Workshop 1
Addressing the
Process & Economic Dimensions of ICB
Chairs:
Suzanne Farid (University College London)
Andrew Sinclair (BioPharm Services)
ECI ICB, Castelldefels, Spain, 20-24 Oct 2013
Proposed Workshop Format
16.05-16.10
16.10-16.20
16.20-16.30
16.30-16.45
PART 1 (45 min)
Intro to workshop and format
Speaker: Timothy Johnson, Genzyme (Theme 1)
Speaker: Jonathan Coffman, Boehringer Ingelheim (Theme 2)
Audience discussion on theme questions
16.45-16.55
16.55-17.05
17.05-17.10
17.10-17.25
17.25-17.30
PART 2 (45 min)
Speaker: Veena Wariko, Genzyme (Theme 3)
Speaker: Paul Jorjorian, Gallus BioPharmaceuticals (Theme 4)
Speaker: Thomas Daszkowski, Bayer (Theme 4)
Audience discussion on theme questions
Session wrap-up
Themes
PART 1
Theme 1 Labile v. stable products – business case for continuous bioprocessing?
Timothy Johnson, Genzyme
Theme 2 Best timing and scale for implementation of continuous bioprocessing?
Jonathan Coffman, Boehringer Ingelheim
PART 2
Theme 3 Cost analysis of continuous bioprocessing over a product’s lifecycle
Veena Wariko, Genzyme
Theme 4 Is tomorrow’s process a hybrid of batch and continuous operations?
Paul Jorjorian, Gallus BioPharmaceuticals (CMO perspective)
Thomas Daszkowski, Bayer Technology Services (Innovator perspective)
Themes
PART 1
Theme 1 Labile v. stable products – business case for continuous bioprocessing?
Timothy Johnson, Genzyme
Theme 2 Best timing and scale for implementation of continuous bioprocessing?
Jonathan Coffman, Boehringer Ingelheim
PART 2
Theme 3 Cost analysis of continuous bioprocessing over a product’s lifecycle
Veena Wariko, Genzyme
Theme 4 Is tomorrow’s process a hybrid of batch and continuous operations?
Paul Jorjorian, Gallus BioPharmaceuticals (CMO perspective)
Thomas Daszkowski, Bayer Technology Services (Innovator perspective)
Workshop 1:
Business Case Discussion for Integrated Continuous
Biomanufacturing
Tim Johnson, Ph.D.
October 21, 2013
Jade (with her mother) Fabry disease USA
www.genzyme.com
|
Integrated Continuous BioManufacturing
Media
Bioreactor
Capture
Intermediate
Purification
Viral
Inact.
Polish
Unform.
Drug
Substance
CAPEX
• Parameters
− Number of unit operations, tank sizes, utilities, etc.
• Upstream Example:
− Assume a market demand
Reactor Volume
Market Demand =
Average VCD × SPR
− For a given market demand
− Increasing VCD  decreases reactor size  decreases CAPEX
− Perfusion can lead to >100 Mcell/ml and substantially reduced bioreactor size
Reactor Volumefed−batch
Average VCDcontinuous
=
Reactor Volumecontinuous
Average VCDfed−batch
OPEX
Continuous vs. Fed-Batch
• Parameters
− Upstream: Media, single use systems, etc.
− Downstream: Resins, buffers, etc.
− Labor
• Upstream Example:
− Media usage and cost is an important contributor to OPEX
− Facilities with equal production rates  equal number of cells and duration
− Simplifies comparison to media consumption rates (or CSPR)
Media Volumecontinuous CSPR continuous
=
,
Media Volumefed−batch
CSPR fed−batch
1
𝐼𝑉𝐶𝐶 =
𝐶𝑆𝑃𝑅
− Decreasing CSPR  decreases media usage  decreases OPEX
Cell-Specific Perfusion Rate
CAPEX/OPEX sensitivity analyses
Red = More Savings
CAPEX Savings
OPEX Savings
(Fed-Batch mAb – Continuous mAb)
(Fed-Batch mAb – Continuous mAb)
Viable cell density
Factors influencing costs for continuous manufacturing
mAb OPEX
Overall: –54%
Overall: –20%
% of overall cost
mAb CAPEX
Themes
Theme 1 Labile v. stable products – business case for continuous bioprocessing?
Timothy Johnson, Genzyme
Theme 2 Best timing and scale for implementation of continuous bioprocessing?
Jonathan Coffman, Boehringer Ingelheim
Theme 3 Cost analysis of continuous bioprocessing over a product’s lifecycle
Veena Wariko, Genzyme
Theme 4 Is tomorrow’s process a hybrid of batch and continuous operations?
