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Future Trends inBiopharmaceutical Operations and Facilities
Johannes R. Roebers, PhDSenior Vice President, Biologic Strategy, Planning and Operations
Elan Pharmaceutical International Ltd, Dublin, Ireland
PresentationISPE-Workshop on “Single-Use Technologies in Biomanufacturing Processes”
26-27th May 2011, Marseilles, France
Disclaimer
The content and views in this presentation are the views of the author and not necessarily the view of Elan.
Elan and the author do not make any representation regarding the accuracy or completeness of the data presented or data used from referenced sources.
This presentation contains forward-looking statements about Elan’s financial condition, results of operations and business prospects that involve substantial risks and uncertainties.
A list and description of these risks, uncertainties and other matters can be found in Elan’s Annual Report on Form 20-F for the fiscal year ended December 31, 2010 and in its Reports of Foreign Issuer on Form 6-K filed with the SEC.
Elan assumes no obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise.
Outline
• Trends in Licensed and Future Biopharmaceuticals
• Advances in Biopharmaceutical Operations
• Technology Trends in Biopharmaceutical Operations
• Elan Facility Case Study: “Traditional” vs. “Mini-Mill”
• Future Trends in Biopharmaceutical Operations
Top Biologic Products of 2010
Product CompanyProduct
CategoryIndications
Revenue
(2010, $
M)
Rank
2010 2008 2006
Enbrel (etanercept)
Amgen; Pfizer;
Takeda
Pharmaceutical
Co.
Antibody
Rheumatoid arthritis, ankylosing
spondylitis, plaque psoriasis,
psoriatic arthritis, juvenile
rheumatoid arthritis
7,287 1 1 1
Avastin (bevacizumab) Genentech;
Roche; ChugaiAntibody
Metastatic colorectal cancer, first-
line NSCLC, breast cancer, renal
cancer6,973 2 6 10
Rituxan/MabThera
(rituximab)
Genentech;
Roche; Biogen-
IDEC
Antibody
Non-Hodgkin's lymphoma, chronic
lymphocytic leukemia (first-line
therapy), rheumatoid arthritis
(second-line therapy)
6,859 3 4 3
Humira (adalimumab) Abbott; Eisai AntibodyRheumatoid arthritis, ankylosing
spondylitis, Crohn's disease,
plaque psoriasis, psoriatic arthritis 6,548 4 5 12
Remicade (infliximab)
Centocor (J&J);
Schering-
Plough;
Mitsubishi
Tanabe Pharma
Antibody
Rheumatoid arthritis, ankylosing
spondylitis, Behcet's syndrome,
Crohn's disease, psoriatic arthritis,
ulcerative colitis
6,520 5 2 4
Herceptin
(trastuzumab)
Genentech;
Chugai; RocheAntibody
HER2-positive metastatic breast
cancer5,859 6 7 6
Lantus (insulin
glargine)Sanofi-aventis Protein Type 1 and 2 diabetes 4,834 7 10 11
Ranked higher No change in rank Ranked lower
Source: IMS Midas and Knowledgelink;
Pipelinereview.com - Top 30 biologics 2010, Special Edition1/2011
Top Biologic Products (contd.)
Product CompanyProduct
CategoryIndications
Revenue
(2010, $
M)
Rank
2010 2008 2006
Epogen/Procrit/Eprex/
ESPO (epoetin alfa)
Amgen; Ortho
Biotech/Janssen -
Cilag (J&J);
Kyowa Hakko
Kirin
Protein Renal anemia 4,590 8 3 5, 7*
Neulasta (pegfilgrastim) Amgen Protein Neutropenia 3,558 9 9 8
Lucentis (ranibizumab)Genentech;
NovartisAntibody
Wet age-related macular
degeneration 3,106 10 13 -
Aranesp/NESP (darbepoetin
alfa)
Amgen; Kyowa
Hakko Kirin
Pharma
Protein Anemia 2,995 11 8 2
Avonex (interferon beta-1a) Biogen Idec ProteinRelapsing forms of
multiple sclerosis2,518 12 11 15
Rebif (interferon beta-1a) Merck Serono ProteinRelapsing forms of
multiple sclerosis2,297 13 15 16
Novolog, NovoRapid
(insulin aspart)Novo Nordisk
Protein Glycemic control in
children and adults with
diabetes mellitus2,198 14 22 -
Actrapid (EU)/Novolin (US)
(rhu insulin)Novo Nordisk Protein Type 1 and 2 diabetes 2,185 15 12 9
Source: IMS Midas and Knowledgelink;
Pipelinereview.com - Top 30 biologics 2010, Special Edition1/2011
*In 2006 Epogen and Procrit were ranked separatelyRanked higher No change in rank Ranked lower
Top Biologic Products (contd.)
