2.2. DPP is a provider of chemical- and biotechnologies



Similar documents
DPP - DSM in motion: driving focused growth DSM and JLL create leading pharma services company in US$ 2.6bn transaction 19 November 2013.

Brand Quality with Asian Advantages

Presented at: Jefferies 2015 Global Healthcare Conference

Luca Romagnoli, Ph.D. Business Development Manager

C 5. chemical development contract research custom synthesis cgmp API manufacturing commercial production. Welcome to

LFB GROUP & SANOFI combine their bioproduction capabilities to provide integrated CMO services for biopharmaceuticals

Company Presentation

Pharmaceuticals Production Services Boehringer Ingelheim. Our expertise in world-class contract manufacturing for your success

LFB GROUP & SANOFI combine their bioproduction capabilities to provide integrated CMO services for biopharmaceuticals

PlantForm Corporation

Eden Biodesign ebook Monoclonal Antibody Production: Building the Platform

Manufacturing CUSTOM CHEMICALS AND SERVICES, SUPPORTING SCIENTIFIC ADVANCES FOR HUMAN HEALTH

2014 Wells Fargo Healthcare Conference June 17, 2014 NYSE: Q

Valentina Gualato, Ph.D. Process Development Scientist

Annual Report on Form 20-F

INDUSTRY OVERVIEW. Our business segments. (ii) Global drug development service market Preclinical drug development services

Commercial Insight: Cancer Targeted Therapies and Immunotherapies -Top monoclonal antibody brands will resist competitive pressures through to 2019

STATS WINDOW. INDUSTRY REVIEW AT A GLANCE Global Pharmaceutical Industry

Table of Contents. Presented by

Highly Potent APIs The right platform, people and procedures for successful development and manufacturing

Flamel Technologies Provides Update on Corporate Progress

BioBusiness Biopharmaceutical Ingredients Recombinant albumins & albumin fusion Dermot Pearson, Strategic Product Director, NZ Biopharma

An integrated global healthcare company

Providing Trusted and Innovative Solutions t o the Life Science Communities

LifeTein in Industrial Production of Therapeutic Peptides. Phil Moore, PhD Director of Business Development LifeTein LLC, NJ, USA

Biotechpharma company profile

NEW CHEMICAL ENTITIES

Catalent Biologics & Clinical Supplies The SMART Solution

GMP Pharma BV. Netherlands

Biopharm Roundtable. 1. What, in your opinion, is currently the single largest trend with respect to biopharmaceutical outsourcing and manufacture?

An Industry White Paper

Challenges in the cgmp Manufacturing of hescs: Lessons Learned from Monoclonal Antibodies

[Indian Stem Cell Banking Market: Trends & Opportunities ( )]


Dr. Reddy s Q3 and 9M FY16 Financial Results

The Cell Therapy Catapult

The Future of Consumer Health Care

A Private Investor Guide to Regenerative Medicine: Unique Opportunities in an Emerging Field

Triskel: a strategic consulting firm for biopharmaceutical companies

BIOTECH MANUFACTURING SOLUTIONS 4 YOUR SUCCESS. a Novartis company

Adocia reports positive results from phase IIa clinical study of ultra-fast acting BioChaperone Lispro

EVT Execute & EVT Innovate Leading drug discovery

Comprehensive Medical Waste and Unused Medication Management Solutions Provider NASDAQ: SMED

Multiple Sclerosis. Current and Future Players. GDHC1009FPR/ Published March 2013

From Research Services and Process Development to GMP Manufacturing

Cegedim Half-year results 2009 September 2009

Abbott Diagnostics. Durable Growth Business

SWOT ANALYSIS OF INDIAN PHARMACEUTICAL INDUSTRY

RADIOPHARMACEUTICALS BASED ON MONOCLONAL ANTIBODIES

Manufacturing process of biologics

Dedicated Project Management

Ludwigshafen, February 25, 2014

GDChVCW Konferenz February 28, 2013

Tsugio Yamamoto. Financial Institutions Business Unit / Government & Public Corporation Business Unit Business Strategy

Custom Antibody Services

BEST PRACTICES RESEARCH

Ipsen Jefferies Healthcare Conference

How To Improve Profits At Dismana

Economical Approaches to Meeting Global Demand for High Value Biopharmaceuticals

Marken For more information visit:

Introduction to Bioprocessing

The Sage Group and Talentmark Consulting Announce Strategic Alliance for Services to the Global Healthcare & Life Sciences Industry

Orphan Pharma: pathfinders for an increasingly specialised industry

GAO NEW DRUG DEVELOPMENT. Science, Business, Regulatory, and Intellectual Property Issues Cited as Hampering Drug Development Efforts

Facility construction and start up for commercial scale manufacturing of monoclonal antibodies - A case study

U.S. Contract Research Outsourcing Market: Trends, Challenges and Competition in the New Decade. N8B7-52 December 2010

China has become the world s factory, second only to the USA in terms of CO 2 emissions among major industrial countries.

