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

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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. Structured Approaches to Risk
Assessment
• Standard Risk Assessment;
• Failure Mode Effects Analysis;
• Hazard and Critical Control Point Analysis.
Nov 2013
ISPE Strasbourg
22

23. Interacting Elements for Contamination Control
Nov 2013
ISPE Strasbourg
23

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. 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. 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. 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. 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. 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. 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. 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. 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. 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. Going Forwards – What If?
•
•
•
•
•
•
Compliant;
Low capital cost;
Low running cost;
Reliable;
In country;
Orphan drug manufacture.
Nov 2013
ISPE Strasbourg
34

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. Thank you for Listening
• Any Questions?
• Robin Payne - robin@biophorum.com
• www.biophorum.com
Nov 2013
ISPE Strasbourg
36