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BioProcess Technology Consultantswww.bptc.com
Howard L. Levine, Ph.D.Continuous Processing & Flexible Manufacturing2014 Jan 15-16Palm Springs, CA
Economics of Modular Facility Design and Construction
Top Ten Biopharmaceutical Products Total 2012 sales of almost $65 billion
Six are produced in cell culture
Seven are monoclonal antibody‐related products
CAGR for top ten selling monoclonal antibody‐related products for the period 2003‐2012 was 24%
CAGR for all monoclonal antibody‐related products for the same period was 25%
Source: bioTRAKTM database
From Clone to Commercial®
USProduct Name Company 2012 Sales
(Billions USD)
Humira AbbVie 9.265
Remicade J&J/Merck & Co. 8.215
Enbrel Amgen/Pfizer 7.973
Rituxan Roche/Genentech 7.161
Lantus Sanofi 6.377
Herceptin Roche/Genentech 6.288
Avastin Roche/Genentech 6.154
Novolog Novo Nordisk 4.324
Neulasta Amgen 4.092
Lucentis Roche/Genentech/Novartis 3.979
2013 Global Demand for Top Selling MAbs
Product Non‐US DemandKg/Yr
Non‐US DemandL/Yr
US DemandKg/Yr
US DemandL/Yr
Humira 303.7 379,669 228.4 285,498
Remicade 800.3 1,333,831 601.2 1,002,065
Enbrel 679.3 2,229,390 544.8 1,787,908
Rituxan 1,406.1 1,952,963 656.7 912,066
Herceptin 988.7 980,815 303.1 300,702
Avastin 1,079.8 1,499,722 553.5 768,755
Total 5,257.9 8,376,420 2,887.7 8,913,988
From Clone to Commercial®Source: bioTRAKTM database
Demand for Mammalian Cell Culture Capacity…
From Clone to Commercial®
Capacity Utilization Rate
2012 46%
2015 55%
2018 86%
Source: bioTRAKTM database
Well matched to supply
Current Capacity Adequate but Potentially Misaligned
From Clone to Commercial®
Increase in number of products and expanding markets will increase demand by approximately 1.75 million liters by 2016 and almost 2.25 million liters by 2018
• Current supply of capacity is sufficient to meet the market needs for commercial and clinical products
Existing capacity may not be available or appropriate• Product companies control >70% of total capacity• Utilization rates for the majority of the industry will reach 75% or higher by 2016 and exceed 85% by 2018
• Companies without manufacturing capacity or secure manufacturing contracts may experience difficultiesin accessing capacity in the coming years
• Increasing demand for “in country/for country” production will require multiple local facilities producing the same product
Challenges in the Evolving Manufacturing Landscape
From Clone to Commercial®
• Changing expectations as regulatory authorities gain experience and familiarity with biologics, especially biosimilars• Unpredictable review cycles
Regulatory
• Volume forecasts are difficult to predict and are subject to multiple variables• Number of competitors and order of market entry• Tendering cycles
Commercial
• Local and regional policies and practices can create a favorable or unfavorable environment• Reimbursement schemes• IP concerns
Economic/Legal
Adapted from Noffke T, Falexible Facilities & Manufacturing of the Future (2013)
Time
Man
ufac
turin
g S
cale
Smaller markets
Improved potency
Increased titer and yields
20,000 L
2,000 L
200 L
Future Capacity Requirements for Monoclonal Antibodies 2012 requirements for each of the top five monoclonal antibody products ranged
from 1 – 5 metric tons 2012 demand for all other monoclonal antibody products combined was
less than 4 metric tons Anticipated demand for new antibody‐related products approved between now
and 2018 is expected to be less than 100 Kg per year per product• Personalized medicine puts focus on smaller markets and niche products• Improved product potency (e.g., ADCs) reduces capacity requirements
From Clone to Commercial®
1990 2000 2010 1
10
10000
1000
100
1 100.1
Titer
Increased Productivity Lowers Capacity Requirements Cell lines
• Expression systems: GS, UCOE, SGE, GPEx etc.