Paul Jorjorian, Gallus BioPharmaceuticals (CMO perspective)
Thomas Daszkowski, Bayer Technology Services (Innovator perspective)
Workshop
Biopharma CMB - Standard Presentation 2012
Discussion on best timing and scale
for continuous bioprocessing
Jon Coffman
12
Perfusion example: mAb production
Given
• Typical fed batch integrated viable cell densities: 150 Mcells/mL day
• Average perfusion cell density: 75Mcells/mL
• Fed Batch duration: 12 days
• Perfusion duration: 12 days (minimum cell culture time)
Then for the same amount of product produced:
• The perfusion bioreactor is about 1/6th the size of the fed batch (smaller
if culture extended)
• The downstream size is 1/12 the size of the downstream to support the
fed batch, if the material is harvested continuously through the
downstream,
How suitable is continuous
processing for Phase I / II
clinical manufacturing?
Biopharma CMB - Standard Presentation 2012
13
Perfusion Bioreactors and downstream have a size
advantage over fed batch, but use more media
12 Day Perfusion
12 day Fed
Batch
800L
133L
Effectively
Continuous
Downstream
Downstream
3200L Media for Perfusion at
2 v/v/day
Volume/area to Scale
Capital cost scales roughly with
diameter
800L Media
for FB
Can continuous Processing be useful for Phase
I/II manufacturing?
 Capital costs lower
 Raw material costs lower
 Small size allows more products in the same suite
 But there are significant drawbacks that must be addressed
Biopharma CMB - Standard Presentation 2012
15
Can Continuous Processes Decrease Cost of
Quality?
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does not scale with
size, and does not
automatically
decrease with
continuous processing
How can continuous processing impact
development costs?
??
Batch
Process
Development
Cost
Continuous
Process
Development
Cost
Is continuous processing inherently easier to develop?
Easier to make a platform?
Biopharma CMB - Standard Presentation 2012
17
How can continuous processing impact tech
transfer costs?
??
Batch
Process Tech
Transfer Cost
Continuous
Process Tech
Transfer Cost
Is continuous processing easier to make a
platform? Easier to tech transfer to an existing
continuous processing suite?
Biopharma CMB - Standard Presentation 2012
18
Discussion
VOTE:
Do you anticipate using continuous processing in your company in the next 5 years?
Theme 1: Labile v. stable products – business case for continuous bioprocessing?
1. What strategies are needed to cope with the extra complexity in perfusion processes?
2. How can we improve our clone screening methods to ensure long-term production stability?
3. Are there nuances that could inhibit the use of conti processes for non-mAb stable products?
Theme 2: Best timing and scale for implementation of continuous bioprocessing?
1. When is the best time for implementing continuous processing – Ph I/II? Ph III? Post approval?
2. Does continuous processing increase or decrease the cost of QC/QA for a single campaign eg
for Ph I/II?
3. Does continuous processing need to be able to cope with multiple products to be a valid
option?
Themes
PART 1
Theme 1 Labile v. stable products – business case for continuous bioprocessing?
Timothy Johnson, Genzyme
Theme 2 Best timing and scale for implementation of continuous bioprocessing?
Jonathan Coffman, Boehringer Ingelheim
PART 2
Theme 3 Cost analysis of continuous bioprocessing over a product’s lifecycle
Veena Wariko, Genzyme
Theme 4 Is tomorrow’s process a hybrid of batch and continuous operations?
Paul Jorjorian, Gallus BioPharmaceuticals (CMO perspective)
Thomas Daszkowski, Bayer Technology Services (Innovator perspective)
Cost analysis and Continuous
Bioprocessing over a Products Lifecycle
Veena Warikoo, PhD
Genzyme A Sanofi Comapny
Erik Familial Hypercholesterolemia USA
www.genzyme.com
|
21
genzyme
A SANOFI COMPANY
Process Validation
2011 FDA guidance defines process validation as:
“The collection and evaluation of data, from the process
design stage through commercial production
which establishes scientific evidence that a process
is capable of consistently delivering quality product”
Scientifically sound design practices (QbD)
Robust qualification (MFG reproducible)
Process verification (continued over lifetime)
State of control
• Inherent to continuous process - robust
control strategies, PAT, steady state product
quality, limited scale up
• Leverage perfusion Brx strategies
22
Regulatory challenges
 FDA encouraging of integrated continuous biomanufacturing approach
 Need new approaches
– Viral clearance studies etc.
 Definition of a lot
–
–
–
–
–
traceability of raw materials
Per manufacturer’s requirements
Time based
Amount based
Currently well defined in perfusion cell culture based processes
 Definition of steady state
– Product quality
 How to handle deviations
– Process control critical
– Engineering solutions
23
Quantify Intangible Benefits
 Ease of scale up
 Reduced cycle time
 Flexibility: batch size, multi-product
 Steady state product quality
24
Themes
PART 1
Theme 1 Labile v. stable products – business case for continuous bioprocessing?
