Published by NNE Pharmaplan April 2012

Biopharmaceuticals: entering a new world

2 Angle April 2012 Angle is published three times a year Circulation: 7000 Editor-in-chief: Iben Schmidt Helbirk Editor: Elisabeth N. Gronemann Editorial staff: Patrick Buckner Gert Mlgaard Niels Guldager Frank Nygaard Gunhild Diness Contact: engr@nnepharmaplan.com Text and layout: NNE Pharmaplan and DDB.

How much is health worth?

Since the first biopharmaceutical medicine was launched several decades ago, biopharmaceuticals have grown in importance as they offer hope for people with debilitating and life-threatening conditions for which there was previously no treatment or cure. However, the success of biopharmaceuticals also presents a challenge the much higher development and production costs mean that biopharmaceuticals can be much more expensive than conventional chemical drugs. This high price tag places extra pressure on healthcare budgets and forces payers to prioritise diseases and treatments and define how much a life is worth. To many countries and regions the possibilities offered by biopharmaceuticals are simply out of reach. But biosimilar products may provide an opportunity to improve treatment options. As many companies face the patent expiry cliff for some of their blockbuster products, other types of products, perhaps even biosimilars, will become more important for their future product portfolio. Going forward, biosimilars will make some treatments affordable for more patients. And biosimilars will encourage innovative pharmaceutical companies to invest in the development of new and improved treatments as well as more cost-effective manufacturing solutions forexisting products including biosimilars. In this issue of Angle, we will take you through some of these interesting challenges and opportunities. Please take the time to be inspired with us. Best wishes Morten Nielsen CEO NNE Pharmaplan

Printing: Innographic ApS Head office: NNE Pharmaplan Nybrovej 80 2820 Gentofte Denmark Phone: +45 4444 7777 Fax: +45 4444 3777 Website: www.nnepharmaplan.com

NNE Pharmaplan is the worlds leading engineering and consulting company dedicated to pharma and biotech.

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Biosimilars provide competition for off-patent biopharmaceuticals. But a number of challenges must be overcome for successful market penetration.
Get in the game, page 10

The biopharmaceutical production facility of the future is alreadyhere.

Biotech on demand, page 29

5 15

Saving lives, saving money Medicines for those inneed?

19 23

Innovation for good health Joining forces to change lives

38 46

Treatment at any cost? NNE Pharmaplan News

Saving lives, saving money

As the global population grows and life expectancy rises, biopharmaceuticals are in ever greater demand for the treatment of life-threatening and chronic diseases. But this class of medicine often comes with a high price tag.

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Biopharmaceuticals are one of the fastest growing segments of the pharmaceutical industry, with more than 200 products on the market and over 500 estimated to be in development. Representing approximately 16% of total pharmaceutical sales, biopharmaceuticals had a market value of USD 138 billion in 2010, according to IMS Health.

Biopharmaceuticals are used to treat a wide range of complex and devastating diseases, some of which are life-threatening while others drastically reduce quality of life. Often there is no other available treatment for the condition, which means that biopharmaceuticals can be truly life-saving. But with aging populations worldwide treatment of chronic conditions comeswith a significant financial cost. In 2010 the Swiss Federal Supreme Court ruled that the maximum cost to a health insurer that could be considered reasonable per human life year saved was 100,000 Swiss francs (about USD 100,000). However, this is less than the annual cost of some biopharmaceuticals. Until recently biopharmaceuticals have experienced little competition. But with patents now expiring for many of the first generation compounds, this is changing.

Often there is no other available treatment for the condition, which means that biopharmaceuticals can be truly life-saving.
Furthermore, EvaluatePharma predicts that by 2016 seven of the top ten pharmaceuticals worldwide will be biopharmaceuticals including five monoclonal antibodies.

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There is a significant difference between the traditional small molecules pharmaceuticals and large molecules biopharmaceuticals: while the manufacturing of small molecules can be copied and verified as exactly the same product, large molecules are difficult to copy because production is based on or derived from a living organism.

20-30% lower than that of the original biopharmaceutical. According to the European Generic Medicines Association, just a 20% price reduction on five off-patent biopharmaceuticals could save the EU over EUR 1.6billion peryear. Biosimilars are making treatment of chronic diseases more affordable which is good news for patients in developing countries, where healthcare costs are often paid outof-pocket, and also for developed markets where healthcare budgets are already overstretched. With more competition in the coming years these costs could drop even lower, making treatment more affordable and therefore more attainable for the millions of people around the world in desperate need of these essential medicines.

Frost & sullivan have estimated that usD 100 billion worth of biopharmaceuticals will have lost patent protection by 2020.
Instead a biopharmaceutical copy is called a biosimilar. Such a product must be verified as similar in terms of quality, safety and efficacy to the reference biopharmaceutcial medicine with which it has been compared. The first biosimilar products were approved for the European market in 2006 and today 14 biosimilars have been approved in Europe and very few in the US. But there are many products in thepipeline. Frost & Sullivan have estimated that USD 100 billion worth of biopharmaceuticals will have lost patent protection by 2020. Biosimilars therefore represent one of the most exciting and rapidly evolving areas ofproduct development in the pharmaceutical industry.

Biosimilars are making treatment for chronic diseases more affordable.

While not as discounted as generics for small molecule medicines which can achieve price reductions of 70-80% the cost of a biosimilar is currently around

BiOPhArmAcEuticAls AND mONOclONAl ANtiBODiEs First used commercially several decades ago, biopharmaceuticals are medicines whose active substance is made by or derived from a living organism using biotechnology. They can consist of relatively small molecules such as human insulin or erythropoietin (EPO) (a hormone that regulates the red blood cell production), or more complex molecules such as monoclonal antibodies. Monoclonal antibodies (MAbs) are antibodies produced in pure form by a single clone of cells. They can be made in large quantities and have a specific affinity for certain target molecules called antigens. These are found on the surface of cells including those that are malignant such as cancer cells. See page 43 for more details.

