DECEMBER 2017 # 36

Upfront In My View NextGen Sitting Down With Continuous processing Why Brexit is a concern for Lending a helping hand to Richard Markus, Amgen meets cell therapies academic research specialty vaccines biosimilar champion

12 18 – 19 40 – 42 50 – 51

The Innovation Awards 2017

What is the most innovative technology to hit the pharma manufacturing market this year? 22 – 31

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2017 Highlights Pharma’s Green Rush Exploring Pharma’s Far Future June 2017 November 2017 Global Vigilance Medical cannabis may be Delving into the possibilities of February 2017 controversial, but there could be healthcare and medicine a century Following the heparin tragedy, other ways that pharma can make from now throws up interesting something needed to be done in terms use of the cannabis plant; certain questions. Will we end up in a utopian of global safety. Rx-360 was created to cannabinoids may be useful sources or dystopian era of health? help improve supply chains. for new drug discovery. http://bit.ly/2nOSqh3 http://bit.ly/2l8gbi2 http://bit.ly/2hKQtPT

The Power List 2017 Heal the World April 2017 August 2017 The best and brightest of the industry There’s a large philanthropic side to are highlighted in our celebration of pharma that’s often overshadowed the 100 most influential people in by negative press. Here, we show the drug development. effect corporate social responsibility http://bit.ly/2qVocVY has on the world. http://bit.ly/2fLqGq6 Delivering on a Promise May 2017 Twenty-First Century Cell Therapy Drug delivery approaches have September 2017 been growing in complexity. This Following the first FDA-approved article highlights the advanced T cell therapy this year, all eyes have techniques being developed for future been on the field of cell and gene therapeutics. therapy – an area full of promise, and http://bit.ly/2knr2Bt possible pitfalls. http://bit.ly/2C64LAw

And Coming Up in 2018... Nominations Closing for the 2018 Power List

The Medicine Maker 2018 Power List will be published in April – and nominations will draw to a close on February 1. The list celebrates 100 prominent and inspirational individuals involved in drug development and manufacture across four categories: Masters of the Bench, Industry Influencers, Business Captains, and Champions of Change. Who will be included on the list? It’s up to you to decide – just fill out the quick nomination form to tell us who you want to see on the list: http://tmm.txp.to/2018/powerlist We accept nominations from all corners of the industry and for individuals in all roles – from top CEOs, down to unsung heroes making a mark in R&D or process development. www.themedicinemaker.com Power List 2017 ISSUE 36 - DECEMBER 2017 Contents Editor - Stephanie Sutton [email protected] Associate Editor - James Strachan [email protected] Parenteral drug Associate Editor - William Aryitey [email protected] Content Director - Rich Whitworth [email protected] Editorial Director - Fedra Pavlou development services [email protected] Publisher - Richard Hodson [email protected] Sales Manager - Helen Conyngham [email protected] We make drugs smarter. Head of Design - Marc Bird [email protected] Junior Designer - Hannah Ennis [email protected] Digital Team Lead - David Roberts [email protected] Digital Producer Web/Email - Peter Bartley Brookwood Evonik Transferra [email protected] Digital Producer Web/App - Abygail Bradley Pharmaceutical Services™ Nanosciences® [email protected]

Audience Insight Manager - Tracey Nicholls z feasibility studies, process z leader in lipid nanoparticle [email protected] development, scale-up & (LNP) drug delivery Traffic & Audience Database Coordinator - Hayley Atiz commercial manu- [email protected] facturing of extended z targeting & stabilizing Traffic and Audience Associate - Lindsey Vickers [email protected] release formulations for oligonucleotide drugs Traffic and Audience Manager - Jody Fryett local & systemic delivery [email protected] z solubility & bioavailability Social Media / Analytics Associate - Ben Holah [email protected] z microparticles, enhancement of HPAPIs Events Manager - Alice Daniels-Wright nano particles, implants, [email protected] liposomes, nano- z LIPEX® extruders for Marketing Manager - Katy Pearson [email protected] medicines, conjugates benchtop to commercial Financial Controller - Phil Dale production of LPNs [email protected] z formulations with small Accounts Assistant - Kerri Benson [email protected] molecules, peptides, Chief Executive Officer - Andy Davies proteins, nucleic acids, [email protected] vaccines, HPAPIs, Chief Operating Officer - Tracey Peers controlled substances [email protected] Change of address: [email protected] Hayley Atiz, The Medicine Maker, evonik.com/parenterals Texere Publishing Ltd, Haig House, Haig 12 Road, Knutsford, Cheshire, WA16 8DX, UK [email protected] General enquiries: www.texerepublishing.com [email protected] +44 (0) 1565 745200 [email protected] 03 Distribution: Online This Month Upfront The Medicine Maker (ISSN 2055-8201), and The Medicine Maker North America (ISSN 2514-7536), is published monthly by 10 Flu Fighters Texere Publishing Ltd and is distributed in 09 the US by UKP Worldwide, 3390 Rand Road, Editorial South Plainfield, NJ 07080 Wise Words, by Stephanie Sutton 11 S pray it Again, Sam Periodicals postage paid at South Plainfield, NJ POSTMASTER: Send US address changes to The Medicine Maker C/O 3390 Rand Road, South Plainfield NJ 07080. 12 Continuing the Trend Single copy sales £15 (plus postage, cost available on request [email protected]) On The Cover Annual subscription for non-qualified DECEMBER 2017 # 36 14 Sh aring is Caring recipients £110

Upfront In My View NextGen Sitting Down With Continuous processing Why Brexit is a concern for Lending a helping hand to Richard Markus, meets cell therapies academic research specialty vaccines Amgen 08 – 09 16 – 17 40 – 42 50 – 51 Celebrating the technology stars Reprints & Permissions – [email protected] The opinions presented within this publication are those of the authors of 2017 with the annual and do not reflect the opinions of The Medicine Maker or its publishers, Texere Publishing. Authors are required to disclose any relevant financial

The Innovation Awards 2017 Innovation Awards arrangements, which are presented at the end of each article, where relevant. What is the most innovative technology to hit the pharma market this year? 20 – 29

www.themedicinemaker.com © 2017 Texere Publishing Limited. All rights reserved. Reproduction in whole or in parts is prohibited.

17-01-392 AZ, parenteral drug delivery, 266x210mm.indd 1 14.11.17 09:28 Parenteral drug development services We make drugs smarter.

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z feasibility studies, process z leader in lipid nanoparticle development, scale-up & (LNP) drug delivery commercial manu- facturing of extended z targeting & stabilizing release formulations for oligonucleotide drugs local & systemic delivery z solubility & bioavailability z microparticles, enhancement of HPAPIs nano particles, implants, liposomes, nano- z LIPEX® extruders for medicines, conjugates benchtop to commercial production of LPNs z formulations with small molecules, peptides, proteins, nucleic acids, vaccines, HPAPIs, controlled substances

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17-01-392 AZ, parenteral drug delivery, 266x210mm.indd 1 14.11.17 09:28 PERFECT FUSION Your Molecule + Optimized Media Introducing EX-CELL® Advanced™ HD Perfusion Medium. The first off-the-shelf high-density cell culture medium available for continuous processing. It’s never been easier to be more productive.

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The life science business of Merck operates as MilliporeSigma in the U.S. and Canada. In My View PERFECT 50 16 How do we tackle metabolism- based causes of drug attrition? 44 FUSION asks Guy Weber. 17 Bioprinting could revolutionize Reports Your Molecule + Optimized Media drug development and testing, Introducing EX-CELL® Advanced™ HD Perfusion says Erik Gatenholm. NextGen 15 How to Cultivate a Medium. The first off-the-shelf high-density cell Quality Mindset culture medium available for continuous processing. 18 Steve Marginn is concerned 40 Fantastic Vaccines and Where about the impact of Brexit on to Find Them: Lessons Learned 20 The Problem with Poloxamers It’s never been easier to be more productive. UK academic research. with Nima Farzan The CEO of PaxVax talks us 32 The Innovators Learn More through the challenges – and sigmaaldrich.com/perfusion opportunities – that lie within 48 The Transformation Feature the specialty vaccine field. to Excellence

22 The 2017 Innovation Awards 44 The Best Defense Is Which new product launches Good Science for pharma development and Read the story behind the Sitting Down With manufacture stood apart from winning entry of the 2016 the crowd in 2017? The results Innovation Awards: Centinel, 50 Richard Markus, Vice are in and the top 15 winners a CHO cell line resistant to President of Global have been chosen. minute virus of mice. Development, Amgen, USA.

The life science business of Merck operates as MilliporeSigma in the U.S. and Canada. www.themedicinemaker.com FILLING YOUR NEEDS

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ROMM-AZ-17-080_CMO_BFS_if_Interim_210x266_EN_medicinemaker_RZ.indd 1 16.02.17 18:03 FILLING YOUR NEEDS Wise Words Editorial Ten top quotes from medicine makers

hroughout 2017, the editorial team has had the pleasure and honor of interviewing inspiring and gifted individuals in the industry. Given that the end IF IT’S LIQUID, WE CAN Tof the year is traditionally a time to reflect on the last 12 months, I thought it would be fitting to seek words of wisdom from our 2017 “Sitting Down With...” interviews. BLOW-FILL-SEAL IT FOR YOU. “This industry is changing rapidly and we need to keep pace by fostering an industry culture of lifelong skills acquisition.” Dominic Carolan, January 2017 Want to fill your liquid or semisolid products quickly, flexibly, and aseptically, without having to invest in “I’d like to see more collaboration between pharma companies machines, tedious logistics processes, and GMP environment? It’s easy with Rommelag CMO. We offer quick – not only in terms of developing a given cell therapy, but in the and easy access to blow-fill-seal technology and the many advantages of aseptic filling in break-proof plastic development of combination treatment strategies.” Catherine containers. Tell our experts what you need, and we’ll provide impressive possible solutions – from container Bollard, February 2017 design to assembly. Find out more about BFS technology and get in touch directly with your Rommelag CMO “I get intellectual stimulation from working with very bright contact person at www.rommelag.com people, and it’s scientifically rewarding to look at the new techniques that are coming through and to try and introduce them to the labs that I work with.” Fiona Greer, March 2017 “I hope that as our understanding of disease improves we will see new therapies – not just new, advanced therapies, but also older drugs being repositioned and repurposed for different diseases.” Daniel O’Connor, April 2017 “Taking the risk of stepping outside your area of expertise exposes you to other aspects of the industry and provides a wider perspective, necessary for reaching full career development potential.” Ian Muir, May 2017 “We need to make it easier for patients to participate in clinical trials. Many patients still do not even know anything about how to get involved with a clinical trial.” Elisa Cascade, June 2017 “There tends to be something of a trickle down model in the pharma and biotech industry, where poorer communities are an afterthought of the target population. I would love to see more companies working to develop therapies with vulnerable communities in mind from the very beginning.” Steve Davis, July 2017 “The generics industry seems to go through highs and lows, and I think it’s currently going through a bit of a low, but I keep telling people that now is the time to be resilient and to have confidence in your values.” Abhijit Mukherjee, September 2017 “It’s important for everyone participating in the pharma and biotech industry to have some understanding of the critical role that outsourcing providers play today.” Cornell Stamoran, October 2017 “We are living in a world where science is increasingly devalued and the role of expertise is often dismissed. But so much of what we do is underpinned by science.” Margaret Hamburg, November 2017

Stephanie Sutton Editor

www.themedicinemaker.com

ROMM-AZ-17-080_CMO_BFS_if_Interim_210x266_EN_medicinemaker_RZ.indd 1 16.02.17 18:03 10 Upfront

Upfront

Reporting on research, personalities, policies and partnerships that are shaping pharmaceutical development and manufacture.