Timothy Johnson, Genzyme
Theme 2 Best timing and scale for implementation of continuous bioprocessing?
Jonathan Coffman, Boehringer Ingelheim
PART 2
Theme 3 Cost analysis of continuous bioprocessing over a product’s lifecycle
Veena Wariko, Genzyme
Theme 4 Is tomorrow’s process a hybrid of batch and continuous operations?
Paul Jorjorian, Gallus BioPharmaceuticals (CMO perspective)
Thomas Daszkowski, Bayer Technology Services (Innovator perspective)
Implementation of Continuous
Processing for Biologics
Manufacturing
- a CMO Perspective
23rd October 2013
Paul Jorjorian M.Eng.
Head of Purification Development (STL)
Gallus BioPharmaceuticals
quantitative market research results
200 survey respondents: 49% use CMOs for PD
► Survey
group
► Big Pharma/Biotech – 34%
► Midsized Pharma/Biotech – 37%
► Emerging Pharma/Small/Virtual Biotech – 31%
Source: Gallus BioPharmaceuticals’ sponsored survey
Motivations for Engaging CMOs for PD :
►
69% Upstream process development
► 53% Purification process development
► 40% Batch-fed process development
► 40% Perfusion process development
► 34% Perfusion methods with centrifugation, cell settling
devices, alternating tangential flow, internal spin filter
27
what are customers looking for?
Assessing choices for best process fit
technology – the historical default and still
perceived as lowest risk (today)
►disposable technology – flexible capacity
►perfusion technologies – alternating tangential flow
(ATF), internal spin filter, centrifugation and cell settling
devices
►flexible stainless steel – the benefits of disposable with
the comfort of SS
►hybrid technologies – used for commercial processes
►fully continuous – still in the early stages of development
at large pharma/biotech companies although some
small/mid-sized companies are looking to adapt.
►stainless
28
perfusion technologies
How reliable is perfusion? Gallus’ experience:
►
No Bioreactor Contaminations Since 2007
► 140+ / 60 day runs & >2100 passages
► On Schedule: 97% of Run Start on time
► On Track: >94% Batch Release Rate
De-risking perfusion processes? (f SS)
► Bioreactor
prep outside of the suite for rapid
turnaround
► Disciplined, tenured manufacturing team
► Equipment sterilization via autoclave
► Single use tubing w/ Terumo sterile welders,
filters, and elastomers for each equipment build
► Exceptionally stable, clean environment
500L flexible SS bioreactor
29
hybrid options
Hybrid Solution
►
Decouples upstream and downstream
► Reduced footprint
► Reduced risk
► Used for multiple commercial processes
Perfusion + SUT
► SUB
are adaptable to perfusion
processes
► Easily increase process output
► Massively reduced capital costs
30
Themes
PART 1
Theme 1 Labile v. stable products – business case for continuous bioprocessing?
Timothy Johnson, Genzyme
Theme 2 Best timing and scale for implementation of continuous bioprocessing?
Jonathan Coffman, Boehringer Ingelheim
PART 2
Theme 3 Cost analysis of continuous bioprocessing over a product’s lifecycle
Veena Wariko, Genzyme
Theme 4 Is tomorrow’s process a hybrid of batch and continuous operations?
Paul Jorjorian, Gallus BioPharmaceuticals (CMO perspective)
Thomas Daszkowski, Bayer Technology Services (Innovator perspective)
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MoBiDiK
ModularBiologicsDisposableKonti
A. Vester, J. Magnus
MoBiDiK: Process Design
Upstream
Perfusion
Clarification
Concentration
Downstream
Viral Inactivation
Page 33 • MoBiDiK – Update • Oct 2013
Polishing
Capto adhere/ AEX
Virus Filtration
Chromatography
Prot A
Formulation
UF/ DF
MoBiDiK –
Demonstrator Laboratory
A
USP
Page 34 • SCM MoBiDiK • Sep, 2013
DSP
A
Layout 1st floor –
Production Level
Cleanroom classification
Black
Class E
Class D
Class C
Flows
Personnel
Material
Product
Waste
Page 35 • BTS 4:3 Template 2010 • June 2011
Discussion
VOTE:
Will we have the process analytics needed for integrated continuous processes in 5 y?
Theme 3: Cost analysis of continuous bioprocessing over a product’s lifecycle
1. Will continuous processing lengthen or streamline validation times?
2.
What are the ways to model the cost of intangible benefits such as steady state
product quality, flexibility, short cycle times, etc.?
Theme 4: Is tomorrow’s process a hybrid of batch and continuous operations?
1. In your organization who are the biggest advocates and opponents of
implementing continuous processes?
2.
Where do you feel it makes sense to retain batch processing?
3.
What gaps exist to create an integrated whole continuous process?
ECI ICB, Castelldefels, Spain, 20-24 Oct 2013