Product CompanyProduct
CategoryIndications
Revenue
(2010, $
M)
Rank
2010 2008 2006
Advate/Recombinate
(octocog alpha)Baxter Healthcare Protein Hemophilia A 2,095 16 17 -
Humalog Mix 50:50
Premix (insulin lispro)Eli Lilly
ProteinType 1 and 2 diabetes 2,054 17 14 18
Erbitux (cetuximab)Eli Lilly; BMS;
Merck SeronoAntibody
Metastatic colorectal
carcinoma1,791 18 18
Pegasys (peginterferon
alpha -2a)Roche Protein
Chronic hepatitis C virus
infection1,775 19 20 20
Betaseron/Betaferon
(interferon beta-1b)
Berlex; Bayer
Schering PharmaProtein
All relapsing forms of
multiple sclerosis1,661 20 19 19
NovoSeven (eptacog
alpha)Novo Nordisk Protein
Hemophilia, stroke, surgery,
trauma 1,483 21 25 -
Novomix 50 (insulin
aspart)Novo Nordisk Protein Type 1 and 2 diabetes 1,445 22 - -
Botox
(onabotulinumtoxin A)
Allergan
Pharmaceuticals;
GlaxoSmithKline
Protein Medical and aesthetic
indications1,414 23 - -
Source: IMS Midas and Knowledgelink;
Pipelinereview.com - Top 30 biologics 2010, Special Edition1/2011
Ranked higher No change in rank Ranked lower
Top 7 Biologic Products of 2010
Product CompanyProduct
CategoryIndications
Revenue
(2010, $
M)
Rank
2010 2008 2006
Enbrel (etanercept)
Amgen; Pfizer;
Takeda
Pharmaceutical
Co.
Antibody
Rheumatoid arthritis, ankylosing
spondylitis, plaque psoriasis,
psoriatic arthritis, juvenile
rheumatoid arthritis
7,287 1 1 1
Avastin (bevacizumab) Genentech;
Roche; ChugaiAntibody
Metastatic colorectal cancer, first-
line NSCLC, breast cancer, renal
cancer6,973 2 6 10
Rituxan/MabThera
(rituximab)
Genentech;
Roche; Biogen-
IDEC
Antibody
Non-Hodgkin's lymphoma, chronic
lymphocytic leukemia (first-line
therapy), rheumatoid arthritis
(second-line therapy)
6,859 3 4 3
Humira (adalimumab) Abbott; Eisai AntibodyRheumatoid arthritis, ankylosing
spondylitis, Crohn's disease,
plaque psoriasis, psoriatic arthritis 6,548 4 5 12
Remicade (infliximab)
Centocor (J&J);
Schering-
Plough;
Mitsubishi
Tanabe Pharma
Antibody
Rheumatoid arthritis, ankylosing
spondylitis, Behcet's syndrome,
Crohn's disease, psoriatic arthritis,
ulcerative colitis
6,520 5 2 4
Herceptin
(trastuzumab)
Genentech;
Chugai; RocheAntibody
HER2-positive metastatic breast
cancer5,859 6 7 6
Lantus (insulin
glargine)Sanofi-aventis Protein Type 1 and 2 diabetes 4,834 7 10 11
Ranked higher No change in rank Ranked lower
Source: IMS Midas and Knowledgelink;
Pipelinereview.com - Top 30 biologics 2010, Special Edition1/2011
RANK PRODUCT MOLECULE MOLECULE CLASS EXPRESSION/MFGESTIMATED
PROTEIN MASS*
1 Enbrel Fusion Protein Antibody CHO/BATCH 900 kg
2 Remicade Chimeric Antibody Antibody MMC/PERFUSION 1000 kg
3 Rituxan Chimeric Antibody Antibody CHO/BATCH 2100 kg
4 Humira Human Antibody Antibody CHO/BATCH 260 kg
5 Avastin Humanized Antibody Antibody CHO/BATCH 1100 kg
