Sitting Down with Christian Schneider, Director Of

APRIL 2016 # 18

Upfront In My View Business Sitting Down With Reducing the manufacturing Why pharma must address Can small biotechs bear the Christian Schneider, costs of gene therapies environmental discharges burden of innovation? Director of NIBSC

10 17 48 – 49 50 – 51

www.themedicinemaker.com We’re Backing Batch Pharma is investing in continuous manufacturing for the future, but batch-based processing is the here and now!

From powder to coated tablet and from R&D to full-scale Designed with integration in mind, you can select from a variety manufacturing, no other supplier offers such a comprehensive of standard process modules to suit your project needs. Plus, as range of batch-based technologies for oral solid dosage form containment experts, we not only offer the largest portfolio of production. Whatever your application, no matter how contained processing solutions, we can assist with the selection challenging, GEA’s powder handling, granulating, drying, process and optimise your entire production line, making it compression and coating solutions will meet and exceed efficient, safe and cost-effective. Contact [email protected] your individual requirements. today for more information or talk to an expert at POWTECH (booth 3A-237) or INTERPHEX (booth 2421).

gea_batch_ad_medicine_maker.indd 2 24/03/2016 15:00 Online this Month

Controlling Crystallization lecturer in the Department of Chemical Engineering at Imperial College London, We all know that crystallization is crucial UK, and focuses on understanding the in the pharma industry when it comes role of surface properties in particle to manufacturing active pharmaceutical engineering. Recently, he has examined ingredients (APIs) – and on page 12 of the feasibility of establishing template- We’re Backing Batch this issue you can read a snapshot about induced polymorphic domains for API the fascinating work from Jerry Heng crystallization. You can read a Q&A Pharma is investing in continuous manufacturing for the future, and his team, who hope to be able to give with Heng online. manufacturers greater control over the but batch-based processing is the here and now! crystallization process. Heng is a senior http://tmm.txp.to/0416/Heng Better Bioprocessing

From powder to coated tablet and from R&D to full-scale Designed with integration in mind, you can select from a variety The Medicine Maker recently manufacturing, no other supplier offers such a comprehensive of standard process modules to suit your project needs. Plus, as teamed up with GE Healthcare to Matt Hutchings (University of East range of batch-based technologies for oral solid dosage form containment experts, we not only offer the largest portfolio of learn more about the trends and Anglia, UK) – who is studying bacteria production. Whatever your application, no matter how contained processing solutions, we can assist with the selection challenges of bioprocessing. You found on South American leafcutter challenging, GEA’s powder handling, granulating, drying, process and optimise your entire production line, making it can read a collection of interviews ants in the hope of discovering new compression and coating solutions will meet and exceed efficient, safe and cost-effective. Contact [email protected] covering topics such as extractables antibiotics – has come up with a list and leachables, vaccine production, of weird and wonderful places where your individual requirements. today for more information or talk to an expert at bioprocessing bottlenecks and more scientists are seeking new microbes and POWTECH (booth 3A-237) or INTERPHEX (booth 2421). in the online supplement. the drugs they produce. Check out our infographic online. https://themedicinemaker.com/ Around the World in issues/0316/bioprocess-insights/ 80 Microbes http://tmm.txp.to/0416/Hutchings

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gea_batch_ad_medicine_maker.indd 2 24/03/2016 15:00 Contents

21 48

03 Online This Month Upfront In My View

08 Mega-Merger Not To Be 16 A hepatitis C treatment is a 07 Editorial well-deserving winner of the Battle of the Sexes, 09 Bio-Responsive Insulin Delivery 2015 Drug Discovery of the by Stephanie Sutton Year Award, says Ann Hayes 10 Harnessing Adeno-Associated Vectors 17 Johan Bengtsson-Palme and D.G. Joakim Larsson believe it’s 11 Parting Shot time for companies to live up to On The Cover their ethical responsibilities 12 As Clear as Crystallization Celebrating the Power List 18 Will aerosol-based detectors with artwork inspired by the 13 Affliction Prediction ever meet all the needs of the Revolver album cover pharma industry? asks (the Beatles). 14 Moving from Batch to Continuous Dorina Kotoni ISSUE 18 - APRIL 2016

Editor - Stephanie Sutton [email protected] Associate Editor - James Strachan [email protected] Editorial Director - Fedra Pavlou [email protected] Content Director - Rich Whitworth [email protected] Publisher - Richard Hodson [email protected] Sales Manager - Helen Conyngham [email protected] Senior Designer - Marc Bird [email protected] Designer - Emily Strefford-Johnson [email protected] 50 Digital Content Manager - David Roberts [email protected] Mac Operator Web/Print - Peter Bartley [email protected] Tablet Producer - Abygail Bradley [email protected] 42 Best Practice Audience Insight Manager - Tracey Nicholls [email protected] 42 Beyond Keeping Traffic and Audience Associate - Lindsey Vickers Up Appearances [email protected] 10 Is film coating strictly necessary Traffic and Audience Associate - Jody Fryett for all tablets? There are many [email protected] reasons to decide against Apprentice, Social Media / Analytics - Ben Holah [email protected] coating, but there are also Events and Office Administrator - many benefits that go beyond Alice Daniels-Wright optimizing drug release. [email protected] Financial Controller - Phil Dale [email protected] Chief Executive Officer - Andy Davies [email protected] Business Chief Operating Officer - Tracey Peers [email protected] 48 Making Small Biotech Work

The industry is increasingly Change of address: Features reliant on small biotechs [email protected] Tracey Nicholls, The Medicine Maker, for innovation, but drug Texere Publishing Ltd, Haig House, Haig Road, 21 The Power List development is expensive Knutsford, Cheshire, WA16 8DX, UK The Power List is back! It’s for anyone, let alone a small General enquiries: www.texerepublishing.com time to celebrate the Top 100 company. A sound strategy [email protected] +44 (0) 1565 745200 inspirational professionals can go a long way in helping to [email protected] involved in drug development secure success. and manufacturing, as Distribution: nominated by readers. The Medicine Maker (ISSN 2055-8201), is published monthly by Texere Publishing Ltd and is distributed in the USA by UKP Worldwide, 1637 Stelton Road B2, Sitting Down With Piscataway, NJ 08854. Periodicals Postage Paid at Piscataway, NJ and additional mailing offices Reports 50 Christian Schneider, Director POSTMASTER: Send US address changes to The Medicine Maker, Texere Publishing Ltd, C/o of the National Institute for 1637 Stelton Road B2, Piscataway NJ 08854 38 The Medicine Maker × Catalent Biological Standards and Single copy sales £15 (plus postage, cost available on request [email protected]) More Trial, Less Error Control (NIBSC), UK. Annual subscription for non-qualified recipients £110 Accelerate your bioprocess journey Speed and efficiency are crucial aspects of biomanufacturing. The right supplier can contribute to your success. Discover how our pioneering technologies, agile services, and ability to design and construct complete facilities improves speed to market.

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29204212 AA 04/2016 A Battle of the Sexes Editorial The Power List is back, but is it a fair representation of the male to female ratio in our industry?

pring (and controversy) is in the air at The Medicine Maker. As well as celebrating longer (and hopefully sunnier) days, we are also celebrating influential professionals in the world of drug development and manufacture. April is the season of The Power List! SWe’ve been busying ourselves with the 2016 Power List since the inaugural list last year. What is the process? First, we ask you, our readers, to submit nominations and then seek the advice of an expert (but anonymous) judging panel, who whittle the names down to 100 – and rank the Top 20. Not all of you will agree with the list, but at the very least, we hope that it promotes both celebration and discussion. Some of you may be aware that The Medicine Maker has four sister publications across science and medicine, each publishing its own annual Power List. And although the names and faces are clearly different, a common trend runs across all the lists: both the nominees and the final list are heavily dominated by men. In fact, women make up just 18 percent of The Medicine Maker’s 2016 Power List (but more than double the number of women in 2015). So are women simply not being nominated? Or does the List reflect reality? In the US, female employees make up less than 25 percent of the science, technology, engineering and maths (STEM) workforce (1), and in other countries the percentage can be much lower; for example, just over 14 percent of STEM jobs go to women in the UK (2). It’s a recognized problem worldwide, particularly in light of the fact that STEM jobs are considered to pay higher wages. Fortunately, much is being Accelerate your References done to encourage more women to take an interest in STEM – 1. Executive Office of the President, a few examples include efforts from organizations such as the “Women and Girls in Science, Technology, European Centre for Women and Technology, the New York bioprocess journey Engineering, and Math (STEM),” Academy of Sciences 1000 Girls – 1000 Futures campaign (February, 2013). (US), and the Organization for Women in Science in the Speed and efficiency are crucial aspects of biomanufacturing. http://1.usa.gov/1OLqMFi Developing World. The right supplier can contribute to your success. Discover 2. L. Smith, “Girls in STEM: These figures Although women only make up a small percentage of the how our pioneering technologies, agile services, and ability to show why we need more women in science, 2016 Power List, four of them made it into the Top 20, which tech, engineering and maths,” is surely testament to the fact that women can certainly do very design and construct complete facilities improves speed The Business Times (January, 2016). well in “a man’s world”. Oh – and I should probably mention to market. http://bit.ly/1TpwnUY that the top two spots are also taken by women! Clearly, there’s definitely no lack of female role models in the industry, and Engage with GE to access industry expertise and with more focus on getting young women interested in science, insights to accelerate your bioprocess journey. I can’t help but wonder what The Power Lists will look like in a decade or two… gelifesciences.com/bioprocess Stephanie Sutton GE and GE monogram are trademarks of General Electric Company. © 2016 General Electric Company. First published Apr. 2016 Editor GE Healthcare Bio-Sciences AB, Björkgatan 30, 751 843 Uppsala, Sweden

29204212 AA 04/2016 www.themedicinemaker.com 8 Upfront

Upfront

Reporting on research, personalities, policies and partnerships that are shaping pharmaceutical place within the previous three years. Much development and Mega-Merger of Allergan’s size is a result of their merger manufacture. with other companies including Actavis, Not To Be Forest Laboratories and Warner Chilcott We welcome information – which when taken together equal around A newly introduced tax law $90 billion dollars, which the US Treasury on any developments in in the US puts an end to would not include when estimating the size the industry that have the would-be mega-merger of Allergan. This would mean that Pfizer’s really caught your eye, between Pfizer and Allergan shareholders would own more than 80 in a good or bad way. percent of the combined company and Pfizer and Allergan have mutually agreed would therefore be subjected to US taxes. Email: stephanie.sutton@ to terminate their $160-billion merger The US government has also issued texerepublishing.com after the US Department of the Treasury regulations against ‘earnings stripping’, introduced new tax rules at the start of whereby recently merged companies – who April, specifically aimed at preventing still have their headquarters in the US – corporate tax inversion deals (1,2). The freely lend money to the subsidiary in the merger, first announced in November foreign country. This allows them to escape 2015, caused a huge stir within the the US’s relatively high corporate taxes. pharma industry – and also within US The new rules mean the government has government, since the transaction would more authority to treat those transactions mean that Pfizer could avoid US taxes by as equity movements – which are taxed. moving its corporate residence to Ireland, In a statement, Pfizer stated that the where Allergan is located. merger was terminated because of the Prior to April, US tax rules stipulated “actions announced by the US Department that, following a merger, if the shareholders of Treasury on April 4, 2016, which the of the former US company owned at least companies concluded qualified as an 80 percent of the combined firm, the ‘Adverse Tax Law Change’ under the merger government would subject the business to agreement”. Allergan, however, will not be US taxes, even if the address was abroad. walking away empty handed – Pfizer has With the proposed merger, Pfizer’s US agreed to pay the company $150 million to shareholders would have owned an estimated reimburse expenses from the deal. JS 56 percent of the combined company – well below the 80 percent threshold, and even References below the 60 percent threshold where some 1. Pfizer, “Pfizer Announces Termination of restrictions still applied. Proposed Combination With Allergan”, April, Under the new rules, however, when 2016. www.pfizer.com. the US Treasury calculates the size of the 2. US Department of the Treasury, “Treasury foreign firm (and thus the amount of tax the Announces Additional Action to Curb Inversions, new company would have to pay) it does not Address Earnings Stripping”, April, 2016. www. take into account mergers that have taken treasury.gov Upfront 9

platform. “The cells naturally secrete make sure the beta cells can ‘hear’ the Bio-Responsive insulin on the patch while the needles call from rising blood-sugar levels and act as a bridge between the physiological respond accordingly.” Insulin Delivery signals within the body and the The patch has been tested in mice therapeutic cells outside the body to models of type-1 diabetes and was A “smart” synthetic patch keep glucose levels under control,” says able to help lower blood sugar levels uses live pancreatic cells to Ye, principal author of the study (1). for 10 hours at a time. In the future, painlessly deliver insulin In simple terms, when glucose levels Ye believes the therapy could be through microneedles in the blood rise, the beta cells secrete personalized by using beta cells derived – on demand insulin, which is delivered through the from the patients themselves. microneedle patch. But how do the beta The group has also been investigating Frequently injecting insulin to respond cells sense the rise? the potential of the bio-responsive to rises in blood-sugar levels can be both In an earlier stage of the work, microneedle delivery platform to treat painful and inconvenient. But given that the researchers only integrated cells different diseases. “In our latest study, replacing dysfunctional beta cells with with the patch – hoping that, under we applied a microneedle patch loaded healthy donor cells has a number of a hyperglycemic state, glucose could with anti-PD1 antibody (a cancer rejection risks, injections are often seen diffuse through the needle and interact immunotherapeutic drug) for treating as the lesser of two evils. Is there a better with beta cells to promote insulin melanoma,” says Ye. “We have other alternative? Yanqi Ye, PhD research secretion. However, due to the limited ongoing projects too.” JS assistant at the University of North diffusion of glucose, the patch did not Carolina at Chapel Hill, US, and her effectively respond, and an insignificant Reference colleagues have developed a synthetic increase in insulin secretion was 1. Y. Ye et al, “Microneedles Integrated with patch, filled with natural beta cells, that detected. Ye and the team met the Pancreatic Cells and Synthetic Glucose-Signal can secrete doses of insulin to control challenge: “We have created ‘glucose- Amplifiers for Smart Insulin Delivery,” Adv. blood sugar levels on demand. signal amplifiers,’ which are synthetic Mater (Epub ahead of print, 2016). PMID: The patch is based on a microneedle vesicles filled with three components to 26928976.