• Cells: High viable cell density, suspension and medium adapted
Process• Media: Animal component free,
defined medium, cell protectants• Culture conditions: Feed strategies,
catabolite control, gas exchange
From Clone to Commercial®
Productivity has roughly doubled every 1.5 years over the last 20 years
State of the art late 1990s: 1 g/L expression; 60% overall yield
Then: 100 Kg requires 17 runs at 10,000 L
State of the art 2013: 5 g/L expression; 70% overall yield
Now: 100 Kg requires 15 runs at 2,000 L
Meeting Global Manufacturing Requirements
From Clone to Commercial®
Single use manufacturing assets can be brought on‐line more rapidly and at lower capital investment than conventional fixed stainless steel assets
Noffke T, Falexible Facilities & Manufacturing of the Future (2013)
Up to 40% reduction in capital and utility
Single‐use bioreactors available up to 2,000 L
Enables co‐location of manufacturing facilities with markets
Solutions for Future Biomanufacturing Needs Design and build standardized, pre‐engineered modular solutions
that can be readily configured and combined to provide a facility that can be rapidly designed, built, and deployed globally• Minimize cost by minimizing need for re‐engineering• Maximize flexibility by allowing easy re‐configuration• Improved flexibility to support a variety of biopharmaceutical
products Reduce project risk through off‐site design, construction, and pre‐
qualification of modules, including process equipment
From Clone to Commercial®Adapted from F. Eneqvist Achema 2012
Ca. 10%
Ca. 75%
Ca. 15%
Site Specific
Global StandardDesign Solution
Customization
Overall project cost distribution
Modular BioSolutionsTM – The Facility for the Future Standardized design based on standard platform process for monoclonal
antibody production• Readily adaptable to alternative processes and product types• GMP manufacturing areas built using modular construction
Overall facility design includes• Administration• Process development laboratories• Bulk manufacturing facility• Aseptic fill/finish facility• QC laboratories• Warehouse
Process and facility design developed incollaboration with KeyPlants AB and ModWave
From Clone to Commercial®
Facility design based on standard monoclonal antibody platform process• Titer of 5 g/L; overall yield 70%; 15 batches per year
Design incorporates maximum use of disposable and single‐use technologies• Disposable bags for media, buffer, and product storage• Single use bioreactors for upstream (2,000 L production bioreactor)• Pre‐packed columns and membrane adsorbers for downstream
Biomanufacturing Facility Design Basis
From Clone to Commercial®
Cost Comparison – Stainless Steel vs. Single Use
From Clone to Commercial®Ref: Wareheim D. ISPE Conference (2008 )
Raw Material Media and Buffer
Bulk Manufacturing Area GMP production area divided into six functional modules:
• Material Staging and Dispensing• Media and Buffer Preparation and Storage• Cell Culture and Purification
― Inoculum preparation― Bioreactor harvest― Pre‐virus removal purification operations
• Final Purification― Post‐virus removal purification operations― Formulation and bulk filling
• Support Areas• Air Locks and Corridors
Multiple air handling zones coverdifferent process areas
Maximize use of closed processeswherever possible
From Clone to Commercial®
Media and Buffer Preparation/Hold
Support areas
Final Purif.
MaterialStaging andDispensing
Airlocks and Corridors
Inoculum
Airlocks and Corridors
Cell Culture and Purification
Standardized Modular Manufacturing Facility
From Clone to Commercial®
Flexible design to adjust area segregation Standard design – open ballroom configuration
Media and Buffer Preparation/Hold
Support areas
Final Purif.
MaterialStaging andDispensing
Airlocks and Corridors
Inoculum
Airlocks and Corridors
Cell Culture and Purification
Standardized Modular Manufacturing Facility
Add segregation between cell culture and initial purification
From Clone to Commercial®
Flexible design to adjust area segregation Standard design – open ballroom configuration
InitialPurification
A/L Cell Cultureand
Harvest
Media and Buffer Preparation/Hold
Support areas
Final Purif.