BIOTECHNOLOGY OPERATIONS

We add value as one company

IP throughout the life cycle of Xencor a biotech company

Herman Miller, Inc. First Quarter Fiscal 2015 Investor Conference Call September 18, 2014

Life Sciences and Materials Sciences Presentation to Investors Q3 Results 2014, 4 November Page

The Clinical Trials Process an educated patient s guide

March 5, First Quarter Conference Call

Repligen Reports Third Quarter 2015 Financial Results

Abbott Nutrition. Attractive Profile and Compelling Growth Opportunities

Working with ICH Quality Guidelines - the Canadian Perspective

Hitachi Announces Progress of 2015 Mid-term Management Plan

Continuous manufacturing moving towards real-time release. Creating innovations for the pharmaceutical industry. siemens.

Mab manufacturing today and tomorrow. Reducing risk, reducing cost. Reducing costs, informing decisions, insight for innovation.

The majority of pharmaceutical companies in

Medicines for Neglected Diseases Workshop. Dennis Liotta, Ph.D. Director Emory Institute for Drug Discovery Atlanta, Georgia

The Commercialization of Technology Concepts into Medical Products

Biomanufacturing Vision for the Future

Bayer Invests Heavily in R&D and is committed to innovation Sustained Innovation Output from all Subgroups

Procurement must be more than just cost cutting

Introduction. The Healthcare Sector in Asia - Current Situation. Projected Healthcare Expenditure

Emerging Clinical Sites: India and China. Patrycja Doba, Clinical Research Coordinator

From cells to therapeuticsvivalis. Humalex Fully human antibody discovery platform An integrated therapeutic development offering

Clinical Trial Trends Outline Complexity for Supply Chain. Scott Ohanesian, VP Commercial Operations APAC

Introduction to Enteris BioPharma

ICH Topic S 1 A The Need for Carcinogenicity Studies of Pharmaceuticals. Step 5

1. What are the key strengths and weaknesses of the UK s innovation system in relation to business-university collaboration?

New Advances in Cancer Treatments. March 2015

Company Presentation June 2011 Biotest AG 0

Transcription:

2.1

2.2 DSM Pharmaceutical Products (DPP) together with DSM Anti-Infectives are the constituent parts of DSM s Pharma cluster. Net sales in 2006, for the Pharma cluster was 1 billion, 60% of this being DPP. DPP is a provider of chemical- and biotechnologies and advanced manufacturing capabilities to the pharmaceutical industry while complying with a range of regulatory requirements (cgmp). DPP focuses predominantly on patented products. End 2004, the head quarters of the Business Group DPP has been relocated from Sittard, The Netherlands to Parsippany, NJ, USA. The main aim of this relocation was to create a stronger US presence (the US representing 60% of the total market opportunity for DPP), and to enhance our ability to recruit from the US market, especially at senior management level. DPP is made up of 4 individual Business Units. The four Business Units of DPP each have their particular market and technology focus: DSM Pharmaceuticals Inc. (DPI), with operations in Greenville, NC, USA is a finished dosage custom manufacturer. DPI is a recognized industry leader in sterile (injectable) production and a strong player in the manufacturing services for oral dose products (tablets, capsules). DSM Biologics is focused on the development and licensing of the mammalian cell culture technology, used in the development and production of bio-pharmaceuticals (biologics). In this context, DSM s Groningen facility provides manufacturing services for clinical trial materials. DSM Pharma Chemicals (DPC) provides active pharmaceutical ingredients and intermediates. DPC holds a strong market position among the top pharma houses, based on its ability to handle complex chemistry, its depth of knowhow and IP in enzymatic conversions, and its proprietary technology in chirality. DSM Exclusive Synthesis & Intermediates (ESIM) is strictly speaking not a 100% pharmaceutical business unit, although it produces some building blocks for DPC. Its main focus is custom synthesis aimed at pharma and fine chemicals markets (of which the agro-chemicals sector is a main market). Furthermore ESIM produces maleic anhydride and derivates, an activity which will be transferred to the new Base Chemicals & Materials Cluster.

