressure drop
– Easier to clear up
Nov 2013 ISPE Strasbourg 31
Typical
Single Use Bags /
Containers
Flow Transition Spaces,
separate or combined, as appropriate to facility
Flow Transition Spaces, separate or combined,
as appropriate to facility
Matls. Matls. Matls.
Matls.
Common
Media Prep. Common Buffer Prep
Chromatography Line 1
Cell Culture Line 1
Final Purification
Line 1
Matls.
Materials
Personnel
Equipment
Waste
Typical
Bio-Reactor
SS or Single Use
Chromatography Line 2
Final Purification Line 2
Matls. Matls.
Matls.
Matls. Matls.
Matls. Matls.
Cell Culture Line 2
Materials
Personnel
Equipment
Waste
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
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 33 ISPE Strasbourg
Going Forwards – What If?
• Compliant;
• Low capital cost;
• Low running cost;
• Reliable;
• In country;
• Orphan drug manufacture.
Nov 2013 ISPE Strasbourg 34
Acknowledgements • Co-Authors
– 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
• Reviewers/Collaborators
– Marc Pelletier, CRB Engineers
– Steve Buchholz, Gallus Biopharmaceuticals
– Martyn Becker, GSK
– Joe Rogalewicz, GSK
– Beth Junker, Merck
– Teresa Feeser, BMS
Nov 2013 35 ISPE Strasbourg
Thank you for Listening
• Any Questions?
• Robin Payne - [email protected]
• www.biophorum.com
Nov 2013 ISPE Strasbourg 36