We welcome information on any developments in the industry that have really caught your eye, in a good or bad way. Email: stephanie.sutton@ What inspired a centralized texerepublishing.com Flu Fighters gene approach? I was introduced to this concept while Researchers look to the working on HIV vaccines. Both ancestral genes of influenza influenza and HIV have very high to develop a new approach to degrees of diversity in the surface vaccination glycoproteins. The centralized genes act to reduce the genetic distance between A truly universal flu vaccine continues the vaccine and the contemporary to evade scientists, but it should be wildtype strains. Therefore, they offer possible to develop a vaccine maximal genetic identity to unknown that offers broader strain or mismatched challenge viruses. We protection – and lasts have published many research articles longer. Eric Weaver, describing this approach and showed assistant professor that it was a superior approach to using at the University a wildtype immunogen as a vaccine. of Ne b r a s k a , certainly believes How successful was your vaccine in we can do better the study? when it comes I believe that in the context of a prime/ to influenza boost viral vectored vaccine platform, vaccines; his team our vaccine is superior to any vaccine that have developed a has been tested. The level of protection vaccine that carries the against highly divergent lethal influenza centralized genes for H1, challenges is underscored in our recent H2, H3, and H5, with the aim of study. The fact that the vaccinated mice providing immunity against all evolved showed no disease when challenged strains (1). We speak with Weaver to with 100 MLD50 of influenza virus is learn more. incredible, given this is enough virus to Upfront 11

kill 50 mice. We don’t know if this will happen if the generating immunity against the more Our vaccine has vector is used for influenza. The second conserved stalk domain. If successful, great potential for vector we used, Ad4, has been given to this approach would certainly increase proving high levels millions of military recruits and is FDA- the breadth of immunity against of cross-protective approved for use in vaccines. It is very divergent influenza strains. Perhaps a immunity against a likely that we could translate this vector combination of this approach and our very wide array of divergent for human use. approach could lead to even better influenza, and the prime/boost strategy influenza vaccine results… that we used could establish a foundation What other influenza projects have for immunity that will last longer than caught your eye? Some have said development of a today’s vaccines. I think there is a lot of promise in the universal flu vaccine is impossible… approaches by Paleses, Krammer and It may be impossible to make a universal What thoughts have you given to Garcia-Sastre with their HA “stalk” vaccine for everyone because people scale up? directed immunity. The stalk domain don’t respond to vaccines in the exact We are very excited to move forward! of influenza is much more conserved same way, but that argument can be One major caveat to this approach is than the globular head, but the immune made for any vaccine that has ever been that we are using a viral vector. One system recognizes the head domain used and should not be a limitation to vector, Ad5, has been used extensively predominantly and therefore does the pursuit of new vaccine research. in clinical trials, but it was not induce dominant immune found that, in adults, there is responses against the Reference a high level of pre-existing stalk. These researchers 1. A Lingel et al., “Efficacy of an adenoviral immunity that impaired are investigating novel vectored multivalent centralized influenza the vaccine’s efficacy in approaches to “trick” vaccine”, Sci Rep, 7, 14912 (2017). PMID: preventing HIV infection. the immune system into 29097763.

Spray It The research team has already tested But would such a novel technology a variety of APIs, including caffeine, be readily embraced by the pharma Again, Sam paracetamol, ibuprofen, tamoxifen, BAY industry? Shtein points out that the 11-7082 and fluorescein. first printed drug was approved in Vapor jet printing of small “Low solubility results in a significant 2015, and that there is much interest molecule drugs could have number of candidate molecules being in the field. “We are in the midst of potential in candidate rejected before it is known if they are a revolution in the pharmaceutical screening – or even delivery effective at the cellular level,” says industry, so the timing is fantastic for Shtein, before pointing out a striking the deployment of organic vapor jet With extensive experience in vapor benefit of his solvent-free solution to the printing technology. The FDA is also jet printing small molecular organic problem: “The resulting morphologies encouraging a transition towards more electronic materials, a team from the from vapor jet printing tend to dissolve personalized medicine and printing University of Michigan led by Max in water much faster (10 times or technology could be used to create Shtein (professor of materials science more) without changing the molecular custom-dosed medications.” and engineering) has more recently composition.” recognized that the technology could The potential of vapor jet printing doesn’t Reference have potential in small-molecule drugs end with solubility. The technique can print 1. O Shalev et al., “Printing of small molecular (1). By thermally evaporating an API drug compounds directly onto drug delivery medicines from the vapor phase”, Nat into a stream of inert gas and spraying the devices, such as patches, ingestible strips, Commun, 8, 711 (2017). PMID: 28955031. vapor onto a cool substrate, the technique microneedles, and bandages, opening up Available at: http://go.nature. can create a crystalline film of API. other avenues to explore. com/2xHAmGN.

www.themedicinemaker.com 12 Upfront

Continuing the Trend

Continuous processing is being adopted in pharma and biopharma. Could continuous cell therapies be next?

Continuous manufacturing has been a growing trend in pharma for some time, but now researchers are urging cell therapy manufacturers to get in on the act. “Given the increase in the number and relative success of cell therapy clinical trials, treating a larger number of people is expected over the next decade,” says Che Connon, Professor of Tissue Engineering at Newcastle University, UK. “Cell manufacturing processes need to scale alongside this growth, as current systems won’t be able to meet the expected demand. For example, allogeneic heart failure therapy may require the approach’s ability to support continuous An especially wide manufacture of around 109 cells per dose. production for one month with no If existing batch processing can only enable reduction in cell production rate. The spectrum of solutions. lot sizes of 10–50 billion cells every two cell yield is around one percent per hour. For an especially to three weeks, then the industry would “Unlike traditional batch processing, require millions of batch bioreactors to be yield is not a suitable comparator; the wide smile. running simultaneously just to keep up process is continuous so the number of with demand.” structure, such material can form a stable cells produced is theoretically unlimited,” Currently, cellular therapies are produced coating upon a variety of surfaces,” says explains Connon. “However, the rate of www.boschpackaging.com by growing cells on a surface until no free Connon. “Thus, it is possible to control cell production is limited to the surface space remains, at which point all the cells the spatial and temporal positioning of area used. The greater the surface area, are detached and collected. The process is cells across a surface if the lipopeptide the less time it will require to generate As a full-service provider of process, packaging and inspection repeated for the next batch. Connon and contains a contiguous cell binding a specific number of cells. For example, technology, intelligent software, and comprehensive services for his lab have been developing a continuous and endogenous protease cleavage site using current stacked plate technologies the pharmaceutical industries, we are always at your side: along approach by coating the surface with a within the peptide sequence. In our new with our coating would provide one the entire value-added chain and across the entire life cycle of functional coating (lipopeptides) before continuous bioprocessing approach, we billion cells every week. A standard Double success for your systems. For solutions that excite in every respect: simple, Bosch Packaging seeding with cells (1). After the cells grow tuned the system such that the rate of cell sized benchtop incubator filled with economical, reliable. Processing. Packaging. Excitement. Technology! they “self-detach” from the lipopeptide proliferation equalled endogenously-driven these plates could produce 5-10 billion coating, allowing other immature cells cell detachment by growing the cells on a cells per week – continuously.” to take their place, so there is no need to rationally designed lipopeptide coating.” chemically or enzymatically detach the Although Connon initially focused Reference whole batch. “A peptide sequence can be on human stromal cells, other types 1. M Miotto et al., “Developing a continuous chosen to affect the function and stability of adherent cells could also use the bioprocessing approach to stromal cell of the lipopeptide, and we have shown that lipopeptide-based continuous approach. manufacture”, ACS Appl Mater Interfaces 9, once self-assembled into a supramolecular Connon has demonstrated the 41131–41142 (2017). PMID: 29145726.

PAPH_MedicineMaker_2017_en_266x210_final.indd 1 12.12.17 15:43 An especially wide spectrum of solutions. For an especially wide smile.

www.boschpackaging.com

As a full-service provider of process, packaging and inspection technology, intelligent software, and comprehensive services for the pharmaceutical industries, we are always at your side: along the entire value-added chain and across the entire life cycle of Double success for your systems. For solutions that excite in every respect: simple, Bosch Packaging economical, reliable. Processing. Packaging. Excitement. Technology!

PAPH_MedicineMaker_2017_en_266x210_final.indd 1 12.12.17 15:43 14 Upfront

The two organizations aimed to member companies had adhered to Sharing Is boost the industry’s commitment to the principles, and to try and quantify openness in 2013 when they released a their data sharing, between 2014 and Caring set of principles outlining responsible 2016, with the overall aim of promoting data sharing, which covered five main the benefits and responsible use of EFPIA and PhRMA team up areas: enhancing data sharing with information sharing. to promote responsible use of researchers, enhancing public access clinical data dissemination to clinical study information, sharing References results with patients who participate in 1. PhRMA, “EFPIA-PhRMA principles for Data sharing can be a touchy subject, clinical trials, certifying procedures for responsible clinical trial data sharing”, (2017). and there is a perception that pharma sharing clinical trial information, and Available at: http://onphr.ma/2AbRhWt. companies don’t exactly jump at the reaffirming commitments to publish Last accessed December 6, 2017. chance of disseminating clinical trial clinical trial results (2). 2. EFPIA, “Principles for responsible clinical information. However, the European The principles were offered as trial data sharing”, (2013). Available at: Federation of Pharmaceutical guidelines to be followed on a voluntary http://bit.ly/2jYAqeX. Last accessed Industries and Associations (EFPIA) basis, but the survey results suggest December 6, 2017. and Pharmaceutical Research and that the principles have resulted in a Manufacturers of America (PhRMA) positive effect – 98 percent of EFPIA recently published survey results and PhRMA member companies share showing that pharma companies are, in more clinical data than is required by Member fact, open to data sharing when given law or regulators. The 30-question companies collectively the opportunity (1). survey was used to find out how much reported 1,062 requests for data

KEY FINDINGS

Ways in which companies share of member companies have systems clinical trial information: and processes in place to facilitate routine data sharing • Participation in an external data sharing platform • Publication of trial results in peer-reviewed journals • Presentations at scientific congresses routinely post synopses of Clinical of requests are for • Posting trial results on Study Reports soon after first patient-level data sponsors’ own websites registration of a new medicine • Sharing data with qualified researchers

of the requests that had been have a strategy for publishing reviewed by the close of the survey clinical trial results were approved Sponsored Feature  15

immune responses, viscosity issues, and for biosimilars, as well as in the various How to Cultivate so on, to avoid costly safety and efficacy pharmacopeias often referred to as problems further down the line. a technology to use for various ligand a Quality Mindset A central regulatory standard is the binding assays, such as receptor binding or International Council for Harmonization’s as “surrogate” potency assay. There are Using precise and reliable analytical (ICH) Q5E guideline, which thoroughly more than 15 drugs on the market that use tools to ensure the successful describes comparability (1) and forms the Biacore systems as a release test, such as development and manufacture of basis of what is required for characterization GlaxoSmithKline’s TanzeumTM and Nucala®. In your candidate molecule from the and QC. Characterization measures the addition to the drugs already on the market, outset – and right through to quality influence of process changes against a there are a number of batch release assays control – helps avoid costly pitfalls reference standard, and often involves a in several clinical programs also using SPR. In along the way. number of analyses. QC, on the other hand, the coming years, I expect to see a number often requires fewer tests, but must confirm of new SPR-based release assays approved By Fredrik Sundberg manufacturing consistency and product by health authorities globally. quality. In the US, a New Drug Application I believe SPR will become a standard tool Characterization and quality control (QC) (NDA) must include analytical procedures for release testing of biologics, including regulations demand that manufacturers that show the identity, strength, quality, vaccines. Moreover, the standardization demonstrate consistency and control purity and potency of the drug. and validation guidelines for the industry are over the manufacturing process. To have currently being further developed, which I the best chances of success in getting Robust tools think will further drive the implementation your biopharmaceutical molecule from Reliable product characterization and QC of SPR as a standard tool for QC. Another development to regulatory approval, I believe are best supported with robust and precise interesting development is the move towards it is imperative to think about “developability” analytical tools, such as surface plasmon process analytical technologies (PAT), which and “manufacturability” as early as possible. resonance (SPR). Biacore’s SPR technology could involve integrating SPR sensors into Large and complex biomolecules are delivers label-free, real-time data, such upstream and downstream processes on- produced through a variety of processes, as affinity kinetics, concentration, and line, off-line or in-line, allowing real-time many of which can affect the protein biosimilarity assessment, that are critical for feedback during production of each batch. composition. If you look at common causes understanding biomolecular interactions. The Ultimately, advanced PAT could significantly of attrition, efficacy issues that arise from potency and stability data generated can be reduce the number of tests required at the the process are frequently involved and used to characterize drug substance and QC lab, potentially reducing the time-to- often lead to insufficient bioavailability. product in pure and complex cell matrices. market allowing batches to be released Safety concerns, on the other hand, tend Essentially, SPR allows you to discriminate immediately after production. to be a result of unwanted modifications between candidates and study CQAs all the to the structure of the molecule, which can way from early research to QC. Modern References cause immunogenicity issues. SPR systems are multiplexing, with several 1. ICH, “Comparability of biotechnological/biological During discovery and early development, flow channels, so you can measure different products subject to changes in their manufacturing thousands of molecules are screened and interactions in different channels and address process Q5E,” (2004). Available at: http://bit. evaluated in several cycles before arriving multiple CQAs in a single assay. SPR-based ly/2i0TM29. Last accessed November 28, 2017. at a clinical lead candidate. The key? To assays also have unparalleled precision and 2. FDA, Guidance for Industry, “Quality only take forward molecules with the accuracy when compared with classical Considerations in Demonstrating Biosimilarity of a right critical quality attributes (CQAs) and immunoassays, such as ELISA. Difficulties Therapeutic Protein Product to a Reference then to link those CQAs to critical process with labeling, secondary reagents, incubation Product” (2015). Available at: http://bit.ly/2j6OXsC. parameters (CPPs) to understand the effect and wash steps do not apply to SPR – and the Last accessed December 8, 2017. on the attributes during development more straightforward direct binding format and manufacture. From the beginning, can detect process drift early, allowing you to Fredrik Sundberg is Global Director for you should be looking at potential post- identify and solve issues before your batch is Strategic Customer Relations and Market translational modifications, the effect of released to market. Development at GE Healthcare. GE, GE temperature, pH and various buffers, and SPR technology is mentioned in several monogram and Biacore are trademarks of you should even try to predict undesirable regulatory guidelines – from the FDA (2) General Electric Company.

