Transcript PAT-Konferenz 2006 in London

World Vaccine Manufacturing Congress
Microbial Services Approach to QbD and
Process Characterization Case Study
Dr. Axel Erler / Lonza Ltd / 12th April 2012
“Quality Can Be Planned.”
Joseph M. Juran
slide 2
Process Knowledge Generation Lifecycle of a
Manufacturing Process
Phase 1
Phase 2
Phase 3
Development
Optimization
Characterization
Validation
Commercial
Knowledge
Tox
Fixed Process
Filing
Costly post-approval changes
slide 3
Lonza`s New Approach to QbD and
Process Characterization in Biomanufacturing
A model bioprocess with 10 unit operations
Step1
Step 2
Step 3
Step 4
Step 5
Step 6
Step 7
Step 8
Step 9
Step 10
43-70
43-70
43-70
43-70
43-70
43-70
43-70
43-70
43-70
43-70
# experimental runs for process characterization
Industry Standard
≈ 500
Experimental Runs
New Approach
≈ 250 to 375
Experimental Runs
Reduced Cost
and Timeline
slide 4
Key to Keep Process
Characterization Cost low is ...
Efficient
Multivariate
Experimental Strategies
slide 5
Lonza Expands it`s DoE Toolbox
by the Use of Efficient Multivariate Designs
Process
SDM
Risk Assessment
1. Main-Effect
2. Main-Effect
Screening Study
Modeling Study
?
No
Statistical
Model
Simulation
Capability
Yes
Yes
~25 to 50%
fewer runs
Modeling Study
Effect
Resolution
?
New Approach
No
1. Main-Effect
Confirmatory
Run(s)
2. Augmentation
Validation
slide 6
Lonza`s New Approach Reduces
the Number of Required Experimental Runs
slide 7
Case Study – Formaldehyde Treatment of
a Purified Protein Vaccine
Formaldehyde Treatment Reaction
Formaldehyde in Water
(Paraformaldehyde)
Formaldehyde
+
Protein
Crosslinked side chains
(Protein aggregates)
slide 9
Process Representative Scale Down Models (SDMs)
Can Be as Small as a 50mL Spinner Flask
slide 10
Lonza Continuously Expands it’s DoE Toolbox
by the Use of Efficient Multivariate Designs
Six input parameters  only 17 experimental runs
Three test levels  covers non-linear effects
Five center points  estimates pure experimental error



Input Parameters
Output
1
2
3
4
5
6
Pattern
Protein
(g/L)
Quencher
(Lysine-HCl, g/L)
Time (h)
pH
Temperature
(°C)
Formaldehyde
/ Protein Ratio
1
----+0
0.1
4
40
7.2
39
2.0
2.9
2
+-+-0-
0.2
4
56
7.2
36
1.5
14.9
3
000000
0.15
5
48
7.4
36
2.0
14.4
4
++0-++
0.2
6
48
7.2
39
2.5
27.5
5
000000
0.15
5
48
7.4
36
2.0
14.6
6
0+----
0.15
6
40
7.2
33
1.5
3.6
7
-++0+-
0.1
6
56
7.4
39
1.5
2.5
Run
Aggregate
Level (%)
8
-+-+0+
0.1
6
40
7.6
36
2.5
8.5
9
000000
0.15
5
48
7.4
36
2.0
14.1
10
+0-++-
0.2
5
40
7.6
39
1.5
22
11
-0+--+
0.1
5
56
7.2
33
2.5
4.2
12
000000
0.15
5
48
7.4
36
2.0
14.2
13
--0+--
0.1
4
48
7.6
33
1.5
2.7
14
000000
0.15
5
48
7.4
36
2.0
15.3
15
0-++++
0.15
4
56
7.6
39
2.5
28.2
16
++++-0
0.2
6
56
7.6
33
2.0
30.7
17
+--0-+
0.2
4
40
7.4
33
2.5
31.9
slide 11
Parameter Estimates Provide Insights into
Correlations Between Input Parameters and Outputs
slide 12
Leverage Plots of the Statistical Model
Illustrate Actual by Predicted Output Values
Prediction formula
slide 13
Statistical Models Allow Process
Output Simulations Including Input Uncertainties
Spec




SD = 20% range on every input parameter (worst case)
Assumption: normal distribution for input uncertainties
Simulation of 10000 batches
Aggregate level specification: <25%
No single batch out of specification.
slide 14
Sound Process Characterization
Has Significant Benefits for Compliance and Business
Compliance

