The document discusses the definition and applications of biologics, highlighting the growth opportunities in monoclonal antibodies and vaccines within the biopharmaceutical industry. It details the complexities of biologics manufacturing, global market trends, and emphasizes the need for effective process development as a key determinant for product quality and commercialization success. Additionally, it notes a shift from mature to emerging markets, and discusses the potential challenges and strategies for navigating the evolving landscape of biopharmaceuticals.

1. November 26 2009
Academia Sinica
NanKang, Taiwan, R.O. China

2. - Biologics – definition & applications
- Process is the Product
- Monoclonal antibodies & vaccines as growth opportunities
- Changes in global biopharmaceutical industry
- Paradigm shift in development process for bioloigcs
- Effective process development and manufacturing strategy
- Integrated CMC team
- Select/establish cell line(s) critically
- Establish knowledge-based process for commercialization
- Pursue revolutionary manufacturing technologies
- Summary

3. Biologics
• Include a wide range of medicinal products such as vaccines,
blood/components, allergencis, somatic cells, gene therapy,
tissues & recombinant therapeutic proteins created by biological
processes (as opposed to chemically)
• Composed of sugars, proteins or nucleic acids or complex
combinations of all, or living entities such as cells and tissues
• Isolated from a variety of natural sources – human, animal or
microorganism, or produced by biotechnology methods and
other technologies (e.g. recombinant DNA)
 Gene-based and cellular biologics promise to treat a variety of
medical conditions for which no other treatments are available
Quotes from Wikipedia 6 July 2009

4. Glucophage® 166
Rituxan®
Taxol® 854 145,000
Chemical Biologics
Size (M.W.) < 500* 20,000 - 200,000+*
Complexity Low High
Process Conditions (T/P) High Ambient
In-Process Concentration Concentrate (~100g/L) Dilute (.5 -5g/L)
Reactor Volume < 8,000 L ~20,000+L
Reaction Steps Multiple chemical Complex product
reactions/isolations made by living cells
Production Solvents Organic Aqueous
Isolation/Purification Crystallization Chromatography
Product Definition Few simple assays Many complex assays
Process Changes Equivalency Comparability
maybe clinical trials
Patent/IP Molecules Process Knowhow
IP Expiration Threat Generics dominant Biosimilars evolving
 PROCESS is the product

5. • Global pharmaceutical market Before global financial crisis…
 Revenue US$ 773 bn in 2008
 Projected growth rate of 5%
• Global biopharmaceutical market
 Revenue US$75 bn in 2008
 Projected growth rate 12%
• Growth in biopharmaceutical market
to reach US$138 bn by 2014
 dominated by products from
mammalian cell cultures (>75%)
• Opportunities in biopharmaceuticals
 Novel & biosimilar r-proteins
 Vaccines
Source: Global Trends and Drivers of Biopahrmaceutical
Manufacturing, Frost & Sullivan, Asia Biomanufacturing Summit
28 October 2009

6. Therapeutic Proteins = Biopharmaceuticals
• 75 FDA approved therapeutic proteins
• > 500 additional proteins under development
• Broad applications:
 Cancers & autoimmune diseases (treated by
monoclonal antibodies and interferons)
 Heart attacks, strokes, cystic fibrosis and Gaucher's disease (treated by
Enzymes and blood factors)
 Metabolic diseases: diabetes (treated by insulin)
 Blood diseases: anemeia (treated by erythropoietins), hemophilia
(treated by blood clotting factors).
• Worldwide sales approximately $57 billion in 2006 with projected growth of
13% , or >$90 bn by 2010.
• Monoclonal antibodies (Mabs) ~32bn in 2008, growing rapidly to 30% global
biologics market
Piribo, “Global Protein Therapeutics Market Analysis", ProLOG Feb 13, 2008