www.gelifesciences.com/biacore 16  In My View

potential problems, but I believe that De-risking Drug one of the most important is metabolic In My risk. Drug metabolism is often critical Development to a product’s success, but I find it is under-appreciated by drug developers. View Metabolism-based causes of After administration, drugs may be drug attrition must be tackled acted on by members of one or more through intelligent and early families of drug metabolizing enzymes In this opinion section, risk mitigation strategies. (DMEs), of which the most important experts from across the is the cytochrome P450 (CYP) family. world share a single Such metabolism can have a significant effect on the pharmacokinetic profile strongly held view or of small molecule drugs: it may drive key idea. clearance (especially for neutral, lipophilic molecules), influence Submissions are welcome. population exposure in poor- and rapid-metabolizer sub-groups, result Articles should be short, By Guy Weber, Scientific Manager for in drug-drug interactions, and cause focused, personal and In Vitro and Drug-Drug Interaction some forms of toxicity. Consequently, passionate, and may Sciences, Envigo, UK. the metabolites resulting from drug- CYP interactions have a major impact deal with any aspect Risk management has become an on the incidence of drug-related side- of pharmaceutical important discipline for firms developing effects; for example, as a consequence of development or new prescription drugs. It is said that post-metabolic interactions between co- only one of the 10,000 molecules administered medications. These side- manufacture. entering drug discovery will ultimately effects may cause approval delays at best They can be up to 600 reach the market – and, even then, it is – and, at worst, result in commercially words in length and not certain that expensive development catastrophic post-market withdrawal. costs will be recouped. A de-risking assessment for drug written in the first person. There can be few industries where metabolism should focus on how the the risk of failure is higher than in drug is metabolized – for example, how Contact the editor at: the drug development sector. Is it it interacts with CYP enzymes and stephanie.sutton possible to shorten the odds a little? I drug transporters – in in vitro assays. believe so, but we need to understand Early detection of metabolic liability @texerepublishing.com the causes of drug attrition and deploy not only gives developers the option appropriate resources to gauge the level of excluding high-risk molecules, but of associated risk. In short, we need to also may provide an opportunity to get better at identifying molecules that change the structural chemistry of the have a better chance of surviving the drug candidate. development process. There are three main elements of One successful technique for de- metabolic de-risking. The first element risking is to use advanced in vitro is drug-induced liver injury (DILI) – the technologies and analytical techniques. single biggest cause of liver transplant in These methods are ideal for early humans, and a major cause both of post- phase development because they are market safety-related drug withdrawal fast and require just milligrams of and of development-stage drug attrition. investigative compound (perfect for Where preclinical assessments indicate scarce or expensive materials). De- that a drug candidate has an elevated risking can focus on various sources of DILI risk, further development is In My View  17

highly risky. Although the causative candidate, regulatory authorities of potential MIST issues is crucial to pathways behind DILI remain unclear, recommend a range of in vitro studies help guide the choice of animal models there is increasing evidence that a key (basic models) designed to identify both used in safety assessment – models role is played by reactive metabolites “victim” and “perpetrator” interactions. must be metabolically relevant to the (RM) formed as a consequence of Perpetrator studies are designed to human condition. drug metabolism. Consequently, RM assess how the test drug will affect Application of an intelligently detection is a key component of de- other medications, while victim studies designed and rigorous de-risking strategy risking strategies. are intended to assess how the test drug will provide a comprehensive data set The second element is drug-drug will be affected by other medications. to support major investment decisions; interactions (DDIs). As populations They usually determine which enzymes indeed, de-risking the pipeline in this expand and individuals live longer, and transporter proteins are involved in way increases the chances of developing the frequency of individual patients drug clearance (substrate/phenotyping a safe drug, and therefore increases the being prescribed multiple, concurrent interactions). Greater risks are associated value of the pipeline. Increased value is medications is increasing. This means with drug candidates that exhibit a clearly important to companies seeking the risk of adverse drug reactions due victim profile. to win external investment or aiming to to DDIs is also growing, and this area The third element focuses on sell/out-license their portfolio. of drug development is coming under metabolites in safety testing (MIST). I strongly advise integrating metabolic increasing regulatory scrutiny. Hence, Much industry attention and regulatory de-risking strategies into the drug drugs with a high DDI potential may concern has focused on the importance development program, especially be at risk of non-approval, excessive of drug metabolites as sources of given the increasingly risk-adverse labeling or post-market withdrawal. drug toxicity. For any new drug in environment in which the pharma To test the DDI potential of a drug development, an early understanding industry operates.

my perspective, the ideal future would technology. With that data analysis, we can Think (Bio)Print give everybody access to healthcare, and build better models, which help us further would enable everybody to live a long, understand new areas, which help us build Great strides are being made healthy life. Three-dimensional printing better models, and so on. Bioprinting is in bioprinting, and the end and artificial intelligence were two key heading in a few different directions, with result could revolutionize technologies discussed last month, but R&D groups and academic researchers pharmaceutical development another technology that will certainly wanting to experiment and play around and testing. have an important role in the future of with the possibilities. The next market step medicine is bioprinting. The possibilities will be to break into specific industries. of bioprinting are potentially endless. Toxicology and drug discovery are obvious My company specializes in “bioinks” areas where bioprinting could be a real and I like to tell people that, if you benefit – think of how commercial drug collected all of the tissues being printed development might change if companies by our customers, you’d almost be able could test candidate molecules in human to build an entire human body! Other models early on. And it could also affect companies are printing other tissues, such personalized medicine. as cancer tumors, which can be useful in Beyond that, the far future potential drug development. that we all have in our minds is organ Like most shifts in the industry, transplants. There’s a great deal of By Erik Gatenholm, CEO of Cellink, USA. bioprinting will come to the forefront research and technological evolution incrementally, rather than with a single that needs to be done to reach that point, In the November issue, The Medicine big breakthrough. With each passing year, however, and we need a few champion Maker discussed the far future of we gain more knowledge about how cells institutions to help push it forward. With healthcare and drug development. From react and work with the latest bioprinting the current organ donor system, there

www.themedicinemaker.com 18  In My View

will never be a surplus – rather there they’re widely available? It’s important knowledge and it won’t be long before will always be a waiting list. And we can for companies operating in the space to smart decisions start being made. We never unleash the potential for research keep an open dialogue with regulatory need some good, solid, successful institutes to test theories with human bodies to make them aware of the various applications to move things forward. It organs. Bioprinting could pave the way processes so these questions can be has been the same with the 3D printing for human organs for transplant and brought up and answered alongside the of metals and plastics – everybody knew research – eventually. The big questions evolving technology. that it could deliver fantastic benefits, then will revolve around regulation. The It’s a very exciting stage for bioprinting but it has taken time for everyone to industry will be massive, but will it be right now – and it’s only going to get more figure out how 3D-printed parts can be controlled by a pharma patent perspective exciting in the years to come. Currently, best used. We just need to decide how or by more general regulations? How do the industry and regulators are amassing bioprinting can genuinely bring benefits we decide who gets priority and when, if a tremendous amount of fundamental to pharma development and patients.

Qiagen is looking to potentially invest in a one could expect post-Brexit research in the Brexit Hits Home genomics research campus in Manchester. UK to be conducted by more UK nationals. And though this additional investment is to So where is the necessary investment in It’s all swings and roundabouts be warmly welcomed, does it really equalize education to keep high quality research in in the UK’s life sciences sector the equation? In my view, definitely not. the UK? Companies like MSD and Qiagen with no clear view of what the The MSD investment, for example, is have a choice as to where they base their Richard Jähnke future holds. being portrayed by the media as bringing activities, and they could move elsewhere “950 new jobs”; however, on reading the if they can’t sustain UK facilities, so we formal press release on MSD’s UK website, need to make sure they have access to I discovered that there will only be 150 new appropriately skilled employees. posts created, all in drug discovery research. So far, the industrial end of the research The other 800 jobs (in process research and spectrum seems to be weathering the Meet the Winner other functions) will be relocated from uncertainty of Brexit, but without the existing facilities in Hoddesdon, UK, and fundamental support of the academic By Steve Maginn, Cambridge, UK. elsewhere. The number of new jobs to be sector, this resilience could prove to be Richard Jähnke Could it be you in 2018? created by Qiagen in their partnership with unsustainable and short lived. One solution In November, the relocation of the European Health Innovation Manchester is not yet may be government financial support for Richard Jähnke from the Global Pharma Health Analytical science has been at the heart of many Medicines Agency (EMA) from London clear, but is stated as having “the potential industry (which will be allowable once the to Amsterdam was confirmed, with the loss to create up to 800 jobs.” (2) UK is out of the EU) and/or academia, but Fund (GPHF) has received the 2017 Humanity in scientific breakthroughs that have helped to improve of around 1000 UK-based jobs, many of Perhaps more worryingly, academic surely this investment of public money, Science Award for “development and continuous people’s lives worldwide. And yet analytical scientists which are highly skilled. The unsurprising research in the UK is also suffering from the made necessary by Brexit, is money that improvement of GPHF Minilab™ (www.gphf.org), rarely receive fanfare for their humble but life- but nevertheless bad news is a direct and uncertainty of Brexit – and it is the nation’s could have been spent elsewhere – the which represents a breakthrough for the rapid and changing work. The Humanity in Science Award was inevitable consequence of Brexit, and there vibrant, innovative and inclusive academic “leave” campaign’s poster child, the inexpensive identification of substandard and falsified launched to recognize and reward analytical scientists will certainly be further reaching effects life sciences research scene that underpins National Health Service, perhaps? on employment and the UK skills base – its industrial sector. A large chunk of medicines in low- and middle income countries in who are changing lives for the better. especially given that many pharmaceutical funding for UK-based academic research References Africa, Asia and Latin America”. Has your own work had a positive impact on people’s and biotech jobs in the London area exist comes from the EU – can we expect the UK 1. Merck, Sharp & Dohme, “MSD announces plan because of the EMA’s presence. government to provide the same or a better to establish UK Discovery Centre in London,” Richard received his award at a special jubilee health and wellbeing? Details of the 2018 Humanity It’s not all job losses. In late November, level of funding? We have had no such (2017). Available at: http://bit.ly/2ABF4dy. Last reception in Berlin, Germany on October 2, 2017 in Science Award will be announced soon. we heard of investments by Merck, Sharp & commitment to date. Now that the British accessed December 12, 2017. hosted by KNAUER to celebrate the company’s 55th Dohme (MSD) and Qiagen into their UK people have voted to remove freedom of 2. Manchester Evening News, “Life sciences birthday this year. Richard’s work will feature in an operations (1,2). MSD is set to establish a UK movement to the UK from nationals of investment will bring 800 jobs to Manchester,” upcoming issue of The Analytical Scientist. Discovery Centre in London, with a target other EU states (and give up their own (2017). Available at: http://bit.ly/2kBRqeP. Last @Humanityaward Humanity in Science Award date of 2020 for operational readiness, while freedom of movement within the EU), accessed December 12, 2017. www.humanityinscienceaward.com Richard Jähnke Meet the Winner

Richard Jähnke Could it be you in 2018?