MaterialStaging andDispensing
Airlocks and Corridors
Inoculum
Airlocks and Corridors
Cell Culture and Purification
Standardized Modular Manufacturing Facility
Add segregation between cell culture and initial purification
From Clone to Commercial®
Flexible design to adjust area segregation Standard design – open ballroom configuration
InitialPurification
A/L Cell Cultureand
Harvest
Add column cleaning and packing areas for reusable columns
Capital Costs Stainless Steel Facility Single‐Use Facility
Capital Equipment 23,779,504 17,753,538
Installation & Fit out 12,335,618 9,209,648
Pipework 4,755,901 3,550,708
HVAC 8,180,149 6,107,217
Electrical Power 5,944,876 4,438,385
Plant Utilities 713,385 532,606
Building (including control) 19,069,841 14,237,351
Validation 11,216,891 8,374,418
Design 11,964,684 8,932,713
Construction Management 2,991,171 2,233,178
Total Installed Capital $ 100,952,020 $ 75,369,762
CapEx Comparison – Stainless Steel vs. Single Use
From Clone to Commercial®
Pre-packed Reduce Operating Costs Even Further….
From Clone to Commercial®
Additional benefits include:
Quality
• Reduced cross contamination risk
Speed to market
• Improve campaign turnaround time
Operating CostsStainless Steel Facility Single‐Use Facility
Annual Batch Annual Batch
Quantity of Product Produced 105 Kg 7 Kg 105 Kg 7 Kg
Materials 607,428 40,495 561,190 37,413
Consumables 3,611,689 240,779 4,694,809 312,987
Labor (Direct/Indirect) 17,133,065 1,142,204 11,515,860 767,724
Maintenance/Utilities/Waste 2,268,686 151,246 1,328,590 88,573
Total $ 23,620,868 $ 1,574,724 $ 18,100,449 $ 1,206,697
Cost Per GramMonoclonal Antibody $ 225/gram $ 172/gram
Single Use Technologies Reduce COGS
From Clone to Commercial®
Easy expansion and connections according to needs• Add on for utilities• Connection to administration areas• Connection to development and QC laboratories• Connection to warehouse• Add on separate module for aseptic
fill/finish, packaging, and labeling
Standardized design and modular constructionallow predictable schedule• Approximately 12 months
from initiation to delivery
Fully Integrated Facility
From Clone to Commercial®
Greener More Efficient Facility Combination of single‐use technologies and standardized modular design and
construction results in a greener facility• Up to 40% less land than traditional stainless steel facility• Clean steam and WFI requirements reduced up to 80‐90%• Chilled water and steam demands reduced up to 60%• Reduction of 50‐95% in chemical usage• Less wastewater generation• Overall energy savings of 50% or more with a 25‐50% smaller carbon footprint
than traditional stainless steel facility
Lower capital investment and operating cost• Capital investment 25% lower than traditional stainless steel facility• Operating costs 23% lower than traditional stainless steel facility
From Clone to Commercial®Ref: Nelson K. Interphex (2011 )
Modular BioSolutionsTM Biomanufacturing Facility Predictable 12 month construction
schedule Flexible design to meet multiple
process needs GMP Compliant – High quality Expandable and movable
From Clone to Commercial®
Single‐use bioreactors and other technologies reduce validation• Standard design 1 x 2,000 L SUB• Scalable up to 2 x 2000 L SUBs
Higher predictability and lower risk Lower total cost of project
• Approximately $30 Million, including equipment
Acknowledgements BioProcess Technology Consultants
• Tom Ransohoff• Susan Dana Jones• Rick Stock
KeyPlants AB• Jan Lilja• Åsa Gaasvik• Hans Hummel
Modwave• Pär Almhem
From Clone to Commercial®
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