2.3 Although the longer term market perspective for the pharmaceutical industry is very favorable, in recent years the industry, including the supply industry, had to deal with a set of unfavorable dynamics. Following the increase in the number of new product approvals in mid/late nineties, the decline in New Molecular Entities (NMEs) approved by the FDA has continued in recent years. Moreover, there have been some high profile product withdrawals and black box warnings for well established products where the FDA required warnings for serious side effects. The FDA has been criticized for perceived lack of diligence in approving new drugs. The result is a more cautious FDA, requiring more data and more extended testing, also after product launch. While the R&D expenditure of large pharma houses has increased over the years, R&D productivity, as measured in new products approved, has declined, and in general the pipeline for autonomous growth for large pharma houses has disappointed. There has been explosive growth in the generic pharmaceutical segment, with good financial rewards for first movers under so-called FDA paragraph IV filings. However, once a product loses its patent protection, the originators the traditional pharma houses lose market share rapidly. The generic segment has fueled volume growth at the expense of very substantial value erosion (85-90%). In the generic segment, costs dominate the value proposition, with increasing penetration of Indian generic pharma houses. Whereas India is an active player in the formulated products, Generic APIs (active pharmaceutical ingredients) are increasingly supplied from China. Over-capacity in the pharmachemical industry became very apparent in 2002 and 2003, and DSM reacted by closing and/or restructuring some 50% of its capacity, and by withdrawing from the increasingly unattractive generic segment, by selling the South Haven site. In our Biologics business, it became clear that becoming a capacity provider through large investments, without a strong proprietary technology base, would create exposures towards the future. Montreal has been divested, and the business has been repositioned to become a technology provider. In its cause for efficiency improvement and cost reduction, the pharmaceutical industry is looking for manufacturing partners with a broad portfolio of technical capabilities, with a deep understanding of Regulatory Compliance across a broad range of regulators (FDA, EMEA and others). A key factor is the ability to offer longterm stability through operational and financial strength. DSM is consistently amongst the partners of choice for the pharma industry. As a result of the measures taken by DSM, the BG DSM Pharmaceutical Products has emerged as a leading player.

2.4 Despite the issues of the last 5 years, the pharma industry remains a field with attractive opportunities. The growth rate of large pharma houses, accelerated in the past by substantial annual price increases, has reduced to below 10%. The industry is trying to improve its development pipeline and R&D productivity, while bolstering innovation and growth through acquisition of start-ups. The bio-pharma segment is seen as the fastest growth area. Consensus forecast is an average growth rate of around 15% per annum. DSM is positioning itself to participate through technology offerings of the PER.C6 human cell line. Start-ups/VCs have emerged as important drivers of innovation and are the take-over targets for established pharma houses. Through its R&D capabilities and its Rescom site for pre-clinical and early clinical synthesis (Regensburg, Germany) DSM is well-positioned to serve emerging pharma. The generic segment will continue to grow with a rich pipeline of products coming off-patents. Early movers will enjoy a short period of good returns, followed by a rapid decline of margins when multiple players enter the market. In both the pharma-chemical synthesis business and the solid dose business DSM has de-emphasized its participation with regard to generics.

2.5 Healthcare (a USD 6 trillion global market) and the sub-segment pharmaceuticals (a USD 600 billion market) offers above average long-term growth perspectives. In addition to market growth based on developing economies, growth in the developed markets will be driven by technological advancements and demographics. Chronic diseases and medical conditions, linked to life style, are better understood and treated. Statistics of drug usage as a function of age shows a sharp increase in use of medication starting around the age of 40 (for the average US population), marking a shift from disease management to treatment of chronic conditions, such as high blood pressure, cholesterol and diabetes. Continued progress is made in the treatment of cancer, including an array of advanced pharmaceutical products. Scientists are at the verge of breakthroughs in the treatment of Alzheimer and dementia. Despite these advances, the Biopharmaceutical industry is still in its infancy. Genetic profiling is an emerging science, aiding the development of differentiated, personalized drugs, with improved efficacy and reduced sideeffects. There is growing understanding of the impact of nutrition on physical and mental health and well-being, and how this may be affected by individual genetic make up. Whereas currently there is a clear distinction between pharmaceuticals and nutrition, longer term that gap will narrow. Advances in life sciences and medical sciences are impacting our life expectancy, our quality of life and keep us healthy and active till advanced age. Our longevity and improved health and wellbeing at later age comes at a steep price. Spending on healthcare and pharmaceuticals is growing exponentially. The US Center for Health Statistics has made an estimate of anticipated healthcare spending for the coming 25 years. These are US statistics, there is however, no reason to assume the trend will be any different for Europe. Pressure to contain the cost increase in healthcare treatment is evident, from patients, politicians, policy makers, and healthcare providers. The pharmaceutical industry has been a high profile target and will remain under pressure to reduce cost and improve value delivery, while trying to maintain earnings. There is a continuous assessment at most pharma houses of what is core business, and where overall efficiency will benefit from outsourcing. This is a gradual process, but the trend is clear from the large number of manufacturing sites sold, rationalized or closed by the pharma houses.

