Post on 09-Apr-2018
Dr. Berthold Boedeker, Bayer AG, Biological Development
Cell World Conference, San Francisco, May 25-26 2017
Continuous Processing Progress in Manufacturing
Continuous Processing Progress in Manufacturing Page 2
Agenda
• Biologics at Bayer
• Regulatory support / drivers aof continuous processing
• Bayer’s approach to continuous processing
• Most common perfusion systems
• Set-up, characteristics, cell retention system
• Integration of downstream processing
• Options and limits of continuous processing
• Technical feasibility, economics, plant design, validation
• Concept study: plant design standard fed batch vs. disposable continuous processing facility
• Conclusions and Outlook
Bayer Group Structure
Continuous Processing Progress in Manufacturing Slide 3
Board of Management
Pharmaceuticals Consumer Health Crop Science
Animal Health
Corporate Functions & Business Services
Covestro (around 64%) Currenta (60%)
One of the leading innovative companies in the healthcare industry
Continuous Processing Progress in Manufacturing Page 4
Pharmaceuticals Division
• Largest division of Bayer in terms of sales
• One of the fastest growing pharma companies worldwide
• Sales of 16.42 billion Euro in 2016
• Global headquarter in Berlin, Germany
• 40,100 employees worldwide in 2016
• Largest German pharma company
• Focus on prescription products, especially for cardiology, oncology, hematology,
women’s healthcare, and ophthalmology
• Radiology franchise with contrast-enhanced diagnostic imaging equipment and
contrast agents
Biologics @ Bayer Pharmaceuticals
Product
Betaferon® /Betaseron® Kogenate® Eylea®
Indication Multiple sclerosis Hemophilia A Wet Age-related
Macular Degeneration
Market Worldwide Worldwide Ex-US
Product
presentation Lyo-vial in kit Lyo-vial in kit Liquid-vial
Volume High
(double digit million vials)
Medium
(one digit million vials) Growing
Manufacture External In-house External
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FDA encourages manufacturers to use continuous processing because of the perceived advantages:
Improvement of product quality because of steady state operations (limiting processing variables)
Improved patient access because of lower costs
Indeed also industry expects pronounced advantages:
Improved product quality
Reduced CoGs
Modular manufacturing in standardized plants using standard processes
Less facility investment
Easy site to site transfer
Continuous Processing Progress in Manufacturing Page 6
Regulatory support / drivers of continuous processing
Preconditions to enable continuous processing
Continuous
Processing
Advancement of disposable technologies
On-line or in-line analytics
Perfusion culture experience
PAT Technologies
Advancements in closed processing Processing automation
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• Mainly within Bayer Engineering & Technology department
• Participation in German state funded consortium program
• Established a 10 L model processing unit for completely continuous processing from production fermenter to
virus filtration (classical mAb process)
• Disposable settlers or ATFs used for cell retention
• Multi-column chromatography systems
• Dual set-up for UF/DF/membrane operations
no true continuous processing but continuous product flow in discontinuous individual systems
• --- unit is running and can be visited in Leverkusen
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Bayer’s approach to continuous processing
Conclusion; doable, but very difficult to run and control
• 30 + years of production of rec Factor VIII in perfusion
• Batch/fed-batch not suited because of fragility of the protein in culture
• short residence time of the product
• “open” cell retention system removing dead cells and debris (inclined plate settler)
• 10-15 fermenter volumes/day yield in high volumetric production
• Extensive process validation efforts compared to batch
• BLA: 2-3 run of full length preparing several qualifying lots, duration 6-12 months,
show seed to seed as well as early/mid/late fermentation consistency
Continuous Processing Progress in Manufacturing Page 9
Bayer‘s experience with perfusion
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Long term continuous fermentation of rec FVIII
Time t [d]
Cell
co
ncen
trati
on
[10
6 v
c/m
L]
Via
bil
ity [
%]
10
100
1
10
100
0 20 40 60 80 100 120 140
1
Cell concentration
Viability
production of unstable
protein q/V = 10 /d
Dr. Konstantinov, Bayer Corp.,
Dechema 2002, Frankfurt
External filtration unit
favorite ATF (alternate tangential filtration)
Continuous centrifugation
now also available as disposable unit
Continuous Processing Progress in Manufacturing Page 11
Commonly used perfusion systems
All systems have a limited use time, therefore for continuous processing always 2
systems are set up in parallel: 1 in use, 1 to switch to
(presented at the Biomanufacturing Summit, San Diego, 2013
Commercial Perfusion System: ATF Perfusion System from Refine Technol.