www.themedicinemaker.com 10 Upfront

Harnessing Adeno- Associated Viruses

AAV vectors are a promising tool for gene therapy and regenerative medicine, but only if they can be manufactured efficiently

Adeno-associated virus (AAV) is a small, non-enveloped virus with a genome of single-stranded DNA, and for many years nobody paid it much attention of viral vectors in that they can attach to and deficiency (UniQure’s Glybera). It has because it’s not known to cause disease. enter the target cell, and transfer to and be been estimated that 20–25 new AAV- But in recent years, researchers have expressed in the nucleus. Their increased based products will start early phase realized that this lack of pathogenicity use over other delivery methods for gene trials each year between 2015 and 2025. – in addition to other characteristics – therapy stems from the fact that they are makes AAV vectors perfect for use as a non-pathogenic, as well as having the What are the aims of your collaboration? delivery vehicle in gene therapy. ability to transduce non-dividing cells and The project is being led by Cobra, However, manufacturing AAV vectors provide long-term expression of delivered which has a lot of experience in biotech, is no easy task, which is likely to make transgenes. The wide variety of serotypes including viral manufacturing and gene final therapies very expensive. Hurdles and long-term stable expression also means therapies. They were interested in CPI include possible contamination with they offer great potential for gene correction because of our high-throughput process adenovirus or baculovirus, long lead in a broad range of therapeutic areas. development and analytical capabilities times for cell line production and virus Different AAV serotypes can be exploited that allow for in-depth characterization. seed generation, low productivity, and to specifically target different tissues types, In addition, we have experience in high costs. To tackle the challenges, the and also help evade pre-existing immunity taking processes developed at small scale UK’s Centre for Process Innovation (CPI) to the vector, thus expanding the therapeutic and translating them to a commercial or has teamed up with Cobra Biologics, a application and commercial potential of industrial environment. contract development and manufacturing AAV-based gene therapies. Our aim is to develop a greater organization, to develop an industrial understanding of AAV vectors and manufacturing platform. The project is What progress has been made so far? to develop effective – and scalable – funded through Innovate UK via their In terms of gene delivery, viral vectors manufacturing methods. In particular, competition for the development of are now the preferred vehicle for therapy we are looking to develop a toolbox of regenerative medicines and cell therapies – and they are being used in around 83 improved analytical methods that will – and is one of five projects in the area. percent of the 483 current on-going enable each unit operation to be fully Juliana Haggerty, public/private program gene therapy trials. Within these trials, characterized. We’ll be investigating manager at CPI’s National Biologics AAV is the most commonly used vector each step of the manufacturing process Manufacturing Centre, sheds more light (41 percent, equating to 103 trials). using design of experiments and high- on AAV vectors and the collaboration. Several AAV gene therapy products throughput approaches where possible, are in late-stage clinical development, with the aim of investigating a range What is the potential of AAV vectors? and one product is approved in the EU of different manufacturing approaches AAV vectors fulfil the basic criteria required as a therapy for Lipoprotein Lipase and technologies. Gaithersburg Marriott Hotel, Gaithersburg, MD

versions of GSK medicines in LDCs, Parting Shot LICs (lower income countries) and most LMICs,” said Witty in a press release Sir Andrew Witty seeks to (1). “Implementation of these proposals cement his legacy as GSK will be subject to local laws… GSK will addresses patents and now consult with its licensing and co- medicines access in the development partners on these changes.” developing world Additionally, GSK outlined its intent to commit its future portfolio of cancer treatments to patent pooling and will explore the concept with the Medicines Patent Pool (MPP) to help address the increasing burden of cancer in developing countries. July 18-19, 2016 The MPP has been used to accelerate access Emerging Strategies in to HIV, TB and hepatitis C medicines in Drug Product Comparability low and middle income countries through and Process Validation voluntary licensing arrangements. GSK Forum Co-chairs: now say they want to expand this approach Howard Anderson, CDER, FDA Last month, Sir Andrew Witty announced to oncology – enabling generic versions of Yves Aubin, Health Canada Zahra Shahrokh, STC Biologics that he would be stepping down as CEO of GSK’s immuno-oncology and epigenetic Andrew Weiskopf, Biogen GlaxoSmithKline after 31 years with the therapies, currently in clinical development, company. Witty’s tenureship hasn’t been to be made available in LDCs, LICs and without its troubles; large settlements for certain middle income countries, if and off-label promotion will be a lasting blemish when they receive regulatory approval. July 20-21, 2016 on his record. And with the company not The move has drawn considerable praise Change Happens: Technical performing as well as investors had hoped from industry critics, including the head and Regulatory Considerations of late – particularly in China – Witty’s of Knowledge Ecology International, for Pharmaceutical Product resignation will come as no surprise to some. Jamie Love. “Sir Andrew Witty has Lifecycle Management But there have also been highs, and shown exceptional leadership, and we Forum Co-chairs: many see Witty as one of pharma’s good look forward to the implementation of Julia Edwards, Biogen Joseph Kutza, MedImmune, A member guys – increasing access to medicines this ambitious set of initiatives,” he said of the AstraZeneca Group in the developing world, for example, in a separate press release (2). Emanuela Lacana, CDER, FDA by capping the price of GSK’s patented “Changes to patents and IP systems Ingrid Markovic, CBER, FDA medicines in “least developed countries” will not solve the multi-faceted challenges (LDCs) at no more than 25 percent of of improving healthcare in developing developed world prices, and reinvesting countries,” said Witty. “However we believe 20 percent of any profits made in LDCs the measures outlined today add to the wider back into training community health contribution GSK makes to improve access workers in those countries. to effective healthcare around the world.” JS In a similar vein, GSK recently announced that it will not file for patent References protection in Least Developed and Low 1. GSK, “GSK expands graduated approach to Income Countries. They will also seek to patents and intellectual property to widen access to grant licenses to generic manufacturers medicines in the world’s poorest countries,” (April, to supply versions of GSK medicines in 2016). www.gsk.com. “lower middle income countries”. 2. Knowledge Ecology International, “KEI statement “The changes we are setting out aim to on GSK’s announcement of policies to expand access make it as clear and simple as possible for to patented medicines,” (March, 2016). generic manufacturers to make and supply www.keionline.com. SHARING SCIENCE SOLUTIONS Please browse the Forum Web site for program updates: www.casss.org 12 Upfront

a recent study, Jerry Heng and his The researchers used computational As Clear as colleagues at the Department of molecular modeling methodology to Chemical Engineering, Imperial understand how the glass interacts Crystallization College London, have demonstrated with the API crystal. “Contrary to that even a normal glass surface – when conventional wisdom, this Functionalized glass is shown modified through surface treatments study has shown that to trigger nucleation of – can trigger nucleation of specific i nt e r mol e c u l a r specific crystal forms crystal forms of a small-molecule interactions API (1). Polymorph control in between the Over the past few decades, immeasurable pharmaceutical crystallization template resources have been spent trying to surface and understand the crystallization process. the crystalline But despite research efforts, a delicate phase impact balance of several influencing factors the polymorphic continues to make crystallization outcome,” says a difficult problem for medicine Heng. He suggests makers to deal with. that the molecular Crystallization is crucial modeling calculations in the pharmaceutical outlined in the study could industry as a separation be used to predict the process for intermediates propensity for preferential and as the final step in nucleation on new the manufacture of engineered surfaces. active pharmaceutical With further ingredients (APIs) development of the – precise control of results, Heng hopes the crystallization is vital approach could be used to ensure polymorphic by manufacturers to have purity and batch-to- additional control over the batch product consistency. crystallization process by Because different crystal improving predictability of forms (polymorphs) of APIs the outcome and to ensuring exhibit different physicochemical product consistency. properties and can behave very Moving forward, Heng hopes to differently once inside the body, develop design rules to engineer new understanding the factors affecting templates for other crystallization systems, crystallization is vital to manufacturers making his approach easily acceptable hoping to control the process. is typically ensured by seeding the and applicable for newer drugs, and to Studies have revealed that the solution with the desired crystal form explore means of applying his findings outcome of a crystallization process is and by operating the process at a to large scale production processes, and dependent on a crystallization triangle preset solute concentration. “However, to next generation therapeutics – such as of solvent conditions, nucleation variations in the properties of seed biomacromolecules. JS initiators, and process conditions crystals and solution conditions, at (including stirring, geometry of vessel, times, result in crystallization of Reference flow pattern, etc.) of the system. unwanted polymorphs,” says Heng. 1. J. Heng et al., “Establishing template Many researchers have reported “The current work is important for the -induced polymorphic domains for API that special glass surfaces have the understanding of selective nucleation crystallization: the case of carb potential to nucleate crystals of of polymorphic forms on different amazepine,” CrystEngComm17, therapeutic proteins. However, in chemically-modified surfaces.” 6384-6392, 2016. Upfront 13

small subset of similar drugs to build prediction models for specific Affliction Prediction drugs, which makes it more robust for those hard-to-predict, rare side effect cases,” says Jianhua Ruan, group leader of the project. Could drug development be guided by a new The model developed by Ruan and his team uses a technique algorithm that predicts the side effects of called “ensemble classification”. The researchers identified a potential medicines? set of similar drugs for each drug based on their chemical substructures and then constructed a number of base classifiers – these can be any machine learning classifiers, such as a decision tree, support vector machine or a random forest. “Our method could also be used to identify chemical substructures related to different side effects, which means that pharma companies may be able to investigate the underlying mechanism that causes the side effect. This potential could make predictive models like ours crucial in guiding the development of new drugs,” says Ruan. JS

Reference 1. M.J.Jahid and J. Ruan, “Structure-based prediction of drug side effects using a novel classification algorithm,” Int. J. Comput. Biol. Drug Des., 9, 1/2, 87 (2016).

Side effects are inherently unpredictable, often first detected in clinical trials or even by patients after approval. What if drug developers could predict side effects before the drug goes to trial? Researchers at the University of Texas San Antonio have developed an ensemble-based classification algorithm to predict side effects associated with different drugs – and so far it has outperformed previous methods and standard classifiers (based on evaluation results of 1385 side effects for 888 FDA- approved drugs). The team have also applied their method to a number of uncharacterized drug molecules in the DrugBank database to predict their side effects, which have subsequently been validated using literature mining. The software works by assessing the chemical structure of a drug molecule and then determining whether there are any key sub-structures that are known to cause side effects in other drugs. “Some previous studies used ordinary canonical correlation analysis (OCCA) and sparse canonical correlation analysis (SCCA) to predict side effects,” says Jamiul Jahid one of the authors on the research paper (1). “We compared our results thoroughly with the SSCA method in our manuscript and found that our method significantly outperformed SCCA.” “One unique feature of our new approach is that it identifies hard to predict rare side effects which can be easily ignored by other approaches. Our model uses chemical sub-structure to identify a 14 Upfront

and production techniques being used. That’s because not much has changed in pharmaceutical production over the last 50 or so years,” he wrote (3). “Today, a new and exciting technology — continuous manufacturing — enables much faster production and more reliable products through an uninterrupted process.” For time-traveling scientists from the 1960s then, will familiar batch processes soon be a thing of the past? Several manufacturers are beginning to adopt continuous manufacturing, but announcements to date have been for new products; for example, Vertex Pharmaceuticals has been using continuous manufacturing for its cystic fibrosis drug Orkamvi since its approval date in July 2015. Janssen is the first company to make the switch for an already approved drug – and the company is likely planning for more in the future. Last year, Janssen expanded its collaboration with Rutgers School of Engineering, with the hopes of transitioning “several” products to switch from batch to continuous – and continuous manufacturing (2). Other Moving from the agency hopes that more will follow big pharma giants are also jumping on suit. Janssen pursued the change for the the continuous processing bandwagon. Attain supply Batch to production of Prezista (darunavir) via the GlaxoSmithKline, for example, is in Continuous FDA’s recently-released draft guidance the process of building a continuous to industry, Advancement of Emerging manufacturing plant in Singapore. confidence Technology Applications to Modernize “Although it is not easy for drug The first switch from batch the Pharmaceutical Manufacturing manufacturers to transition from batch to continuous manufacturing Base, which was introduced in 2015 to continuous manufacturing, there are Trusted and reliable product supply is essential throughout has been made – and with the specific aim of helping significant rewards. FDA encourages your biologic’s lifecycle. At GE, we are dedicated to delivering approved by the FDA. pharma manufacturers to implement others in the pharmaceutical industry sustainability, continuity, and transparency. Strengthened Will pharma’s future new technology. to consider similar efforts,” says Yu. JS by rigorous quality standards and continuous investment be continuous? The reason for the FDA’s focus in global facilities, we provide assurance for your security on new technologies is a desire to References of supply. There has been encouragement from update the industry and its processes. 1. L. Yu, “Continuous Manufacturing has a many industry stakeholders, including the In a recent blog post (1), Larence Yu, Strong Impact on Drug Quality”, April, 2016. Count on GE’s dedication to security of supply, and FDA, to switch from batch to continuous Deputy Director at the FDA Office www.blogs.fda.gov accelerate your bioprocess journey. manufacturing. Implementing this of Pharmaceutical Quality, Center for 2. Rutgers School of Engineering, “Janssen change for already approved products is Drug Evaluation, suggested that a time- Supply Chain Expands Collaboration with considered to be easier said than done, traveling pharmaceutical scientist from Rutgers School of Engineering with $6 Million gelifesciences.com/securityofsupply but it’s not impossible; in mid-April, the 1960s would be very much home in Funding Arrangement to Implement the FDA for the first time approved today’s industry. “They would already be Continuous Manufacturing Initiative,” a pharma manufacturer (Janssen) to very familiar with most of the processes (May, 2015). http://soe.rutgers.edu GE and GE monogram are trademarks of General Electric Company. © 2016 General Electric Company. First published Apr. 2016 GE Healthcare Bio-Sciences AB, Björkgatan 30, 751 843 Uppsala, Sweden

29206530-AA 04/2016 Attain supply confidence

Trusted and reliable product supply is essential throughout your biologic’s lifecycle. At GE, we are dedicated to delivering sustainability, continuity, and transparency. Strengthened by rigorous quality standards and continuous investment in global facilities, we provide assurance for your security of supply.