Scan with your smartphone to watch an interview with Judy Orem from Oregon Health & Science University

JuDy OrEm wAs 51 yEArs OlD when diagnosed with chronic myeloid leukemia (CML), a cancer of the white blood cells. Three years later, her CML was no longer responding to therapy and Judy was told she had very little time left to live. Then a friend told her about a clinical trial of a new drug called Gleevec andJudy was able to join the trial. Scientists had identified the specific genetic alteration that causes the white blood cells in CML to grow out of control and Gleevec was the first approved drug to directly turn off the signal of a protein known to cause a cancer. CML used to be considered a death sentence, but today 95% of patients who take Gleevec are alive after 5 years. Judy has now been taking the drug for over 12 years and is one of thelongest-living Gleevec patients in the world.

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Get in the game

With the introduction of biosimilars into the market, blockbuster biopharmaceuticals are facing significant competition.
Biosimilars are helping to make treatment more affordable for chronic and life-threatening diseases by competing with biopharmaceuticals that have lost patent protection. This competition lowers the cost of treatment and challenges the manufacturers of the original biopharmaceutical to discover new innovative medicines. biosimilar. While producing a biosimilar carries less risk than producing an original biopharmaceutical, it must be proven to be sufficiently similar to the originator in terms of mechanism of action and have comparable efficacy, safety and quality. Production is highly sophisticated, requiring specialist training and dedicated production lines. It can take approximately 8 years to develop a biosimilar at a cost of up to USD 250 million. Compare this to the development of a generic small molecule medicine, which can take just 2 years at a cost of USD 2 million, and it is easy to understand why only a few manufacturers have so far ventured into the production of biosimilars.

there are a number of barriers to overcome for a company to successfully launch a biosimilar.
While Europe and emerging pharmaceutical, socalled pharmerging, markets are leading the way, the US is expected to be the largest market for biosimilars in the future. IMS Institute for Healthcare Informatics predicts global spending on biosimilars will exceed USD 2 billion annually by 2015, against USD 311 million in 2011, and that by 2020 the overall penetration of biosimilars within the off-patent biopharmaceuticals market will reach 50%. Furthermore, Decision Resources anticipates that in 2020, biosimilar versions of monoclonal antibodies for oncology indications alone will reach more than USD 4 billion in sales in the US, France, Germany, Italy, Spain, the United Kingdom and Japan. There are a number of barriers to overcome for a company to successfully launch a

it can take approximately 8years to develop a biosimilar at a cost of up tousD 250 million.
The approval process for biosimilars has also been a major barrier. While China and India have had follow-on biopharmaceuticals for some years, it wasnt until March 2004 that the European Medicines Agency introduced a new abbreviated approval pathway and guidelines for biosimilars. Other countries, including Canada and Japan, have now implemented or proposed biosimilar approval guidelines. The US, however, has so far not embraced biosimillars with open arms.

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TheUS Food and Drug Administration (FDA) has only recently in 2012 introduced guidelines for approval. Convincing doctors to prescribe a biosimilar rather than the original drug is another barrier to success. Companies must be able to effectively brand and market the biosimilar and have specialised sales forces which are not necessarily key competences of all biotech companies. Given all these barriers to entry, it is not surprising that penetration of the marketplace has been slow. But the market is predicted to develop as more regulatory authorities and healthcare professionals gain experience and confidence with biosimilars. Currently, Europe has the largest market, accounting for 80% of global spending on biosimilars according to IMS Health but only covering three originator products (erythropoietin EPO, human growth hormone and granulocyte colony-stimulating factor), and just six manufacturers are responsible for these biosimilars.

However, with many more biopharmaceuticals facing patent expiration and several biosimilars at various stages of development, the number of therapeutic areas covered by biosimilars will increase. Companies in Europe, the US, Canada, India and Israel are all set to compete in this market and originator biopharmaceutical companies are investing in this area, with the giants Merck & Co, AstraZeneca and Eli Lilly all showing signs of entering the biosimilars market in the next few years.

Biosimilars present a significant market opportunity and more choice for prescribers.
Whatever the future holds for biopharmaceuticals, everybody agrees that biosimilars present a significant market opportunity and more choice for prescribers which should ultimately lead to a better quality of life for patients suffering from chronic diseases around the world.

Brain cancer 8 Sarcoma 4 Head/neck cancer 3 Skin cancer 3 Leukemia 17 Lymphoma 22 Lung cancer 15 Breast cancer 10 Solid tumors 12 Liver cancer 4 Pancreatic cancer 9 Kidney cancer 5 Ovarian cancer 7 Stomach Cancer 4 Bladder cancer 1 Colorectal cancer 10 Multiple myeloma 7 Prostate cancer 5 Cancer-related conditions 2 Other cancers 10 Unspecified cancers 5

NumBEr OF mONOclONAl ANtiBODiEs iN DEVElOPmENt AGAiNst cANcEr. MAbs give hope in the fight against cancer. According to the World Health Organization, 7.6 million people died of cancer in 2008, accounting for 13% of deaths worldwide. About 70% of all deaths from cancer occur in low and middle-income countries but more than 30% of cancers could be cured if detected early and treated adequately. There are over 100 different types of cancer and by the end of 2011 almost 200 monoclonal antibodies were in development for cancer treatments.

Medicines for those in need?

Innovative biopharmaceuticals have made it possible to treat diseases that were fatal or severely reduced quality of life a decadeago. But the reality is that these innovative medicines arestill not accessible to all.

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A major barrier to health is the affordability of drugs.

Pharmaceutical companies must balance their responsibility to shareholders with their social responsibility to make innovative medicine generally accessible. A major barrier to health is the affordability of drugs and the price tag on some biopharmaceuticals is high. Take for example Shire Pharmaceuticals Elaprase for Hunters syndrome, which according to Forbes costs USD 375,000 per patient per year in 2010. Pharmaceutical companies are under increasing pressure to reduce prices, but in their defence they claim that there are

huge costs associated with research and development (R&D) and that drugs for rare conditions have such small markets. But even with these high prices, some are concerned that the pharmaceutical industry as a whole is not generating a return on R&D investment. A report by EvaluatePharma estimates that the net present value of new products between 2008 and 2010 averaged USD 70 billion per year, while R&D investment was USD 127 billion per year.

some may suggest that the industry is exacerbating the access-to-health problem.