2.6 DSM Pharma Chemicals (DPC) is DSM s Pharmachemical custom manufacturing business, headquartered in Vienna, Austria. Its main manufacturing sites are in Linz, Austria and in Venlo, The Netherlands. A dedicated small scale facility (Rescom) is operated in Regensburg, Germany while there are dedicated capabilities to produce products through fermentation in Capua, Italy a shared DSM site. In 2003, the need for restructuring and business improvement in DPC was discussed extensively. Measures were discussed, and new measures were announced. Since this period DSM Pharma Chemicals has achieved a real turn-around: In addition to closure of surplus capacity, divestment of the generic API business, and a strong focus on cost reduction, during 2004, DPC has reviewed its strategic positioning, focusing on segmentation and differentiation. This has been done as an integral part of the reviews leading up to Vision 2010. This has created a clear focus on actions required to grow the pipeline and improve the portfolio of activities.

2.7 Active Pharmaceutical Ingredient production is a multi-step process, often requiring over ten discrete steps. DSM can be asked to make the final API, and all previous steps involved. Alternatively the business opportunity may not be the final API, but a product somewhere in the synthesis chain, such as a registered intermediate (the process and process conditions are part of the regulatory filing of the final product), a registered starting material, or something that could be considered a raw material or intermediate early in the reaction chain. The customer may opt to do the final reaction step to the Active Pharmaceutical Ingredient in house, for strategic or control reasons, or often times for tax optimization reasons. with little opportunity for differentiation other than (labor) cost. The industry is increasingly looking to source these materials from low cost countries, and so is DPC. The steps with best opportunity for value addition are those where there is a strong (DSM proprietary) technological component and/or there is a need for stringent Quality Assurance and cgmp control. The Starting Materials and so-called non- Registered Intermediates, are steps in the production chain that do not require cgmp control, and are basically fine chemicals (specification chemicals). DSM can add value through technology for example by reducing the number of steps required through smart synthesis, or by producing a chiral building block. However, a substantial percentage of these materials are based on established technology,

2.8 The opportunity for value recognition is strongly influenced by the dependency of the customer on the services offered. Basic Raw Materials, non-registered Intermediates based on well established technologies and most generic APIs are, based on generic competences are widely available. The key differentiator is labor cost, hence the increased participation of Chinese and Indian players. Customers source on price, the hurdle for change is low, and as a consequence the relationship between the customer and the supplier, for these type of services is tactical by nature. The opportunity to capture value is low. hurdle to change suppliers is significant. In this segment of custom manufacturing there is a strong, longer term, mutual relationship between the customer and DSM. These simple principles are forming the backbone to DPC s strategic repositioning. DPC is seeking selective growth in non-registered intermediates where it can add value through complex chemistry. Furthermore, in registered intermediates and innovative APIs through its competences in QA/cGMP and in areas requiring specialty handling such as cytotoxic and high potency APIs. With increasing dependencies on supplier competences, ranging from proprietary technology, know-how, regulatory capabilities and compliance, and specialty handling capabilities such as cytotoxic substances (oncology products), the relationship as viewed by the customer becomes more strategic and the opportunity to capture value increases. When the processes and the supplier are part of the regulatory filing (the cgmp segment), the