Count on GE’s dedication to security of supply, and accelerate your bioprocess journey. gelifesciences.com/securityofsupply

29206530-AA 04/2016 16  In My View

principles being applied to move the drug What Price from discovery, through development, In My and into the clinic. Glory? Sovaldi is highly effective in 90 to 100 percent of patients, and brings about a View The pharmaceutical industry complete cure in many. It is very well receives its fair share of both tolerated, with an excellent safety praise and scorn. Behind the In this opinion section, profile, and a high barrier to resistance. politics, the hard work and The drug is so effective that a number experts from across the impressive achievements of companies have abandoned their of legions of industry hepatitis C research programs altogether world share a single researchers often strongly held view or in favor of hepatitis B; they have been go unnoticed. advised that Solvaldi has effectively key idea. removed the medical need for further hepatitis C therapies. Submissions are welcome. In terms of the pharmacology, the Articles should be short, researchers have been very clever. They’ve made a pro-drug that facilitates entry of focused, personal and the molecule into hepatocytes (where the passionate, and may hepatitis C virus resides) at which point deal with any aspect it is metabolized into the active drug, which means that it only works at the of pharmaceutical site of disease and is thus very effective development or By Ann Hayes, Pharmaceutical Consultant, and has a good side effect profile. It acts manufacture. The Ann Hayes Consultancy, UK. against all six genotypes of hepatitis C, it’s a once-a-day tablet, and there are no They can be up to 600 The British Pharmacological Society’s food effects or drug interactions – it’s words in length and Industry Committee, of which I was simply a really good drug. Fifteen years written in the first person. chair until the end of 2015, launched ago when I left GlaxoSmithKline, there the Drug Discovery of the Year award was no good treatment for hepatitis C, so in 2012 to recognize the hard work of Contact the editor at: scientists in research and drug discovery. stephanie.sutton By the time a new drug is launched, @texerepublishing.com the commercial team often receives the majority of the feedback on the “The drug is so new drug from doctors and patients. You rarely hear about the individuals effective that a involved in the early stages of the drug’s development, which is why our award is number of given to the R&D team, rather than the company as a whole. companies have This year’s winners – a team of scientists who worked on Gilead’s sofosbuvir abandoned their (Sovaldi) – were easily the top choice for the Industry Committee, for two reasons. hepatitis C research The first is the drug’s significant impact on an obvious unmet medical need – programs hepatitis C – and the second is that it is a great example of pharmacological altogether.” In My View  17

this has been a remarkable step change. pharma industry itself can often be quality of life, which are harder to put In my view, these positive stories are cautious, failing to communicate just a price on, and Sovaldi starts to look not given enough attention. Hepatitis how amazing some of these advances like pretty good value. What the public C is not the only disease to witness are – and that leaves the media to often don’t realize is the enormous costs a revolution over the past decade; we concentrate on negative stories rather of bringing a drug to market, taking into have made huge strides in multiple than celebrating success. account just how few drugs make it into sclerosis and rheumatoid arthritis, for I think there is an element of that the clinic, and how few of these make a example. I spoke with a doctor who negativity in the controversy over the substantial profit. It’s a difficult argument told me he regularly walks through pricing of Sovaldi. The drug is expensive; – healthcare systems are being stretched the rheumatoid arthritis clinic on his there is no disputing that. But compared and need to keep costs down, but pharma way to oncology. Ten years ago, he was with the direct medical and economic companies are also facing tough times. constantly tripping over wheelchairs, cost associated with ongoing hepatitis If the industry stops investing in drug but now almost none of the patients are C infection – the lost days of work, discovery and development, who will wheelchair-bound, thanks to disease- the drug treatments, the risk of liver fund these activities? Ultimately, the key modifying therapies like anti-TNF cirrhosis or cancer – Sovaldi represents factor is the value that the drug brings drugs. And yet few people sit down large savings for healthcare systems. to patients – and Sovaldi brings huge and write about those successes. The Factor in the huge improvements to value to patients.

Time to Limit “Companies with Antibiotic foresight can benefit Pollution by making early The use and misuse of antibiotics is a major efforts to reform driver behind the drug- Over the last decade, antibiotic resistance their production resistance problem, but large has put increasing pressure on human environmental discharges healthcare and is estimated to account chains towards of antibiotics from pharma for 700,000 deaths every year (1). The manufacturing can also use (and misuse) of antibiotics in both green contribute. It’s time for human medicine and agriculture is a companies to live up to their well-known cause of resistance; a much- manufacturing.” ethical responsibilities. less discussed driver is the environmental discharge of pharmaceuticals (2). By Johan Bengtsson-Palme, doctoral student Both the development and spread of has been neglected – presumably because at the Department of Infectious Diseases, resistant bacteria in the environment the potential impact of the problem has The Sahlgrenska Academy, and D. G. can be promoted by antibiotic selection, not been recognized. Slowly, awareness Joakim Larsson, Director of the Centre for and so release of antibiotics into the is growing, but we need improved Antibiotic Resistance Research (CARe) environment can accelerate the problem. national and international regulation – at the University of Gothenburg, and Importantly, in contrast to the use of and established limits for environmental Professor in environmental pharmacology antibiotics, environmental discharges releases, if we are to make a difference. at the Department of Infectious Diseases, are not associated with any benefits – At the moment, there is little public the Sahlgrenska Academy, University of only risks. information about where and how Gothenburg, Sweden. For a long time, the subject of medicines are produced, because of a environmental pollution with antibiotics lack of transparency in the production

www.themedicinemaker.com 18  In My View

also the upper boundaries for selective and new legislation. Companies with concentrations. The actual selective foresight can benefit by making early “Demands for the concentrations are likely to be even lower efforts to reform their production – but exactly how much lower is still chains towards green manufacturing to sustainable, ‘green’ not known. By accounting for limited get ahead of the enactments to come. sampling of species and the extent A transformation to documented production of of available data, we used the upper sustainable production may have other boundary concentrations to predict benefits for pharmaceutical producers pharmaceuticals no effect concentrations (PNECs) for too, by providing environmentally each antibiotic. friendly products to conscious customers, have already been These PNECs for resistance selection which could set responsible companies can be applied in regulatory contexts, apart from the negligent. Most raised and this is and may eventually be refined or companies will want to avoid distrust supplemented with experimental data associated with not taking action (see likely to accelerate.” as they become available (5). The the “Bad Medicine” report by Sum Of recent O’Neill report on antimicrobial Us (7) for an example of this). With a resistance, commissioned by the British large number of proposed discharge chain. This also means that it is difficult Government, specifically highlights limits now at hand (4), we think the time to know which companies are making the urgent need for enforceable is ripe to take action. an effort. regulations on antibiotic discharges In our view, companies producing and (6). The concentrations we report can References formulating antibiotics have an ethical be used by local authorities to define 1. Review on Antimicrobial Resistance, responsibility to minimize the discharge emission limits for antibiotic-producing “Antimicrobial Resistance: Tackling a crisis for of antibiotics into the environment. With factories, or for pharma companies to the health and wealth of nations” report available treatment options for bacterial assess and manage risks for resistance (December, 2014). http://bit.ly/1yCt7re infections deteriorating rapidly, we need selection associated with their own 2. R.L. Finley et al. “The scourge of antibiotic to act fast. Unfortunately, the current discharges. They also fill an important resistance: the important role of the systems for assessing risks associated knowledge gap to make the proposed environment,” Clin. Infect. Dis., 57, 704–710 with pharmaceutical pollution do not environmental certificates within the (2013). account for resistance promotion (3). good manufacturing practice framework 3. M. Ågerstrand et al. 2015. “Improving Ecotoxicological data for antibiotics is for antibiotics concrete. Similarly, environmental risk assessment of human scarce and, even when such data exist, further development of environmental pharmaceuticals,” Environ Sci Tech, 49(9), the identified effect concentrations are criteria as part of public procurement 5336-5345 (2015). often higher than those that kill many processes for antibiotics, as implemented 4. J. Bengtsson-Palme and D.G.J. Larsson, bacterial species, and hence do not by Sweden and considered by the “Concentrations of antibiotics predicted to protect against resistance selection. WHO, will eventually require defined select for resistant bacteria: Proposed limits for Recently, we broadly estimated the discharge limits. There are also strong environmental regulation,” Environ Int., 86, concentrations that promote resistance incentives to introduce evaluations based 140–149 (2016). based on the EUCAST (European on scientific data in the environmental 5. S.V Lundström et al., “Minimal selective Committee on Antimicrobial risk assessment of antibiotics within the concentrations of tetracycline in complex Susceptibility Testing) database on guidelines of, for example, the European aquatic bacterial biofilms,” Science of the Total the antibiotic susceptibility of clinical Medicines Agency. Environment, 553, 587-595 (2016). isolates (4). We based our estimates Demands for the sustainable, ‘green’ 6. Review on Antimicrobial Resistance, on the fact that a given antibiotic production of pharmaceuticals have “Antimicrobials in agriculture and the concentration that kills or inhibits already been raised and this is likely to environment: Reducing unnecessary use and growth of some bacterial species will, accelerate, which means that pharma waste,” report (December, 2015). http://bit. by consequence, be selective under at companies should be prepared for ly/1SLeZYn least some conditions. Thus, the lowest increased pressure in the future in the 7. Sum Of Us, “Bad Medicine” report (June, inhibitory concentrations reported are form of sharpened procurement criteria 2015). http://bit.ly/1FS6Adq In My View  19

HPLC instruments, cost effectiveness, frequently prove even more challenging. The Search as well as a good understanding of the Analytes eluted in HILIC often require response curves, are fundamental for an alternative detection technique due for the Ideal the purchase and implementation of a to low UV absorption (sugars, aliphatic new detector. amines, lipids, amino acids). There is Detector The truth is, although we are promised ongoing research in the field but so far, great things, we are still waiting for most publications describe work done Will aerosol-based detectors a commercially available and truly under mainly isocratic elution conditions. ever meet all the needs of the universal detector! In my opinion, we still have a long way pharmaceutical industry? to go in understanding aerosol-based detection under HILIC conditions. A HILIC expert once told me “we never use gradients in HILIC, they are too “Pharma’s ‘ideal’ complex”, showing that there is still a big gap to cover, model and understand, both detector should be in terms of separation and of detection. A universal response model for non-volatile By Dorina Kotoni, Analytical Expert - sensitive and molecules in HILIC is inherently more Principal Scientist, Novartis, complex and needs to consider not only Basel, Switzerland. robust.” the gradient effects, but also the detector settings, the mobile phase interference, When developing impurity-profiling and the polarity of the analytes. methods for pharma applications, detection Manufacturers need to investigate and sensitivity can be challenging. On The next best thing to a universal detector, the fundamentals of nebulization and one hand, the high variability of physico- according to instrument manufacturers, is particle formation further to design chemical properties of the analytes requires an aerosol-based detector, but, in reality, detectors with increased sensitivity and that we use universal detection systems, this only delivers what it promises for greater uniformity in their response. In while on the other hand the expectations detecting non-volatile components under some cases, it might not be enough to of regulators drive the need for higher isocratic elution conditions. While there widen the dynamic range of the detector sensitivity and detectability (for trace analysis, have been significant advances in this by data interpolation through algorithms degradation by-products, and so on). field, there is still a lot to be understood introduced between the analog and the The pharmaceutical industry has been in the responses obtained with light digital output of the signal. We need to basing most of its release methods on liquid scattering and charged aerosol detectors detect more and better – and I don’t think chromatography (LC) with UV detectors – for example, gradient effects, detector that, in the case of aerosol-based detection, and gas chromatography with flame settings, influence of compound properties an algorithm (as refined as it may be) will ionization detectors, with the occasional on the detection. Interestingly, a few save the day. use of fluorescence and mass spectrometry. recent studies highlight that volatility of I am convinced, however, that when There is still a reluctance to introduce other a compound is not sufficient to explain there is a better understanding of the “universal detectors”. Moreover, pharma’s differences observed in detection. For non- response model for aerosol-based detection “ideal” detector should be sensitive and volatiles and semi-volatiles, parameters under a variety of analytical conditions, robust, ideally showing a universal such as molar volume and diffusivity, as the pharma industry will be very happy response independently of the properties well as net charge of the compound seem to introduce them routinely. The need of the sample. It should be able to detect to play a role in detection. These new is there. In the meantime, we are still and quantify all components, including aspects still need further investigation looking for that ideal detector... unknowns for which no reference standards and explanation by theoreticians and are available (which is typically the case instrument manufacturers. This article was originally published for early phase projects). Ease-of-use, the Understanding the response model of in The Analytical Scientist (www. ability to interface with high-performance aerosol-based detectors under hydrophilic theanalyticalscientist.com), a sister liquid chromatography (HPLC) and ultra interaction LC (HILIC) conditions can publication to The Medicine Maker.

www.themedicinemaker.com Targeting Patient Compliance

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8617 Colorcon Targeting Compliance ad V3b.indd 1 12/04/2016 17:53 22 The Power List

James Agalloco President, Agalloco María José Alonso & Associates Professor of Biopharmaceutics and Stéphane Bancel Pharmaceutical Technology, University Chief Executive Officer, James is a past president of the Parenteral of Santiago de Compostela Moderna Therapeutics Drug Association and frequent author on the subjects of sterilization, aseptic processing, Maria has pioneered the design and development Prior to Moderna, Stéphane was CEO of and process validation. “I am very grateful for of novel nanostructures for the targeted delivery bioMérieux and he has also held leadership the opportunities I’ve been given to share my of drugs and vaccines. She has also made positions at Eli Lilly. He was elected a 2009 personal and professional experiences with critical contributions to the understanding of Young Global Leader by the World Economic others through publications, presentations the interaction and transport of biodegradable Forum in France, and was chosen as the Best and training,” says James. “It’s brought nanoparticles through biological barriers. Maria CEO in the Biotechnology Sector, according me lifelong friends, colleagues and more has published over 200 scientific papers and has to the 2011 Thomson Reuters Pan European throughout my career.” 11 licensed patents to her name. EXTEL Study.