6 Herceptin Humanized Antibody Antibody CHO/BATCH 900 kg
7 Neulasta Pegylated Filgrastin Therapeutic Protein ECOLI/BATCH < 5 kg
8 Lantus Modified Insulin Therapeutic Protein ECOLI/BATCH 1500 kg
9 Aranesp Modf. Erythropoietin Therapeutic Protein CHO/BATCH < 1 kg
10 Prevnar Vaccine Vaccine MIRCOBIAL/BATCH < 1 kg
11 Procrit/Eprex Erythropoietin Therapeutic Protein CHO/BATCH < 1kg
12 Epogen Erythropoietin Therapeutic Protein CHO/BATCH < 1 kg
* Antibodies calculated from IMS MIDAS Data. Others Extrapolated from BioPlan Associates, 4/2008 and G.
Jagschies, IBC Conference Boston, 9/2007
Top Biotech Products 2008
Why Antibodies?
AntibodiesTherapeutic
ProteinsTherapeutic
Vaccines
Growth Drivers
Unmet Need +++ + +++
Novel Targets +++ + +
Development Speed ++ ++ -
Growth Resistors
Generic Exposure ++ + +++
Market Performance
Revenue/Product +++ ++ +
Who is and will be driving Mfg?
• Most Therapeutic Proteins and all Vaccines have small Protein Mass Requirements
• Insulins are manufactured in Large-Scale Specialty Mfg Facilities
• Antibodies continue to be the leading class of Biologics in Clinical Development
Antibodies are and will continue to drive Biopharmaceutical Mfg!
Top 12 Antibodies 2008
RANK* PRODUCT COMPANY SALES ’08*EST. PROTEIN
MASS †INDICATIONS
1 Enbrel Amgen/Wyeth $6.4B 1000 kg R. Arthritis, Psoriatic Arthritis, …
2 Remicade J&J/Centocor/Scher. $6.2B 1100 kg R. Arthritis, Crohn’s Disease, …
3 Rituxan Roche/Genentech $5.5B 2100 kg NHL, R. Arthritis,…
4 Avastin Roche/Genentech $4.8B 1100 kg Colorectal, Breast, Lung Cancer, …
5 Herceptin Roche/Genentech $4.7B 900 kg Breast Cancer
6 Humira Abbott $4.5B 270 kg R. Arthritis, Psoriatic Arthritis, …
7 Erbitux Lilly/BMS/ImClone $1.8B 700 kg Colorectal, Head & Neck Cancer
8 Lucentis Roche/Genentech/Nov. $1.7B <5 kg Macular Degeneration
9 Synagis Astra Zeneca/Medim. $1.2B 100 kg Respiratory Tract Disease
10 Xolair Roche/Genentech $0.7B 200 kg Allergic Asthma
11 Tysabri Elan/Biotech IDEC $0.6B - Multiple Sclerosis, Crohn’s Disease
12 ReoPro Lilly/J&J/Centocor $0.2B - Cardiac Ischemic Complications
* Datamonitor, 09/09; †calculated from Datamonitor 09/09 and 2008 IMS MIDAS sales data.
Future Antibody Trends
• Licensed, top selling Antibodies will continue to grow and retain their leading position
• The number of licensed Antibodies will grow from 23 in 2008 to around 50 by 2014
• New “Blockbuster” Antibodies will attack new Targets:
Examples: Rankl, A-Beta
• There will be more Antibody Competition for each Target and Therapeutic Area:
Examples: CD-20, TNF Alfa, Rheumatoid Arthritis
• There will be “Biobetter” and “Biosimilar” Competition for current Antibodies
Antibody Competition
Target: CD-20
Rituxan, IDEC/Genentech/Roche
FDA License 11/1997
Arzerra, Genmab/GSK
Likely FDA Licence 2010
12+ Years with no Competition!
