Flexible Production of
Biopharmaceuticals –
A CMO Perspective
Dr. Stefan R. Schmidt MBA
VP Process Science and Production
June 1, 2016 S. Schmidt 2
Agenda
1 Introduction
Development phases 2
Molecules 3
Process 4
Facility/Equipment 5
Conclusions 6
June 1, 2016 S. Schmidt 3
Drug Discovery and Development
Source: Medicines in Development, Heart Disease and Stroke, PhRMA Report 2013
10-15 years and $ 1.2 billion including costs of failure from experimental drug
to FDA approved product!
Currently ~ 30 % of new drugs are biologicals
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FDA Approvals
Morrison, Nature Biotech, 2016
June 1, 2016 S. Schmidt 5
Small Molecule vs. Large Molecule Manufacturing
Jacoby, Deloitte, 2015
Cell factory steps
1. Transcription
2. Translation
3. Secretion
June 1, 2016 S. Schmidt 6
Protein Expression in Eukaryotic Cells
secretion
1
2
3
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Typical Biopharmaceutical Production Process (mAb)
Levine, BioProcessing Int, 2013
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Factors Impacting Manufacturing Flexibility
Molecules
● PTM host cell
● Biosimilars
Development stage
● Entry point
● Clinical development
Facility/equipment
● Scale
● Steel vs. disposable
● Batches, volume
Process
● Titer
● Platform
● Batch vs. continuous
June 1, 2016 S. Schmidt 9
Agenda
1 Introduction
Development phases 2
Molecules 3
Process 4
Facility/Equipment 5
Conclusions 6
Typical entry points for a CMO
● Cell line generation
● Process development
● Process transfer
● Scale up
June 1, 2016 S. Schmidt 10
Different Entry Points for CMO Services
Cell line
development
Process
development Upstream
processing Downstream
processing
Fill &
Finish
Preclinical
development
Clinical
Phase 1
Clinical
Phase 2
Clinical
Phase 3 Market
Typical reasons for using CMOs:
● Special services no available in-house
● Offer capacity without investment
● Expertise in difficult proteins
June 1, 2016 S. Schmidt 11
Decision Tree to Assess Flexibility
PTM
Low titerSensitiveor toxic
Low dose,few patients
MoleculeProkaryotic
host
Eukaryotic host
Batchprocess
Continuousprocess
Yes
No
Yes Yes
No No
Yes
No
Disposableequipment
Stainless steelequipment
● Molecule
● Process
● Equipment
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Agenda
1 Introduction
Development phases 2
Molecules 3
Process 4
Facility/Equipment 5
Conclusions 6
June 1, 2016 S. Schmidt 13
Recombinant Molecules
1. Generation mABs 2. Generation Fut. Therapies
Examples Insulin, EPO,
IFN, HGH
Humira®,
Avastin®
Enbrel® (Fusion)
Kadcyla® (ADC)
Glybera® (VBB)
Provenge® (CT)
Molecule
Types
Low level of
complexity
SS-bridges,
glycosylation
Human design,
complex
Human design,
natural origin
Manufacturing Pro- or eu-
karyotic host
Eukaryotic
host
Complex/simple
manufacturing
Mammalian cells,
low level of DSP
Therapy Replacement Antagonistic,
agonistic
New MoA,
combination
“somatic”,
systemic
Dosing Highly active,
low dose
High dose Lower doses,
less frequent
Singular dose (?)
Manufactured by Rentschler
Biosimilars
Reverse engineering for biosimilar candidates
June 1, 2016 S. Schmidt 14
Biosimilars limit Flexibility
McCamish et al. Clin Pharmacol Ther. 2012 Mar; 91(3): 405-417
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Agenda
1 Introduction
Development phases 2
Molecules 3
Process 4
Facility/Equipment 5
Conclusions 6
June 1, 2016 S. Schmidt 16
Batch vs. Continuous Manufacturing
Jacoby, Deloitte, 2015
● Advantages
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Continuous Bioprocessing
http://www.continuous-bioprocessing.com/
Cost (-) Productivity (+)
• Smaller equipment
• Smaller footprint
• Lower investment
• Higher cell densities
• Higher product concentration
• Higher yield
Quality (+) Flexibility (+)
• Natural process
• Constant nutrient level
• Removal of metabolites
• Less stress
• Efficient facility (resin) utilization
• Less product change overs (CIP/SIP)
• Easier backup through smaller facilities
• Single use for market production?
• No scale up issues (extending perfusion)
June 1, 2016 S. Schmidt 18
Continuous Processes (USP)
18
DSP
Feed
Cell removal
Simplified description
● Feed is continuously added
● Metabolites and product is continuously removed
● Bleeding of cells possible to adjust optimal cell concentration
Disadvantages
● Long cultivation times (sterility)
● Scalability of cell separation device
● Storage of harvest
Different schools of thought:
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Continuous Processes (DSP)
19
No columns:
Continuous Countercurrent Tangential
Chromatography™ (CCTC)
Multiple columns:
Simulated moving bed (SMB)
June 1, 2016 S. Schmidt 20
Platform Process – Pro/Con
Pro
Con
CMO perspective:
Not necessarily beneficial due to huge variability in proteins
But: utilize a modular approach with detail know how
● Highly standardized
● Lower costs (e.g.