Richard Jähnke from the Global Pharma Health Analytical science has been at the heart of many Fund (GPHF) has received the 2017 Humanity in scientific breakthroughs that have helped to improve Science Award for “development and continuous people’s lives worldwide. And yet analytical scientists improvement of GPHF Minilab™ (www.gphf.org), rarely receive fanfare for their humble but life- which represents a breakthrough for the rapid and changing work. The Humanity in Science Award was inexpensive identification of substandard and falsified launched to recognize and reward analytical scientists medicines in low- and middle income countries in who are changing lives for the better. Africa, Asia and Latin America”. Has your own work had a positive impact on people’s Richard received his award at a special jubilee health and wellbeing? Details of the 2018 Humanity reception in Berlin, Germany on October 2, 2017 in Science Award will be announced soon. hosted by KNAUER to celebrate the company’s 55th birthday this year. Richard’s work will feature in an upcoming issue of The Analytical Scientist. @Humanityaward Humanity in Science Award

www.humanityinscienceaward.com 20  Sponsored Feature

chain of propylene oxide flanked by two The Problem hydrophilic chains of ethylene oxide. The lengths of the polymer blocks can with Poloxamers be altered, allowing different forms of poloxamer to be produced with varying Poloxamer 188 has become properties. Commonly, poloxamer is an essential component of cell used for its surfactant properties – and culture media, but lot-to-lot often employed in drug delivery as a variability has been a problem for formulation excipient. Poloxamer 188 is many biopharma manufacturers. a form of poloxamer initially developed By working with customers for the cosmetic industry to improve or directly to understand the change surface properties for products, science of inconsistency, we’re such as hand cream or shower gel. As it able to supply a product that can turns out, it can also play a starring role in be trusted. cell culture media.

By Nina Weis Out with the old Although animal serum traditionally was In previous articles in this series, my an important component of cell culture finally identified as a result of bad lots of colleagues have discussed the importance media, concerns around variability and Poloxamer 188. You can imagine how of well-characterized raw materials, a infectious agents have forced the industry variable manufacturing runs result in much transparent supply chain and trustworthy to seek other alternatives and to develop higher manufacturing costs for companies suppliers (1-4). As an example of how chemically defined cell culture media. to produce biotherapeutics. a well-characterized product leads to One of the challenges was finding a It was very rewarding for us to have benefits for biopharma manufacturers, non-animal derived substitute that could our customers open up to us about I would now like to share the story withstand hydrodynamic stress in the their problems, which highlights the good behind Merck’s Poloxamer 188, which bioreactor. The industry explored various relationships we have built up with them we launched in March 2017. The product options and discovered that poloxamer over the years. We decided that it would is part of our Emprove® Portfolio, which 188 works very well; it increases the be valuable to investigate the issue in detail centers on supporting risk assessment and robustness of mammalian cells to shear – in collaboration with our customers – aiding the development of more robust from sparging, which is the strongest to learn what makes a good or bad lot processes – part of that involves increasing contributor to hydrodynamic stress in of poloxamer, and whether it would be supply chain transparency and offering full a bioreactor. This is why poloxamer 188 possible to develop a well-characterized GMP documentation. became a standard ingredient in the product for biopharma applications that I have been with Merck for almost industry’s cell culture processes. would result in more consistent quality and a decade, working in various functions Over time, however, with process cell culture media performance. focused on cell culture media, including intensification through increasing cell In 2015, Merck purchased Sigma Aldrich product management, strategic marketing densities and productivities in fed-batch and the two cell culture teams became and portfolio management. We are always and perfusion processes, a new challenge one. Now, it was possible to globally work closely watching the market and interacting has emerged: variability between on the problem together – a huge benefit with customers to understand their needs poloxamer 188 lots started to be reported as the project ultimately benefitted from and devise new technologies and products in the industry. Biopharmaceutical different insights, approaches, and combined that will solve biopharma challenges. manufacturers began to approach knowledge in chemical and biological areas. Over the years, I have been involved Merck, explaining that they were seeing in many projects regarding upstream significant variation in their processes that The science of variability chemicals, but recently I have been very caused unexpected loss of cell density and First of all, we had to understand why focused on Poloxamer 188, a surface-active viability in their manufacturing operations. different lots of poloxamer 188 were non-ionic amphiphilic triblock copolymer One manufacturer told us they had seen negatively impacting biopharma processes. composed of a central hydrophobic a 30 percent loss in yield, which was What was the correlation between the polymer, the material-chemical properties, and performance in cell culture media? It made sense to include our customers in our investigation, as we wanted to ensure that we tackled the issues that were important to them; we worked alongside them to exchange samples, characterizing good and bad lots of poloxamer. Over time, we compared our results to ensure we were reaching the same conclusions. We tested Poloxamer 188 EMPROVE Expert cell culture optimized assays to prove shear stress protection. almost 200 different blind samples, which High molecular weight species have a negative impact on performance - our Poloxamer 188 contains led to a reference library that can be used no high molecular weight material. to reliably classify Poloxamer 188. Not only were we able to identify variation, but we began to understand what impact different poloxamer variability would have on cell culture media. Ultimately, we were able to develop and validate two orthogonal biological and analytical methods for both evaluating the critical quality attributes of poloxamer 188 and identifying lot variability that may impact cell culture media. We now have a highly sensitive cell-based assay that classifies the shear protective effect and a cell test for standard product release. We also used size exclusion chromatography and liquid chromatography-mass spectrometry to identify high and low molecular weight difficulties – particularly as poloxamer 188 cell culture media! Just like you, we are impurities, and hydrophobic impurities, is such a critical component for cell culture only satisfied with qualified, high-quality respectively, and have developed an media. A new source of poloxamer gives components when it comes to all our analytical method for reliably separating customers greater flexibility, and I am very media products. good and bad lots of poloxamer 188. proud of the robust supply chain that we Since then, we have found a partner to have developed. Nina Weis is Global Product Manager, manufacture the polymer in a specific way We have put a lot of effort into our Biopharm Materials, at Merck. to ensure that it has consistent quality and quality management systems to ensure cell culture functionality. that our suppliers meet certain standards References Our customers have been very excited – but we also perform regular audits 1. B Lehr, “A Media Match Made in Heaven,” to see a new source of poloxamer 188 to make sure those high standards are The Medicine Maker, 35 (2017). Available at: on the market – particularly one that adhered to. The supply chain is also very http://bit.ly/2jyL4bP. guarantees quality and performance. But transparent; our customers know where 2. C Sharma, “Chasing Traces,” The Medicine perhaps what’s most exciting is that our the polymer is manufactured, where it Maker, 34 (2017). Available at: http://bit. poloxamer was developed with direct is released, where it is filled, packed and ly/2hATxvc insight from customers based on real- so on. Our assay also ensures that only 3. C Sharma, “Know Thy Raw Materials,” world problems. As well as benefitting product with material functionality is The Medicine Maker, 33 (2017). Available at: from improved consistency, customers released and shipped to customers. http://bit.ly/2xnRFLi also have better security of supply. If you need further proof of our 4. K Kayser, “Finding That Special Source,” The Previously, many of our customers relied commitment to poloxamer 188 quality, Medicine Maker, 32 (2017). Available at: http:// on a single supplier, which can create we use the same product in our own bit.ly/2kdAafB 22 Feature

Innovation Awards 2017 Innovation Strikes Back

The Medicine Maker Innovation Awards, now in their third year, celebrate the most exciting drug development and manufacturing technologies of 2017. Every year, a diverse array of equipment and technologies cell line resistant to minute virus of mice. You can read the are released to aid pharma and biopharma manufacture. story behind this innovation on page 40. Which technology stars shone the brightest during 2017? The We will be sharing the story behind one of our 2017 Medicine Maker has been collecting nominations for months Innovation Award winners in a 2018 issue of The Medicine and the judging process is complete. Here, in alphabetical Maker – and it’s up to you, our readers, to vote on which 2017 order, we present the top 15 innovations of 2017. innovation you want to read more about! Vote for your favorite But which technology is the most be innovative? The grand innovation at: http://tmm.txp.to/2017/innovationwinner winner of the 2016 Innovation Awards was Centinel – a CHO

www.themedicinemaker.com CADENCE INLINE DIAFILTRATION MODULE

A tangential flow filtration diafiltration device allows for ≥ 3-log removal in a single-pass, continuous operation

Produced by Pall Life Sciences

The Cadence Inline Diafiltration (ILDF) Module is designed for continuous processing, in-process buffer exchange or contaminant removal in a number of applications. Modules are available with either Delta regenerated cellulose or Omega polyethersulfone membranes to provide high flux, high selectivity and low protein binding characteristics. Pall notes that the modules enable significantly reduced system hold-up volume, and feature an easy to use, holderless design.

Potential impact: According to Pall, a method for performing diafiltration in a truly continuous, single-pass mode of operation does not currently exist. Instead, diafiltration must be conducted as a batch operation, or in a semi-continuous operation that AFG 5000 requires some level of recirculation. The Cadence ILDF device could bring the biopharma industry one step closer Accurately dosing and filling both large and small to implementing an end-to-end integrated, continuous amounts of powder bioprocessing platform.

Produced by Robert Bosch Packaging Technology

Flexibility is the name of the game when it comes to the AFG 5000, with its range of versions and features. The number of filling stations can be individually selected, which leads to an output of up to 480 vials per minute in the high-performance range. Bosch has also developed a new variable transport system that continuously feeds vials into the machine, while adjusting its speed precisely to the rhythm of the individual workstations, such as filling, weighing and stopper insertion, to help avoid idle time or bottlenecks.

Potential impact: Every centimeter in class B cleanrooms counts in terms of operating, maintenance and cleaning costs. The AFG 5000 has been designed to reduce the amount of space that has to be cooled and cleaned with sterile, dry air. In addition, the high output and few parts help accelerate format changes, leading to the potential for more efficient processes and additional savings in space and costs. Feature 25

ESHMUNO P ANTI-A & ESHMUNO P novel synthetic approach. The resins are released by a specific ANTI-B RESINS test method that evaluates performance with less variability compared with classical agglutination methods. Improving patient safety by removing key contaminants from plasma-derived therapies Potential impact: Plasma-derived Ig therapies are used Produced by Merck to treat a variety of diseases, but trace amounts of anti-A and anti-B Eshmuno P anti-A and Eshmuno isoagglutinins have been associated P anti-B are two affinity- with increased patient risk for based chromatography resins hemolysis. Typically, human plasma that help remove anti-A is obtained by pooling the plasma of and anti-B isoagglutinin multiple donors of all blood group antibodies from plasma- types, and therefore contains both derived immunoglobulins anti-A and anti-B antibodies. (Ig) – without negatively Even using traditional filtration impacting process economics; and purification methods, residual the resins can be reused for at trace amounts of anti-A and least 200 cycles, using acid or anti-B blood group antibodies alkaline cleaning. The resins are can remain. Eshmuno P resins manufactured using a combination of the could help mitigate this risk. company’s base matrix technology and a

HAKOBIO (including specifications and functionalities) modelled in realistic 3D, which can be dragged and dropped A 3D and digital reality space for to ensure it fits your lab. The interface simulating and optimizing industrial can also be used for cost and flow processes and plants simulations, as well as training and data management. Produced by OUAT! Potential impact: HakoBio was previously The platform can be used used exclusively by Pall Life to easily simulate different Sciences, but the technology processes and factories to get was commercially launched in an idea of what may fit in a 2017, with users now including facility, without needing to the UK’s Cell and Gene consult experts. Creations Therapy Catapult, Sanofi, and can also be shared with Beckman Coulter. HakoBio is colleagues. OUAT! believes a simple web application that that HakoBio will facilitate allows users to create processes the digital transformation of or design labs, and then view the manufacturing and the switch to creation – and assess ergonomics – Industry 4.0, by providing a visual using virtual reality. Users can select interface to allow configuration of an from a vast array of biopharma technology Internet of Things platform.

www.themedicinemaker.com H3N2 CHALLENGE VIRUS can demonstrate egg-adaptation and amelioration of disease (both infectivity rates and viral shedding). An influenza virus that can be used as a challenge agent to emulate wild-type infection Potential impact: When seeking FDA approval for a vaccine, manufacturers Produced by SGS require proof of real-world efficacy, which can be achieved in studies in the community; however, the trials are expensive and This influenza challenge agent has lineage from the seasonally the low rates of infection can lead to the need for an enormous epidemic, non-haemagglutinating H3N2 viruses that arose in the patient pool. A challenge agent with a high infection rate – 2010-2011 influenza season, and that have come to predominate used in conjunction with controlled, human infection studies – since 2014-2015. Thus, the H3N2 Challenge Virus represents could help reduce reliance of efficacy programs on the seasonal one of the most common current circulating strains of influenza incidence of influenza. The efficacy of the vaccines can be of a pandemic origin and can be used for testing the H3N2 determined directly by measuring both virological and host portion of prospective prophylactic and therapeutic vaccines. It (clinical) endpoints. Maintaining the safety of subjects, whilst shows clear and progressive symptomology characteristics of a maximising data relevance (quality), allows informed go/no go mild influenza-like illness. Previous influenza challenge agents decisions to be made earlier in the pipeline development cycle. Feature 27

KLV 1360

An automated system for leak detection

Produced by Robert Bosch Packaging Technology

The KLV 1360 for vacuum leak detection can measure leaks resulting from hole sizes of less than five micrometers and can achieve an output of up to 600 vials per minute by using inspection chambers that test groups of vials. The system features an integrated robot system and uses automatic individual re-inspection, which only rejects leaky vials within a conspicuous group. Reference samples help continuous internal process control to ensure maximum testing reliability.