Identification of critical process parameters

Interactions between critical variables

Justification for operating spaces and acceptance criteria

Reproducible quality and yields
Business

Improved batch success rates

Yield improvements

Minimize number of process deviations
slide 15
Lonza`s New Approach on Process
Characterization Offers Valuable Benefits
Customer Values
A
More process knowledge at reduced cost
A
B
Robust and flexible process
B
C
Easier process transfer and scale-up
C
Compliant Process
slide 16
CaC2
slide 17
Our Sites Are Able to Handle Your
Development and cGMP Manufacturing Needs
Houston, TX (USA)
Kouřim (Czech Republic)
Viral-Based U.S. Process R&D Group
Mid Scale cGMP
(up to 2000L)
Microbial Fermentation
Mid to Large Scale cGMP
(75L to 75,000L)
Slough, UK
Braine, BE
Houston
Portsmouth
Porriño, SP
Visp, CH
Hopkinton
Key
Injectables
Oral-grade
Kouřim, CZ
Hopkinton, MA (USA)
Visp (Switzerland)
Microbial U.S. Process R&D Group
Small to Mid Scale cGMP
(150L to 2800L)
Microbial European Process R&D
Small to Large Scale cGMP
(20L to 15,000L)
Nansha
Singapore
Headquarter in Basel, Switzerland
Employs >11,000 people
45 major production and R&D facilities
slide 18
slide 19
www.lonzavirtualtours.com
slide 20
Our passion is to deliver sustainable
value to our customers.
...visit www.lonza.com and meet us at booth 39
slide 21
Backup Slides
Lonza’s Interconnected Life-science
Platform Comprises Four Divisions
Life Science
Ingredients
Microbial
Control
Hygiene &
Preservation
Nutrition
Ingredients
Performance
Intermediates
Water Treatment
Materials
Protection
Personal Care
Custom
Manufacturing
Bioscience
Development
Services
Therapeutic
Cell Solutions
Biological
Manufacturing
Testing
Solutions
Chemical
Manufacturing
Research
Solutions
Wood Treatment
slide 23
Market Focus in Biopharmaceuticals
Vaccines
Protein Therapeutics
Cellular Therapeutics
Microbial
Viral
mAbs / Fabs
ADCs
Recombinant proteins
Plasmid DNA
Enzymes
Regenerative medicine
Tissue engineering
Gene therapy
Viral vectors
slide 24
Our Microbial Sites Offer Proximity of
R&D, Scale-up and GMP Manufacturing
Hopkinton, MA
(USA)



Kouřim
(Czech Republic)
Visp / Lalden
(Switzerland)


Employees: ~3000
20L, 50L, 1000L to 2x 15m3

Employees: ~380
15m3, 50m3 and 75m3

Active pharmaceutical ingredients

Biotransformation

Biopharmaceuticals

Secondary metabolites

Antibody drug conjugates (ADC)

Recombinant / technical proteins

Peptides and oligonucleotides

L-Carnitine (CarnipureTM and
CarnikingTM)
Employees: ~350
40L to 2x 800L

Therapeutics and vaccines for
multiple indications such as
cancer therapy and infectious
diseases
slide 25
Houston, TX (USA)
 Lonza Houston, Inc., Houston, TX
 Employees: 20
 Plant/ process:





Process development
Scale-up
cGMP production
Analytical assays
Regulatory support
 Products:

Viral-based therapeutics (viral vector gene
therapy, viral vaccine applications)
slide 26
Our R&D Services Create a Foundation
for Successful cGMP Operations
Strain
development
and cell banking
Fermentation and
recovery
development
Purification
and refold
development
Analytical
development
Process validation
Support services
Lonza Development Services

Economically viable processes

Robust, scaleable, flexible and reliable processes

Broad, full-service offering
slide 27
Categories of Customer Projects
High
Technology
Transfer
Degree of Process Definition
Technology
Transfer
Technology
Transfer
Low
Technology
Transfer
Strain
Development
Fermentation
Development
Fermentation
Development
Purification
Development
Purification
Development
Scale-up
Scale-up
Scale-up
Process
Demonstration
Process
Demonstration
Process
Demonstration
Process
Demonstration
Process
Transfer
Process
Transfer
Process
Transfer
Process
Transfer
Process
Adaptation
slide 28
Permexcis® Virus Production Medium

Optimized for use with PER.C6® cell line

Serum-free and chemically defined

Reduced COGs and time to market due
to high cell density(> 90%) and viability

Saves validation time


No weaning from serum-containing
medium required
Minimal lot-to-lot variation
slide 29
We Have Expertise in All Types of
Microbially Derived Products
Broad experience