2.9 DPC has been successfully restructured and repositioned. DPC has completed an extended phase of restructuring, business improvement and strategic repositioning. The business has turned into a solid contributor to the DPP financial results and is growing again. DPC is now successfully working on a smaller footprint, with fewer sites and lower infrastructure cost. It is aggressively repositioning to higher added value segments, while continuing to build its unique chemical capabilities. DPC s activities in Linz have doubled in the last 2 years, based on a few highly successful projects with large pharma companies. The volume requiring strict cgmp controls (forecast for 2007) has doubled compared to 2005, the outlook for the coming 3 to 5 years is to further increase. Where it brings cost advantage, steps early in the chemical synthesis chain (no specific cgmp requirements) are sourced from China. Surplus pharma-chemical capacity in Greenville, NC, USA was closed. An older plant in Venlo was closed. The generic API business in South Haven, MI, USA was sold to Albemarle. In December of last year, additional cgmp capacity in Linz was acquired from Roche. A state-of-the-art facility, owned by Roche, and operated by DSM for manufacture of one of Roche s products was acquired to add high-end cgmp capability to the DPC network, required for growth in this segment. In the pharma-chemical business, innovation is aimed at extending the tool box of chemical technologies. DPC is recognized for its technology in chiral synthesis. DSM s proprietary technology in this area allows for rapid development of customized homogeneous catalysts. Bio-synthesis and enzymatic conversions is a focal point of innovation, building on a wide skill base in DSM. Technology developments in this field have been fundamental in the recent commercialization of new drugs. This is an important pillar under the custom synthesis business. Microreactor technology is pioneered to intensify chemical reactions, and to deal more safely with potentially hazardous materials.

2.10 DPI, operating out of Greenville, NC, USA, is the business unit within DPP focusing on secondary manufacturing. It uses active pharmaceutical ingredients and other components, to manufacture finished products, ready for use by doctors and patients. Also DSM is looking back at what were turbulent times. Following the acquisition of Catalytica late 2001, DSM was confronted with an FDA warning letter. Having addressed this through investments in state-of-the-art quality systems, processes and some infrastructure adjustments in Steriles manufacturing, the business has emerged as winner leading in the industry. Recognition by FDA for Quality Assurance in Steriles opened also doors for restricted areas in non-sterile final dosage manufacturing, like handling of substances that fall under narcotics legislation.

2.11 DPI s solid dose business has a broad range of capabilities, being able to offer about 95% of all available technologies for the manufacture of tablets and capsules. DPI has focus on specialty markets, and is not actively seeking business in the lower margin OTC (non-prescription, over the counter) and generic segments. The business enjoys a diversified customer base of some 30 customers including 5 of the large pharma houses. Overall DPI s solid dose business operates at high utilization rates and is generating capacity for selective growth through de-bottlenecking, operational excellence and targeted investments. To further expand in high margin specialty handling areas, DPI is currently preparing to invest in cytotoxic solid dose tablet and capsule capabilities for oncology products. In the coming five years this is one of the strongest growth areas in the pharmaceutical industry, and an area with limited available manufacturing capacity. In addition to manufacturing services, DPI is building capabilities in product formulation. This offers opportunities for the development of proprietary drug delivery and drug release systems. DPI is seeking growth in specialty segments. It is one of a limited number of companies licensed to handle scheduled drugs. These pharmaceuticals fall under the US narcotics law and are regulated through the DEA (Drug Enforcement Agency). Quotas for bulk API are strictly regulated. Supply chain, manufacturing and logistics operations are under full surveillance. Access to raw materials, intermediates and finished products is tightly restricted.

2.12 DPI has established itself as an industry leader in aseptic processing for sterile products. The business is specialized in production of injectable products, in freeze dried (lyophilization) and liquid format. It has capabilities in formulation and packaging of ophtalmic (eye) and otic (ear) drops. Steriles manufacturing is a highly specialized niche, operating under the most stringent regulatory requirements. Barriers of entry are extremely high, as: It is highly capital intensive: USD 300 million plus for a large scale facility. Design, construction and validation of a facility takes at least 5 years, and Training and qualifying staff takes 9-12 months. The time from prospect to actual revenue is 2 years plus. for oncology products, and in small scale flexible capability to supply early phase clinical trial materials. With 11 freeze driers and 3,700 sft capacity and an unrivaled reputation for aseptic processing, quality and compliance, DPI is a supplier to most of the large bio-pharmaceutical companies. Steriles is a strategic growth area for DSM. The recent investments in new capacity is over USD 100 million, adding a new line for 50% capacity increase to support growth in lyophilization. In addition to building on its leadership position in freeze dried products, DPI has made investments a in sterile cytotoxic line

2.13 Steriles manufacturing is manufacturing at the frontiers of science and technology. Products injected in the blood stream must be guaranteed free of any micro-organism or particulates. Sterility is of the utmost importance. Biopharmaceutical and some small molecules can not withstand sterilization. Aseptic processing is the only solution. Growth in Steriles manufacturing is largely driven by growth in Biologics. Biologics is in its infancy. The market is expected to grow at 15% CAGR, with most products needing freeze drying. The main aim at DPI, receiving product in deep frozen form, is to manufacture single dose units from bulk product. Lyophilization (a form of freeze drying) stabilizes therapeutic proteins, antibodies and instable small molecules, thus providing shelf life, while maintaining therapeutic activity. Before the product is administered, the physician adds sterile water to instantly dissolve the product.