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Added to the pharmaceutical industrys woes is the poor R&D productivity of recent years, with the number of new drugs approved in the US declining by 24% in 2010. Pfizers response to this has been to announce the removal of USD 1.5 billion from its 2012 R&D budget. GSK began a radical shake up of its R&D department three years ago in an effort to increase productivity and reduce inefficiency but in 2010 still fell out of the worlds top 5 biggest sellers of prescription medicines. And over the last five years AstraZeneca has significantly reduced their manning several times, including a very recent job cut, in order to release more funding for R&D. To overcome the product innovation gap, many pharmaceutical companies are looking at mergers, acquisitions and collaborations with smaller biotech companies to help them find the next big product. Selling drugs for rare or orphan diseases is immensely profitable and therefore in the interests of shareholders although not so much for payers.

Creating greater efficiency in manufacturing and production processes will surely help to lower the cost of both existing and innovative drugs. And if prices were lower, the market should naturally expand as more patients and payers could afford treatment which is good news for shareholders, payers and patients alike. The Universal Declaration of Human Rights states that every person has a right to medical care and that all individuals and organs of society have a responsibility to promote respect for this. This includes the pharmaceutical industry. When a new treatment has been made possible through research and innovative thinking, it should be made accessible to everyone including the most vulnerable members of global society. If it can be done, it should be done.

the universal Declaration of human rights states that every person has a right to medical care.
Some may suggest that the industry is exacerbating the access-to-health problem and that it should instead focus on reducing the cost of existing drugs to make treatment more affordable particularly people who have to pay for treatment out of their own pockets. However, industry experts claim that without innovative research, fatal diseases will not be overcome and medical science will not progress. It should also be remembered that several drugs developed for rare conditions have subsequently been found to work in other indications with a larger market.

Innovation for good health

A biopharmaceutical company is aiming to bring high quality biosimilar monoclonal antibodies to the Chinese market within thenext 4 years.
Interview with Scott Liu, Co-founder of Henlius Biopharmaceuticals, Inc.

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Scott Liu founded Henlius Biopharmaceuticals, Inc. together with Paul Liu and Weidong Jiang: We started Henlius because we feel there is a huge unmet medical need in China and other parts of the world for therapeutic monoclonal antibodies. Usually only the regulated markets have these therapies as they are very expensive. For example, an entire course of treatment with Herceptin against breast cancer in China costs RNB 350,000 [about USD 55,600], which is more expensive than in the US because of the import tax. The treatment is not covered by health insurance in China patients have to pay for imported drugs themselves. And with an average annual income of USD 3000, most people cant afford this treatment. We decided to develop and manufacture high quality monoclonal antibodies in China at a reduced price to increase their affordability, so that these drugs would not only be for those living in rich countries.

Today, Henlius has an R&D facility in Fremont, California, primarily for cell line development and another in Cao-He-Jing High-Tech Park in Shanghai for development and clinical research. When we started Henlius, we licensed technology from the US to generate cell lines, which we then transfer to China. We also acquire equipment in the US and ship it over as tax rates are high in China, so this saves time and money. But to get approval for our drugs in China we must file clinical trials here, and as the government of Shanghai reimburses domestically produced biosimilars, we have development and manufacturing in Shanghai, Scott Liu explains.

in china we are very different our focus is onquality.

NNE Pharmaplan is currently project managing the development of a manufacturing plant for Henlius in Shanghai, which will be ready at the end of 2013. In China we are very different our focus is on quality, says Scott Liu. With my background I have an in-depth knowledge and understanding of quality and our products will stand out because of their quality. Our manufacturing plant will adhere to US FDA and EU GMP standards as well as to the new Chinese SFDA regulatory requirements. Henlius has adopted global product standards but most Chinese companies dont do this. Thismakes us unique. Scott Liu continues: We are installing single use technology as it decreases the cost of building the plant significantly and we have adopted the most advanced technology to increase manufacturing efficiency. Our hightitre manufacturing expression technology will increase productivity and capacity.

Drug sales are expected to increase by usD 40 billion over the next five years.
China has a huge home market and IMS Health predicts that it will be the second largest pharmaceutical market in the world by 2016. Drug sales are expected to increase by USD 40 billion over the next five years, driven by demographic changes such as the rising affluent middle class and the increased prevalence of non-communicable (lifestyle) diseases for which biopharmaceutical drugs offer treatment. It therefore seems that the three founders chose a good time to form Henlius in 2009. We started our company with USD 200,000 borrowed from family and friends and just two or three people working in California; now we are 50 people and still hiring! says Scott Liu.

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Sowhile most other manufactures here may produce 1g/litre or lower, we will produce 2-3g/litre. This means savings that allow us to put money into the quality systems. I believe we will be the first company in China with a single use 2000 litre bioreactor, so we will also stand out in terms of our state-of-the-art technology.

manufacturers will have to adopt new technology to reduce costs.

Henlius is developing the biosimilar version of several complex biopharmaceuticals as its lead products and aims to have its first biosimilar monoclonal antibody therapy, for non-Hodgkins lymphoma, on the market in China by 2016. In China there are many regulations and price controls it is a totally

different system from the US or Europe and it is very complicated. So we teamed up with our major shareholder FosunPharma as they have experience ofdrug distribution in China, explains Scott Liu. We also want to bring our products to other countries outside China, so a collaboration with another pharmaceutical company will absolutely be of benefit and we hope to achieve this in the next fewyears. Looking to the future, Scott Liu concludes: Ibelieve that the prices for biopharmaceuticals will be lowered as the current prices cant be sustained. Manufacturers will have to adopt new technology to reduce costs. I think big pharmaceutical companies will establish R&D and manufacturing in China and other emerging countries to lower the costs of generic as well as innovative drugs. And in this I believe Henlius is leading theway!