7. Best Selling Monoclonal Antibodies 2006-2008 ($33 billion)
FDA Sales ($ billion)
Genetic Name Brand Companies
approval 2006 2007 2008
1 Infliximab c Remicade 1998 J&J 4.2 5.04 6.5
2 Rituximab c Rituxan 1997 Roche 4.7 5.01 5.6
3 Trastuzumab hz Herceptin 1998 Roche 3.14 4.4 4.8
4 Bevacizumab Avastin 2004 Roche 2.4 3.93 4.7
5 Adalimumab h Humira 2002 Abbott 2.04 3.06 4.4
6 Cetuximab c Erbitux 2004 Bristol Myers Squibb, Merck KgA 1.1 1.35 2.0
7 Ranibizumab hz Lucentis 2006 Novartis, Roche 0.38 1.2 1.5
8 Palivizumab hz Synagis 1998 Astra Zeneca 1.1 0.62 1.2
9 Omalizumab hz Xolair 2003 Roche, Novartis 0.52 0.64 0.85
10 Natalizumab, hz Tysabri 2004/2006 Biogen Idec, Elan 0.06 0.46 0.6
11 Panitumumab h Vectibix 2006 Amgen 0.04 0.21 0.3
12 Abciximab c ReoPro 1994 J&J, Lilly 0.28 0.29 0.29
13 Efalizumab hz Raptiva 2003 Genentech, Merck Serono 0.16 0.21 0.28
14 Certolizumab TNFα Cimzia 2008 UCB 0.10
15 Tocilizumab Actemra Japan 2008 Roche
Canada 2008
16 Ustenkinumab Stelara J&J
EMEA 2009
12 approved and marketed monoclonal antibodies with low sales (<$100 million) are not included
Source: Krishan Maggon, Global Monoclonal Antibodies Market Review 2008 (World Top Ten mAbs)

8. • Global vaccines market will grow to over a USD $23.8 bn by 2012,
growing at ~11% per year
• Novel and improved vaccines growing at 58% p.a.
Traditional and combinations
Include mostly pediatric & partially
adult vaccines
Novel and therapeutic vaccines
include both adult & therapeutic
Global Vaccine Market US$ bn
Source: Global Trends and Drivers of Biopahrmaceutical Manufacturing,
Frost & Sullivan, Asia Biomanufacturing Summit 28 October 2009

9. • Pandemic & seasonal Flu vaccines: to reach $7.1 bn in 2010 with
19.8% growth rate, driven by pandemic flu vaccine global supply
shortage (H5N1, H1N1)
• Driven by bird flu (2005) and swine flu (2009), government spending
worldwide on Pandemic Influenza Preparedness tripled to $7 bn in
2009 ($2.2 bn in 2004, 17% CAGR), reaching ~ $10 bn by 2015 (5%
CAGR)
• Global Pandemic Influenza Preparedness Market: estimated @$52
bn in 2010-2015 (5% CAGR)
 Novel cell-based process & manufacturing technology reaching the
market:
 Baculovirus system/Insect cells (Protein Sciences, Novavax)
 Mammalian cells: Vero (Baxter), MDCK (Novartis)
 Per.C6 (Sanofi/Crucell); in serum-free media
 Avian cells: EB66, duck embryonic stem cell line by Vivalis
 DNA vaccines: VGX Pharma (IND) early development
Global Pandemic Influenza Preparedness Market Forecast 2010-2015, Publication: 04/2009 by Market Research Media.

10. • Concerns over global Economy  Increasing global price regulations
 Implement a protectionist and nationalist policies
 Strengthen the local pharmaceutical industry by implementing more
stringent price regulation on foreign manufacturers
• Shift in growth from mature markets to emerging markets
 Emerging economies could generate up to a fifth of global
pharmaceutical sales by 2020
 Changing growth dynamics from the West to emerging economies shift
developer interest in patient groups
 Increasing trend in outsourcing manufacturing and R&D cost-effectively
• Cost containment pressures in major markets worldwide
 Escalating healthcare costs have put pressure on payers to contain
pharmaceutical expenditure
 Multiple stakeholders in the R&D/Product Development process
including payers, patients and pharmacists (for pricing considerations)
Source: Global Trends and Drivers of Biopahrmaceutical Manufacturing,
Frost & Sullivan, Asia Biomanufacturing Summit 28 October 2009

11. Global Pharmaceutical Sales
Global Pharmaceutical: 2009 Market Sizes*
Growth Rate
4.5-5.5% Emerging, 115
US, 302
Japan, 88
* All values
2008 2009 are in US$,
EU, 172 Billions
15%
Growth Rate in Sales (%)
10% Growth in emerging country markets:
 Far outstrip growth in the US & EU
5%
US EU Japan Emerging
Source: Global Trends and Drivers of Biopahrmaceutical Manufacturing,
Frost & Sullivan, Asia Biomanufacturing Summit 28 October 2009