Continuous Processing Progress in Manufacturing Page 12
• Limited scalability
• Easy to operate, but
• moving parts
• Clogging possible (2 systems in parallel)
• Low perfusion rates of max 2 fermenter volumes per day
• Accumulation of dead cells/debris may impact product quality over time
• Cell bleed adds another level of operational complexity
• No real steady state conditions possible
Continuous Processing Progress in Manufacturing Page 13
Features of ATFs
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Integration of perfusion fermentation into continuous downstream operation
• Parallelized small disposable multi-columns operated batchwise in sequence without interrupting product
flow
Well established, several systems available
Chromatographies
• 2-systems-approach 1 in use, 1 to switch to Filtration /
adsorption
• Either continious via low pH elution or
• Batch-wise with 2 units
Collect product upt to a certain volume, decouple, inactivate, continue with continuous operation
pH inactivation
Virus filtration • See filtration
Continuous Processing Progress in Manufacturing Page 15
Technologies of the future to support continuous processing
Disposable
Closed processing
In-line dilution for large liquid volumes
Ball-room facilities
Flexible facilities
Alternatives to chromatographies:
membrane absorbers, precipitation
Higher binding gels
On-line monitoring
PAT tools
Represents innovative concept to enable parallel processing of different products in the same low
classification containment without upstream and downstream seggregation
Concept addressed in the following paper:
Simon Chalk et.al., „Challenging the Cleanroom Paradigm for Biopharmaceutical Manufacturing of Bulk Drug
Substances“, BioPharm International, Aug. 1, 2011.
Based on the key assumptions that technological advances including single use sytems have continuously
reduced the risk of environmental impact on processing.
Most steps can be securely performed closed or functionally closed.
The few remaining open processing steps have to be addressed independently (i.e. portable laminar flow hood,
isolator technology)
Continuous Processing Progress in Manufacturing Page 16
Ball-room plant design concept (1)
Basic thinking is that in a closed or functionally closed system, the process stream is isolated from the
environment
Remaining open operations (cell expansion, column packing, powder additions) have to be addressed
separately, i.e. in small areas with classical containment set up, or closed solutions
Potential breach of the closed system is the major risk, which has to be addressed:
- prove no contamination or cross-contamination
- intense microbial monitoring
Maintaining the closed system status has to be addressed by a risk based approach with appropriate risk
mitigation strategies considering each process step or operation
Continuous Processing Progress in Manufacturing Page 17
Ball-room plant design concept (2)
Most facilities nowadays are of hybrid design combining elements of classical hard-
piped with single use elements.