2.14 DPI develops process conditions for optimum product efficacy. Too much water in the product affects the stability of the product. However, if too much water is removed from the molecule, therapeutic activity can be affected and even lost. The process is tightly controlled for ph and electrolytes in the flash freezing and freeze drying cycle. DSM prides itself in being a foremost player in the Sterile segment, an area for strategic growth. In Steriles manufacturing DPI has become a leader in what is a true specialty field: A strong track-record of regulatory compliance with the FDA, EMEA, and many local regulatory authorities, amongst which: UK, Germany, Japan, and Canada. The fact that in recent years several preapproval inspections have been waived by the FDA is a strong signal of trust and confidence in DSM s quality systems and compliance. DPI is recognized by the largest customers in the industry for its expertise and track-record in lyophilization technology. Given the intrinsic value of biologics, operational excellence programs and continuous improvements, leading to yield improvements create significant value.

2.15 Biologics are a class of pharmaceuticals produced in living cells or living organisms. The products are proteins including monoclonal anti-bodies, too complex to be produced through chemical synthesis. The molecular entities are a factor 100 to a factor 1,000 bigger than APIs produced through chemical route, hence the distinction between large molecules (biologics) and small molecules (traditional APIs). DSM Biologics is a leading provider of manufacturing technology and services to the biopharmaceutical industry. In addition to offering world-class manufacturing services, DSM Biologics has co-exclusive rights, along with the Dutch biotech company Crucell N.V., to license the high-producing PER.C6 human cell line as a production platform for recombinant proteins and monoclonal antibodies. (batch, fed-batch and continuous perfusion) and purification techniques. The combination of the PER.C6 human cell line with DSM s manufacturing services provides companies with a turn-key biologic manufacturing solution that reduces cost, risk and time to market. DSM Biologics main focus is to develop and license technology for improved manufacturing of biological drugs. DSM Biologics FDA-approved facility in Groningen, The Netherlands, was established in 1986, and has a strong track record for using a broad range of cell lines (PER.C6, CHO, hybridoma, etc.) in biopharmaceutical manufacturing. In addition, this site has a wide range of experience using multiple manufacturing

2.16 The Biologics segment of the pharmaceutical market is in relative infancy. While the therapeutic benefits of Biological pharmaceuticals are very promising, the investments needed to develop these drugs and to bring them to market is enormous. It is the domain of huge efforts in innovation. In addition to the established biotech companies, there are over 2,000 start-up and emerging companies, with a rich pipeline in product development. It is a key growth area for the pharma industry, the current market size being approximately USD 50 billion, expecting to grow to USD 200 billion in 2020. In the studies leading up to Vision 2010, DSM has conducted detailed reviews on how best to participate in the Biologics domain and concluded that current manufacturing practices are on the one hand highly capital intensive, while on the other hand based on immature process technologies. The demand curve for the coming 5 to 7 years, and the numerous investments by the industry are based on current status of the manufacturing technologies. Given the scope for technological breakthroughs, there is substantial uncertainty over the actual longer term capacity need. A second factor coming in to play is the long lead times between investment and generation of income from a manufacturing services business. Furthermore, based on today s technology a single facility can only support the production of a few products, making this an intrinsically lumpy business. Based on these strategic reviews, DSM decided in 2005 not to pursue investments in large scale Biologics contract manufacturing. This resulted in the exit and divestment of the Montreal site. Instead, DSM, through DPP s Biologics business unit is focused on the development of proprietary technologies, addressing a number of unmet needs of the industry. An investment in a larger scale facility at some point in the future, based on proprietary DSM technology is not ruled out.