12. Discovery Phase Development Phase Commercialization Phase
(3-6 years) (5-10 years) (8-12 years - Patent Expiration)
Basic Manufacturing
Full Early Stage Late Stage - Full Product
Research Sales
Discovery Development Development Management
Distribution
ECN IND BLA LAUNCH Generics
Biosimilars
10,000
-30,000 ~250 5-10 2-5 2 1
Preclinical
Phase I Phase IIa, IIb Phase III
Testing
Clinical Trial Clinical Trial Clinical Trial
(lab & animal testing)
Small
Biologics Molecules
Drug Development
Outsourcing to CROs, CMOs Process Tech Transfer earlier
Manufacturing Outsourcing to External Facilities

13. Molecular Biology Preclinical Filing, Regulatory
& Clinical Launch &
Cell Line & Process Review & Approval
Development Commercialization
Development
2-3 years 3-4 years 1-2 years
Full Drug Development Capabilities and Infrastructure Required
- CMC: Process development & biologics Manufacturing
- Preclinical and Clinical: Toxicity, Phases 1 and III, comparability studies
- Filing and regulatory challenges
High Barriers to Entry
- $50M – $500M long term investment required
- Competition with existing brands (low price differentials)
- Complexity of products (not API) and manufacturing facilities
Highly Competitive Markets
- Large pharmaceutical companies moved in: Merck, Novartis, Aztrazeneca
- Major generics companies formed alliance: Teva & Lonza

14.  Chemistry, manufacturing and control (CMC)
• Manufacturing Information “pertaining to the
composition, manufacture, stability and controls used
for manufacturing the drug substance and the drug
product”
• Information “ensure that the company can adequately
produce and supply consistent batches of the drug”
 Early development stage
 Evaluate current technology to produce product, begin
cell line and process development, and product
characterization
 Supply GLP material for preclinical toxicology study &
produce GMP material for clinical trials
 Begin developing process with end in mind

16. New cell line? Process changes? Formulation changes?
Process Devt
Biologics Process Commercial
& Medium Scale
Research scale production Fill & Finish
production
<10L 2000lL – 20,000L
10L-500L
• New cell line • Process development, • Process scale up • Vial filling, packing
development optimisation, scale-up • DS Manufcturing • Lyophilization,
• Expression • Productivity enhancement facility operations • Supply chain operations
engineering • QbD, PAT implementation • COGS improvement • COGS improvement
• Media design • Product quality & stability • Lean manufacturing • Lean manufacturing
• Novel product
FUNCTIONAL EXCELLENCE
ONE CMC TEAM
CELL CULTURE ANALYTICS PURIFICATION FORMULATION
• Molecular Biologists • Analytical Biochemists• Chromatographers • Formulation chemists
• Microbiologists • Biophysical Chemists • Protein Biochemists • Protein Biochemists
• Cell Biologists • Protein Biochemists • Biochemical Engineers • Engineers
• Virologists

17. Source: http://www.gene.com/gene/products/information/oncology/herceptin/moa.html

18. 1981 - HER2 gene cloned
1985 - Axel Ullrich and Art Levinson clone HER2 gene
1990 - Creates anti-HER2 monoclonal Antibody (Herceptin)
1992 - Files Herceptin IND, Phase I trials initiated (25-50
patients)
1993 - Herceptin Phases II trials begin (250-200 patients)
1995 - Initiates Phase III, 3 trials (500-1,000 patients)
1996 - Partners with DAKO for commercial diagnostic testing
kits
1997 - Completes Phase III enrollment
1998 - Presents Phase III data demonstrating effect with
chemotherapy and increase time to disease progression
1998 - Herceptin approved by FDA
 Fully integrated high performance team delivers a mAb in <10 years

19. • All key expertise critical for product development available in country
• Government support for infrastructure and high risk investment
• Early development focus
Clinical Commercial
Regulatory hospitals Manufacturing
Consultant? or CMOs
Clinical
Institutes
Or CROs
Discovery Novel drug or
Marketing (internal & external)
Consultant? Biosimilars
Early Development
CMC Preclinical
Institutes Institutes
Legal/IP or CMOs or CROs
Consultants
 Integrate in-country project team with core elements
 Fill gaps in various support areas by appropriate consultants
 Form oversight committee to support Project Team

20.  Selection of cell lines – product specific & IP sensitive
 Many matured cell line platforms to choose from (e.g. mAbs:
CHO, NSO, per.C6)
 Cell line selection and construction in early basic research stage
without considering manufacturing may result in challenges/
delays in commercialization
 Select cell line critically with END in mind: titer, stability,
product glycosylation & manufacturability
 change of cell line post phase I clinical trials undesirable
 process changes post phase II to be minimized
Process is Product  Cell line dictates process