Potential impact: Leaks in vials can pose a serious risk for patients as the active ingredient may be altered. In particular, non-destructive container closure integrity (CCI) testing technologies are becoming increasingly important in the pharma industry, iQ with the US Pharmacopoeia calling for more quantitative, validated CCI test methods. The KLV 1360 is a sensitive Standardizing different drug containers to run on the and non-destructive technology that can aid patient safety, same filling line while protecting manufacturers against product loss and product recalls. Produced by Schott AG

The iQ platform standardizes ready-to-use (RTU) syringes, vials and cartridges within a single tub format to run on the same filling line. By standardizing the format, pharma manufacturers can fill various drug/container configurations on the same filling line with only a few minutes of changeover in between. Schott has collaborated with a number of companies during the development of iQ to make the platform compatible with over 30 machines from leading and upcoming vendors.

Potential impact: Drugs today need to be manufactured in increasingly small batches in shorter periods of time, while adhering to higher quality standards. Currently available RTU solutions require drug manufacturers to fit the filling machines to the specific tub format; by standardizing this part of the process, iQ helps to reduce complexity. With the packaging also being fixed in nests, the risk of glass-to-glass contact is minimized. Schott also believes that the platform could ignite more discussion around issues such as glass breakage and particle reduction.

www.themedicinemaker.com MABSELECT PRISMA

An efficient Protein A resin specifically designed to boost mAb purification capacity

Produced by GE Healthcare Life Sciences

According to GE Healthcare, MabSelect PrismA can help mAb producers to improve their purification capacity by up to 40 percent thanks to enhanced binding properties. Protein A chromatography resins play a fundamental role in mAb purification efficiency thanks to their high selectivity, but the drawback is a lack of chemical resistance and the relatively low productivity of many protein A resins. MabSelect PrismA has been developed using high-throughput screening methodologies to identify and resolve weaknesses in the protein A molecule that make it susceptible to sodium hydroxide degradation – allowing MabSelect PrismA to be cleaned with a higher concentration of sodium hydroxide to better control cross- PRODIGI contamination and bioburden risks. Managing serialization requirements with a cloud- Potential impact: based solution Historically, the binding capacity of Protein A resins has lagged behind other chromatography resins. GE Healthcare Produced by Adents claims that co-optimization of the chromatography bead and the final ligand construct has given MabSelect Prodigi is a cloud serialization solution based on the PrismA a binding capacity on a par with other techniques. Microsoft Trusted Cloud Azure platform (selected by Increasing mAb purification capacity can have a significant the European Medicines Verification Organization to impact on equipment decisions. If overall productivity of build the European Hub). The platform helps pharma existing equipment is improved, capital investments in new companies generate, exchange, manage and analyze columns and facilities can be delayed until financial risks serialization data, and also includes a connection interface are reduced. The increased capacity also allows the use of that facilitates the on-boarding of trading partners by prepacked columns. reducing IT resources, connectors and costs.

Potential impact: Adents has passed the certification process for the European Medicines Verification System (EMVS) – a pan-European system designed so that medicines can be verified at the point of dispensing), meaning that Prodigi can connect securely with the European Hub for the EMVS, and that Adents can now legally vouch for its customers concerning serialization compliance. The platform meets regulatory requirements regarding unit traceability, but is designed to go beyond compliance to deliver business benefits resulting from the generated data. Serialization data can be structured for business intelligence analysis and serialization data can also be enhanced with external information, such as cold chain monitoring data. Feature 29

consumption. It is also a fully automated system – all cell filling MICROCAL PEAQ-DSC and cleaning functions can be performed while unattended.

An automated analytical system for characterizing Potential impact: protein stability DSC is a powerful analytical tool for characterizing the thermal stability of proteins and other biomolecules. The Produced by Malvern PANalytical technique measures the enthalpy (ΔH) and temperature (Tm) of thermally-induced structural transitions of molecules in Based on differential scanning calorimetry (DSC), the solution. This information provides valuable insights into MicroCal PEAQ-DSC analytical system delivers data to guide factors that stabilize or destabilize proteins, nucleic acids, biopharma development, from protein engineering, through micellar complexes and other macromolecular systems. The pre-formulation and process development, to formulation and data can be used, for example, to predict the shelf-life of manufacture of the final product. The system provides high biomolecular products to enable batch-to-batch and biosimilar throughput, sensitive protein stability analysis with low sample versus innovator molecule comparisons.

www.themedicinemaker.com VALOR GLASS

Durable glass packaging designed to eliminate Q EXACTIVE HF-X delamination HYBRID QUADRUPOLE ORBITRAP MASS Produced by Corning SPECTROMETER Valor Glass is engineered with Powerful mass spectrometry system higher internal energy than to garner greater understanding of conventional glass packaging and biomolecules has been developed to address several longstanding challenges Produced by Thermo Fisher Scientific with conventional borosilicate VARIOSYS MOVE packaging. The composition Thermo Fisher Scientific’s Q Exactive and uniform interior surface of An automatic transport system for HF-X Hybrid Quadrupole Orbitrap the new containers eliminates exchanging production modules Mass Spectrometer provides sensitive delamination, resists damage and and processes and reproducible analyses of highly breakage, and reduces particulate complex samples to help improve the generation. In addition, the Produced by Bausch+Ströbel understanding of biomolecules as drug glass is chemically durable with targets, disease markers, and therapeutic uniform surface chemistry and The company’s VarioSys production agents. The system uses a high-capacity low extractables, and has been system comprises custom-fit transfer tube for maximum ion loading, designed to run more smoothly modules – that can be interchanged an electrodynamic ion funnel that on filling lines at high speeds. at any time – interlinked with a Skan accommodates and transmits ions isolator system. VarioSys Move is over a broader mass range, and a high- Potential impact: one of the newest additions to the field Orbitrap mass analyzer. Benefits Valor Glass could offer benefits range. The system that automatically include rapid and accurate mass to both manufacturers and brings machine modules from the analysis, two-to-three-fold sensitivity patients. Glass delamination parking position to the isolator improvements, and up to an eight-fold can cause adverse patient events and back again. It can follow a improvement in signal-to-noise ratio and lead to expensive recalls programed sequence or be controlled compared with previous models. for manufacturers. Damage by an operator using a remote control introduced on filling lines or to bring the module to the isolator, Potential impact: during shipping can create and from there they are transported Harnessing the power of the Orbitrap sub-visible flaws and cracks in automatically. technology, the new system is designed conventional packaging, to help scientists comprehensively profile which could lead to Potential impact: and quantify the proteome, discover contamination. The aim behind VarioSys and verify novel biomarkers, and fully Valor has been is to provide flexibility characterize complex biotherapeutics. designed to via a plug and play According to Thermo Fisher Scientific, resist cracks and format, and VarioSys the system was used by Jesper Olsen, damage during Move enhances associate professor and deputy director processing and the system with of the Novo Nordisk Foundation and transit, as well further automation. Center for Protein Research at the as during in- The right module University of Copenhagen, Denmark, home and clinical is guaranteed to be to identify 1,100 unique peptides per settings. delivered to the right minute – a new world record. place in the VarioSys line. Feature 31

X500B QTOF

Boosting routine biotherapeutic characterization with a benchtop QTOF system

Produced by SCIEX

Built specifically for biologics characterization, the X500B High-Resolution Quadrupole Time-of-Flight (QTOF) system aims to boost analytical capacity, simplify workflows and accelerate throughput. SCIEX has designed the system to simplify standard characterization workflows with intuitive software that allows even novice mass spectrometry users to run intact mass and peptide mapping analyses quickly and easily.

Potential impact: VHP DC-A DECONTAMINATION Biotherapeutic protein development depends on efficient CHAMBER ATMOSPHERIC product characterization at different parts of the process; liquid chromatography-mass spectrometry (LC-MS) Atmospheric VHP biodecontamination chambers for techniques are essential in this endeavor. Many LC- safe particulate-controlled material transfer MS analyses are now mature enough to be adopted in routine and high-throughput labs. SCIEX believes that Produced by STERIS Life Sciences the X500B is a streamlined solution that makes the power of mass spectrometry for standard intact mass and peptide The concept of minimizing bioburden on the surfaces mapping workflows accessible to every scientist, regardless involved in transfer of material to clean room classified of expertise level. areas is not new but, according to STERIS, such equipment is typically designed as material airlocks equipped with gaseous decontamination equipment. The VHP DC-A Decontamination Chamber Atmospheric series is designed to sterilize the surfaces of various loads in a similar way to steam sterilizers, but by using low temperature vaporized hydrogen peroxide. The system also uses a specific fan design for high airflows to ensure a total cycle time of just 45 minutes, as well as an integrated VHP generation process using continuous humidity control that minimizes peroxide consumption down to 20 ml/cycle.

Potential impact: The best outcome for aseptic processing is to minimize the particulate amount – and thus risk of contamination – entering clean rooms. Automated systems can help achieve this and STERIS also claims that its VHP decontamination process accomplishes a 6-log bioburden reduction. From an operations perspective, a stand-alone design, with no HVAC connections required, facilitates install and validation

www.themedicinemaker.com 32  The Innovators

THE INNOVATORS 2017

Whether better ensuring patient safety, improving process efficiency, or just making life in the lab or facility easier – meet the companies advancing pharmaceutical development and manufacture. Sponsored Section  33

iQ™. THE GLOBAL RTU STANDARD.

A holistic concept standardizing ready-to-use containers within a single tub format to run on the same filling line.

With its new iQ™ platform, SCHOTT standardizes percent and running costs by up to 40 percent. The platform ready-to-use (RTU) syringes, vials and cartridges from SCHOTT is compatible with over 30 machine platforms within one tub format to run on the same filling line. of all leading and also upcoming machine vendors. Close cooperation with the world’s largest elastomer component Thus, less changing of machine parts is necessary when suppliers enabled the offering of pre-validated and flexible switching from one container to another. This allows pharma container/elastomer systems. This further reduces testing manufacturers to fill various drug/container configurations on efforts, improves quality and accelerates time to market. the same filling line with only a few minutes of changeover Moreover, the nested configurations of iQ™ containers in between. Considering that drugs today need to be eliminate glass-to-glass contact during filling, transport manufactured in ever-smaller batches in shorter periods while and storage. Thus, the risk of scratches and contamination is adhering to higher quality standards, the iQ™ standardized decreased significantly, which ensures and improves patient tub format increases flexibility and greatly reduces complexity safety. Therefore, the platform also provides a solution to for pharma manufacturers. various industry discussions, such as glass breakage and A case study has shown that iQ™ decreases the need for particle reduction. format parts among others, which enables companies to reduce investments by up to 40 percent, clean room space by up to 60 Learn more at www.schott.com/iQ

www.themedicinemaker.com 34  The Innovators

A TIME FOR VALOR

Corning’s innovative glass solution for injectable drug packaging draws on generations of problem-solving with science