Phil S. Baran David Darlene Shiley Mary Bentley Professor, The Scripps C. Beckerle Vice President and Research Institute Chief Executive Officer and Chief Scientist, Illumina Director of Huntsman Cancer Phil has racked up a number of impressive Institute, University of Utah David was a founding member of the natural product syntheses, and won dozens Sanger Centre (now the Wellcome Trust of chemistry’s highest accolades. He says he is Mary is well-known for her research into cancer Sanger Institute) and led the Centre in their most proud of “educating the next generation of and has defined a novel molecular pathway for contributions to the Human Genome Project. chemists and inventing reactions and strategies cell motility; her lab is currently working to He and his team have been involved in the that can be rapidly translated to aid medicinal understand the effect of this pathway on tumor 100,000 Genomes Project in partnership with chemists in their efforts to discover new life progression. She is also Associate Vice President Genomics England and the UK National saving medicines.” for Cancer Affairs at the University of Utah. Health Service.

Jonathan Bones Principal Investigator, NIBRT Olivier Characterization and Comparability Brandicourt Laboratory, NIBRT – The National Chief Executive Institute for Bioprocessing Research Officer, Sanofi and Training Olivier has 28 years of global experience in “I’m delighted to be a part of NIBRT; it’s fantastic the pharmaceutical industry, most recently to work with a group of talented and dedicated as Chairman of the Board of Management of people, to see the Institute continually grow Bayer HealthCare AG and a member of the and develop to fulfil its mandate of becoming Executive Council of Bayer AG. He started a global center for excellence in research and his career as a physician working primarily training in all aspects of biopharmaceutical on malaria. He practiced medicine in the production,” says Jonathan. Republic of the Congo for two years. The Power List 23

Pierre Chambon John Chair of Molecular Genetics and Chiminski Biology, University of Strasbourg President and Carsten Brockmeyer Institute for Advanced Study Chief Executive Chief Executive Officer, Formycon Officer, Catalent Pierre’s scientific achievements are numerous; Carsten has been working with the biosimilars the discovery of multiple RNA polymerases John joined Catalent after more than 20 years’ of industry from the very beginning; he was (1969); the discovery of animal split genes experience at GE Healthcare and was featured involved in the development of Binocrit (epoetin (1977); and a marked contribution to the on last year’s Power List. He says, “Over the alfa), the world’s first complex biosimilar discovery of the superfamily of nuclear past year, alongside our expansions in consumer anemia drug. He was headhunted for the role receptors (1987). He is also the founder of health and biologics, we introduced our new at Formycon after holding a one-day workshop the Institute for Genetics and Cellular and platform which matches the best drug delivery on biosimilars at the company. Molecular Biology in Strasbourg. technologies to developmental molecules.”

William Chin Chief Medical Officer and Executive Vice President, Scientific and Regulatory Advocacy, Pharmaceutical Jean-Paul Clozel Research and Manufacturers Founder and Chief Executive of America (PhRMA) Officer, Actelion

“While it is gratifying personally to be recognized After eleven years as a clinician, Jean-Paul in this way, I hope that it reflects an appreciation decided to move to applied research – spending of the paramount importance of science and 12 years at F. Hoffmann-La Roche, during medicine in the biopharmaceutical industry. This which time he was responsible for the selection is critical to sustain a pipeline of drugs that have of the first T-channel blocker. He has built the potential to help future patients live better Actelion from a start-up to a multi-billion lives and even to cure diseases,” says William. market capitalization company.

Stephen T. Colgan Meindert Senior Director, Global Danhof CMC, Pfizer Worldwide Professor of Francis S. Collins Research and Development Pharmacology, Director, US National Leiden University Institutes of Health Dr. Colgan has advocated lean stability strategies for more than a decade. These Meindert Danhof’s research focuses on novel Francis is the Director of the US National strategies provide a focus on the highest risk concepts of systems pharmacology, interfacing Institutes of Health, the largest supporter attributes and time points and facilitate rapid theories from systems biology with quantitative of biomedical research in the world. He introduction of medicines into clinical trials. pharmacology. He is former scientific director of is a physician–geneticist noted for his Regulatory filings are more science and risk- the Leiden Academic Center for Drug research, landmark discoveries of disease genes and based without impacting safety, efficacy, or and he is also a Past President of the European his leadership of the international Human quality of the product. Federation of Pharmaceutical Sciences. Genome Project.

www.themedicinemaker.com 24 The Power List

Wendel Doubleday Sir Andrew Dillon Mark Davison Director, Process Chief Executive, UK National Founder, and Chief Executive Research & Development, Institute for Health and Care Officer, Blue Sphere Health Seattle Genetics Excellence (NICE)

Mark Davison is considered an expert on anti- Wendel leads Seattle Genetics’ process After a successful career in hospital counterfeiting, drug traceability (serialization) chemistry department, which focuses on the management Sir Andrew joined NICE – the and patient engagement. “I enjoy helping development of novel chemical processes for body which determines the cost-effectiveness pharmaceutical companies, NGOs and highly potent drug-linkers. He is currently of new drugs for the UK National Health governments to keep patients safe from fake responsible for defining how processes for Service – as its founding Chief Executive in drugs,” he says. “With imagination, the same cytotoxic agents can be safely and efficiently 1999. He has held this position ever since and systems can also improve adherence and drive developed within a biotech environment, and was awarded a knighthood in 2009 for services better clinical outcomes.” transferred to external manufacturing. to UK healthcare.

Suzanne Farid Professor of Bioprocess Systems Engineering, University College London Frances D. Fergusson President Emeritus, Vassar College Suzanne’s research centers on computer-based, decision-support tools – particularly those that Frances has a degree in art history and between help with the design of cost-effective bioprocesses, 1986 and 2006, she served as President of Vassar such as tools that can analyze economic drivers College. But she has also put her administrative and trade-offs in antibody production, or tools skills to use in the pharma industry. She has that help with capacity planning and portfolio served on the Mayo Clinic Board and been management. She has received funding for her a director at Wyeth. Today, in addition to work from a number of large pharma companies. teaching, she sits on Pfizer’s board of directors.

Miguel Kenneth Getz Forte Director, Sponsored Research Chief Operating Programs and Associate Professor, Officer, TxCell Belén Garijo CSDD, Tufts University School Chief Executive Officer, of Medicine; Founder and Board After several clinical, academic and regulatory Healthcare, Merck Group Chair, CISCRP positions in the public sector in Portugal and at the European Medicines Agency, Miguel Belén initially started out as a medical doctor, “CISCRP has recently been developing moved into the private sector, and became specializing in clinical pharmacology. She educational content for a new traveling Vice President of Global Medical Affairs worked as a practicing physician for six years science museum exhibit designed to teach Inflammation Worldwide at UCB. Miguel before moving to the pharmaceutical industry elementary through high school children currently juggles positions at the Lisbon and where she has spent the last 25 years. She has about what it means to be a clinical research Aveiro Universities, the Commercialization held diverse senior functions and worked in a study volunteer and the gift that clinical trial Committee of the International Society of number of countries – and was elected CEO of participation gives to advancing society’s Cellular Therapy, and TxCell. the year in Spain in 2009. health and wellbeing,” says Ken. The Power List 25

Dalvir Gill Chief Executive Officer and Member of the Board of Directors, Fiona Greer TransCelerate BioPharma Laurent Grandidier Global Director, BioPharma Services Chief Executive Officer, Xeltis Development – Life Sciences, SGS Recently, Gill has been involved in launching BioCelerate, a new subsidiary of TransCelerate, “Witnessing the first implant of our Fiona was a founding Director of M-Scan, and its first initiative, Toxicology Data Sharing. bioabsorbable technology in a child with where she pioneered new developments, “TransCelerate delivered some significant congenital heart disease was truly remarkable,” particularly mass spectrometry, for analysis solutions that are positively impacting clinical says Laurent. “In that exact moment, our vision and sequencing of glycoproteins. For over development, including the Shared Investigator of a revolutionary approach to regenerative 35 years, she has characterized a range of Platform and the Investigator Registry that medicine, potentially transforming standards biotechnology products, both novel and work together to streamline investigative site of care in cardiovascular treatment and biosimilar. Following acquisition (2010), she communication, information sharing and allowing patients to live better lives, started became Global Director, Biopharma Services monitoring tasks,” says Dalvir. becoming real.” Development, SGS Life Sciences.

Helen Hobbs Professor, Internal Medicine and Molecular Genetics; Director, Eugene McDermott Center for Human Growth and Development, University of Texas Jane Griffiths Southwestern Medical Center Company Group Chairman, Janssen, Europe, Middle Helen was awarded the Breakthrough East & Africa (EMEA) Life Sciences Prize in 2015 for her work on identifying key genes involved in lipid Jane is privileged to lead an “amazing team at Janssen, providing medicines every day metabolism and fatty liver disease. Her work to millions of people, helping to extend and improve lives”. Recently, she’s been getting has also led to the development of a novel ready to launch new medicines, continuing to develop Janssen’s people in the organization, class of drugs for lowering LDL cholesterol and working on establishing more companies in Africa. by blocking PCSK9.

SeungSuh Robert Mir (Stanley) Hong J. Hugin Imran President and Chief Executive Chairman & Executive Officer, Chairman, Chief Executive Celltrion Healthcare Co. Ltd Celgene Officer, InCube Labs Stanley is both a scientist and a business Robert joined Celgene back in 1999 – initially man. He joined Celltrion in 2002 and is as Senior Vice President and Chief Financial After attending medical school, Mir began his said to have made many contributions to Officer. In March 2016, he was appointed career as a healthcare entrepreneur and has since the successful development of the company; Executive Chairman. He is also a member of founded more than 20 life sciences companies, he was also involved in the development of the Board of Trustees for a number of institutes, more than half of which have been acquired. Remsima, the first biosimilar monoclonal including Princeton University, The Medicines Mir has been running his R&D lab, InCube antibody to be approved by the European Company, and The Darden Foundation, Labs, since 1995 and is recognized as one of the Medicines Agency. University of Virginia. leading inventors and entrepreneurs in the field.

www.themedicinemaker.com Bahija Jallal Executive Vice Jayasree K. Iyer President, AstraZeneca, Executive Director, Access and Head of MedImmune to Medicine Foundation Bahija has guided the MedImmune R&D Jayasree leads the strategic direction, research organization through the growth and programs and stakeholder outreach of the Access expansion of its biologics pipeline from 40 to Medicine Foundation and is responsible for drugs to more than 120 today. She also serves the Access to Medicine Index. She spearheads as a member of the Board of Directors for the Foundation’s discussions with, among the Association of Women in Science, and as others, companies, governments and key an advisory board member of the Healthcare investors in the pharmaceutical industry. Business Women’s Association. Siu Ping Lam Carl June Director, Licensing Division, Richard W. Vague Michael UK Medicines and Healthcare Professor in Kopcha products Regulatory Agency Immunotherapy, Director, Office of University of Pennsylvania Pharmaceutical Quality Siu Ping became the Director of MHRA’s (OPQ), FDA Licensing Division in April 2014. He has Carl is also Director of the Center for Cellular over 24 years’ experience in medicines Immunotherapies and an investigator at the From 2013, until he took up his position as regulation. During this time he has shaped Abramson Family Cancer Research Institute, Director of the OPQ in 2015, Michael led many changes in European directives for both located at the University of Pennsylvania. R&D for Novartis’ cough, cold and respiratory pharmaceuticals, set up the traditional He maintains a research laboratory that division as Vice President. He has also herbal medicines registration scheme, the studies various mechanisms of lymphocyte served as Vice President for pharmaceutical homeopathic medicines registration scheme activation that relate to immune tolerance development at KV Pharmaceutical, and as an and the medicine/device combination and adoptive immunotherapy for cancer and adjunct assistant professor in the Department consultation operation. chronic infection. of Pharmaceutics at Rutgers University.