Henlius staff, from left to right: Dr. Weidong Jiang, Henlius co-founder Scott Liu, and Dr. Paul Liu

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Joining forces to change lives

By working together, an innovative biotechnology company and a global biopharmaceutical giant have given hope to patients with lupus, launching the first new drug for this incurable autoimmune disease in more than 50 years.
Interview with Jerry Parrott, Vice President of Corporate Communications and Public Policy, Human Genome Sciences

On 9 March 2011 the US Food and Drug Administration approved Benlysta (belimumab) for the treatment of adults with active systemic lupus erythematosus (SLE or lupus) who are receiving other lupus medicines. While ground-breaking for patients and doctors as there has been no significant advance in this area for over half a decade, it was also a major milestone for Human Genome Sciences (HGS) and GlaxoSmithKline (GSK), collaborators on thedrugs development.

The early idea for the HGS business modelwas to discover and understand genes and proteins, and use that knowledge to develop biopharmaceutical therapies forpatients. I think we were unusual in the way we developed as a company. In 1993 we began a relationship with GSK and now they are our longest-standing partner. Essentially, GSK acquired access to our technology and intellectual property for use in developing small-molecule drugs along with certain opt-in rights to large-molecule drugs that HGS would develop, and HGS received USD 125 million. In 1993, this was quite a large amount I believe it was the largest deal of its kind in the biotech industry at the time. The reality is that the biggest challenge for a biotech company focused on new therapies is the huge need for capital. The risks at the outset, the ever-increasing expense of clinical development, and the timelines of perhaps 12-15 years to develop a product

the reality is that the biggest challenge for a biotech company focused on new therapies is the huge need for capital.
We started out in 1992 as a very small biotech company with just 4 people, explains Jerry Parrott, VP of Corporate Communications and Public Policy at HGS.

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require a lot of investment. Without GSK we would have needed other capital. Would we have found it so early? Who knows, but unquestionably we were able more quickly to develop an infrastructure, preclinical and clinical capabilities, manufacturing and process capabilities, and get to the next level thanks to the expression of confidence by GSK in our science, our early business model and the people who founded HGS.

there are about 325,000 slE patients under the care of rheumatologists in theus.
In 1996, researchers at HGS identified a naturally occurring protein in the human body called BLyS, or B-lymphocyte

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stimulator. Research eventually showed there was an association between higher levels of BLyS and disease activity in certain autoimmune diseases, including lupus. HGSwent on to develop Benlysta, a human monoclonal antibody drug, which is the first in a new class of drugs called BLySspecific inhibitors that recognise and inhibit the biological activity of BLyS. GSK wasnt involved in the early development of Benlysta, but our deal with them meant that they had the right to opt in to co-develop and commercialise this product after Phase 2. So in 2006 we entered into an operating agreement with them on a 50/50 global basis, under which we would share Phase 3 and 4 expenses and all profits for Benlysta. The GSK alliance made it possible for us to bring Benlysta more quickly through late-stage development and to the market, where it can be available to patients who may need it.

process development capabilities at an early stage. Today, we regard these capabilities as an important strategic advantage. In fact, our large-scale manufacturing facility is now devoted entirely to the production of Benlysta so you can certainly say the investment paid off. The collaboration between HGS and GSK has certainly been a great success, with Benlysta already being used to treat thousands of people suffering from lupus in the US and Europe. The Benlysta programme is a working example of how collaboration between a small biotech and a much larger biopharmaceutical company can ensure that innovative drugs make it successfully to the marketplace.

the collaboration between hGs and GsK has certainly been a great success.
The Benlysta programme success has continued with the European Commission granting marketing authorisation for the drug in July 2011. With a cost in the US of approximately USD 35,000 per patient per year, Benlysta has been predicted to reach blockbuster status. There are about 325,000 SLE patients under the care of rheumatologists in the US and about 250,000 patients in Europe. Under our co-development and commercialisation agreement with GSK, we have responsibility for global supply of Benlysta. Our company is unusual in that we focused on building world class manufacturing and

Systemic lupus erythematosus is an incurable autoimmune disease where the immune system produces autoantibodies which attack the bodys own healthy tissues. It is non-communicable (lifestylerelated), probably genetic and mainly affects women. Lupus can cause painful and swollen joints, extreme fatigue, unexplained fever and skin rash, kidney failure, hair loss, weight gain and depression. The name lupus stems from the Latin word for wolf Lupus vulgaris as the severe facial rash was thought to resemble a wolfs bite. Unfortunately lupus often goes undiagnosed, sometimes resulting in irreversible damage to major organs including the kidneys, skin, heart, lungs and brain. It fluctuates over time, and treatment for lupus therefore varies depending on whether a patient is experiencing a severe disease flare. Treatment can include antiinflammatory drugs, anti-malarial compounds, high-dose or low-dose steroids, immunosuppressant drugs such as those used to treat cancer drugs and now,for appropriate patients, the new human monoclonal antibody drug Benlysta.

hOw much is A humAN liFE wOrth? This is the challenging question which governments must answer in order to set a threshold for healthcare coverage decisions. One popular approach is to use the quality-adjusted life year (QALY) measure, which combines the length of time that life is extended by a medical treatment and the quality of that life. Using this measure, the price of one year of quality life has previously been set at USD 50,000 but research in 2008 suggested the value should be closer to USD 130,000.

Biotech on demand
Chinas pioneering biopharmaceutical companies free from traditional constraints are reinventing biotech manufacturing.
Interview with Frank Nygaard, Process Specialist, Monoclonal Antibody Manufacturing, and NielsGuldager, Senior Technology Partner, Biopharmaceuticals, both from NNE Pharmaplan.

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Integrated system for cell culture media preparation. Sartorius Stedim FlexAct.

By 2016, five of the top ten biopharmaceuticals are expected to be monoclonal antibodies (MAbs). Follow-on (biosimilar) versions of these blockbusters will most likely become available in the coming years due to patent expiry and the introduction of legislation for biosimilars. Personalised therapies will further drive the fractionation of the biopharmaceuticals market, thus increasing the need for smaller batch sizes and campaign-based production schemes. A growing need for flexible, multipurpose and more cost-effective manufacturing will have a significant impact on the design of the production facilities in the future. Demographic and market forces place China in a position to lead the way in the transformation of biopharmaceutical manufacturing.

require relatively high doses and therefore traditionally necessitate high-volume manufacturing facilities, explains Niels Guldager. Many biopharmaceutical facilities are still designed as traditional stainless steel facilities with fixed piping and tank layout and large bioreactor volumes. But such facilities require a significant financial investment with total installation costs in the range of USD 100-300 million. Recent increases in cell culture yields have led to significantly reduced bioreactor volume requirements, which again has opened the door for single-use manufacturing technologies such as pre-sterilised assemblies of plastic bags, tubing and filters that are only used once and then disposed of. With a concomitant financial investment reduction and simplified installation, singleuse technology can be more appealing than stainless steel technology. Combining single-use technology and high-yield processes can further reduce theprice tag for comparable facilities by

maybe it is now time to exit the stainless steel temples?