2.17 Cost of goods in Biologics is 5 to 10 times higher as percentage of the cost of the end product, when compared to chemical APIs, but when expressed in absolute terms (cost per kg), are several orders of magnitude more expensive. This has resulted in high cost to patients and providers, and restricted overall market development. Biopharmaceutical manufacturing facilities are highly capital intensive, depending on size, scale and complexity in the range of USD 200 million USD 500 million. While unattractive for the larger players, the high capital cost and the long lead times in design, construction and validation are an insurmountable barrier for the smaller biotech houses. At the same time, current manufacturing concepts are inflexible, and less suited for smaller volume products. There is a strong need for flexible manufacturing technologies. When the amino-acid skeleton of the protein is formed, subtile chemical modifications to the basic protein may occur in the cell, glycosylation (chemical binding of sugars) being currently a subject of industry focus. There is an array of these so-called post-translational modifications, which are far from fully understood and subject of much research. Currently the most predominant host cells used in the industry are based on Chinese Hamster Ovary (CHO) cells. When introducing the human DNA sequences, these cells are capable of expressing human amino-acid sequences. However, their native capability for post translational modifications is non-human. Further bio-engineering can address this, but there is increasing interest in the industry in a fully human cell line. Biologics are produced by introducing foreign DNA into a host cell; the foreign DNA codes for the production of a desirable protein or anti-body. By using human DNA, proteins with human amino-acid sequences can be produced, which has been important in addressing immunogenecity of early biologics.

2.18 DSM s developments in Biologics are strongly centered around the development and licensing joint venture with Crucell on PER.C6. PER.C6 is a human retina cell, bio-engineered so that it will continue to replicate itself, so-called immortalization. It is capable of expressing foreign DNA. It is versatile and as such very suitable as a production platform for mammalian fermentation. PER.C6 has been extensively tested in independent laboratories for human and animal viruses and has met or exceeded both US and EU regulatory requirements for cell line safety. Unlike CHO, the origin and development of PER.C6 as a biopharmaceutical production platform are known and fully documented. It is the best documented cell line in the industry. In 2002 DSM and Crucell entered into a coexclusive licensing arrangement for the use and development of PER.C6 in the field of protein and anti-body production. The partners co-fund technical development, jointly market and sell licenses and share 50/50 in the royalties. PER.C6 is versatile and can be used in traditional batch, fed-batch and perfusion processes. A remarkable feature of the cell line is its capability to grow in vitro to extremely high cell densities, about 10 times higher than CHO. The number of cells in suspension is directly proportional to the potential productivity of the cell line, thus giving the opportunity for high product yields. Being a human cell line, it gives all the promise of human post translational modification. There are currently no other human cell platforms that can challenge PER.C6. Starting ab initio it will take a challenger up to 10 years in development, safety testing and regulatory filings to bring a human cell line to the point where the DSM/Crucell joint venture is today.

2.19 The DSM/Crucell joint venture aims at developing a comprehensive technology platform. The technology joint venture addresses a number of fundamental aspects of cell culturing and the production processes with as primary aim to achieve yields which are 10 times current industry standard. This will form the basis for fundamental change in the way biologics will be produced in the future, addressing many of the unmet market needs as discussed before. To generate the best cell lines, DSM and Crucell have embarked on a program for improved clone generation, technologies for introducing the DNA into the cell, and for selection of stable clones with the highest possible yield. Cell densities and thus yield are strongly impacted by process variables and cell culture media, areas addressed in the joint venture. Separation and downstream processes are an integral part of the manufacturing design. To speed up developments, to enhance the ability to attract international top talent from the biotech industry, and to enhance overall visibility with the prospective customer base, DSM and Crucell last year established Percivia. Percivia is a state-ofthe-art research center in the heart of the biotech industry in Cambridge/Boston, fully dedicated to the development of the PER.C6 technology platform. There are currently some 50 scientists employed. DSM Biologics Groningen has been positioned as a PER.C6 center of excellence for scale-up, and production of clinical materials. Here the design parameters will be developed for commercial scale processes.

2.20 Earlier this year DSM announced the development of a new mammalian fermentation process, the so-called XD process. Based on the specific properties of PER.C6, scientists in Groningen developed a process operating at extreme high cell densities, and maintaining productivity of the cells, thus achieving record yields. A typical growth curve is shown for PER.C6, comparing the XD process with the traditional fed-batch process. The curve represents cell growth as function of time (days), showing an order of magnitude increase in cell growth and a yield of 10g/l for monoclonal antibody production. These results are a breakthrough in mammalian cell culturing. The XD process, with its high product yield, is fundamental to the feasibility of this concept. It has attracted wide-spread attention in the biotech industry. Patent applications have been filed. The ultra high yields allow for down-sizing of fermentation reactors and has opened avenues for new manufacturing concepts. DSM is pioneering the use of single-use bioreactors (disposable inserts for stainless steel containers) for commercial use. The benefits are ample. Much reduced capital investment, and significant reduction in cleaning and validation between batches, resulting in overall reduced operational costs and higher plant output.

