Economics of modular facility design and construction - · PDF filequalification of modules,...

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…


Capacity Utilization Rate

2012 46%

2015 55%

2018 86%

Source: bioTRAKTM database

Well matched to supply

Current Capacity Adequate but Potentially Misaligned


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


• 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


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


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


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


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


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


Media and Buffer Preparation/Hold

Support areas

Final Purif.

MaterialStaging andDispensing

Airlocks and Corridors

Inoculum


Cell Culture and Purification

Standardized Modular Manufacturing Facility


Flexible design to adjust area segregation Standard design – open ballroom configuration


Support areas

Final Purif.



Inoculum




Add segregation between cell culture and initial purification



InitialPurification

A/L Cell Cultureand

Harvest


Support areas

Final Purif.



Inoculum




Add segregation between cell culture and initial purification



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


Pre-packed Reduce Operating Costs Even Further….


Additional benefits include:

Quality

• Reduced cross contamination risk

Speed to market

• Improve campaign turnaround time

Economic Advantage of Pre-packed Columns


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


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


12 Months from Start to Start-up


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


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


Thank You!

BioProcess Technology Consultants, Inc.12 Gill Street, Suite 5450Woburn, MA 01801

+1.781.281.2703

[email protected]

Howard L. Levine, Ph.D.

Economics of modular facility design and construction - · PDF filequalification of modules,...

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