Compared with other biopharmaceutical products, MAbs are large proteins that

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70to 90 percent. This combination is being pursued in a number of biopharma facilities in China today the full effect is truly a newbiopharma manufacturing paradigm. Maybe the time has come to exit the stainless temples? China is reinventing biotech manufacturing because the future is now in this market, says Niels Guldager.

contribution from the manufacturing facility is limited compared with development costs. This is where the facility lifecycle enters the picture with single use technology it becomes possible to optimise facility installations based on anticipated life cycle stages. For instance, the strategy could be to start with just one single use bioreactor to get material for clinical trials and then upgrade the facility with additional bioreactors later in anticipation of market supply production while clinical trials are taking place. As the next pipeline product must be developed, the facility can change the lifecycle stage back to clinical production and the extra bioreactors can be moved to a market supply expansion facility. Such a strategy becomes possible because single use technology is so decoupled from the facility building itself.

there is a need for speed in securing market shares.

Frank Nygaard elaborates on the subject: Additionally, as products contacting surface are used only once, single use technology runs a much lower risk of batch-to-batch contamination, which is of particular importance in multipurpose facilities. A facility based on single use technology is easy to reconfigure and can therefore be ready for a new product in a matter of days. This flexibility translates to reduced development timelines and thus accelerated time-tomarket peak. In an increasingly fractionated market the need for speed to secure market shares is more important than initial minimal cost of manufacturing. And with markedly increased cell culture yields, the cost

Going green by going single use.

As an interesting side effect, our environmental impact studies show that single use technology is perhaps 50%

Lipitor Plavix Advair Remicade Enbrel Humira Avastin Rituxan Diovan Crestor 2010 2011 2012 2013 2014 2015 2016 2017 2018

Top ten pharmaceuticals 2011 and years of patent expiry.

Biopharmaceuticals

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less energy intensive than stainless steel manufacturing, Niels Guldager points out and continues: It may appear counterintuitive, but the emissions from disposing plastics are more than offset by elimination of the cleaning and sterilisation processes required for reusable technology, basically because heating up many tons of water is extremely energy intensive. Full implementation of high yield processes and single use technology results in facilities with a markedly reduced carbon footprint per kg product compared to the stainless steel facilities of the 1990ies. Soto that end you will most likely be going green by going single use, but the high yield process itself is the most important factor, Niels Guldager concludes. The local aspect should also be factored in. Most facilities are designed for local supply, and a further reduction of carbon footprint by energy optimisation for local climate conditions and using locally available building materials will appear as new facility features.

one central facility for global supply. Such facilities must clearly meet local manufacturing regulations but also increasingly adhere to global Good Manufacturing Practice (GMP) standards. So here we see two new features of the biopharma facilities of the future. They are adaptable to local conditions and yet comply with global regulations as quality requirements are being harmonised. A blueprint facility concept that can be established as interesting markets develop will become an important strategic asset for biopharma players with global aspirations, predicts Frank Nygaard.

china is moving ahead of mature markets.

Niels Guldager continues: You can talk of innovative production techniques in the sense that our emerging markets customers are highly innovative and open-minded and therefore capable of leveraging technologies and market dynamics radically. Obviously, the traditional stainless steel production concept may not be the right solution going forward; but while single-use facilities are still regarded as the plants of the future in mature markets, they are fast appearing as a preferred solution to the blooming biopharmaceutical industry in emerging markets. In China, new technologies and quality systems are being taken up at a rapid pace, so this emerging market is moving ahead of mature markets. China does not have a specific biosimilar regulatory path today, and any new therapy will need to go through all clinical development phases. This situation favours the development of biobetters or biosuperiors (products that promise additional advantages as opposed to just being similar). The patient population allows for extremely fast clinical trials and therefore fast and cost-effective product development.

its not about low cost manufacturing hubs.

The need for local biopharma manufacturing capacity is increasing in the fast growing emerging markets as the customer base expands and national initiatives manage the markets. The trend is being amplified by blockbuster patent expiry and the implementation of regulatory legislation for accelerated pathways for biosimilars. Frank Nygaard says: For biopharmaceuticals, emerging markets are not about low cost manufacturing hubs, but about being on location to get access to the local market. Consequently, many big pharmaceutical companies as well as local manufacturers are investing in new facilities in these countries. Because of the local focus, its a matter of several local facilities instead of

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Since full clinical data will be produced, we see the emergence of new business models based on relatively fast initial product registration in China, followed by a strategy to leapfrog back to mature markets and obtain market approval, and perhaps based on a limited additional data set. When that happens, the blueprint facility concept will again be a strategic asset in order to expand capacity for global supply, says Niels Guldager.

Biotech on demand will become an important capability.

In reality, the important issue is not stainless steel or single-use technology, but rather how technologies can be combined to provide the most productive and costeffective process in a fast and predictable way. Choosing one or the other technology concept or a hybrid of the two depends on both strategic considerations and feasibility studies of each individual case. The future

will change biopharmaceutical manufacturing paradigms from stainless steel to hybrid combinations of single-use and stainless steel and complete single-use facilities. That is clear by now and we see these opportunities being aggressively explored in China, states Frank Nygaard. Today new biopharma manufacturing facilities have to be smaller and more flexible, efficient and cost-effective, and able to adapt quickly to changes in market demand. In the end it is not really about technology, but more about product and process know-how to get to the market. In this respect, single use technology is a magnificent enabler. Forinstance, we can now place an entire small-scale clinical production line inside a 100 m2 environment with these technologies. Biotech on demand the ability to rapidly establish local manufacturing capacity based on new market opportunities will become an important capability for successful companies in the future. And single use technology combined with next generation facility design will do just that, concludes Niels Guldager.