2.21 The DSM/Crucell joint venture is developing and licensing a new mammalian fermentation platform, addressing the unmet needs of the industry. The stated aim of the joint venture is to capture 25% of the market for new proteins and antibodies, between now and 2020. License activity has benefited from the recent breakthroughs in the developments. processes. Process intensification is now a major technical objective. XD has provided new opportunities for the Biologics Plant of the Future and generated wide-spread attention in the industry. Royalty rates at or above 2% of end-market sales create an opportunity of > 200 million annual royalty income for the joint venture. Establishing Percivia has been key in creating momentum. XD is exciting, but the PER.C6 cell line can be used in traditional fed-batch and perfusion processes. It gives the benefits of the human cell line, and yields are currently challenging CHO. The new XD process can cause a paradigm shift in the industry. It produces the high product yields that many in the industry have been aiming for, without genetic amplification technology. It enables the use of small single use bioreactors, increasing flexibility. The much reduced cost of crude bulk product increases the viability of alternative isolation and purification

2.22 The strategic landscape of DPP as depicted by this slide, has been guiding in developing the portfolio of activities. The key principle has been the ability to develop strong strategic dependencies, as seen from the customer perspective. Key to this is the ability to offer differentiated (specialty) capabilities and competences. Important components are technology offering, either in the form of IP or know-how and regulatory capabilities and compliance. The segments at the bottom left of the chart are the areas of tactical sourcing, with cost (labor cost) being the main differentiator. DPP is deemphasizing its presence in these segments and has opted to divest the generic API activities. Custom Manufacturing for the pharmaceutical industry offers rewarding growth areas. Across a wide range of activities, in the production of active pharmaceutical ingredients and intermediates, in the production of finished solid dose products, and in particular in the areas of aseptic processing (steriles) and development of the PER.C6 technology platform there are rewarding segments for high value growth.

2.23 With a clear strategic focus, DSM has addressed a number of critical issues in its Pharmaceuticals business. The business is now strongly focused on advanced manufacturing services and innovation. Overall DSM Pharmaceutical Products has established itself as an industry leader. The repositioned business offers attractive opportunities for (non)-organic growth. DSM Pharmaceutical Products is on track to deliver its Vision 2010 targets (EBITDA > 20%) and has identified a number of attractive growth areas. Investments have been made or are underway in segments with clear potential to differentiate and with a solid value proposition: cgmp segments in pharmachemical synthesis. Specialty handling in solid dose, such as cytotoxic products and DEA controlled substances. Aseptic manufacturing of sterile injectable products is a field of particular focus, with recent expansion in capacity and more extensive capabilities. DSM Biologics is developing strong positions in patented technologies, building on the PER.C6 platform. Income will be mainly generated through licensing income for PER.C6, and the XD process.

4.29 DISCLAIMER This document contains forward-looking statements. These statements are based on current expectations, estimates and projections of DSM management and information currently available to the company. The statements involve certain risks and uncertainties that are difficult to predict and therefore DSM does not guarantee that its expectations will be realized. Furthermore, DSM has no obligation to update the statements contained in this document.

4.30 Abbreviationlist AFSSA AGA API BG bn CAGR cgmp CHO DAI DEA DGCCRF DHA DPC DPI DPP EBA EGAN EMEA ESIM FDA GI GRAS ICCL IGA IP LPH m NBD NME nri OTC QA R&D RSM UHMWPE UV Agence Française de Sécurité Sanitaire des Aliments Accelerated Growth Area Active Pharmaceutical Ingredient Business group billion Compound Annual Growth Rate current Good Manufacturing Practice Chinese Hamster Ovary (Cells) DSM Anti-Infectives Drug Enforcement Agency Direction Générale de la Concurrence, de la Consommation et de la Répression des Fraudes Docosa Hexaenoic Acid DSM Pharma Chemicals DSM Pharmaceuticals inc DSM Pharmaceutical Products Emerging Business Area European Genetic Alliance Network European Medicines Agency for the evaluation of Medicinal Products Exclusive Synthesis and Intermediates Food and Drug Administration Glycemic Index Generally Recognized as Safe Innovation Cocreation Lab Internarional Gentic Alliance Intellectual Property Large Pharma House million New Business Development New Molocular Entities non-registered Intermediate non-prescription Over The Counter Quality Assurance research & development Registered Starting Material Ultra High Molecular Weight Polyethylene Ultra Violet