Robert Langer Andrew David H. Koch Lees Institute Professor, John Scientific Director, Massachusetts Institute C. Lechleiter Fina BioSolutions LLC of Technology Chairman, President and Chief Executive “My most significant contribution is the Considered one of the most prolific inventors Officer, Eli Lilly and Company development of CDAP chemistry for in medicine, Robert Langer has over 1100 conjugate vaccines,” says Andrew. “CDAP issued and pending patents. He previously John joined Lilly in 1979 as a senior organic is perhaps the simplest and most efficient served on the FDA’s Science Board and has chemist in process research and development, chemistry for making conjugate vaccines. been elected to the Institute of Medicine of the and became head of that department in 1982. It is used by GSK in their pneumonia and National Academy of Sciences, the National He has served as president and CEO since meningococcal vaccines and emerging market Academy of Engineering, and the National April 2008 and became chairman of the board manufacturers are using CDAP chemistry to Academy of Inventors. of directors in January 2009. develop more affordable conjugate vaccines.” The Power List 27

Claus Olivier -Michael Lehr Loeillot Professor, Helmholtz-Institute for Arthur General Manager of Pharmaceutical Research Saarland D. Levinson Genomics & Cellular (HIPS); Helmholtz Center for Infection Chief Executive Research, GE Healthcare’s Research (HZI); Saarland University Officer, Calico Life Sciences business

Claus-Michael was included in last year’s Power As well as heading up biotech company Calico, Olivier has around twenty years’ experience List. “Over the past year, in continuation of our Arthur (‘Art’) Levinson serves as Chairman of in the global life sciences and pharmaceutical approach to improve the delivery of drugs across the Board of Apple and Genetech – where he industry. Previously, he was General Manager biological barriers, we have expanded our focus spent 14 years as CEO. He’s authored or co- of BioProcess Asia and Enterprise Solutions, to those barriers which are particularly relevant in authored more than 80 scientific articles, holds a global business unit of GE Healthcare’s Life the context of infectious diseases, such as immune 11 US patents and has received numerous Sciences division. In 2014, he was awarded cells, bacterial biofilms and the gram negative awards, including the US National Medal of the Bioprocess Industry Award for Excellence cellular envelope.” Technology and Innovation. in Leadership.

Archie Ruth Lovatt McKernan Scientific Operations Chief Executive, Director, SGS Life Sciences Innovate UK

Between 1996 and 2007, Archie was Scientific Ruth was previously the Chief Scientific Director of Q-One Biotech-BioReliance- Officer of Pfizer’s Neusentis Unit, which Invitrogen. In early 2007, he co-founded has funded groundbreaking work in Vitrology, which was acquired by SGS in regenerative medicine. Scientifically, 2012. “Since last year’s Power List, I have been Ruth is best known for her research working on developing new methods for virus in neuroscience on ligand-gated ion detection, and have joined USP expert panels channels with over 130 publications and for viral vaccine safety, and cell banking and 15 patents. She has also won awards for characterization,” says Archie. science writing.

Christian Luber Richard Line Manager, Protein A. Miller Randy Mrsny Characterization, Co-Founder President Professor, Department Protein Engineering and Chief Executive Officer, of Pharmacy and Novo Nordisk A/S Corvus Pharmaceuticals Pharmacology, University of Bath Christian has industry experience from In previous roles, Richard led the initial positions at Pfizer, Novo Nordisk USA and discovery and development efforts for Before taking up professorships, first at Thermo Fisher. He joined Novo Nordisk, ibrutinib (developed at Pharmacyclics) and Cardiff University and now the University Denmark, as line manager in 2015 and research efforts on lymphoma, culminating in of Bath, Randy led research groups in together with his team is developing and the development of rituximab (developed at two companies: ALZA and Genentech. applying cutting-edge mass spectrometry- IDEC; now Biogen). Today, he is also Adjunct He has also been involved in starting two based technologies to progress next- Clinical Professor of Medicine (Oncology) at new biotech companies through venture generation diabetes and obesity medicines. Stanford University Medical Center. capital funding.

www.themedicinemaker.com 28 The Power List

Niclas Nilsson Head of R&D Open Innovation, LEO Pharma

Kary Mullis Niclas says his proudest moment was “finally Ian Muir Chief Scientific Advisor, pressing the web portal’s GO-button and Managing Director, Aesica Altermune Technologies officially launching a truly open innovation platform”. Niclas is a strong supporter of Ian holds a PhD in pharmaceutical science and Kary serves on the board of scientific advisors exploring new external pharmaceutical has over 20 years’ experience in the pharma of several companies, provides expert advice in collaborations that focus on science – and industry. He has worked in senior commercial legal matters involving DNA, and lectures at was recently instrumental in launching Leo positions for Catalent, Cardinal Health and college campuses, corporations and academic Pharma’s open innovation platform. “Our RP Scherer. Today, in his current role, Ian has meetings around the world. He received a Nobel platform could only have been completed by ultimate responsibility for driving growth across Prize in chemistry in 1993, for his invention of the inter-disciplinary and combined efforts of API and finished dose. the polymerase chain reaction (PCR). all involved,” he says. Daniel O’Connor Brian Expert Medical Overstreet Assessor, UK Medicines Co-Founder and President, and Healthcare products Advera Health Analytics Regulatory Agency Elizabeth Brian has more than fifteen years of experience Parrish A medical assessor at MHRA, Daniel is building and managing companies in the Chief Executive Officer, instrumental in the UK’s Early Access to healthcare data and analytics industry. “Since BioViva Sciences Medicines Scheme (EAMS). “My work has the last Power List, we’ve grown our data helped UK patients with life threatening or capabilities and coverage, and expanded our Liz is a strong proponent of gene therapy seriously debilitating conditions benefit from customer markets from payers and providers R&D, and frequently seeks to inform innovative medicines before they are licensed. to also include pharmaceutical companies and engage the public in this field. She is Being part of the team that helped to set up who want to leverage real world evidence for actively involved in international educational EAMS has been an incredibly rewarding everything from outcomes research to trial media outreach and sits on the board of the journey,” says Daniel. design,” says Brian. International Longevity Alliance (ILA).

Nicholas A. Peppas Professor of Chemical Engineering, University of Texas at Austin Daniel Podolsky Nicholas is a leading researcher, inventor and President, University of Texas pacesetter in the field of drug delivery and Southwestern Medical Center controlled release. He has been the recipient of over 150 national and international awards. Daniel is a world-renowned researcher who has advanced knowledge of underlying mechanisms In 2008, he was selected as one of the 100 of disease and new therapies for gastrointestinal disorders. He is considered an international Engineers of the Modern Era by the American authority on trefoil proteins and innate immunity, and is past editor-in-chief of Gastroenterology Institute of Chemical Engineers. and immediate past president of the American Gastroenterological Association. The Power List 29

G. V. Prasad Chris Porter Chief Executive Officer, Professor, Monash Institute of Dr. Reddy’s Laboratories Pharmaceutical Sciences Prasad has spearheaded Dr. Reddy’s foray into In 2009 Chris was awarded the American biosimilars and differentiated formulation Association of Pharmaceutical Scientists as the architect of the company’s global Lipid Based Drug Delivery Outstanding generics and API strategies. He received the Research Award. More recently, his interests 2009 Distinguished Alumnus Award from have expanded into the mechanisms of cellular Purdue University and he was identified as a transport of lipophilic drugs and the potential ‘Young Global Leader for 2007’ by the World utility of dendrimers as drug delivery systems. Economic Forum.

Clive Ian C. Read Roberts Chairman of the Board and Professor, School Chief Executive Officer, Pfizer of Pharmacy, Guido Rasi University of Ian began his career with Pfizer in 1978 as Executive Director, Nottingham an operational auditor. In 2000, he became European Medicines Agency Executive Vice President, Europe, and was “I have been fortunate to have been involved in a then named a Corporate Vice President in Guido is serving his second term as Executive number of medicine development and spin-out 2001. He came to assume responsibility for Director of the EMA, having served as the projects, and to work with talented academic and Canada and Europe, and later for operations EMA’s Principal Adviser in Charge of industrial colleagues, most memorably to date in both the Africa/Middle East region and Strategy between terms. He has previously in working with Marcus Brewster at Janssen on Latin America. He is a past Chairman of worked as a physician and has published more the formulation of Intelence (Etravirine) used the Board of PhRMA. than 100 scientific papers. in the treatment of HIV,” says Clive.

Tomasz Robin Sablinski Robinson Co-Founder and Retired Chief Executive Officer, Charles L. Sawyers Transparency Life Chair of the Human During his time in the pharma industry, Sciences Oncology and Pathogenesis Robin has developed patented platform Program at Memorial Sloan vaccine technologies including virus-like Tomasz’s most satisfying achievement to Kettering Cancer Center particles and subunit protein vaccines for date is the ongoing experience of building human pathogens. He recently retired from a clinical-stage drug development company Charles Sawyers is past President of the the position of Director of Biomedical based on a vision of patient-centric clinical American Association for Cancer Research. Advanced Research and Development trials that use crowdsourcing and 21st He serves on the National Cancer Institute's Authority; and Deputy Assistant Secretary century technologies; with goals that include Board of Scientific Counselors and his research for Preparedness & Response, at the US increasing the availability, affordability and focuses on the signaling pathways that drive the Department of Health and Human Services. utility of new medicines. growth of cancer cells.

www.themedicinemaker.com Andreas Seidel-Morgenstern Director, Department of Physical and Chemical Foundation of Process Engineering, Max Planck Dolores Schendel Institute for Dynamics of Complex George Scangos Chief Executive Officer, Medigene AG Technical Systems Chief Executive Officer, Biogen Idec Dolores has been a member of the German Andreas’ research focuses on developing George’s claim to fame is that he created the first Research Foundation, German Cancer Aid concepts to better link the various steps involved transgenic mouse as a young postdoc. Before and the European Research Council. She in drug production. “Recently, we’ve worked joining Bayer in 1987, George was a professor joined Medigene in 2014, when the company on developing continuous processes combined of biology at Johns Hopkins University for six acquired Trianta Immunotherapy. She claims with chemical synthesis and purification steps,” years, where he is still an adjunct professor. to be passionate about bringing individualized he says. “We would like to extend this concept In March 2016, he was elected Chairman of immunotherapies from bench to bed-side by by including, as a first step, the extraction of the Board of Pharmaceutical Research and moving herself and her team from in-depth natural products.” Manufacturers of America (PhRMA). research to the forefront of the biotech industry. Joseph Schlessinger William H. Prusoff Professor and Chairman of the Andy Skibo Pharmacology Department, Severin Head of Global Biologics Yale School of Medicine; Director, Schwan Operations and Global Yale Cancer Biology Institute Chief Executive Engineering at AstraZeneca/ Officer, Roche Group MedImmune “The focus of my research during the past 12 months has been the identification of the ligand After completing his studies at the University Andy is a past Chair of the International Society for the orphan receptor tyrosine kinase (RTK) of Innsbruck in Austria, Severin Schwan for Pharmaceutical Engineering. He considers ALK, and elucidation of the mechanism of action joined the Roche Group in 1993 as a trainee his proudest achievement to be helping launch of a therapeutic antibody using structural and in corporate finance. Thirteen years later, he at least four new medicines. “Nothing gives you biochemical studies, as well as exploration of was appointed CEO of Roche’s Diagnostics a greater sense of why we’re in this industry,” he signaling pathways that are aberrantly activated Division and in 2008 he became CEO of the says. “At Genentech, they used to hand out flags by oncogenic RTKs in cancer,” says Joseph. Roche Group. on launch day and I still have every single one.”

Manish Soman President and Chief Executive Officer, Sciformix

“It is an honor and very humbling to again be selected among such elite company,” says Moncef Slaoui Manish. “It gives all the people on the list Chairman of Vaccines, GlaxoSmithKline further motivation to take steps to boost the pharmaceutical industry, formulate long term Moncef was professor of immunology at the University of Mons, Belgium before his move into solutions to industry problems, and find smarter industry. He has published more than 100 scientific papers and is a member of the PhRMA and sustainable ways to innovate, grow and Foundation Board of Directors. Moncef has been at the helm of GSK’s global vaccines business contribute to the enhancement of healthcare through its integration of the Novartis vaccine acquisition in 2015. products and services worldwide.” The Power List 31

Abbe Steele Founder and Chief Executive Lars Rebien Officer, HealthiVibe Sørensen President and Chief Pascal Soriot Abbe was featured on last year’s Power Executive Officer, Executive Director and List because of her work in patient-centric Novo Nordisk A/S Chief Executive Officer, AstraZeneca clinical trials. Over the past year, she’s been working on clinical trial simulations, Lars Rebien Sørensen joined Novo Nordisk’s While at Roche, Soriot was in charge of where patients participate in a mock study Enzymes Marketing in 1982 and in May integrating Genentech, the Californian setting to help sponsors gain patient 1994 he was appointed a member of biotech company, after a $47 billion takeover. insights into the impact of trial design Corporate Management. Seven months He also led AstraZenica in a successful defense and study requirements, and determine if later, he was given special responsibility against acquisition by Pfizer in 2014 – a feat these would hinder patient participation within Corporate Management for Health few envisaged before he took the reins. Soriot and compliance with the protocol. Care. He was appointed president and CEO worked as a vet before embarking on his career in November 2000. in business.

Martin Nigel Tolar Theobald Founder, President Founder and and Chief Executive Chief Executive Officer, Alzheon Officer, N4 Pharma During his academic career, Martin served as an Assistant Professor in the Department “For a small company to be recognized, and for of Neurology at Yale University School of me to receive a nomination for 2 years running, Medicine from 1992 to 1997, where he focused is a great achievement and only the start of on movement disorders. Since then he has things to come,” says Nigel. “As we bring our served as head of business development at Pfizer skills to play for a host of drugs and vaccines, and more recently founded Alzheon, a clinical- I hope we will continue to feature prominently stage biopharmaceutical company focused on with such industry wide recognition.” brain health, memory and aging.