Frank Nygaard (left) and Niels Guldager (right) are some of NNE Pharmaplans experts on biopharmaceuticals.

withiN iNFOrmAtiON tEchNOlOGy, Moores Law states that the number of transistors which can be placed on an integrated circuit doubles every two years. Biotechnology now has its own version of Moores Law with the exponentially falling time and cost of sequencing the human genome for the purpose of identifying possible genetic diseases: It took 13 years at a cost of USD 3 billion to sequence the first human genome, but in a couple of years the cost could drop to USD 1000 and in 5 years further still to USD 100, with the results ready in a matter of weeks making it possible for the total sequencing of an individuals DNA to be a routine medical test.

thE GlOBAl stAtus OF APPrOVAl PAthwAys. While the European Medicines Agency launched an abbreviated approval pathway for biosimilars in 2004, the US which has the potential to be the largest market for biosimilars has significantly lagged behind. In a report in 2008, the Congressional Budget Office predicted that creating a pathway for biosimilars could save the US about USD 25 billion over 10 years from 2009. However, it wasnt until March 2010 that President Obama signed The Patient Protection and Affordable Care Act (PPACA), which allowed the creation of a shorter approval pathway for biosimilars. But still it took until 9 February 2012 for the US Food and Drug Administration (FDA) to release its draft guidance to assist in the development and approval of biosimilars. The guidance could however be in danger if the lawsuit currently before the US Supreme Court, which aims to overturn the PPACA, is successful in voiding the health reform law in its entirety as it would also nullify the biosimilars pathway provision.

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Biosimilar pathways Law in place Biosimilar pathways under development No laws or pathways

We are pleased that the FDA has developed these important guidances, marking another important step forward on the pathway to biosimilars. Jim Greenwood President and CEO of Biotechnology Industry Organization

These draft documents are designed to help industry develop biosimilar versions of currently approved biological products, which can enhance competition and may lead to better patient access and lower cost to consumers. Janet Woodcock M.D., director of FDAs Center for Drug Evaluation and Research.

Treatment at any cost?

The prices of biopharmaceutical drugs support the creation of a two-tier society: those who can afford to survive and those who cant.

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Global spending on healthcare is declining, from USD 251 billion in 2005 to an estimated USD 210-240 billion in 2015, according to the IMS Institute for Healthcare Informatics. At the same time, the cost of innovative biopharmaceuticals is rising pricing a drug at USD 100,000 used to be unusual, but now this price level has become routine.

thatdemands innovative treatments. In the US the government health programme for the elderly Medicare Part B is barred from considering price when it decides whether to cover injected drugs. So where should publicly funded healthcare systems draw the line? Some have the controversial opinion that public funds should not be used to treat people with an unhealthy lifestyle such as smokers, heavy drinkers and the obese for medical conditions which they argue are selfinflicted. Should a smoker receive expensive monoclonal antibody lung cancer therapy for a year when the same funds could be used to perform cataract operations on 12 people, for example? A survey conducted by Doctor magazine among family and hospital doctors in the UK sparked outrage in 2008 as 94% of respondents said an alcoholic who refused to stop drinking should not be allowed a liver transplant, 50% said smokers should be denied a heart bypass and 25%believed that the obese should bedenied hip replacements. However others argue that doctors and indeed governments should not play God by making judgements on lifestyle and that it is morally wrong to deny treatment on financial grounds. But the reality is that with many countries battling the economic recession, healthcare budgets are not inexhaustible and tough decisions need to be made. What is clear is that in this ethical dilemma there are no easy solutions. But can survival of only the richest and those with health insurance be the answer?

unsurprisingly, old and elderly people are the biggest consumers of drugs.
Publicly funded healthcare systems, such as the National Health Service (NHS) in the UK, must evaluate the benefit of a treatment against its cost. To do so, they must assign a monetary value to a human life. Apparently one year of quality life is worth USD 50,000 so states the international standard used to determine whether a treatment should be provided. But many biopharmaceuticals cost more than this and the strain on healthcare budgets to treat a patient with a chronic, life-long condition is therefore significant particularly as people are living longer.

so where should publicly funded healthcare systems draw the line?

Unsurprisingly, old and elderly people are the biggest consumers of drugs and it is estimated that worldwide the number of people aged over 65 will double by 2030 tomore than 1 billion. Emerging countries such as China are experiencing huge growth, with an increasing middle-class

PAtiENts with PArOxysmAl NOcturNAl hEmOGlO-BiNuriA (PNh) suffer from a rare genetic, life-threatening disease that causes the breakdown of red blood cells, which can lead to various medical complications and premature death. In 2007 the FDA approved the first product for the treatment of PNH a monoclonal antibody called Soliris. Today Soliris is the worlds most expensive drug at a price of USD 500,000 per patient per year, reflecting the USD 800 million and 15-year investment it took to develop this orphan drug.

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Trojan horses and bugs

What will be the next big thing in the biopharmaceutical industry?
Interview with Juan Harrison, Vice President, Business Innovations, New Frontier Sciences, Takeda Pharmaceuticals International

According to Juan Harrison, Vice President for Business Innovations, New Frontier Sciences at Takeda, one of the fastest growing areas of interest in the pharmaceutical industry is monoclonal antibodies, and many pharmaceutical companies with atraditional focus on small molecule chemical products are now investing in thisfield of research.

monoclonal antibodies are able to circulate and remain active in the blood stream for up to one month. So whereas small molecule drugs may need to be taken a few times a day or week, monoclonal antibody therapy may only have to be administered once a month. Added to this is the high variety of ways in which monoclonal antibodies can be used such as neutralising specific proteins, turning a receptor on or off, or recruiting an immune response against disease-causing cells and it is easy to understand the excitement about possible future therapies and indications for monoclonal antibodies, explains Juan Harrison. Most recently, antibody-drug conjugates have been in the news and in August 2011, Adcetris, the first treatment for Hodgkin lymphoma in more than 30 years, was approved by the FDA. While Adcetris was discovered and is marketed in North America by Seattle Genetics, Takeda holds the rights outside North America.

so whereas small molecule drugs may need to be taken a few times a day or week, monoclonal antibody therapy may only have to be administered once a month.
Monoclonal antibodies are able to specifically target proteins on cells unlike small molecule drugs which may also bind with peripheral targets so causing side effects. Evolved from biological systems, human

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One problem with monoclonal antibodies is their sheer size.