materials, documents…)
● Accumulated experience
● Process understanding
● Rapid procedure
● Predictability of results
● Sequence of steps with
minimal conditioning
● Ability to react on variations
(titer, pI, aggregation)
● Low interest to implement
improvements
● Favouring of compatible
molecules
(manufacturability vs.
efficacy)
● Pipeline with similar
molecules needed
Productivity has doubled every 1.5 years
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High Titer Processes
Issues
● Higher cell density
● Longer process time
● Higher solids content
● More particle diversity (size and physical
properties)
● Higher proportion of fine particles
● Use of flocculants (CaCl2, K2HPO4) to
remove cells, debris, HCPs and DNA
● Precipitation and removal by centrifugation
or filtration
P. Ball, W. Noe, P. Seymour (bptc) 2011-14
June 1, 2016 S. Schmidt 22
Evolution of Mammalian Biomanufacturing
Odum, ISPE, 2013
1980 1985 1990 1995 2000 2005 2010 2015
0.01 g/L
$ 10.000/g
0.5 g/L
$ 1000/g
5 g/L
$ 300/g 10 g/L
$ 100/g
Fixed single product
facilities
FDA Guidance
Multi-Prod MFG Fixed Multi-Product Facilities
Emerging Contract Manufacturers
Flexible
manufacturing
Next generation
bioprocessing
Intro 15K 6-pack plants Intro disposable tech
June 1, 2016 S. Schmidt 23
Agenda
1 Introduction
Development phases 2
Molecules 3
Process 4
Facility/Equipment 5
Conclusions 6
June 1, 2016 S. Schmidt 24
Utilization of Disposables
0% Hybrid 100% [DSP]
[USP]100%
Hybrid
0%
Disposable
Technology
Stainless
Steel
R&D, clinical
production
Small scale
Production
<2000L
Large scale
production,
Dedicated facility
Is this really true?
Shire 4x 2000L
single-use
bioreactor facility for
Gaucher’s disease
drug VIPRV
Disposables offer many advantages but are not always optimal
June 1, 2016 S. Schmidt 25
SWOT Analysis of Disposables in Biomanufacturing
Strength
• Low investment (fast amortization)
• Small footprint (no piping)
• Simple & quick expansion (flexibility)
• Short implementation time
• Reduced qualification & maintenance
• Elimination of cleaning (QA/QC)
• Fast product change over (capacity)
• No cross-contamination risk (safety)
Weakness
• Scalability (reactors, columns, TFF)
• Transport sensitivity (columns)
• Increased waste
• Repetitive consumable costs
• Long supply lead times
• Storage requirements
• Limited standardization
Threat
• Supplier dependency
• Extractables & leachables effect
Opportunity
• Continuous processing
• Orphan drug manufacturing
• Scale suitable for clinical supply
June 1, 2016 S. Schmidt 26
CMO Perspective on Disposables
Cost
Time Quality
● Suite savings
● Flexibility
● Customer ownership
● Investment/Inventory
● Shipping
● Storage space
● Monopoly of suppliers
● Delivery times
● Supply chain
● Labor savings
● Changeover
● Supplier qualification
● Certificates
● L&E data
● Customizable
● Transportation
● Performance
June 1, 2016 S. Schmidt 27
Disposables at Rentschler
● Very fast establishment, locations close to market
● Preferred use of disposables
● Easy to scale out and multiply
● Ballroom concepts
● Optimal process flow
June 1, 2016 S. Schmidt 28
Modular Facilities
Advantages: construction
● HVAC cost saving: containing the equipment, surrounding area can be
reclassified
● Rapid reconfiguration of the facility, easy cleaning and fast construction.
Disadvantage: Container movement
● Moving heavy weights can often be challenging and require special safety
precautions
● A “non-value add” operation (wasted effort).
● Increased possibility of mix-up
Disadvantage: Inventory
● Increases risk of stock-out
● Larger volumes of inventory
● Higher cost
June 1, 2016 S. Schmidt 29
Ballroom Concept
● Closed processing protects the product from the room environment
● Allows the facility requirements to be dramatically reduced in terms of product
protection—in other words, the facility is a non-impact system (as defined in
ISPE’s Baseline Guide)
● As the facility is no longer protecting the product, it can be simplified:
o reduced risk of product contamination
o reduced project cost and schedule
o improved operations
o reduced operational costs
● Best utilization of mobile equipment
● Reconfiguring to match any process
● Low CAPEX ideal for early phases
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Design Requirements: Impact of Closed Systems
June 1, 2016 S. Schmidt 32
Agenda
1 Introduction
Development phases 2
Molecules 3
Process 4
Facility/Equipment 5
Conclusions 6
Development stage
● The later in the process the less flexibility is possible
● CMOs can accept projects at any development stage
Molecules
● Mammalian cells are capable to express a wider range of molecules than
microbes
● Flexibility is reduced in the case of biosimilars that need to match certain quality
attributes
Process
● Platform processes limit flexibility
● Continuous process can cover same capacity at smaller footprint
● High titer processes put pressure on DSP
Facility/Equipment
● The introduction of disposable equipment improves flexibility
● Mobile equipment can be reconfigured to match any process (scale limit!)
● Modular facilities allow faster adaptation to new processes
June 1, 2016 S. Schmidt 33
Conclusions
4th Laupheim Biotech Days
June 13 to 14, 2016
Schloss Großlaupheim, Laupheim, Germany
June 1, 2016 S. Schmidt 34
Announcement
Topic
Fusion Proteins –
delivering novel
therapeutic options
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