Bernhardt Trout Timothy Raymond F. Baddour, ScD, Wright Vikramaditya (1949) Professor of Executive G. Yadav Chemical Engineering, Vice President, Assistant Professor, Massachusetts Institute Translational Sciences, Calibr Department of Chemical of Technology and Biological Engineering, Timothy began his career in academia and The University of Bernhardt’s laboratory focuses on the worked his way up to Chief of the Division of British Columbia development and application of molecular based Rheumatology and Clinical Immunology at computational and theoretical methods for the the University of Pittsburgh – and was awarded ‘Biosynthonics’ – a novel paradigm for design of chemical systems and processes. He is an endowed Professorship in 1998. He has discovering and synthesizing potent bioactive also Director of the Novartis-MIT Center for previously worked in clinical development at molecules – is a focus of Vikramaditya G. Continuous Manufacturing, which develops Pfizer and Novartis, and also serves as a scientific Yadav’s research group. The group also focuses new technologies to replace traditional batch- advisor to several organizations, including the on formulation and assembly of drugs and their based processes. Bill and Melinda Gates Foundation. translation to certain pathological conditions.

www.themedicinemaker.com 18 Bill 20 Ibraheem Lundberg “Ibs” Mahmood 19 Rino Rappuoli Chief Scientific Officer, President and Chief Executive Chief Scientist and Head of External CRISPR Therapeutics Officer, DrugDev R&D, GSK Vaccines Bill has extensive experience across all aspects Ibs hopes to make clinical trials faster, Rino is the author of over 600 research and phases of drug development in both academic smarter and more efficient. DrugDev was papers and has introduced a number of novel and industry settings. He was previously vice recently chosen to develop and host the scientific concepts, with widespread impact president and head of translational medicine Investigator Databank, a global collaboration on the vaccines industry, including genetic at Alexion Pharmaceuticals, where he oversaw involving several large pharma companies. detoxification (1987), cellular microbiology the progression of numerous compounds from Ibs also co-founded the DrugDev Innovation (1996), reverse vaccinology (2000), and the early research to clinical proof-of-concept. Lab, a technology incubator to identify and pangenome (2005). Rino is the former Global Before that, Bill held senior positions at Taligen, develop innovative clinical solutions. Head of R&D at Novartis Vaccines. Antisoma, Xanthus Wyeth and Genzyme.

16 Keith Thompson 15 J. Craig Venter 17 John Talley Chief Executive, Founder, Chairman and Chief Chief Scientific Officer, Euclises Cell and Gene Executive Officer of the Pharmaceuticals Therapy Catapult J. Craig Venter Institute

John is a co-inventor of eight marketed drugs, Keith established a team of over 100 cell and John Craig Venter has made significant with several still in development, and has been gene therapy experts in laboratories in London contributions to genomic research and his honored with the PhRMA Discoverers Award. and is now building a large-scale manufacturing team has sequenced hundreds of genomes. This past year, John has been working on the center. Keith joined the Cell and Gene Therapy He’s authored more than 280 research papers role of prostaglandins on immune surveillance Catapult from the Scottish Blood Transfusion on subjects such as environmental genomics, in tumor micro-environment. “I am genuinely Service where he was National Director, focused the first complete diploid human genome, and delighted to be chosen for the Power List for a on modernizing the blood supply from vein-to- the creation of the first self-replicating bacterial second time,” he says. vein and expanding into cell and gene therapy. cell constructed entirely with synthetic DNA. The Power List 33

14 Gert Riethmueller Professor Emeritus of Immunology, Ludwig-Maximillian University of Munich 13 Martin Van Trieste Gert is a prolific researcher with a strong Senior Vice President of Quality, Amgen interest in autoimmune diseases and cancer. He is considered a pioneer in tumor immunology A judge praised Martin for his quality leadership in biologics, and more widely he is known and was one of the first to introduce monoclonal throughout industry for his work on advancing quality assurance and helping to ensure a more antibodies and immune cells into medical reliable supply of high-quality medicines. At Amgen, Martin is responsible for aspects such as practice. In 1994, he published a landmark quality assurance, quality control, compliance and operational excellence, but he is also actively clinical study in The Lancet on the treatment involved with trade organizations including, but not limited to, the United States Pharmacopeia, of metastatic colon carcinoma, which led to the Pharmaceutical Manufacturers and Researchers of America, and the Pharmaceutical Quality approval of the world’s first monoclonal cancer Research institute. He is a founder of Rx-360 – and remains a board member today. antibody (17-1A).

11 Peter Seeberger Director at the Max-Planck Institute for Colloids and Interfaces, and 12 Shinya Professor, Yamanaka Free University Director and Professor, Center of Berlin for iPS Cell Research and Application (CiRA), Kyoto University Peter’s research covers a broad range of topics from engineering to immunology, and has been documented in over 420 peer-reviewed Another returnee from last year’s Power List; Shinya has stormed journal articles, more than 40 patents, and more than 750 invited lectures. into the top 20 for his work in stem cells. After reprogramming adult His work on continuous chemistry, which he hopes will make drugs mouse (2006) and human (2007) somatic cells into what are now against malaria and HIV more affordable, won him and his collaborator, called induced pluripotent stem (iPS) cells, he was awarded a 2012 Andreas Seidel-Morgenstern, the 2015 Humanity in Science Award. “It’s Nobel Prize. In the past year, Shinya has been working on an iPSC motivating to be able to appear on this list twice!” says Peter. “Since the stock project in which iPSC clones are established from donors with last list, we’ve had two big breakthroughs: the proof-of-principle for an a homologous HLA haplotype. “Homologous HLA lessens the risk expanded synthetic vaccine against S. pneumoniae and the development of of transplant rejection and promises quality-assured iPSCs for future a continuous process to produce the most important HIV medication. We cell therapies,” says Shinya. “We started distributing iPSC stock clones are also about to submit several manuscripts describing vaccine candidates to corporate and medical institutions last year.” against dangerous hospital acquired infections.”

www.themedicinemaker.com 34 The Power List

10 Kiran Mazumdar-Shaw Chairperson and Managing Director 9 Robert of Biocon A. Bradway Chairman and Chief From a tiny start-up company launched in 1978 with seed funds of Executive Officer, Amgen Rs 10,000 and run from her garage, Kiran Mazumdar-Shaw has grown Biocon into a leading producer of generics, floated on the In 2006, Robert joined Amgen as Vice President, Operations Strategy. stock market in 2004 with a valuation of $1.1 billion. And Kiran He was appointed to the Amgen Board of Directors in October 2011, has no plans to slow down– aiming to bring revenue up to the $1 and became Chairman in January 2013 and CEO in May 2012. billion mark by 2018. She is also known for her philanthropic Before Amgen, he was a managing director at Morgan Stanley in work, through the Biocon Foundation, which provides healthcare London where he had responsibility for the firm’s banking department for marginalized communities. and corporate finance activities in Europe.

8 Carol Lynch 7 Thomas Cech Global Head of Biopharmaceuticals Distinguished Professor, & Oncology Injectables, Sandoz University of Colorado Boulder

Judges praised Carol for her role in the biosimilars industry and in Thomas holds multiple roles. He is a scientist with the Howard Hughes the launch of the first US biosimilar. She joined Sandoz in 2014 Medical Institute, and also a Distinguished Professor at the University and is focused on leading efforts in the development, manufacture of Colorado and Director of the university’s BioFrontiers Institute. and commercialization of biosimilars and oncology injectables. In His research speciality is RNA – specifically the structure and February 2016, she was elected as Chair of the European Generic mechanism of long noncoding RNAs and RNA-protein complexes Medicines Association’s European Biosimilars Group, where she will – and he shared a Nobel Prize in Chemistry for the discovery of the be working to improve stakeholder awareness and understanding of, catalytic properties of RNA in 1989. A more recent achievement is his and confidence in biosimilars and advocating for policies that support induction to the 2016 class of Fellows of the American Association the growth of the biosimilars industry. for Cancer Research. The Power List 35

4 Raman Singh President, Mundipharma Asia Pacific, Latin America, Middle East and Africa

During his career, Raman has worked in many markets including Thailand, Singapore, South Korea, Australia, the US and the UK. He has been in his current role since October 2011, where he oversees all aspects of the Mundipharma business across his territories, which operate as a network of independent companies. “It’s been a fascinating opportunity to change the way a company is looked at as a business. When 6 Anthony Fauci I started in 2011, the emerging markets contributed to less Director, US National Institute than one percent in terms of global turnover. Now, we’re of Allergy and Infectious close to 14 percent – and we’re aiming for around 30 by Diseases (NIAID) 2017,” he says. Prior to Mundipharma, Raman was the Vice President Anthony Fauci has been vocal on the challenges of important global of Commercial Operations for Emerging Markets at health issues, including Ebola and Zika, and he has been instrumental GlaxoSmithKline. in US efforts to tackle these outbreaks and to quell public panic. Despite his heavy workload, Fauci is also known for donning hazmat suits to directly work with US Ebola patients. He is also one of the most prolific researchers of this century; in a 2016 analysis of Google Scholar citations, he ranked as the 18th most highly cited researcher of all time.

5 David Baltimore President Emeritus and Robert Andrews Millikan Professor of Biology, California Institute of Technology

David Baltimore’s love for experimental science was born after spending a summer at the Jackson Laboratory in 1955. And since then his achievements have been numerous, including a Nobel Prize in 1970 for the discovery of reverse transcriptase, which implied that cancer could be caused by genetic means, which was a wide-open question at the time. Today, his laboratory at Caltech focuses on the basic investigation of the development and functioning of the mammalian immune system, as well as translational studies using viral vectors.

www.themedicinemaker.com 36 The Power List

2 Catherine Tuleu Reader, University College London School of Pharmacy

Catherine was featured in the 2015 Power List, but this year she has stormed her way into the top two. Catherine is a UK-qualified French pharmacist and her first experience of University College London (UCL; The School of Pharmacy, University of London until 2012) was as a postdoc student, and then a research assistant in the Department of Pharmaceutics with Professor Michael Newton. After a stint as a lecturer at Kingston University, she returned to UCL in January 2003 as Pfizer Paediatric Drug Delivery Lecturer for the then newly established Centre for Pediatric Pharmacy Research, of which she is now director. She was promoted to reader in 2011. Catherine has traditionally been interested in gastrointestinal drug delivery, particularly colonic targeting, but since 2003 her main focus of research has been on drug delivery systems for neonates, infants and children. “In the last year, my research has focused on the most challenging pediatric subset: neonates – with a focus on those in low resource settings, as well as formulating for rare and neglected diseases,” says Catherine. She has been involved in various projects ranging from repurposing drugs, designing fast disintegrating tablets for a nipple shield to dose babies while 3 Harold Varmus breastfeeding, to exploring the rectal route of drug delivery, and Lewis Thomas University Professor, gaining knowledge on the acceptability of flexible solid oral dosage Weill Cornell Medical College forms, such as multiparticulates. She has also been working on establishing methods to assess the taste of medicines in vitro. Harold Varmus originally obtained a degree in English literature – As well as her work at UCL, Catherine is involved in a number of with a desire to be a writer – before deciding to pursue a career in paediatric initiatives; she leads the European Paediatric Formulation medicine. He worked at a missionary hospital in India and then turned Initiative, and is an external technical expert on pediatric formulations his attention to research – and has since been involved in numerous for EMA, the UK’s MHRA and WHO. She is a partner in the FP 7 groundbreaking discoveries connected to cancer. In 1989, he was the funded network of excellence Global Research in Paediatrics (GRiP). co-winner of a Nobel Prize (alongside Michael Bishop) for the discovery of the cellular origin of retroviral oncogenes – how malignant tumors are formed from normal cells. As well as his research accomplishments, Harold has held a number of high-level positions. From 1993 to 1999, he was director of the US National Institutes of Health (NIH) where, among other achievements, he was involved in establishing PubMed Central in order to enhance access to scientific papers through the Internet. Since leaving NIH, he has been president of Memorial Sloan-Kettering Cancer Center in New York, a co-chair of President Obama’s Council of Advisors on Science and Technology, and director of the US National Cancer Institute, a post he held until March 2015. In April 2015, Harold took up his role at the Weill Cornell Medical College faculty. He is also a Senior Associate Core Member at the New York Genome Center where he promotes the use of cancer genomics throughout the New York region. 1 Heather Bresch Contributions to industry & healthcare Chief Executive Officer and Executive Director, Mylan • Contributed to the development of the 2003 Medicare Prescription Drug, Improvement, and Modernization Act. Heather has spent her entire pharma career at Mylan. She became • A strong advocate for the Generic Drug User Fee Amendments. CEO and Executive Director of Mylan in January 2012, but her • Actively involved in the Generic Pharmaceutical Association first job at the company in the 1990s was anything but glamourous (GPhA) – in February 2016 she was elected to serve as chair of – she was first employed as a data-entry clerk, tasked with typing GPhA’s board of directors; she previously served two one-year out labels. Over the years, she moved onto other departments terms as the chair of the association in 2004 and 2005, and two within the company and eventually stepped up to executive roles, one-year terms as vice chair in 2003 and 2006. including Senior Vice President of Corporate Strategic Development, • Championed initiatives to raise awareness of anaphylaxis, Head of North American Operations, Chief Operating Officer particularly in schools. and Chief Integration Officer, where she led the integration of • Championed initiatives to give patients in developing countries Matrix Laboratories and Merck KGaA following acquisitions. Her greater access to HIV medicines. appointment to CEO was announced in 2011 and she is one of the first women to take the reins of a western pharma company. Her Judge’s comment: goals as CEO are to double the size of Mylan’s product portfolio, “Mylan and Heather Bresch have been involved in a lot of manufacturing capacity and earnings by 2018. drama in the past 12 months, including fighting a hostile Heather has been included in Fortune magazine’s annual 50 Most takeover bid from Teva and then failing to acquire Perrigo Powerful Women in Business list since 2012. in Mylan’s own hostile takeover attempt, but she is also undoubtedly a powerful leader and has greatly influenced the generic drug industry, among other things.”