A revolution is forming in the way cutting-edge medicines are television tubes, were among Corning’s innovations in the early manufactured and delivered to patients. At the heart of it all – a 20th century. new-age version of one of the world’s oldest materials. And in the post-World War II era – as the company consistently Corning Incorporated – the New York State-based technology invested more than 10% of its revenues into research and company – this year introduced Corning Valor™ Glass, damage- development - Corning continued its discoveries that changed resistant and chemically durable pharmaceutical packaging for everyday life and transformed industries. today’s medicines. The innovation will create opportunities for pharmaceutical • Telephone systems in the late 1960s were built on copper companies to manufacture their products more efficiently and wire that couldn’t reliably handle growing traffic. Corning to more safely deliver their products to patients. invented low-loss optical fiber, unleashing a Corning began developing what would become Valor Glass communications revolution. after a 2011 advisory issued by the U.S. Food and Drug • When the US government introduced the Clean Air Act in Administration. The FDA noted at the time that several drug 1970, Corning developed an innovative honeycomb structure products had been recalled due to a formation of glass lamellae for trapping emissions. It has helped automakers meet in certain injectable drugs. The formation of these glass flakes is stringent new regulations for decades. called delamination. • Corning’s precision glass for advanced displays has helped The delamination process can lead to fine glass particle bring flat-screen TVs and monitors to homes and contamination in the drug. A longtime customer and leading offices everywhere. pharmaceutical company looked to Corning for a damage- and • And the consumer electronics innovation that has defined delamination-resistant glass. the past decade – smart mobile devices with brilliant Corning was up to the challenge, bringing more than a century touchscreens – has been made practical by Corning® and a half of glass science and manufacturing leadership to the table. Gorilla® Glass. The tough, beautiful cover glass is on more than 5 billion devices worldwide. Long history of innovation Since its earliest days in the mid-1800s, Corning attracted A remarkable innovation researchers with a passion for glass science, optical physics, and Corning glass scientists have a deep understanding of how manufacturing engineering. different formulation and fabrication techniques combine to They discovered that the ancient material – mostly familiar to determine the atomic state and structure of a glass, which in the world in ordinary soda-lime compositions - could be endlessly turn control the glass’ mechanical, thermal, and optical properties. changed, enhanced, and transformed to create new properties. The company is well known for its quality-by-design From its lab in upstate New York, Corning began partnering approach – combining material and process knowledge to create with the great innovators of the day. groundbreaking technologies. Corning Valor™ Glass is a perfect In the 1880s, Thomas Edison turned to Corning to develop case study for the company’s approach to innovation. The inventors a clear, heat-tolerant encasement for his electric filament. Later, designed a glass for pharmaceutical packaging and leveraged the Corning created a process for mass-producing those bulbs quickly company’s existing manufacturing and engineering platforms to and cheaply, bringing electric lights to the masses. develop and manufacture it. Durable cookware and labware, along with mass-produced Valor Glass has its own unique composition optimized to address Sponsored Section  35

longstanding quality issues with conventional pharmaceutical Valor Glass as a large opportunity for the company. packaging. Through a root-cause analysis, Corning scientists were “We are thrilled to be working with development partners able to eliminate the root cause of delamination (1). In addition, and customers on the adoption of Valor Glass to store and the glass was designed to prevent the formation of stable through protect medicines. The manufacture of sterile injectable drugs cracks and dramatically reduce the probability of glass particulate is not an easy thing to do, it has its challenges, but the glass formation (2,3). Valor Glass containers provide a safety benefit for package intended to protect medicines should not contribute patients using sterile injectable drugs by lowering the potential risk to those challenges.” of contamination or loss of sterility due to cracks and particles. “We want the glass to enable pharmaceutical companies to In addition to helping protect patients, Valor Glass improves efficiently manufacture and deliver quality drug products to patients.” operational efficiency for manufacturers. Valor Glass was designed to be compatible with existing filling lines as a drop-in solution References for manufacturers, requiring no capital investments to modify 1. Schaut, Robert A. et al. “Historical Review of Glasses Used for Parenteral equipment or lines in order to adopt. Packaging.” PDA Journal of Pharmaceutical Science and Technology. July/ Glass on filling lines is a rate limiting factor in terms of speed August 2017. and throughput. Valor Glass improves the operational efficiency 2. Schaut, Robert A. et al. “Enhancing patient safety through the use of a of filling lines, as it enables smoother overall operations. For pharmaceutical glass designed to prevent cracked containers.” PDA Journal manufacturers this means fewer line interventions and glass-related of Pharmaceutical Science and Technology. 19 September 2017. rejects, which improves the effective throughput of the line. 3. Timmons, Christopher et al. “Particulate Generation Mechanisms during Ron Verkleeren, vice president and general manager of Bulk Filling and Mitigation via New Glass Vial.” PDA Journal of Corning Pharmaceutical Technologies, says Corning sees Pharmaceutical Science and Technology. 15 May 2017.

www.themedicinemaker.com 36  The Innovators

REIMAGINE CAPACITY FOR SUCCESS – MABSELECT™ PRISMA PROTEIN A CHROMATOGRAPHY RESIN

The area of therapeutic monoclonal antibodies (mAbs) is growing rapidly, and much effort is put on intensifying processes to increase productivity and cost efficiency. Ever increasing titers in upstream production demand increased efficiency in downstream purification. GE Healthcare works intensively to help improve throughput in the large-scale manufacturing of mAbs.

As most of today’s upstream processes are of high feed ligand, MabSelect PrismA offers significantly increased capacity concentrations, mass throughput rather than volumetric compared with its predecessor resins. The improved capacity throughput is the main target for downstream process allows for handling of the increasing upstream titers to resolve improvements. Protein A capture is the initial downstream bottlenecks in downstream mAb processing. The high capacity purification step of most mAb processes. As such, the protein of MabSelect PrismA enables an increased mass throughput A capture step is subjected to large quantities of crude sample per purification cycle, improving productivity of current feed. To prevent protein A capture from becoming rate-limiting chromatography columns and systems without costly capital for the manufacturing process, high efficiency of this step is expenditures. MabSelect PrismA allows for up to 30 percent more crucial. To improve performance of protein A capture, GE product to be purified using current equipment. Alternatively, Healthcare has worked on optimizing both the ligand and the the increased binding capacity can be used to decrease the resin base matrix to develop a next-generation protein A resin that volume required to achieve a given mass throughput. exhibits increased productivity over current protein A resins. Co-optimization of the ligand and the base matrix is Optimizing cleaning and sanitization for necessary, as large pores reduce steric hindrances but at the improved process efficiency expense of available surface area, and long ligands increase the Efficient cleaning prevents impurities from building up on the number of binding sites but can increase steric hindrances. To chromatography column and reducing the capacity of the resin. improve cleaning efficiency, weak points in the protein A ligand Efficient cleaning and sanitization protocols also help prevent were identified and subjected to mutations to enhance alkaline growth of microorganisms and inactivate potential endotoxins. stability. More than 400 different constructs were evaluated A high alkaline stability of the resin enables the use of high using high-throughput screening methodologies. A library of concentrations of low-cost sodium hydroxide as a cleaning agent, ligands was generated using a design of experiments approach, supporting both cleaning efficiency and good process economy. and Biacore™ surface plasmon resonance technology enabled MabSelect PrismA exhibits more than 90 percent retained quick evaluation of the different modifications introduced to dynamic binding capacity after cleaning with 1.0 M NaOH the protein A ligand upon decision of final resin design. or more than 95 percent retained dynamic binding capacity after cleaning with 0.5 M NaOH between runs for 150 cycles. Addressing higher demands for The significantly enhanced alkaline stability of MabSelect maximized productivity PrismA ensures a better process economy, while meeting the The final product, MabSelect PrismA, is built on the heritage requirements of a stringent bioburden control. of former MabSelect products. However, with the enhanced properties of both the agarose base matrix and the protein A Learn more at www.gelifesciences.com/mabselectprisma Sponsored Section  37 SINGLE-USE THAT’s READY WHEN YOU ARE

®

Introducing The Mobius MyWay Portfolio ® MOBIUS In biopharmaceutical manufacturing, time isn’t always on your side—but we are. With three MyWay options, SELECT you get customizable single-use solutions that 6 Weeks move as fast as the market does.

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MOBIUS® STOCK: ® On-demand repeat assemblies, MOBIUS ready in just 24 hours. STOCK 24 Hours MOBIUS® CHOICE: Highly customized solutions from our expansive component library, shipped in standard lead times.

MOBIUS® CHOICE Pick Up the Pace 14 Weeks emdmillipore.com/singleuse-myway

The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada.

MilliporeSigma and the vibrant M are trademarks of Merck KGaA, Darmstadt Germany.

Mobius and Millipore are registered trademarks of Merck KGaA, Darmstadt, Germany. NextGen

R&D pipeline New technology SINGLE-USE THAT’s Future trends READY WHEN YOU ARE

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Introducing The Mobius MyWay Portfolio ® MOBIUS In biopharmaceutical manufacturing, time isn’t always on your side—but we are. With three MyWay options, SELECT you get customizable single-use solutions that 6 Weeks move as fast as the market does.

MOBIUS® SELECT: Configure-to-order assemblies from an optimized component library, shipped in only 6 weeks.

MOBIUS® STOCK: ® On-demand repeat assemblies, MOBIUS ready in just 24 hours. STOCK 24 Hours MOBIUS® CHOICE: Highly customized solutions from 40-42 our expansive component library, Fantastic Vaccines and Where to shipped in standard lead times. Find Them: Lessons Learned with Nima Farzan With many companies focusing on the bigger vaccine areas, specialty vaccines are often overlooked. Nima Farzan aims to change this. MOBIUS® 44-46 CHOICE The Best Defense Is Good Science Pick Up the Pace 14 Weeks Centinel – a CHO line resistant emdmillipore.com/singleuse-myway to Minute Virus of Mice – was the The life science business of Merck KGaA, overall winner of The Medicine Darmstadt, Germany operates as MilliporeSigma Maker 2016 Innovation Awards. in the U.S. and Canada. Here, Kevin Kayser reveals the story MilliporeSigma and the vibrant M are trademarks behind its development. of Merck KGaA, Darmstadt Germany.

Mobius and Millipore are registered trademarks of Merck KGaA, Darmstadt, Germany. 40 NexNextGen tGen

blood (no pun intended!) and I have never to be developed without any living virus. Fantastic looked back. Companies are also focusing on vector vaccines, although none of these are yet Vaccines and Manufacturing challenges are significant on the market. In comparison to pharma As fulfilling as working with vaccines is, fields, however, vaccines still have a lot of Where to Find there are definitely many unique challenges. room for growth. The first, and most obvious, challenge is The anti-vaccine movement can also have Them: Lessons the significant safety hurdles you have to an impact on public perception of vaccines. jump over. Vaccines are given to healthy Anti-vaxers generally target high-profile Learned with people and there can be no severe side vaccines rather than smaller, specialty effects. Imagine developing a new pediatric ones, but they have a noticeable effect – Nima Farzan vaccine that you aim to give to 4 million the immunization rate in Marin County, healthy American babies every year – no California, is lower than some countries in The field of specialty vaccines one will agree to the vaccination if there the developing world. As an industry, we can feel underloved, but with are any health risks. haven’t done much to combat the impact growing interest from public A second challenge is scale of production. of anti-vaxers, but there have been huge health groups, previously Whereas a chemotherapy drug may reach debates between public health leaders, under-served diseases may production levels of 10,000-30,000 doses academics, and pharma companies about soon have hope. per year, vaccines need to be produced to how to tackle the issue. Do we engage, or the tune of over one million doses per year – do we ignore them and remain silent? It’s Vaccines are one of the greatest public seasonal flu vaccines can even reach the scale a tough debate, but undoubtedly public health achievements of 70 million doses. Being able to get your health is being damaged. I’ve been working in life sciences since my costs to a reasonable level per dose is essential undergraduate days, starting with a human – and there are many potential vaccines that Market gaps allows smaller vaccine biology degree at Stanford University, have never seen the light of day because it players to succeed California. Following business school, I would be impossible to manufacture them Big pharma is consolidating its vaccine worked for Novartis for a number of years cost effectively at the necessary scale. efforts. Novartis, for example, sold its covering different roles that took me from vaccines business to GlaxoSmithKline Switzerland to the US, and from marketing Vaccines are not always appreciated by in 2015. Today, there are only a handful to R&D. Then an opportunity opened the public of big pharma companies working with up to enter the vaccines space. Novartis Governments, payers and individuals do vaccines and most tend to focus on the acquired Chiron for their vaccine work and not seem to have the same willingness to bigger opportunities; the routinely used wanted to open up a vaccine division; I was pay for new vaccines as they would new vaccines sold at large scale. Smaller, offered a position and ended up loving it. drugs. I think it’s partially psychology; specialty vaccines, such as vaccines for The passion of the team working in that we humans invariably wait for a problem travelers, the military, and the developing space and the impact your work can have to emerge before dealing with it, rather world, are being neglected, which could on patients is unparalleled. When working than taking steps to avoid it. There is also ultimately impact the developed world with vaccines, you are combating powerful the concept that vaccines are a right and a (consider Ebola). diseases and working to strengthen public public good, and therefore the price needs After leaving Novartis in 2011, I joined health, which are powerful drivers for to be as low as absolutely possible (which PaxVax, which focuses on providing motivation. At Novartis, I had previously I certainly do not disagree with). Very vaccines in underserved markets. At first, worked in hypertension. High-blood low vaccine prices, however, lead to less PaxVax was based on a more traditional pressure kills many people, but each new innovation. For example, even large-scale biotech structure, focusing on the drug is only usually marginally better than products, like seasonal flu vaccines, still technology around vectors to develop new the previous one. Having the opportunity use egg techniques that have been around vaccines – many of which can be found in to develop an entirely new vaccine, which for over 70 years. Of course, this doesn’t the clinic today. But, along the way, we could substantially change disease and mean there is no innovation – there are had a bit of a pivot while working on new health rather than incrementally managing exciting technologies in use such as virus- technologies. It was frustrating to see so it, is exhilarating. It really gets into your like particles (VLPs), which enable vaccines many diseases being overlooked and we started to pay greater attention to specialty vaccines. Our journey began when we licensed CVD 103 HgR from UMB and then developed Vaxchora, a vaccine for cholera, approved by the FDA in 2016.We also spotted an opportunity with Johnson & Johnson’s typhoid vaccine, Vivotif. The vaccine was similar to Vaxchora – both are live attenuated oral vaccines. We were able to acquire Vivotif and J&J’s manufacturing facility in Switzerland, which was a great opportunity for us; it gave us access not only to high capacity but also to a team well used to FDA and European inspections – extremely valuable for a small company just entering the market. Today, Vaxchora and Vivotif are commercially available in the US, and Vivotif is also commercially available in Europe. We’ve ramped up our R&D pipeline to include vaccines for chikungunya, Zika, hepatitis A and HIV. We also co-promote some smaller products for other partners in Europe. It’s actually quite unusual for a small company to manufacture and commercialize their own products; many instead look for partners. But there is a danger: your commercial partner may not be as interested in your product as they are in their own portfolio. And it’s very easy for niche products to get lost in a large portfolio. With J&J and Vivotif, for instance, we hypothesized that the product was largely being ignored in the larger suite of drug and vaccine opportunities because it was a specialty product. There are very few vaccine-focused companies out there, which is why I think there is a real market opportunity for a company like PaxVax! Small companies can be very successful in the vaccine space. Development costs can be lower for specialty indications, and as production is scaled down with specialty vaccines, manufacture is much easier. Building out a full manufacturing facility can be extremely challenging for a small company, but there are options out there; for example, we have used pod technologies – mobile suites – that enable us to get a