Novel protein therapeutics
Antibody fragments
Vaccines
(recombinant and attenuated)
Cytokines
Growth factors

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




Interferons
Polysaccharide-protein
conjugates
Recombinant peptides
Plasmid DNA
Fusion proteins
PEGylated products
Products requiring BL2
slide 30
Aligned with 7 Markets
slide 31
Our Hopkinton, MA (USA) Site Multiple
Capacities to Meet Your Clinical Needs
Location

26 miles from Boston
History

Founded in 1987
Biopharma CMO since 1997

Lonza acquired Feb 2007

Key productions

Ontak®, ATryn® and Increlex®
cGMP Capacities (total volumes)
 1 x 150L
 1 x 800L
 1 x 2,000L
 1 x 2,800L
(over 500 batches produced since 1998)
slide 32
The Facilities at Our Visp, Switzerland
Focus on Clinical and In-market Supply
Location

150 km east of Geneva
Key facts




Lonza R&D and production
center
World’s largest microbial
biopharmaceutical facility
dedicated to CMO industry
25-year history in microbial
biotechnology
Producing Cimzia®
cGMP capacities (total volumes)
 1 x 20L
 1 x 50L (new)
 1 x 1,000L
 2 x 15,000L
 Additional mid- and large-scale
expansion planning under way
slide 33
Milestones
Short History of Lonza
1897
1965
1969
1971
1983
Lonza founded in
Gampel (CH)
Commissioning
of the naphtha
cracker in Lalden
(CH)
Expansion
into the US;
Foundation of
Lonza Inc.
Verbund and
Niacin plant in
Visp (CH)
Start of the
biotechnology
research
activities in
Visp (CH)
slide 34
Milestones
Short History of Lonza
1984
1992
1996
2003
First, new multi-purpose
plant constructed.
Opening of the fine
chemicals complex in
Visp (CH)
Acquisition of the
Biotec plant in
Kouřim (CZ)
Acquisition of Cell-Tech
(Lonza Biologics)
Commission of the SSP
(small scale plant) in Visp
(CH). Expansion of the
production capacities with
two new 15m3 plants for
HAPIs (highly active
pharmaceutical ingredients)
in Kouřim (CZ)
slide 35
Milestones
Short History of Lonza
2004
2005
2006
Start up of two further 75 m3 biotechnology plants in
Kouřim (CZ)
Construction of a
second Niacinamide
plant in China with a
capacity of 6000 tons
Acquisition of UCB
bio-products peptide
business.
Braine l’Alleud, (BE)
Extension of the cGMP mammalian cell culture
capacities with three 20’000 liter fermenters in
Portsmouth, NH (USA)
Start operation of the BPMSS (biopharmaceutical
manufacturing small scale) plant with a 1000 liter
fermenter and down stream processing at Visp (CH)
Larch arabinogalactan
acquisition, Cohasset,
MN (USA)
Sale of Pasadena site, TX (USA)
slide 36
Milestones
Short History of Lonza
2006
2007
2007
Acquisition of Genentech’s mid-scale
mammalian biopharmaceutical plant
(4 x 10’000 liter) in Porriño (ES)
Acquisition of the research
bioproducts business and the
microbial biopharmaceutical
business of Cambrex
Start-up of largescale microbial
manufacturing in
Visp (Cimzia for
UCB)
Commence construction of the first
large scale mammalian cell culture
facility in Singapore (4 x 20’000L)
slide 37
Milestones
Short History of Lonza
2008
Acquisition of
amaxa, a technology
leader in cell
discovery.
Cologne (Germany)
is the new product
development site for
the Research
Solutions business
of Lonza Bioscience.
2009
Acquisition of Algonomics NV
(Gent, BE) strengthens
Lonza‘s technology offering
for biopharmaceutical
development.
2009
Joint venture
between
TEVA &
Lonza (TL
Biopharmac
eutical Ltd)
to develop,
manufacture
and market
a portfolio of
biosimilars.
2010
Acquisition of Vivante GMP
Solutions in Houston, TX (USA) a
viral-vaccine and gene therapy
company to enter the viral-based
manufacturing market.
Acquisition of MODA Technology
Partners for paperless qualitycontrol solutions to strengthen the
rapid testing solutions platform.
slide 38
Milestones 2011
2011
2011
Continued growth…
Acquisition of Arch Chemicals Inc. to build
the world’s leading microbial control
business.
Secondary listing on the Main Board of
the Singapore Exchange Securities
Trading Limited (“SGX-ST”)
slide 39