www.themedicinemaker.com 38  The Medicine Maker × Catalent Applied Drug Delivery Institute

well as to stockpile the finished patient Instead of pushing out large batches of More Trial, kits,” says Joseph. “It is also industry packaged patient kits to clinics based on practice to overshoot expected targets preliminary estimates, a continuous flow Less Error – often by 200 percent or more – which of kits is generated and they are only sent generates waste of both the product out in accordance with patient demand,” The pressure for increased being trialed, and also the comparator says Joseph. efficiency pervades the products.” But the opposite can also Regional GMP facilities each pharma industry, including happen in that demand may turn out hold small stocks of primary packed the clinical trials sector, to be far higher than expected, which material, or “bright stock”, which are where traditional supply can lead to stock outs, putting patients then secondary packaged, labeled and models can lead to or the whole study at risk depending on released only in response to specific overstocking, waste and the severity of the delay. requests from clinical sites, allowing higher costs. Is there a more Another big challenge comes with companies to adapt to slower or faster effective supply strategy? changes. Indeed, the inflexibility of the recruitment in different countries. Since traditional system hinders one’s ability the bright stock is locally held prior to The traditional approach to clinical to modify the trial design in response labeling, shipping times also tend to be trials’ supplies involves a centralized to early data. There are also added faster and clinical sites can receive their supply model, whereby primary packed difficulties when attempting to modify supplies in a matter of a few days. materials are stored in bulk at a central the trial design, such as the addition of warehouse and labeled with multi- new countries or territories. It’s clearly lingual booklets, allowing central stock not the most efficient method and, as to be shipped to any site, regardless of Joseph adds, an inefficient supply chain local language. It’s a well-used model “exponentially increases the cost of “A fixed model costs that appears to make sense. But does it? running trials”. Even the multilingual Wetteny Joseph and Stephen Flaherty booklets themselves are a problem; not more than a have both been instrumental in building only can there be delays in getting the Catalent’s clinical supply services. Joseph text approved (and a delay from one demand-led system is President of Clinical Supply Services, country will delay all of the booklets) but originally started out by working in but, from a usability point of view, it because it’s so the finance sector before transitioning to can also make it awkward for patients clinical supplies and using his experience to find the relevant information. wasteful.” to examine the cost drivers in the industry. Flaherty, on the other hand, Tradition on trial: the DLS approach has been leading the development of A few alternatives to centralized supply Catalent’s demand-led supply offering, have emerged in recent years, including One might think that a central supply which both he and Joseph believe is a far the ‘Just in Time’ model. “In reality, this model would save costs due to its fixed, more flexible approach to clinical trials. is just an enhancement on the traditional predicted demand and budget, but this model whereby stocks of partially isn’t actually the case. “A fixed model Trials and tribulations finished patient kits are labeled and costs more than a demand-led system There are many problems with a held at central depots, but there’s some because it’s so wasteful,” says Joseph. centralized supply model, most of customization that happens just before “In the traditional model, patient kits which are caused by its inherent shipment, such as adding an investigator are distributed to clinical sites based on inflexibility. Supplies are sent to sites name. It still has some of the drawbacks recruitment forecasts, but we all know that based on preliminary forecasts and of the traditional model in that you need patient recruitment is unpredictable, so planned recruitment at the start of the to build up bulk supplies,” says Flaherty. stock often goes unused. And, as already program. “This model is very static and Instead, Catalent is developing a indicated, there are also extra costs and linear – and tends to require long lead demand-led supply (DLS) approach, time delays if anything needs to change.” times in order to generate the batches which is a decentralized approach to Furthermore, DLS eliminates the and the unique labeling information, as clinical supply. “It’s fast and efficient. need for a multilingual booklet, which The Medicine Maker × Catalent Applied Drug Delivery Institute  39

Catalent Clinical Trial Supplies Under the Lens

5... that’s million a total of over patient clinical kits Over ... which equals more than Catalent have supplied over 15 kits 80 shipped every 5,000 minute countries receive clinical trial 200,000 studies in the past clinical trial ... that’s a new trial every alone supply shipments 5 HOURS years every year 3 is replaced with single panel labels. staged at regional facilities, you can today’s complex and far more sophisticated “Each label can be patient- and country- use it across multiple protocols because clinical trials. So far, it’s drawn a lot of specific, so it’s much easier for patients you’re only secondary packaging and interest because of its flexibility and speed, and clinic staff to use rather than finding labeling it when the demand arises,” and the fact that it can be used for virtually the right page in a thick booklet,” says says Flaherty. “Also, the flexibility of any study, so Joseph and Flaherty are also Flaherty. “As soon as you have a label DLS permits items with the shortest positive about the future. approved for a given country, you could expiry time to be used first; thus, with “Importantly, I think DLS also reflects supply to that country, without the need DLS, efficiency is increased, enabling the growing importance of the ‘voice of to wait for the final, approved label material with varying expiry dates to be the patient’ in the pharma industry,” says text from the other countries within a used much more effectively.” Joseph. “We need to meet the needs of booklet, which can be a bottleneck and DLS is a relatively new model of individual patients, including ensuring delay start up of a trial.’’ supplying clinical trials, but both Joseph that they are not inconvenienced or placed Another aspect of improved efficiency and Flaherty are positive that it is an at risk when patient kits are not supplied associated with DLS is the ability to innovation genuinely needed by the on time. DLS allows this – it’s a win for pool supplies. “With the bright stock industry in order to meet the challenges of the patient, not just for the industry.”

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Technology Quality Compliance

42-45 Beyond Keeping Up Appearances Manufacturers often ask if they need to coat their tablets or not. Coated tablets certainly look nicer than their uncoated counterparts, but is that all there is to it? 42 Best Practice

multiparticulates, but its usage varies. one product it’s easy enough to use it to Beyond Keeping Most tablet manufacturers choose to film coat another. However, if you have a drug coat every product, whereas others will in a solid dosage form that does not require Up Appearances only apply a coating if they feel that it is a specialized coating then an obvious essential. The most popular reason for question is, should you coat or not? You have the perfect drug applying a film coating is to enhance and and the right packaging to protect the dosage form, provide branding Creating the perfect finish … protect it. All is well until or modify the drug release profile. For It seems reasonable to assume that the medication reaches the example, enteric coatings can be used to choosing not to film coat a tablet patient, who habitually pops protect a tablet from dissolution in the will save money, but I believe this is the tablets into another stomach, or extended release coatings can a misconception when the multiple container for easy storage or (as the name suggests) provide drug release benefits of coating are considered, leaves them exposed to the over an extended period of time. alongside the fact that the cost per tablet atmosphere. Film coatings are The film coating process is a proven is tiny. An uncoated tablet can still be more than just a pretty face. and well-used practice, whether using a therapeutically effective – but only if the company’s own equipment or through patient takes it. By Charlotte Miller a contract manufacturer. A variety of Tablet design is becoming an different coatings are available and, increasingly important issue for Film coating is a well-established generally speaking, most coatings work in manufacturers, especially given that technique in the pharma industry for the majority of standard coating machines; polypharmacy, the practice of prescribing solid oral dosage forms, like tablets and so once you’ve invested in the process for multiple medications to the same patient, Best Practice 43

“The FDA, in particular, has been paying a lot of attention to tablet design...” is becoming more common among the elderly population. Good design can be used to provide product differentiation, avoid medication mix-ups and deter counterfeiting (1). It can also affect patient compliance. When looking at a tablet, you Myth Busting that previously used solvent coating need to ask if patients will want to take it. are transitioning the same products to The FDA, in particular, has been “A coating will impact my drug aqueous coatings. paying a lot of attention to tablet design release profile.” – and has just recently (April 2016) issued Immediate release coatings do not “I’m concerned that pigmented guidance on Safety Considerations for impact drug release; there are specific coatings will lead to regulatory issues.” Product Design to Minimize Medication coatings formulated to extend or delay Yes, there are regulations for Errors (2), in addition to earlier draft drug release and coatings can also be ingredients that mean certain pigments guidance on Size, Shape, and Other applied to multiparticulate dosage forms. may not be approved for use in all Physical Attributes of Generic Tablets markets, and there may be aversions and Capsules (2014). One good reason “A coating might not work with to some colors in certain markets. to add a coating to a previously uncoated my equipment.” Nevertheless, there are palettes of tablet would be to improve patient Optimization of the process is key, as the colors that are acceptable for use in compliance through brand identification best coatings will work across a range of the major international markets – and and to bring the tablet into line with the equipment and coating specialists work expert coating suppliers should be able FDA’s current recommendations. closely with machine manufacturers. to advise on these. Purely from an aesthetic point of After all, it’s pointless to develop a view, uncoated tablets are uninspiring. coating that only works on one machine. “My product cannot be coated.” In addition, an especially rough-looking If there are mechanical problems, they Great! Because coating specialists love a tablet can appear as poor quality; it’s can usually be resolved easily. challenge! And most have some special human nature to question the condition skills up their sleeves to demonstrate of something with a poor appearance, “I don’t want to use organic solvents.” that the seemingly “impossible to coat” especially a medicine. Some uncoated There are two types of coating – can indeed be coated. Even tablets that tablets also have a surprisingly bad odor. aqueous and organic, the latter involves are highly sensitive to water can be Any negative aspect of a medicine can use of volatile solvents, and historically, coated (it’s even possible to coat orally affect patient compliance – if the patient many tablets were coated using organic dispersible tablets that disintegrate has a poor impression of their medicine the solvent, due to their sensitivity to in seconds). Some tricky products moment they take it out of the packaging, it water. But coatings have advanced so may be more testing to coat and the could be destined for failure simply because much that aqueous is now the preferred biggest challenge would be an API the patient doesn’t take it as prescribed. – and most common – coating method that is sensitive to both temperature Moreover, if patients do get beyond the around the world. Many companies and water.

www.themedicinemaker.com 44 Best Practice

Coat of Regulations Some uncoated tablets have been on the market for a long time, and I’ve By Kevin Hughes, seen companies add a coating to a Regulatory Affairs Manager, Colorcon previously uncoated tablet to improve the product’s position in the market Back in the 1950s and 1960s, before the and present a stronger brand identity. advent of film coatings, sugar coatings This is a bigger regulatory change than were widely used on pharmaceuticals. changing a coated tablet, because you A small number of companies still use are adding a new component rather sugar coating, but for the most part than changing one component to film coating is the most widely used another. There needs to be some process today. Film coatings continue stability work, which any company to advance, so even if a tablet could would want to do anyway, and you not previously be coated, it does not will need to assess the impact on drug mean that it cannot be coated today. In release both in vitro and, in rare cases, addition, there is potential for improving in vivo. However, you may encounter tablets that currently use an older more hurdles for BCS Class 2 and 4 technology coating. Some companies drugs due to their poor solubility and have concerns about changing a coating permeability (the BCS classification due to the regulatory impact. But from system categorizes drugs based a regulatory standpoint, changing a upon their solubility and intestinal be able to achieve a bio-waiver for cosmetic coat is relatively simple since permeability, i.e., how easy it is for BCS class 1 and 3 drug substances, it’s not expected to impact drug release. them to be absorbed by the body) and if you can justify that demonstrating For example, changing a white coated you may require a Type 2 variation, bioequivalence is unnecessary. In tablet to a red color coated tablet is seen which will involve bioequivalence general, regulators like to see changes as a Type 1A variation in Europe. This is work. Companies usually try to avoid that improve product quality and a minor change; drug companies make this due to the work involved, but patient compliance. these changes all the time and can even for some drug substances there are There will always be a workload and a bundle up all of their Type 1A and 1B options you can explore to keep the cost to making a variation – but isn’t that changes together in one submission. changes as 1B. For example, you may what regulatory departments are for?

aesthetics and the smell, they often find tablets and even capsules are more likely to ability, but some are better than others. A that uncoated tablets are more difficult to become stuck (3,4). particularly pungent odor may start to come swallow. They can be chalky or gritty, and And though there are a few approaches through the coating with time, in which may stick in the throat because they start to that can be used to make an uncoated tablet case a coating that has been specifically disintegrate the moment they are exposed more palatable (for example, adding color, designed to conceal odor may be needed. to moisture. A film coating gives the tablet taste masking ingredients or changing the a smoother, more finished appearance and shape to make swallowing a little easier), Contingency coating helps maintain the tablet integrity. As generally speaking, your options are more Aside from maintaining appearances, human beings, we tend to perceive glossier limited compared to simply adding a film film coatings offer protection, helping things as being more slippery and therefore coating. Film coatings give you access to to prevent tablet breakage and acting easier to swallow – and adding a coating is not only a wide range of colors, but also to as a barrier against moisture and other known to enhance swallowability and aid other useful functionalities. Most coatings environmental conditions. The protective oesophageal transit; in contrast, uncoated offer some sort of taste- and odor-masking aspect is a well-known benefit – but is Best Practice 45