21. Selective to infection;
reduces risk to
adventitious agents
 Swine cell lines: EB66 duck embryonic stem cell line by Vavilis shows promises
A-Bio notes: process information is gathered from EPAR sources and published literature; CELVAPAN information is from Baxter

22. • Product design & selection in early basic research stage without
considering manufacturing may result in challenges/delays in
commercialization
• Characterization of desired product driven by clinical needs
impacts significantly downstream
• Product characterization requires advanced analytics
• Product complexity presents challenges in consistent supply to
patients (eg. blood factors, live virus vaccines)
 Multiple cell hosts developed at early stage for strategic decision
including manufacturability
Process is Product  Product quality challenges
process (eg. glycosylation pattern)

23.  Glycan homogenity
• Large statistical population of variants
• Difficult to achieve due to macro and microhetergenity
• Achievable via process design and manufacturing consistency
 Immunogenicity - injection site reactions/threat of anaphylaxis
 Change in efficacy – ADCC response (Rituxin, tumor killing)
 Product incomparability after scale up (Lumizyme, Genzyme)
• Myozyme (160L) = Lumizyme (2,000L)
• New BLA requested submission over carbohydrate structure
changes
 CMC comparability issues (Erbitux, Imclone)
• pre-clinical PK issues: sBLA for non-small lung cancer withdrawn
• Additional PK requested by FDA for Erbitux 1st line head & neck
cancer
Biopharm Bulletin. March 13, 2009

24. Traditional Approach (fixed controls)
Failures; variation
detected late
Variability in
raw materials, High variability in
conditions product; Possible
recalls; Product
safety concerns
Dynamic Control Strategy (multidimensional) Rapid correction of
Characterized Space process parameters
Design Space
Variability in PAT Product
Adaptive
raw materials, Adaptive Control Space consistency;
conditions Control Space Lower failures
Acceptable Operating Space

25.  Genentech has built a deep knowledge base for Quality by
Design (QbD) approaches:
• 5 licensed & 26 mAbs in active development
• 6 licensed sites for mAb DS production & 9 successful DS site transfers
• 7 successful major version changes
• 13 major Drug Substance Comparability Protocols approved
 40 planned comparability efforts through 2010 based on QbD
 Expanded Comparability Protocols: to bundle ‘like’ changes
within a single submission
 Successful transfer to Singapore: Lucentis DS plant (microbial
1,000L) late 2006-2010 FDA license
 Avastin DS plant (Cell culture, 80,000L)
Early 2007 -2010 FDA license (~37 mths)
“The Progress of Biotechnology manufacturing and Process Sciences”
Patrick Yang, Genentech, Inc., Nov. 5, 2007, APBioCheDSC, Taiwan.

26. High Cell Process Facility
Productivity Simplification Efficiencies
Current mAb platform Using disposable systems
improvement: Higher reduces SIP and CIP
capacity resins, One column requirements
TREND: process, No Protein A
Higher cell productivity and Reduction of Process
Chromatography Alternatives
process optimization result Equipment Size
Crystallization, Ppt, Q filters
in smaller and less complex
manufacturing facilities Chemical Process like - Process and facility
(20,000L vs. 2,000L) Continuous Processing modularization reduces
construction time
Automated sampling and
monitoring with new sensors
Moving of process
equipment into gray space
Equipment with Integrated reduces cleanroom space.
instrumentation for real time
control and release
“The Progress of Biotechnology manufacturing and Process Sciences”
Patrick Yang, Genentech, Inc., Nov. 5, 2007, APBioCheDSC, Taiwan.

27. Upstream Process
Downstream Process
 Disposable Technology: Eliminates CIP, SIP, utilities
 Controlled Environment Modules: Gowning ,
operator mobility , protects product & people
 Advantages: 60%++ reduction in capital investment,
40% less space needed, 85% reduction in water and
waste, 32% reduction in COGS
 Faster deployment: 12-18 months vs. 4+ years

28.  For biologics, Process is the Product – effective process
development for manufacturing critical for product quality and
consistency, hence commercialization.
 Monoclonal anitbodies and vaccines present significant
opportunities among future biologics being developed –
advanced manufacturing platform available to improve
productivity and reduce COGS.
 Emerging market will enjoy significant growth in
biopharmaceuticals driven by global changes
 Drug development process paradigm shift towards earlier tech
transfer around phase I for biologics – integrated cross
functional CMC team, formed early to guide process
development with END manufacturing ability in mind essential
for successful commercialization.