Antibody Competition
Target: TNF
Product Company Launch Year
Enbrel Amgen/Wyeth 1998
Remicade Centocor/J&J/S.-Pl. 1999
Humira Abbott 2003
Cimzia UCB 2009
Simponi Centocor/J&J/S.-Pl. 2009
Future Antibody Mfg Capacity
• Mfg Capacity +1000kg/yr:
Licensed, top selling Antibodies
• Mfg Capacity >500kg/yr:
New “Blockbuster” Antibodies for new Targets
• Mfg Capacity 50-500kg/yr:
New Antibodies in “competitive” Target/Therapy situations
New Antibodies for “niche” Targets/Therapies
New “Biobetter” Antibodies
“Biosimilar” Antibodies
There will be a greater need for Antibody Mfg Capacity of 50-500kg/yr!
Biopharmaceutical Operations Parameters
• Success Rate
• Yield
• Number of Bioreactors
• Bioreactor Size
• Number of Production Bioreactor Starts/Year
• Titre
• Downstream designed to match Upstream
Improvements of Operational Parameters
PARAMETER RANGE IMPROVEMENT
Success Rate 50% or less to >95% Operational Experience
Engineering Improvements
Operational Excellence
Yield 50% or less to >70% Harvest and Purification Improvements
Bioreactor Size 10,000 to 25,000 litre Engineering Improvements
Titre <0.5 g/l to >5 g/l Cell Culture Improvements: Cell Line, Selection, Feed/Media Improvements
Industry Typical “Six Pack”6 x 15,000 litre, 25 Starts/Bioreactor/Year
Impact of Improvements
Varied Parameter
RangeFixed
ParameterProtein Mass
Success Rate 70%
95%
Titre 0.5 g/l
Yield 70%
551 kg
748 kg (+30%)
Yield 50%
70%
Titre 0.5 g/l
S. Rate 90%
506 kg
708 kg (+40%)
Titre 0.5 g/l
3 g/l
5 g/l
Yield 70%
S. Rate 90%
708 kg
4252 kg (+500%)
7087 kg (+900%)
Current and Future Industrial Titres
6
5
4
3
2
1
‘08 ‘09 ‘10 ‘11 ‘12 ‘13
Mfg
Tit
re (
g/l
)
2007 Industrial Avg Titre is appr. 1.7 g/l *
* BioPlan Associates, 4/2008
High Titres in the News
UPDATE 1-DSM, Crucell JV boosts human cell yieldsMon Jun 16, 2008 8:06am BST
AMSTERDAM, June 16 (Reuters) - Biotechnology firm Crucell (CRCL.AS: Quote, Profile,
Research)(CRXL.O: Quote, Profile, Research) and chemicals group DSM (DSMN.AS: Quote, Profile,
Research) said on Monday they had made progress in the development of a technology which could
cut the costs of pharmaceutical materials.
The two Dutch firms have created a technology, called PER.C6, to produce biopharmaceutical
materials such as drugs and vaccines by using human cell lines instead of a chemical process.
The companies said they had boosted fermentation yields in human cells to a
record level of over 27 grams per litre compared with 15 grams per litre in
March. Higher yields enable smaller and cheaper production units.
Thompson Reuters, 15/6/08
Fed-Batch Antibody Mfg Titres of 3-10 g/l can be routinely achieved today!