In order to evaluate differences of a closed systems, disposables and continuous
processing based ballroom facility to such a fed-batch hybrid set-up, a concept
study was performed by Bayer:
Joergen Magnus, Bayer Technology Services
at 12th Annual Biolog. Production Forum, Düsseldorf (2013)
Continuous Processing Progress in Manufacturing Page 18
Facility of the future: Comparison of standard fed-batch to disposable based continous processing facility
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Comparison to facility with traditional design and similar production capacity
Purpose
• Produce material for phase 3 clinical trials
Design
• Stainless steel equipment
• Functionally closed processing
• Fed-batch fermentation
• Operations are separated in different rooms
Building concept
• 5 levels
• ~ 5000 m² total area
• ~ 1400 m² cleanroom (class D+C)
Purpose
• Production for market
Design
• 100 % single use process equipment
• Closed processing
• Continuous processing
• Ball-room production
Building concept
• 2 levels
• ~ 1200 m² total area
• ~ 360 m² cleanroom (class D+C)
Cell culture pilot plant (Wuppertal) Biofacility of the future
Continuous Processing Progress in Manufacturing Page 20
Design principle: 100 % single use technology
Media bag Buffer bag Buffer bag
Fermenter Filter – UF/DF Chromatography Product bag
Single use Bioreactor
+ single use tubings,
bags, sensors, etc
Single use
filter cartridges
Pre-packed columns
No need for CIP or SIP
Continuous Processing Progress in Manufacturing Page 21
Design Principle: Continuous Processing
• Continuous fermentation with cell retention
• Continuous depth
• Continuous chromatography using
simulated moving bed technology
• Continuous UF / DF
• Continuous virus inactivation
Upstream Downstream
• Cell specific productivity
• Cell density
• Perfusion rate
Bioreactor performance depending on
Continuous Processing Progress in Manufacturing Page 22
Closed processing in single-use systems
Γ-sterilized
Γ-sterilized
Γ-sterilized
Sterile tubing
fuser or aseptic
connector
Continuous Processing Progress in Manufacturing Page 23
Design Principle: Ball-room Production
Ball-room includes:
All process units
All media and buffer containers
All media and buffer preparation tanks
But does not include
Seed lab
Bulk filling room (post viral area)
Design Principles
• 100 % S.U. process equipment
• Continuous processing
• Closed processing
• “Ball Room” production in class D (except seed lab and final filling)
Benefits
• Shorter engineering, construction, commissioning, qualification and validation times
• Decoupling of equipment from building
• Smaller building footprint
• Energy and water saving
• Reduced investment and production cost
Continuous Processing Progress in Manufacturing Page 24
Benefits of continuous processing in a biofacility of the future concept
Reduced complexity
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Pro‘s and Con‘s of continuous processing
• lower plant footprint
• lab-like infrastructure
• easier to build and validate
• easy to operate, if fully
automated
• easy site to site transfer
• lower CoGs
• individual unit operations difficult to get
continuous
• risk of product quality issues because of
perfusion operation
• glycosylation depends on specific
perfusion rate
• glycosylation different to fed-batch
(transition issues)
• no real steady state possible
• same quality over complete run length
needed
• titer dilution (harvest)
• batch definition
• increased process validation effort
• immature technologies yet (especially in DSP)
• scalability problematic
• process characterization problematic
• scale down models upstream
• extended validation effort
• development/operations/facilities in-house
infrastructure for fed-batch
• cell lines/culture media optimized for long fed-
batch process with cells in stationary phase
Continuous Processing Progress in Manufacturing Page 26
Bottlenecks of continuous processing
• lack of automation
• on-line monitoring and control
• complex biological systems
• regulatory acceptance and experience
• maintaining microbial control
• Integrate disposables use, closed systems operation and parts of continuous
processing to obtain a flexible, easy to validate and operate facility using lowered
containment classification than current standard
• Fermentation preferred fed-batch, in few cases perfusion (molecule dependent)
• DSP could be done partly continuous, if technologies advance correspondingly
- chromatographies via multi-column units
- membrane adsorbers instead of chromatographies
- filtration in parallel mode
Continuous Processing Progress in Manufacturing Page 27
Currently preferred processing strategy
This website/release/presentation may contain forward-looking statements based on current assumptions and
forecasts made by Bayer management.
Various known and unknown risks, uncertainties and other factors could lead to material differences between
the actual future results, financial situation, development or performance of the company and the estimates
given here. These factors include those discussed in Bayer’s public reports which are available on the Bayer
website at http://www.bayer.com/.
The company assumes no liability whatsoever to update these forward-looking statements or to conform them
to future events or developments.
Continuous Processing Progress in Manufacturing Page 28
Forward-Looking Statements