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Microbial Services Approach to QbD and Process Characterization Case Study. World Vaccine Manufacturing Congress . Dr. Axel Erler / Lonza Ltd / 12 th April 2012. “Quality C an B e Planned .”. Joseph M. Juran. Process Knowledge Generation Lifecycle of a Manufacturing Process. - PowerPoint PPT Presentation
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Microbial Services Approach to QbD and Process Characterization Case Study
Dr. Axel Erler / Lonza Ltd / 12th April 2012
World Vaccine Manufacturing Congress
slide 2
“Quality Can Be Planned.”
Joseph M. Juran
slide 3
Tox
Kno
wle
dge
Phase 1 Phase 2 Phase 3 Commercial
Process Knowledge Generation Lifecycle of a Manufacturing Process
Development Optimization Characterization Validation
Filing
Costly post-approval changes
Fixed Process
slide 4
Lonza`s New Approach to QbD andProcess Characterization in Biomanufacturing
Industry Standard
≈ 500Experimental
Runs
New Approach≈ 250 to 375
Experimental Runs
Step1
A model bioprocess with 10 unit operationsStep 2 Step 3 Step 4 Step 5 Step 6 Step 7 Step 8 Step 9 Step 10
# experimental runs for process characterization
43-70 43-70 43-70 43-70 43-70 43-70 43-70 43-70 43-70 43-70
Reduced Cost and Timeline
slide 5
Key to Keep ProcessCharacterization Cost low is ...
EfficientMultivariate
Experimental Strategies
slide 6
Process SDM
Risk Assessment
Validation
1. Main-Effect
Screening Study
2. Main-Effect
Modeling Study
Capability
Confirmatory Run(s)
Yes
No
Lonza Expands it`s DoE Toolboxby the Use of Efficient Multivariate Designs
SimulationStatistical Model
2. AugmentationNo
Yes
Effect Resolution
?~25 to 50%fewer runs
?
Process Characterization
1. Main-Effect
Modeling Study
New Approach
slide 7
Lonza`s New Approach Reducesthe Number of Required Experimental Runs
Case Study – Formaldehyde Treatment of a Purified Protein Vaccine
slide 9
Formaldehyde Treatment Reaction
Formaldehyde in Water(Paraformaldehyde)
Formaldehyde+
Protein
Crosslinked side chains(Protein aggregates)
slide 10
Process Representative Scale Down Models (SDMs)Can Be as Small as a 50mL Spinner Flask
slide 11
Lonza Continuously Expands it’s DoE Toolboxby 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
1 2 3 4 5 6
Run Pattern Protein(g/L)
Quencher(Lysine-HCl, g/L)
Time (h) pH Temperature(°C)
Formaldehyde/ Protein Ratio
AggregateLevel (%)
1 ----+0 0.1 4 40 7.2 39 2.0 2.92 +-+-0- 0.2 4 56 7.2 36 1.5 14.93 000000 0.15 5 48 7.4 36 2.0 14.44 ++0-++ 0.2 6 48 7.2 39 2.5 27.55 000000 0.15 5 48 7.4 36 2.0 14.66 0+---- 0.15 6 40 7.2 33 1.5 3.67 -++0+- 0.1 6 56 7.4 39 1.5 2.58 -+-+0+ 0.1 6 40 7.6 36 2.5 8.59 000000 0.15 5 48 7.4 36 2.0 14.110 +0-++- 0.2 5 40 7.6 39 1.5 2211 -0+--+ 0.1 5 56 7.2 33 2.5 4.212 000000 0.15 5 48 7.4 36 2.0 14.213 --0+-- 0.1 4 48 7.6 33 1.5 2.714 000000 0.15 5 48 7.4 36 2.0 15.315 0-++++ 0.15 4 56 7.6 39 2.5 28.216 ++++-0 0.2 6 56 7.6 33 2.0 30.717 +--0-+ 0.2 4 40 7.4 33 2.5 31.9
Input ParametersOutput
slide 12
ProteinHCHO / ProteinTemp.pHLysineTime(Lysine-10)*(pH-7.4)(pH-7.4)*(Temp.-36)(Time-48)*(pH-7.4)
Term16.00
9.336.646.15
-5.183.22
-2.642.502.38
t-Wert<.0001*<.0001*0.0003*0.0005*0.0013*0.0146*0.0333*0.0409*0.0487*
Wahrsch.>|t|
Sortierte Parameterschätzer
Parameter Estimates Provide Insights intoCorrelations Between Input Parameters and Outputs
slide 13
Leverage Plots of the Statistical ModelIllustrate Actual by Predicted Output Values
0
5
10
15
20
25
30
Pro
tein
Agg
rega
tes
(%) M
easu
red
0 5 10 15 20 25 30Protein Aggregates (%) PredictedP<.0001 r2 =0.99 RMSE=1.295
Diagramm „Beobachtete Werte über Vorhersage“
Prediction formula
slide 14
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.
Statistical Models Allow ProcessOutput Simulations Including Input Uncertainties
Spec
slide 15
Sound Process CharacterizationHas 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 16
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 17
CaC2
slide 18
Portsmouth
Singapore
Visp, CH
Slough, UK Kouřim, CZBraine, BE
Porriño, SP
Nansha
Key Injectables
Oral-grade
Our Sites Are Able to Handle YourDevelopment and cGMP Manufacturing Needs
Hopkinton, MA (USA)Microbial U.S. Process R&D GroupSmall to Mid Scale cGMP(150L to 2800L)
Visp (Switzerland)Microbial European Process R&DSmall to Large Scale cGMP(20L to 15,000L)
Kouřim (Czech Republic)Microbial FermentationMid to Large Scale cGMP(75L to 75,000L)
Headquarter in Basel, SwitzerlandEmploys >11,000 people45 major production and R&D facilities
Houston
Houston, TX (USA)Viral-Based U.S. Process R&D GroupMid Scale cGMP(up to 2000L)
Hopkinton
slide 19
slide 20www.lonzavirtualtours.com
slide 21
Our passion is to deliver sustainablevalue to our customers.