Summary of Manufacturing Trends
• Success Rates and Yields have improved over time
• Mfg Titres have also greatly increased over time
• Mfg Titre has the highest potential to further increase and therefore will reduce the Biopharmaceutical Mfg Capacity
Single-Use Processing Technology
• Replacing traditional fixed, stainless steel (SS) tanks, SS piping, and SS bioreactors with sterilized, disposable plastic bags and flexible tubing
• Emerged over the last 15 years and rapidly growing
• Two important, early Innovators:
Wave Bioreactors:Bioreactors
Stedim Biosystems:Films and Bags
Single-Use Innovation: Bioreactors
1000 L Wave Bioreactor
1000 L Xcellerex Bioreactor
1000 L ThermoFisher Bioreactor
200 L Sartorius Biostat Bioreactor
1000 L ATMI Nucleo Bioreactor
200 L Kuehner/ExcellGene OrbShake Bioreactor
Potential of Single-Use Bioreactor
0.0
5.0
10.0
15.0
20.0
25.0
30.0
35.0
1 2 3 4 5 6 7 8 9 10
Titre g/l
Bioreactor Starts/Year 25
Bioreactor Size (l) 1,000
Overall Yield 0.70
Mass Produced (kg) 500.00
Success Rate 0.95
Nu
mb
er
of
Bio
reacto
rs
Elan Mfg Facility Case Study:
“Traditional” vs. “Mini-Mill*”
* Term created by M. Kamarck, Keynote Speaker, IBC Conference and Exhibition, Boston, MA, 9/07
Elan “Traditional” Mfg Facility Study
Site Area 30 acres
Floor Area 35,400 m2
Bioreactors 2 x 15,000 l
Stainless
Steel
Mfg Capacity
@ 3g/l Titre
1000 kg/yr
Process Dev.
Labs
No
Clinical Mfg No
Warehouse, QC
Labs, Utilities,
Offices
Yes
Elan “Mini-Mill” Mfg Facility Study
Site Area 20 acres
Floor Area 16,900 m2
Bioreactors 12 x 1,000 l
or 12 x 2,000l
Single-Use
Mfg Capacity
@ 3g/l Titre
580 kg/yr
(1000 l)
1160 kg/yr
(2000 l)
Process Dev.
Labs
Yes
Clinical Mfg Yes
Warehouse, QC
Labs, Utilities,
Offices
Yes
“Traditional” “Mini-Mill”
2 x 15,000 litre 12 x 1,000 litre 12 x 2,000 litre
Mfg Capacity (@3g/l titre) 1000 kg 580 kg 1160 kg
Capital Cost (w/o Start-Up Cost) €350 MM €145 MM €145 MM
Capital Cost/kg 100% 70% 35%
Gas Supply/kg 100% 23% 12%
Electrical Supply/kg 100% 74% 37%
Water Supply/kg 100% 15% 8%
Mfg Area/kg 100% 33% 17%
Production Staff/kg 100% 83% 41%
“Traditional” vs. “Mini-Mill”
Study Results
“Traditional” “Mini-Mill”
Carbon Foot Print* High Lower
Cost of Goods (full capacity) High Lower
Cost of Goods (partial capacity) Higher Lower
Speed to Market “Slow” “Fast”
Flexibility (new Products/Processes) “Painful” “Easy”
“Traditional” vs. “Mini-Mill”
Strategic Comparison
* L. Leveen, IBC Single-Use Applications Conf., San Diego, 6/08
Single-Use “Mini-Mills” are ready for Commercial Manufacturing!
Summary of Future Trends
• More Antibodies will be coming to Market
• More competition among Antibodies,
Competition from “Biobetter” and “Biosimilar” Antibodies
some Competition between Antibodies and Small Molecules
• Will lead to less “Blockbusters” Antibodies
• Titres will continue to increase
• Both trends will lower the demand for new Large Scale Mfg Capacity
Summary of Future Trends
• Increase in Acceptance and Advancement of Single-Use Technology
• Combination of High Titre and Single-Use Technology allows new Breed of Mfg Facilities: “Mini-Mills”
• Existing Large Stainless Steel Facilities for:
Leading “Blockbuster” Antibodies
Biotechs and CMOs producing multiple Antibodies
Less demand for in future
• New Opportunities for Smaller Stainless Steel and “Mini-Mills” Facilities for:
New Antibodies in competitive situations, “Biobetter”, “Biosimilar”, and “niche” Antibodies
Acknowledgements
Product Analysis
• Datamonitor Europe, England
• SmartAnalyst, England
Facility Studies
• PM Engineering, Ireland
• CRB Engineering, USA
• BioPharm Services, England
• RKD Architects, Ireland
• Elan Biologics Team, Ireland