www.themedicinemaker.com 42 NexNextGen tGen

* Figures obtained from the World We may also be able to do something with Facts and Figures Health Organization and CEPI Zika. Our potential chikungunya vaccine uses VLP technology (many vaccines in our pipeline focus on VLPs), and we are An estimated Over 10 years, seeing some interesting pre-clinical results the global costs of by partnering VLPs with Zika antigens. 2–3 million epidemics could total We are working with the Centers for deaths are prevented every Disease Control and Prevention (CDC) on year thanks to vaccines $600 billion further development. Smaller companies will always be limited by resources, rather than the number of Around A virulent respiratory virus opportunities. Working with groups like spreading as fast as flu could the DOD, NIH, and CDC are part of the 116.5 million spread to all major global benefits of working with vaccines – the public children receive basic capitals within health infrastructure really helps provide vaccines every year, but valuable scientific input, as well as helping to 60 DAYS integrate costs. I believe that collaboration is 19.5 million . crucial to overcome the challenges of working miss out Estimates suggest that such in the vaccine space. At the World Economic a virus is capable of killing 33 Forum in January 2016, a new public health million people within alliance launched, called the Coalition for Epidemic Preparedness Innovations (CEPI). 250 DAYS CEPI was founded by the World Economic Forum, Wellcome Trust, the Bill & Melinda Gates Foundation, and the governments of GMP commercial production suite up and overcome the cold-chain hurdle, among India, and Norway, to prepare for the next running really fast. They are only small other things to better serve those regions. potential waves of infectious diseases that scale, but very easy to roll out. could affect public health and to develop Collaboration opens new doors new vaccines (1). CEPI helps bring priority Balancing global need, innovation, and The US Department of Defense (DOD) vaccine candidates through to the end of cost is a challenge is very interested in vaccines for neglected phase II clinical trials and supports vaccine A constant challenge is how we can support diseases because soldiers can also be affected platforms that can be rapidly deployed innovation in overlooked disease areas when – and medical supplies are limited on the against known and unknown pathogens. prices are so low? For example, there is a battlefield. We currently have a number of A few of the diseases identified as global shortage of yellow fever vaccine in partnerships with the DOD. One of our focus points are Lassa fever, Nipah, and both the developing world, and for travelers focuses is on chikungunya, a mosquito-borne MERS. Over 70 organizations are part from the developed world. We could develop viral infection. It’s a disease that has been of the initiative and I am a member of the a new yellow fever vaccine – current yellow infecting people in Sub-Saharan Africa and board. With all of this collaborative power, Auto Culture! fever vaccines are made with egg-based Asia for decades, more recently spreading to we have to be able to make a difference. I No learning curve with BioFlo® 120 Auto Culture modes techniques, and we certainly have a few Brazil and the Caribbean. Similar to Zika, truly believe that one day we will be able to Imagine a bioreactor or fermentor that > Automatic control of critical process innovative ideas – but current vaccines cost chikungunya is episodic – an outbreak may prevent epidemics before they occur. can literally run itself…that’s what we did. parameters around $2 per dose. Agencies don’t want to tear through a community, but be followed by The BioFlo 120 Auto Culture modes allow > Operates glass vessels and BioBLU® pay more, so how can we justify the costs a period of relative stagnation. Unfortunately, Nima Farzan is CEO of PaxVax, 1-touch process control for microbial and Single-Use Vessels of developing a new vaccine? Revenue unlike Zika, an effort to find a vaccine for California, USA. opportunities aren’t huge for vaccines so it’s Chikungunya hasn’t really been a priority for cell culture applications. Developed from > Fine-tune your process with adjustable values important to have multiple products. As we the pharma industry. In collaboration with Reference years of application experience, the Auto focus on overlooked diseases – which almost the DOD, and with technology licensed from 1. CEPI, “Mission”, (2017). Available at: Culture mode will ensure you start your > Store new recipes in the Auto Culture invariably affect the developing world – we the US National Institutes of Health (NIH), http://bit.ly/2yx6Ntu. Last accessed November process off right. library for later use are working to further reduce costs and we have a chikungunya vaccine in phase II. 27, 2017. www.eppendorf.com/BioFlo120 Eppendorf®, and the Eppendorf Brand Design are registered trademarks of Eppendorf AG, Germany. BioFlo® is a registered trademark of Eppendorf, Inc., USA. All rights reserved, including graphics and images. Copyright ©2017 by Eppendorf AG.

tmm_epp_ad_210x266_2017_12.indd 1 22.11.17 13:46 Auto Culture! No learning curve with BioFlo® 120 Auto Culture modes Imagine a bioreactor or fermentor that > Automatic control of critical process can literally run itself…that’s what we did. parameters The BioFlo 120 Auto Culture modes allow > Operates glass vessels and BioBLU® 1-touch process control for microbial and Single-Use Vessels cell culture applications. Developed from > Fine-tune your process with adjustable years of application experience, the Auto values Culture mode will ensure you start your > Store new recipes in the Auto Culture process off right. library for later use

www.eppendorf.com/BioFlo120 Eppendorf®, and the Eppendorf Brand Design are registered trademarks of Eppendorf AG, Germany. BioFlo® is a registered trademark of Eppendorf, Inc., USA. All rights reserved, including graphics and images. Copyright ©2017 by Eppendorf AG.

tmm_epp_ad_210x266_2017_12.indd 1 22.11.17 13:46 44 NexNextGen tGen

The Best Defense Is Good Science

Starting from fundamental virology, Kevin Kayser and the upstream R&D team at Merck discovered the mechanism by which Minute Virus of Mice (MVM) infects CHO cells, and the respective genes involved in viral uptake. Their work culminated in Centinel: the first MVM-resistant CHO cell line.

Before joining Sigma-Aldrich in Minute Virus of Mice (MVM) – and they 2002, Kevin Kayser, now Senior didn’t know whether his goal was remotely R& D Director at Merck (known as feasible. The work culminated in Centinel, MilliporeSigma in the US and Canada), described as “intelligent virus defense”. worked as a professor and researcher, Centinel is a gene-editing technology using gene editing to stabilize proteins in that can make CHO cell lines completely industrial microbial systems. He applied resistant to MVM. Centinel claimed the Why is MVM such a big problem for those skills to the fundamentals of viral top spot in The Medicine Maker 2016 the industry? infection at Sigma-Aldrich, which was Innovation Awards. Here, Kayser talks Going back to the early 1990s, acquired by Merck KGaA in 2015. Their us through the development process, Genentech had a contamination event aim was to genetically engineer a line and why insurance against MVM with MVM which cost them in the of CHO cells that would be immune to contamination is so important. region of $10 million. However, the real Genetic Code Breaking

By Kevin Kayser

I’ve been involved in gene editing for most of my career. When I started, dozens of different components, each we were using microbial systems, and coming from different suppliers, often eukaryotic gene editing was the holy from all over the world. MVM is a grail of the early 2000s. In 2007, I parvovirus. Parvoviruses are quite edited a book that chronicled where common (and most frequently studied) gene editing was at the time – and the in domestic animals; usually found in major techniques used today, such as animal feces and urine. Typically, the CRISPR-Cas9 or zinc finger nucleases virus enters our industry through raw (ZFNs), weren’t even mentioned! materials, such as wheat hydrolysates; CRISPR-Cas9 has placed gene wheat fields can contain potentially editing in the spotlight, but for our infected field mice, and infected mice purposes zinc fingers are preferred. can also get into warehouses. In other You need a lot of skill to design zinc words, when you’re procuring from a fingers, and they can provide greater wide variety of sources, contamination specificity and precision, with little or is a possibility. For this reason, critical no off-target effects – we are always review of vendor supply management concerned about introducing additional is crucial. modifications that might affect the As far as I know, MVM is the only CHO cell line. If we’re doing research virus that has been associated with into how a mechanism works, we’ll use chemically defined cell culture media – CRISPR-Cas9, but in the final product most contamination events come from development we use ZFNs. serum and more complex raw materials. There are, of course, some legitimate “The contamination MVM is extremely durable and virulent, concerns with gene editing. I recently which means just a few viral particles read about a self-titled “biohacker” who disrupted patient in the environment can have fairly was injecting himself with CRISPR- significant implications. Genentech Cas9 in an attempt to build better drug supply, revealed that one virus particle per liter muscles! Clearly, there are issues of cell culture was enough to infect the around who should have access to the facilities had to be entire process. technology and what they should be allowed to do with it, but gene editing shut down, and the How did the Centinel project most definitely has a tremendous get started? amount of potential. I believe that it stock price The project was the brainchild of David should be possible to create a “super” Onions (now Director of Orsus Medical) CHO cell line with a variety of traits plummeted.” and me. We thought that it would be that would allow it to produce safer great to genetically engineer cell lines and more efficacious drugs. Today, that were resistant to common viral we are already seeing new cell lines impact of a viral contamination event contamination events. At the time, being developed with reduced host cell in biomanufacturing was witnessed however, we knew nothing about how the proteins, better glycosylation patterns, during the Vesivirus 2117 contamination viruses actually infected these particular faster growing rates, and so on. at the Genzyme facilities in 2009. The cell lines. Our team spent a lot of time As well as performing gene knock- contamination disrupted patient drug delving into the fundamental science of outs, it’s also possible to do knock-ins supply, facilities had to be shut down, MVM infection, which was rewarding to turn up the expression of genes or and the stock price plummeted. The because in industry you don’t often get endogenous proteins, or to create new impact on the business as a whole the chance to put on your academic hat therapeutic variants. There is also the was tremendous. These types of to do basic research. When we started, potential to introduce more human contamination events are quite rare, we had no idea if we would ultimately characteristics to the cell line to reduce but can be catastrophic when they occur. end up with a commercial product. It the chances of immunogenicity. These Today, cell culture media comprise was possible that the processes involved are the likely routes forward.

www.themedicinemaker.com 46 NextGen

(ZFN) gene editing technology. It just event jumping in right away to partner so happened that some of the mutants with us, which affirmed that this is a resulted in modifications in the binding genuinely desired product. receptor for MVM, which led to the Most of our partners tend to be larger discovery that the virus attached to organizations – and I think that’s likely the membrane associated protein via a down to the fact that they manufacture specific sugar. When we screened our larger volumes of drugs; the larger already existing library, we found some the bioreactor, the greater the risk. EXHIBITION & CONFERENCE 7-8 FEBRUARY 2018 PARIS EXPO, PORTE DE VERSAILLES mutants that were resistant, or partially Smaller organizations tend not to have resistant, to MVM infections. When experienced a contamination event, and we witnessed our “infected” cell lines I get the impression that some believe, growing, and saw that the virus couldn’t “It will never happen to me.” And dock, we knew that we had cracked it. of course there are cost pressures for smaller companies. Pharma’s dedicated packaging