Often lots of nasty toxic drugs are given to cancer patients with the hope that the cancer cells react faster to the toxin than the healthy cells, says Juan Harrison. But with antibody-drug conjugates we can target the cancer cells more specifically. A drug is attached to the antibody which hones in on the cancer cell. This cell swallows the construct and digests the protein part, releasing the drug which is now toxic and kills the cancer cell.

Anotherbreakthrough in personalised therapy came in January 2012, with the first ever drug to treat the underlying cause of cystic fibrosis, rather than just the symptoms. Vertexs Kalydeco, which will cost USD 294,000 a year per patient, has been approved by the FDA for a rare form of cystic fibrosis in patients who have a specific gene mutation. Kalydeco is an excellent example of the promise of personalised medicine targeted drugs that treat patients with a specific genetic makeup, said FDA Commissioner Margaret A Hamburg, MD inthe approval announcement. Juan Harrison explains: Personalised therapy is absolutely critical. Everyone is looking at finding the appropriate drug for the patient. Without personalised therapy, diagnosis is based on imperfect knowledge and only a portion of patients will be good candidates for the drug. This means that a lot of people who dont respond receive the drugs, which creates a burden on healthcarebudgets. Now personalised medicine will mean that therapy can be given with a higher degree of predictability, so improving treatment of patients while lowering overall healthcare costs.

Personalised therapy will further enhance the success of monoclonal antibody therapy in the future.
One problem with monoclonal antibodies is their sheer size. These big molecules do not easily cross blood vessels, meaning that their use is limited. Developers are therefore looking at reducing their size by getting rid of unnecessary parts, leaving just protein skeletons or scaffolds. The resulting fragments retain the targeting specificity of whole monoclonal antibodies but can be produced more economically and possess other unique and superior properties for a range of diagnostic and therapeutic applications. Personalised therapy will further enhance the success of monoclonal antibody therapy in the future as it is already doing today with Herceptin, says Juan Harrison. Herceptin, a monoclonal antibody drug for some forms of breast cancer, works best on patients who are positive for Human Epidermal growth factor Receptor 2 (HER2+).

i believe we only understand about 1% or less of biology

According to Juan Harrison, other exciting areas of research to watch for in the future include regenerative therapeutics and the use of stem cell therapies. But while much of the research into synthetic tissueengineered organs grown in the lab is still in its infancy, the first ever Phase 1 clinical use of human embryonic stem cells (hESCs) was published in the Lancet in January 2012.

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Therapy in the future: A monoclonal antibody.

Steven Schwartz et al reported functional visual improvements in patients with macular degeneration who were injected with hESCs. I believe we only understand about 1% or less of biology and so its an enormous field, still ripe for discovery, says Juan Harrison. For example, we now know the human genome, but it is wrong to think that this is enough. If you count the number of microbes living on a humans skin the bacteria, fungus, mites, etc the number of non-human cells on the surface alone willoutnumber human cells manifold. In fact, the total number of genes associated

with the human microbiome could exceed the total number of human genes by a factor of 100 to 1. Weve evolved over millions of years and so have the bugs which live on and in us they produce genetic products but nobody knows what these do or how they affect our health. Little has happened in this area so far because we simply did not have the tools to sequence the genomes of the thousands of microbes in our bodies, nor the computational tools to analyse the associations of microbial gene products and human health until now. I predict a huge explosion in this space in the future, concludes Juan Harrison.

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NNE Pharmaplan news

NEw cVP OF sAlEs AND BusiNEss DEVElOPmENt Effective 1 November 2011, Morten Holm Christiansen assumed the position as Chief Sales Officer and CVP of Sales and Business Development at NNE Pharmaplan. Mr Christiansen has previously served as Chief Financial Officer (CFO) of NNE Pharmaplan from 2003 to 2005. Morten Holm Christiansen joined the Novo Group in 1994, where he has held a number of executive positions, latest as Vice President of Global IT operations. Prior to that, he worked as senior consultant in the Danish consulting company Accenture. Morten Holm Christiansen is 46 years old and holds anMSc in Economics and MBA from IMD. I am convinced that with his past NNE Pharmaplan experience, combined with an impressive track record, Morten Holm Christiansen can boost our development of Sales and Business Development and at the same time strengthen the NNE Pharmaplan management team, states Morten Nielsen, CEO of NNEPharmaplan.

NEw BiOtEch cONcEPt The dynamic development of the biotech sector has resulted in an increased number of biotech projects and customers worldwide during the last few years, in particular in the emerging markets. NNE Pharmaplan is seeing many smaller, more flexible biotech facilities based on single-use technology, especially in China. To address these requirements, NNE Pharmaplan has established a standard biotech facility concept called Biotech on Demand, which can be built on site in the traditional way or off site as a modular facility. Standardised process and utility modules are combined in various ways to accommodate all the different functions in a modern biotech facility and the need for flexibility and adaption to local building and GMP regulations and practices. The Biotech on Demand concept includes the engineering and supply of a facility as well as related quality systems, Standard Operation Procedures (SOPs) and the organisation of necessary quality tests.

NNE Pharmaplan is currently applying the standard Biotech on Demand concepts in the design of a number of new biotech facilities.

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been on our wish list of countries where we would like to expand our business. TheEmerging Markets region was set up to be the main contributor of our growth, and Brazil is an important market as well as an entrance door to the rest of South America. Brazil is the worlds ninth-largest market for pharmaceuticals and drugs. The office is already engaged in projects and several of NNE Pharmaplans global accounts have production facilities in the country. The project office started out with five employees, including the Brazilian resident manager Isabel Gomez Alvarez and her husband Gustavo Vivacqua (JGVI), who have been part of the NNE Pharmaplan family for several years. A NEw DOt ON thE NNE PhArmAPlAN wOrlDmAP The last piece of the BRIC puzzle fell into place in November 2011 when NNE Pharmaplan opened a new project office in Curitiba, Brazil. NNE Pharmaplan has been represented in Russia, India and China for many years already. Opening of a new project office in Brazil is an important step in NNE Pharmaplans growth strategy. Regional Manager of Emerging Markets Ole Spang-Hanssen explains: For a long time, Brazil has The Brazilian market is really warm and we believe this is the right time to be here. We started the office, after we had enough projects to support the office startup. The Brazilian office has started very promising. We are still working on establishing the office with a lot of focus on hiring the right people and we have been very successful hiring the best people we can find in the market. Customers have been knocking on our doors already. Thats a very good start.