it needed if you are planning on high- then you’ll know it’s a challenging in new ones! It’s fair to say that genuine quality packaging? A common reason environment. Cleaning is a significant reasons not to coat are rare. All coatings, cited by manufacturers not to film coat part of pharmaceutical manufacturing regardless of functionality, will improve their tablets is a belief that packaging to prevent cross-contamination. In the tablet appearance at the very least. alone will suffice. After all, if you are using the case of uncoated tablets, dust is And good tablet design is no longer individual blister packs, then why go the generated as the tablets move through the simply ‘nice to have’. The FDA’s recently extra mile (or spend the associated extra manufacturing lines, which necessitates published guidance continues to drive costs) by coating individual tablets? extensive cleaning. manufacturers to pay more attention to The truth is, once a package is in the tablet design and differentiation. hands of a patient, anything can happen! We now see most new tablets being film Many patients, especially those taking coated; virtually all NDAs are coated. But multiple medications, decant their tablets you don’t need to stop at new tablets – there into tablet boxes or bottles, and others may “There are a number are a huge number of approved tablets on just take a tablet out of the blister pack as the market that are currently uncoated a reminder and leave it on their bedside of approved tablets because of limitations during the time table all day. Most people assume that a they were approved. Most companies don’t given drug will do its job 100 percent of on the market that like to make changes to already-approved the time – and give less thought to the medicines because of regulations, but it’s storage conditions of medicines than they are currently not as difficult as you might think (see do to food. It’s surprising how many people Coat of Regulations). Giving an old tablet keep medicines in a nice moist bathroom uncoated because of a fresh coat can grant it a new lease of life cupboard; although it may not directly and, more importantly, it can improve affect the safety of the medication, it could limitations during patient compliance as well as add brand reduce its efficacy. value. And patient safety should always the time they were be at the top of the agenda. Safety at work We’ve examined the impact that coated approved. ” Charlotte Miller is a Tablet Design tablets have on patients – and that is Technologist, BEST – Unique Tablet typically the first consideration that springs Design Service – at Colorcon, to mind. But from the manufacturer’s Dartford, UK. perspective, a key consideration for film Coating a tablet adds minimal cost, and coating is safety. Once a tablet is coated, the financials are offset by savings that References it’s safer for anyone else who might handle can be attributed to the coating benefits 1. C. Miller, “Dare to be Different,” it. Nurses and healthcare workers often throughout the production line. Coated The Medicine Maker (February, 2015). handle bulk or unpackaged tablets and tablets reduce dust, so your cleaning burden 2. FDA Guidance for Industry, “Safety although they are supposed to wear gloves, will be lower and workers better protected. Considerations for Product Design to Minimize it’s not guaranteed. Absorption of active Another side benefit is that glossy, Medication Errors,” (April, 2016). ingredients, through the skin can cause coated tablets also tend to run faster http://1.usa.gov/1SMyvSN rashes or other problems. Extreme cases through packaging lines because they are 3. C. Wilson et al., “Opadry II / Opadry / Opaglos are rare, but if the tablet was coated, then more slippery than uncoated tablets. And 2”, poster presented at AAPS, Salt Lake City the risk is diminished. Of course, you reject rates can also be down because the (23- 26 October 2003). could also make uncoated tablets safer tablets are less likely to break (5). 4. The Patients Association, “Survey of Medicines by educating people about proper storage Related Care of Residents with Dysphagia in and handling of medicines (no easy task), Is it possible to be uncoated Care Homes,” (October, 2015). but the health hazards of uncoated tablets I’ve focused on all of the reasons why I http://bit.ly/1N8nyOQ also apply to pharma workers, particularly think it makes sense to coat. Are there 5. Colorcon, Application Data, “Investigation into those on the packing lines. any reasons not to coat your tablet? I the Flow Properties of Coated and Uncoated If you’ve ever worked on (or visited) hear a few common reasons (see sidebar: Tablets and Its Relevance to Blister Packing a packing line with uncoated tablets Myth Busting), but I’m always interested Efficiency,” (2009). http://bit.ly/25ZGhCv

www.themedicinemaker.com Waseem Asghar Meet the Winner

Waseem Asghar Could it be you in 2017?

Waseem Asghar, Assistant Professor at the Analytical science has been at the heart of many Departments of Computer Engineering & Electrical scienti c breakthroughs that have helped to improve Engineering, Computer Science, and Biological people’s lives worldwide. And yet analytical scientists Sciences, Florida Atlantic University, USA, has rarely receive fanfare for their humble but life- been chosen as the winner of the 2016 Humanity in changing work. e Humanity in Science Award was Science Award for “development of a new paper and launched to recognize and reward analytical scientists exible material-based diagnostic biosensing platform who are changing lives for the better. that could be used to remotely detect and determine Has your own work had a positive impact on people’s treatment options for HIV, E. coli, Staphylococcus health and wellbeing? Details of the 2017 Humanity aureus and other pathogens.” in Science Award will be announced soon. Waseem will be presented with a humble prize of $25,000 during an all-expenses-paid trip to Analytica 2016 in Munich, and his work will feature in an upcoming issue of e Analytical Scientist. @Humanityaward Humanity in Science Award

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Economic drivers Emerging trends Business strategies

48-49 Making Small Biotech Work How can small companies convince investors to fund promising compounds? By having a solid regulatory strategy, according to Bruno Speder. 48 Business

Making Small Biotech Work

Innovation is increasingly coming from small biotechs, but such companies rely on external funding to develop the compounds. A solid regulatory strategy is essential to convince investors to fund the further development.

By Bruno Speder

Historically, it’s been the large pharmaceutical companies who have obtaining proof of been able to bring treatments to the “Thinking about all concept and reaching market but in the 1990s, industry phase II, is a regulatory strategy still started to see a rise in the number of of this early on will needed? The answer is definitely marketing authorization applications “yes”. With big pharma and investors coming from smaller companies help to optimize becoming increasingly cautious – and (particularly biotechs). During this era, the biotech world becoming more it was traditional for a company to work your development.” competitive – small companies need to alone in taking its compound all the way be more strategic than ever before, and from research to approval, but this has early regulatory due diligence is a must. changed in the past years. companies to take a drug through Even if a small company is intending Pipelines have dwindled and drug to marketing authorization approval to sell a compound rather than taking development costs have risen sharply; in without obtaining external funding. it to marketing authorization approval the 1950s, you could put around 50 drugs Unfortunately, big pharma companies personally, they must be able to on the market with $1 billion in R&D aren’t looking for compounds in demonstrate that the compound is as spending. Today, $1 billion isn’t enough preclinical testing; in general, it is promising as possible to clinch the to get even one drug on the market (1) – expected that the biotech will already deal (and to get the best possible price). see Figure 1. Since 2000, there has been have taken the compound through The same is true if you’re looking for a big increase in the number of industry clinical proof of concept – which still investment – investors want to know that acquisitions, licensing deals and other involves a lot of work and cost. Biotechs the compound is approvable. commercial partnerships. Big pharma can often get funding for promising For the inexperienced company companies still have their own internally compounds through venture capitalists, (and even the experienced company), generated R&D projects, but they are but again investors prefer to have proof developing a regulatory strategy can also increasingly relying on innovation of concept data. be riddled with pitfalls. The most from biotech companies – and, in fact, in important aspect is to remain aware of several pharma companies, a large part Settling on a strategy the long term goals and to have a clear of the pipeline consists of compounds Implementing a regulatory strategy to picture of where you want to go with that have been acquired from small help ensure that a drug in development you compound. A target product profile companies or biotechs. meets the final specifications for (TPP) is an excellent tool to base yourself Today’s huge drug development approval is critical. But given that most on while developing the regulatory costs mean that it is difficult for small small companies have their eyes on strategy of your product. Is your Business 49

Overall trend in R&D eciency (in ation adjusted) company developing a biotech or chemical product? What is the intended indication? 100 Which indication is best

suited to have clear proof 10 of concept? The indication in which you might have the clearest proof of concept data might ugs per billion US$ R&D spending* 1.0 not be the indication in which you might eventually want to market the product. It Number of dr 0.1 is critical to keep the overall goal of the 1950 1960 1970 1980 1990 2000 2010 compound in mind; will you be selling your compound after a certain stage in the development, or will you bring the Figure 1: Overall trend in R&D efficiency (inflation adjusted). Adapted from (1). compound to the market yourself? It is also important to consider the intended market for the drug. For example, if you’re developing a drug Post for use in the tropic regions, it is key to Pre clinical testing Clinical development MAA review marketing (1-3 years) (2-10 years) (1-2 years) design your stability program around surveillance that. In that case, it is also critical Formulation lab testing Phase IPhase II Phase III MMA/NDA/BLA to engage in early discussions with review regulators in that region and to pay Short term animal studies Long term animal studies close attention to local regulations. You Initial Synthesis MAA submission MAA approved should never assume that the North American or European regulations will suit all markets. Thinking about all of this early on will help to optimize your Figure 2: The drug development pathway. Adapted from M. Dickson and J.P. Gagnon, "Key Factors development, as you can decide which in the Rising Cost of New Drug Discovery and Development," Nature Reviews Drug Discovery 3, regional regulations should be taken 417-429 (2004). into account. In addition, it’s worth looking at whether your compound is I single ascending dose/multiple Scientific Advice in order to de-risk your eligible for any kind of special status or ascending dose study is fundamental development program. This gives you fast track for approval in your selected to your clinical development plan. It is a chance to approach potential venture market. This can be very beneficial if critical to have robust safety data at the capitalists and partners earlier because your compound works in multiple intended therapeutic dose to efficiently you will be able to show that the (non) indications – you can pursue the special move to the next stages. Insufficient clinical program has been validated by status for one indication to potentially or incomplete phase I data will create a regulatory authority. accelerate time to market (and return on concerns with potential investors. investment). It may not be the ultimate Even getting a drug to phase II Bruno Speder is Head of Clinical intended indication for your compound, can be extremely costly. As described Regulatory Affairs, at SGS - Life but it is one way to start getting return above, it is important to be as thorough Sciences, Belgium. on investment a little faster – and again as possible in the early stages, but you could be enticing for investors or buyers. may find yourself limited by the available Reference Speed to market is important, but budget. In this case, it is necessary to 1. J.W. Scannell et al., “Diagnosing the Decline robust data is critical. Trying to reach prioritize the essential aspects of your in Pharmaceutical R&D Efficiency,” Nature phase II as quickly as possible is very development. In addition, it is useful Reviews Drug Discovery 11, 191-200 (2012). tempting, but a well-designed phase to engage with regulators early through doi:10.1038/nrd3681

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Sitting Down With... Christian Schneider, Director of the National Institute for Biological Standards and Control (NIBSC), UK. Sitting Down With  51

You took up your new role at NIBSC on trial authorization for the same antibody to accommodate these very specialized April 1 – how does it feel? in Germany. The German trials never products. Advanced therapies are I’m very proud to be the Director of NIBSC went ahead, but we still had to examine mainly made by small companies, – it’s a bit like coming home to biologicals. why we had approved it and look again such as spin-offs from universities, or The early part of my career was spent as to discover if there was anything in the by academic groups, but the European a post-doctoral researcher in the Max data that should have warned us about regulatory system was mainly built on Planck Institute in Germany, working in the dangers of this drug. We scrutinized “big pharma products”. immunology, but later I got involved with everything, but in the end we found that At present, the regulatory requirements regulatory affairs when I became a clinical all of the data were generated according for biologicals are very high – and rightly expert in the area of biotechnology-derived to the then state of the art – and all our so – but some of them may or may not medicines at the Paul Ehrlich Institute decisions were appropriate. fit advanced therapies, and smaller (one of the two German drug regulatory Nevertheless, the event drew attention companies may find it more difficult to agencies). Directly before NIBSC, I was to the fact that standard models for testing meet them. I’m not suggesting we should Medical Head of the licensing division medicine safety – particularly animal have one standard for big companies and at the Danish Medicines Agency in models – are not always completely suitable another for small ones; the regulations Copenhagen, and though it was very for cutting-edge biotech products. We had should apply to all products in the same enjoyable, I missed working more in- to adapt the system to help ensure that way. However, I do think we need to find depth on biologicals. I’m delighted to be the risk for similar events ever happening the right balance in regulating advanced back in this area, especially as NIBSC has again was as small as absolutely possible, therapies. a great deal of sought-after knowledge without, at the same time, hindering in biotechnology. the development of advanced therapies. What do you hope to achieve If we’d over-reacted and prevented the at NIBSC? What is the most rewarding aspect of development of all mAbs then we would I want to expand NIBSC’s network of being involved in regulation? also have prevented some of the major expertise by collaborating with academia. It’s rewarding to know that the application breakthroughs that we’ve seen in the last Academic colleagues have a lot of of your knowledge and expertise – and ten years. There are always new products knowledge, but often lack regulatory the resulting decisions – make a huge coming through and new mechanisms of experience; conversely, in some areas, difference to people. Not just to individual action being found, so there will always our knowledge would benefit from patients, but also – in the case of vaccines, be challenges. You can never reduce the collaboration with academia – it’s a win- for example – to healthy people, including risk to absolute zero, but we now have win situation. children. And though it is rewarding, it processes in place to ensure the risks are In May, NIBSC will be celebrating is also challenging. A medical doctor more fully understood. Appropriate risk its 40th birthday at a symposium that working with a patient can make a big minimization measures are in place too will address questions such as: how do difference to that particular patient; so that no clinical trial should ever be we make best use of “big data” – such but a regulator makes a big difference considered high risk. as from genomics? What are the next to hundreds or thousands of patients at steps for mAbs and advanced therapies? the same time, by approving – or not How challenging is it for regulations to How do we keep the vaccine pipeline approving – a drug. keep up with medical advances? flowing? It will be a networking event I was the first-ever chair of the EMA’s for academics, regulators and industry; What has been the most difficult Committee for Advanced Therapies I think it’s very rare that you get all moment of your career to date? (founded in 2009) and I was lucky these people together in one room. If Almost exactly ten years ago, in 2006, a enough to be directly involved in you have only regulators, they talk only trial of a new monoclonal antibody (mAb) implementing the updated regulations about regulators’ problems, and if you in the UK’s Northwick Park Hospital for advanced therapies. I served in have only industry, they talk only about caused serious adverse events in six that capacity for almost two full industry problems; but if you have all healthy volunteers – the TeGenero event. terms. It was very rewarding to build the stakeholders around one table, you At that time, I was the head of the mAb up the committee and to see the first can go into much more depth. You can section at the Paul Ehrlich Institute, and approvals, but I also became aware that find more details about the event at: my team had just approved the clinical the regulatory system needs to evolve www.nibsc40.co.uk

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