How will you be expanding the “When we witnessed product in the future? & drug delivery event MVM was a logical first choice. Other our ‘infected’ cell viruses can be associated with serum and more complex raw materials, but lines growing, and MVM is the only one to be associated with chemically defined processes. saw that the virus However, we are continuing to expand the program in several areas. I don’t couldn’t dock, we think there will be further “product launches” akin to a catalog item. Rather, knew that we had we’re focusing on custom-made solutions for our clients; if a client has a particular in MVM viral binding and uptake virus they’re concerned with, we will

cracked it.” INNOVATION NETWORKING EDUCATION would be core to the biology of the cell work with them to build a program. If line, making it impossible to knock- major contamination events with new or out the relevant genes. We didn’t know unknown viruses occur then we will of • Innovation Gallery • Networking Areas • Conference whether we would be able to find the How has the industry reacted? course explore those. • Pharmapack Awards & Events • Symposium receptor and characterize the binding Centinel basically acts as an insurance event. It was pure exploratory research policy. Although there are various What other projects are you working on? • Innovation Tours • International Meetings • Workshops and very exciting. methods of limiting your risk of viral It was only a few years ago that the • Pharmapack Start-up Hub Programme • Learning Lab contamination – testing, filtration, bio- CHO genome was sequenced and we When did you know the project clearance studies, and so on – there are actually sequencing our own cell was feasible? isn’t anything else on the market that lines right now. We are experimenting Follow It was actually serendipitous. As part of a can guarantee protection. All it takes is with removing parts of the genome that the link: separate project, the team created a series for a single virus particle to make it into aren’t needed for the cell to produce bit.ly/2uKb0Vr of gene knock outs within the CHO cell the production process and the entire therapeutics, which could potentially FREE line to understand glycosylation patterns. production run is compromised. divert more energy to therapeutic Glycosylation can impact the efficacy For this reason, the industry has protein expression. We can also remove to attend! REGISTER NOW! of the therapeutic protein in human reacted very positively. We have a the retroviral scars that have been patients. So, in our efforts to modify the number of industrial partners working accumulating in the genomes of all sugar structures on the therapeutics, the with us, including Genentech. It was organisms. Once we have done that, team engineered a series of glycosylation great to see one of the first companies we may be able to expand into adjacent mutants using our zinc finger nuclease to publically disclose a contamination industries, like vaccine production. NEWS, WHITEPAPERS #PharmapackEU & EVENT PROGRAMME AT WWW.PHARMAPACKEUROPE.COM

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6460 Pharmapack 2018 266x210+3mm (The Medicine Maker).indd 1 10/08/2017 16:39 48  Sponsored Feature

The Transformation to Excellence How a customer focused mission to boost single-use assembly product quality and supply security led to the Mobius® MyWay Program and a manufacturing site transformation.

Back in 2016, Merck began a multi-phase notes, “Ten years ago, single-use accounted means that there are plenty of opportunities program to prepare themselves – and their for 15 percent of the market, but today it’s to streamline processes and focus on ‘right- customers – for a high quality, scalable and 30–35 percent – and in ten years’ time? It’s first-time’ production to achieve the highest secure single-use future. likely to be more like 75 percent.” Although quality. Reliable delivery and best-in-class Phase 1 of the “Mobius® Transformation” growth is positive and invariably welcomed by quality were two of the key drivers of was underpinned by the launch of the most, it also brings challenges when it comes transformation at the Danvers site – and Mobius® MyWay Program – a segmentation to scaling up production to meet increasing ultimately enabled us to become a Center of Merck’s single-use portfolio into three demand. Merck recognized the potential of Excellence.” product offerings: Mobius® Stock, Mobius® capacity challenge early on – and proactively “Phase 1 of the transformation identified Select, and Mobius® Choice. The aim? To formulated a transformation plan. “We nine work-streams to address critical reduce custom assembly lead times and recognized that it’s not just about solving growth enablers, which fed into five overall enhance supply security (1). Behind the scenes, a short-term problem in capacity, but also objectives,” says Faria (see Sidebar: How however, other high-impact transformations about preparing for continued growth into does transformation occur? Phase 1 in also had to occur to execute the mission, the future,” says Perrotey. action). “I think it’s fair to say that it was an including reorganization of all departments However, capacity isn’t the only challenge. ambitious program! But it actually boiled to support a 24/7 schedule, Lean Six Sigma “End users also want their products faster,” down to three main themes: people, training for employees, and expansion of the says Faria. “Quality expectations are also processes and infrastructure.” Faria notes company’s Danvers, Massachusetts site – changing. How do you get more out the that getting the “people” aspect right ultimately, leading to its new status as a single- door, faster and with higher quality than was absolutely critical – and it involved a use Center of Excellence. before? How do you meet customer complete re-organization of workflows and Phase 1 was completed in early 2017, but needs and requirements when the bar is personnel, from the shop floor to design, Phase 2 – ensuring continuous improvement continuously being raised?” engineering, and quality assurance. and further enhancing supply security – is an The answer lies in a different approach – There was also a cultural shift. “We on-going journey. and a new way of looking at the challenge wanted the whole team to play offense We spoke with Pascal Perrotey, Head of – in other words, a transformation. rather than defense! We wanted a more Operations at the Danvers site, and William proactive attitude to finding solutions. We (Bill) Faria, Production Manager, to discuss The past, present and future of Danvers wanted people to think about what we the single-use market, as well as the Mobius® The heart of the Danvers site is split into could do, rather than should do, and to transformation – and what both mean for two main parts: single-use bag manufacture take big swings and make huge changes for single-use customers. and final assembly, where the appropriate the better,” says Faria. “People were really components are connected. “It sounds motivated not only by knowing that they The exciting challenge of a double-digit straightforward, but the reality is there were improving processes and products for growth market are many different designs, varying in the benefit of our customers, but also that Single-use technology represents an exciting complexity, which forces us to be very they were creating a better place to work.” and rapidly growing market, as Perrotey flexible in production,” says Faria. “It also The process – and the people it seems How does transformation occur? Phase 1 in action For Merck, “transformation” isn’t just a word – it represents a well-defined and multifaceted approach that, in its initial phase, addressed nine work-streams across five areas.

Nine work-streams: • Design and staffing • Performance culture • Output optimization • Prototype lead-time reduction • Segmentation and portfolio members from other sites, who haven’t • Supply chain alignment visited us for a while say it’s a completely • Danvers expansion different site... almost unrecognizable. In • Capacity expansion fact, one customer asked if we had applied • Proactive quality for any external awards to celebrate the work that has been done, which was an Five overall objectives achieved: unexpected compliment!” says Faria. “Other customers have noted how the 1. Capacity Expansion culture that we are instilling matches up to Implemented a 24/7-shift model to – are the product, which is what makes the culture they are trying to build in their increase production capacity and output, the new Center of Excellence the perfect own organizations. We’ve also had more expanded clean rooms, additional partner for the Mobius® MyWay Program interest in collaborations to foster best automated lines and ancillary facility philosophy. “Now, we can offer greater practice, which is great – after all, that’s what requirements to support extra output. quality with more automation, improved being a Center of Excellence is all about!” process control (and so less variability), Customers also recognize the direct 2. Prototyping Capabilities and a highly engaged workforce with benefits of the changes. Perrotey adds, “A Reduce prototype lead times and a defect-free product mindset,” says few weeks ago, one of our top customers enhanced supply security by 50 to 75 Perrotey. “We have improved supply visited and told me that, from his perspective, percent with dedicated prototyping security with fast and reliable on time our transformation represents a real resources, including facilities and team. delivery, higher capacity and a highly competitive advantage – one that would flexible production model.” further reinforce our strong relationship. 3. Portfolio Optimization Given customers are integral to the We were delighted and honored by such a Segmented single-use portfolio into ongoing mission, they also have an comment because it means we’re already three distinct product offerings – essential role to play. “It’s great when being successful.” Mobius® Stock, Mobius® Select, and customers come to visit, because we’re Overall, the transformation is a reflection Mobius® Choice – to drive improved able to have interesting discussions about of the increasingly essential partnership custom assembly lead times. Notably, real-world needs, which leads to the between single-use supplier and customer. custom assembly lead-time for Mobius® opportunity to collaborate and further “We always emphasize that we do not simply Select is now only 6 weeks. improve,” says Faria. produce plastic bags and components,” Adds Perrotey: “As the market continues Perrotey says. “In fact, we are part of a 4. Supply Chain Improvements to evolve, it’s important for us to continue wider promise to improve health and life. Streamlined warehousing with a new to learn from our customers; likewise, they And I know that every single employee feels 35,000 square-foot raw material can also learn from us – it’s this kind of proud to contribute to new solutions and warehouse, reducing the risk of collaborative relationship that really enables our ongoing efforts to help our customers component shortages and improving successful transformation, not just for us, but develop and manufacture better medicines.” supply security. the whole industry.” Reference 5. Quality Enhancements The result 1. S Bell, “Single-Use That’s Ready When You Are,” Instilled a proactive quality culture, with The big question: have people noticed The Medicine Maker, 35, 48-49 (2017). Available “right-first-time” performance, to boost the transformation? “Customers, and at: http://bit.ly/2AXRCvw. product quality. Breaking Barriers to Biosimilars

Sitting Down With… Richard Markus, Vice President of Global Development, Amgen, USA. Sitting Down With  51

How did you get your start in pharma? meaningful differences in function or we have made a meaningful contribution I’ve always been interested in science, activity compared with the originator. to shaping the field and helping patients. especially biology, but my first job after Technology advances in the last two decades college actually involved statistical have not only enabled us to manufacture If you could change one thing about the programming in the pharma industry. As I such complex biologics, but also to evaluate biosimilars field, what would it be? learned more about the industry, my interest them with high confidence. And that’s There was actually a recent change in the in it – and particularly in clinical research allowed us to expand our biosimilar pipeline biosimilars field which we are pleased with, – grew. So my next step was to go back to from three products to ten. and which we will continue to support. In school and earn my MD and PhD, with the the US, the Centers for Medicaid and expectation of going back to the field of drug What have been the biggest highlights of Medicare Services (CMS) reversed a policy development as a physician. I started working the division so far? for biosimilars that used blended billing at Amgen around 11 years ago as a physician I am really proud of our work with and reimbursement codes that ultimately scientist. I worked with a fantastic team to trastuzumab – a biosimilar that we are followed a generics reimbursement develop a bone-targeting agent (XGEVA; developing with Allergan. The collaboration paradigm. As a manufacturer of innovative denosumab) for cancer patients, which was in with Allergan began very early in our biologics and biosimilars, we are pleased phase II trials at the time. It was a very large program and focuses on oncology products. that CMS put patient needs first and effort involving multiple studies in patients We are both mature companies in terms of will now ensure that each biosimilar with different cancers, so it was an exciting our goals; we know who we are and what product will have its own billing code and way to start my career. we want to contribute, which makes for a individualized reimbursement rate. This successful partnership. It’s important for us will facilitate efforts to support product But then you moved into biosimilars… both to have a high-quality product, and traceability and ultimately foster a more Right. My roles progressed until I had to have the clinical data to confirm and competitive biologics market. the opportunity to help start Amgen’s support the level of similarity, because it In the generics world, there have been biosimilars business – an entirely new gives patients and physicians the confidence many shortages of critical chemotherapies, division for the company. Back then, there to make an informed decision about the partly because of how policies have wasn’t much clarity on how to develop drugs they want to use. Trastuzumab is played out in terms of incentivizing (or biosimilars; the regulatory environment currently in review in Europe and the US disincentivizing) certain methods. I think was still evolving (and it still is today). for market authorization and we are looking it is important that we actually learn from Indeed, biosimilars represented a whole forward to the anticipated approval. those issues and make different choices new class of product; they are not innovator for biosimilars. We need to be able to drug products and certainly not chemical And what about personal highlights? ensure consistent quality with continuous generics. It was a once in a lifetime The biggest highlight for me has been competition – both in the short term and opportunity to be involved in the creation working with fellow scientists at Amgen. long term. of a whole new type of product. Many companies outsource much of their The challenge is creating sustainability biosimilars work, as they don’t have the for healthcare assistance – particularly How has biosimilar development changed? capacity to do it themselves. We have built in oncology – because patients are Earlier biosimilars were based on smaller our biosimilars business with the same often treated with two or three product and generally simpler products, but in the laboratories, manufacturing facilities, and combinations at a time, which is expensive last couple of years biosimilars have been the same group of scientists who I’ve been (and a cost that is endured through second involved in much more complex antibody working with for years, which has been a and third line treatments as well). It’s treatments. They are not just more complex great pleasure. great that we can help save lives, but to because of their size, but because they I think I am very fortunate in my role. I maximize the number of lives we can save, consist of multiple parts with different still get the fun of working with scientists the cost of drugs needs to be addressed, functionality or activity. For example, one and data – and making decisions about the and healthy competition is the solution. part may bind the primary target on the program and the molecules themselves. I All of this said, the biosimilar payment tumor, while another binds T cells or the also interact directly with regulators, who environment in the US is still evolving, immune system – the combination is what have been really well engaged with the field but Amgen supports a “level playing field” provides activity, and each different part from the very beginning. Working with for how reference products and biosimilars of the biosimilar must have no clinically regulators is very rewarding; I like to think are paid for.

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