...visit www.lonza.com and meet us at booth 39
Backup Slides
slide 23
Lonza’s Interconnected Life-sciencePlatform Comprises Four Divisions
TherapeuticCell Solutions
TestingSolutions
ResearchSolutions
Bioscience
DevelopmentServices
BiologicalManufacturing
ChemicalManufacturing
CustomManufacturing
NutritionIngredients
PerformanceIntermediates
Life ScienceIngredients
Hygiene &Preservation
Water Treatment
MaterialsProtection
Personal Care
Wood Treatment
MicrobialControl
slide 24
Cellular TherapeuticsRegenerative medicineTissue engineeringGene therapyViral vectors
VaccinesMicrobialViral
Protein TherapeuticsmAbs / FabsADCsRecombinant proteinsPlasmid DNAEnzymes
Market Focus in Biopharmaceuticals
slide 25
Our Microbial Sites Offer Proximity ofR&D, Scale-up and GMP ManufacturingHopkinton, MA
(USA)Visp / Lalden (Switzerland)
Kouřim(Czech Republic)
Employees: ~350 40L to 2x 800L
Employees: ~3000 20L, 50L, 1000L to 2x 15m3
Employees: ~380 15m3, 50m3 and 75m3
Therapeutics and vaccines for multiple indications such as cancer therapy and infectious diseases
Active pharmaceutical ingredients Biopharmaceuticals Antibody drug conjugates (ADC) Peptides and oligonucleotides
Biotransformation Secondary metabolites Recombinant / technical proteins L-Carnitine (CarnipureTM and
CarnikingTM)
slide 26
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 27
Straindevelopment
and cell banking
Fermentation and recovery
development
Purificationand refold
development
Analytical development
Process validation Support services
Our R&D Services Create a Foundation for Successful cGMP Operations
Lonza Development Services Economically viable processes Robust, scaleable, flexible and reliable processes Broad, full-service offering
slide 28
Categories of Customer Projects
Technology Transfer
Process Demonstration
Process Transfer
Technology Transfer
Process Transfer
Technology Transfer
Technology Transfer
Fermentation Development
Fermentation Development
Purification Development
Purification Development
Strain Development
Process Demonstration
Process Demonstration
Process Transfer
Process Transfer
Process Demonstration
Scale-upScale-up
Process Adaptation
Scale-up
High Degree of Process Definition Low
slide 29
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 30
Broad experience Novel protein therapeutics Antibody fragments Vaccines
(recombinant and attenuated) Cytokines Growth factors
We Have Expertise in All Types of Microbially Derived Products
Interferons Polysaccharide-protein
conjugates Recombinant peptides Plasmid DNA Fusion proteins PEGylated products Products requiring BL2
slide 31
Aligned with 7 Markets
slide 32
Location 26 miles from Boston
History Founded in 1987 Biopharma CMO since 1997 Lonza acquired Feb 2007
Key productions Ontak®, ATryn® and Increlex®
Our Hopkinton, MA (USA) Site Multiple Capacities to Meet Your Clinical Needs
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 33
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®
The Facilities at Our Visp, Switzerland Focus on Clinical and In-market Supply
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 34
Lonza founded in Gampel (CH)
Expansion into the US; Foundation of Lonza Inc.
Commissioning of the naphtha cracker in Lalden (CH)
1897 1965 1969 1971 1983
Verbund and Niacin plant in Visp (CH)
Start of the biotechnology research activities in Visp (CH)
MilestonesShort History of Lonza
slide 35
Acquisition of the Biotec plant in Kouřim (CZ)
Acquisition of Cell-Tech (Lonza Biologics)
200319961992
First, new multi-purpose plant constructed. Opening of the fine chemicals complex in Visp (CH)
1984
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)
MilestonesShort History of Lonza
slide 36
Start up of two further 75 m3 biotechnology plants in Kouřim (CZ)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)Sale of Pasadena site, TX (USA)
20052004
Construction of a second Niacinamide plant in China with a capacity of 6000 tons
2006
Acquisition of UCB bio-products peptide business. Braine l’Alleud, (BE)
Larch arabinogalactan acquisition, Cohasset, MN (USA)
MilestonesShort History of Lonza
slide 37
Acquisition of Genentech’s mid-scale mammalian biopharmaceutical plant (4 x 10’000 liter) in Porriño (ES)
Commence construction of the first large scale mammalian cell culture facility in Singapore (4 x 20’000L)
2006 20072007
Acquisition of the research bioproducts business and the microbial biopharmaceutical business of Cambrex
Start-up of large-scale microbial manufacturing in Visp (Cimzia for UCB)
MilestonesShort History of Lonza
slide 38
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.
Acquisition of Algonomics NV (Gent, BE) strengthens Lonza‘s technology offering for biopharmaceutical development.
Joint venture between TEVA & Lonza (TL Biopharmaceutical Ltd) to develop, manufacture and market a portfolio of biosimilars.
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 quality-control solutions to strengthen the rapid testing solutions platform.
2008 2009 2009 2010
MilestonesShort History of Lonza
slide 39
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”)
2011 2011 Continued growth…
Milestones 2011