GrOwiNG BiOtEch strENGth iN NNE PhArmAPlAN iN chiNA Several successful biotech projects continue to enhance NNE Pharmaplans biotech expertise in China. To improve services to customers, a biotech center of excellence has been developed. Biotech project design team. Back row from the left: Jin Wei, Process Engineer; Ruan Zi Jie, Architect; Kang Wei, Project Manager. Front row from the left: Tong Ling, Senior Automation Engineer; Liu Yi, Senior HVAC Engineer; Shu Xia Huang, Manager Architectural Department

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yOull NEVEr wAlK AlONE NNE Pharmaplan is currently expanding its network of partners in the field of modern biotech in order to offer full-service solutions to its customers all the way to approval of product on the market. The cooperation partners include modular construction companies, single-use equipment and consumables suppliers, contract development companies and regulatory experts.

One of the partnerships is with Thalle Integrated Systems (TIS), which has developed a proprietary platform technology called the PlantConnex SystemTM and the BioTypeKitTM. TIS will deliver the facility exterior, i.e. the building blocks that form the walls and skeleton of the facility as well as cleanrooms and HVAC (heating, ventilation and air-conditioning) systems, tailored to single-use biotechnology. Within this framework NNE Pharmaplan will design and deliver the facility interior i.e. process and utilities.

A sample of the Flexplant facility.

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PicturE NNE PhArmAPlAN FrOm thE iNsiDE The NNE Pharmaplan annual report gives you the 2011 highlights and key figures of the NNE Pharmaplan organisation. Together with the annual report, we publish our Communication on Progress (COP 2011) report asustainability report required by NNE Pharmaplans UN Global Compactmembership. Find both reports at nnepharmaplan.com/Who-we-are/Media/Downloads/

sEttiNG NEw hEAlth cArE PAcKAGiNG stANDArDs iN iNDiA West Pharmaceutical Services is the world leader specialising in the manufacture of systems and devices for parenterally administered medicines. The company is headquartered in Pennsylvania in the US. To cater for the fast growing Indian market, they will set up a production facility of rubber stoppers, aluminium caps and flip-off seals near Chennai in the southern part of India.

These products will help avoid contamination of products and thus enhance the quality and safety of injectable drugs produced by Indian pharmaceutical and biotech manufacturers. NNE Pharmaplan is providing the engineering, procurement, construction management and qualification services. The facility will be completed in the fourth quarter of 2013 and is a good example of NNE Pharmaplans proven track record with international customers in India.

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NNE PhArmAPlAN At thE AchEmA 2012 ExhiBitiON/cONGrEss Single-use biotech reactors; design of small-scale fill-and-finish facilities; quality audits at pharmaceutical manufacturer; Manufacturing Execution Systems (MES) within the pharmaceutical industry; pharmaceutical engineering in China and much more whatever your field of interest is, you have a good chance of attending an exciting NNE Pharmaplan specialist lecture at the 2012 ACHEMA event. In addition, our experts will talk on different topics at our booth every day. We invite you to visit NNE Pharmaplan at booth number E4 in hall 9.1, where we will be happy to discuss how your company can benefit from our extensive project and practical experience in the different areas of the pharma and biotech industries. ACHEMA is the world forum of the process industry and the trend-setting technology summit for

biotechnology, chemical engineering and environmental protection. The 30th ACHEMA, taking place on 18 to 22 June 2012 in Frankfurt, Germany, will again be the leading international meeting point for decisionmakers and experts. Around 4,000 pharmaceutical engineering exhibitors from 50 countries will participate, and the organisers expect more than 180,000 visitors, including 30,000 executives. See you in Frankfurt!

Find a detailed description of all NNE Pharmaplan lectures under upcoming events at the front page on our website nnepharmaplan.com. Here you will also see all the other events around the world where you can meet NNE Pharmaplan.

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cAlENDAr where to meet NNE Pharmaplan in the spring of 2012. Check Upcoming events at the front page of our website nnepharmaplan.com for more information. April 3 April Gentofte, Denmark Vendor of services and process equipment to the pharmaceutical industry. NNE Pharmaplan open course. 5-6 April Virginia, usA Flexible facilities and systems. 11 April Gentofte, Denmark ASTM E2500 a science and risk-based approach to achieve qualification compliance. NNE Pharmaplan open course. 12 April webinar How will the new science and risk-based approach impact cGMP regulation? Pre-conference introduction webinar. 16-17 April Beijing, china ISPE China conference 2012. Connecting a world of pharmaceutical knowledge. 20 April Gentofte, Denmark How many batches are needed in process validation? NNE Pharmaplan open course. 23-26 April shanghai, china Vaccines China 2012. Forging successful collaborations and ensuring quality and compliance. 24-25 April Dsseldorf, Germany Pharma Congress 2012. Production and technology. 22 June lyngby, Denmark Green battle. Conference for DTU students. 22 June Frankfurt, Germany ACHEMA 2012. 2-3 may Gentofte, Denmark Design for Six Sigma. NNE Pharmaplan training course. 8-11 may ruds Vedby, Denmark Beyond Project Leadership (BPL). 23-24 may copenhagen, Denmark Computer validation. NNE Pharmaplan/Key2Compliance course. may 27 April Gentofte, Denmark How will the new science and risk-based approach impact cGMP regulation? NNE Pharmaplan open course. April

June

CANADA. With an average of 205 deaths every day, cancer is the leading cause of premature death.

Shanghai Henlius Biotech is building a new state-of-the-art facility for production of MAb-based therapeutics for treatment of malignant tumours.