APRIL 2020 # 64

Upfront In My View NextGen Sitting Down With Tackling cancer with the What is the fastest route to a Overcoming viral vector Pharma forensic, human microbiome COVID-19 vaccine? challenges Stephen Tindal

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www.cambrex.com Fragile Pharma? As individuals, societies, industries, and governments, Editorial we must consider how well prepared we were for this pandemic – and start thinking about the next one

f you are lucky enough to have avoided the more direct and devastating effects of COVID-19, a “lockdown” may feel almost peaceful – a time for quiet reflection. The one Iword that comes to my mind when mulling the upheaval caused by the global pandemic is “fragility.” In the modern age of online shopping (next – or even same – day deliveries!), how many of us have considered the need for an emergency stash? A lack of a replaceable food staple is one thing – but what if we can’t source medication for a chronic illness? What action do we take when the shelves run truly dry? Globalized supply chains certainly result in reduced prices in developed nations, but what happens when we can no longer import food or medicines? When such support systems start to unravel, the costs will be heavy – and there are no easy answers. Times like these remind us that risk isn’t an abstract concept – life- changing events evidently do happen in our lifetime. Viral outbreaks are not just an overused movie plot. Could we all have been better prepared? This is a question individuals, governments, and industries alike must face. The funding of (rapid) vaccine development is one area that will likely come under increasing scrutiny. Though we can only commend the scientists and engineers Reference involved in vaccine development for their hard work now and 1. AC Kalil, “Treating COVID-19 the foreseeable future, the endeavor is reliant on government – off-Label Drug Use, Compassionate Use, funding – as Eric von Hofe points out on page 10. He doubts that and Randomized Clinical Trials During money is currently in short supply, but does believe that developers Pandemics” (2020). Available at could be in a healthier position now, if they had received higher https://bit.ly/3bG8HZv. levels of funding in previous outbreaks. Similarly, Andre Kalil, 2. Time, “COVID-19 Vaccine Shipped, a professor of infectious diseases at the University of Nebraska and Drug Trials Start” (2020). Medical Center, argued that new therapies were not discovered Available at https://bit.ly/2JscaPd. during the Ebola outbreak because of a lack of randomized controlled trials (1). Kalil also highlights the unprecedented speed – “from concept to implementation in just a few weeks” – with which trials have been rolled out. The same could be said of Moderna’s SARS-CoV-2 vaccine, shipped for trials just 42 days after the genetic sequence was released (2). There may have been missed opportunities with previous outbreaks, but the pace of movement does suggest that some lessons were learned – perhaps pharma isn’t so fragile. Sadly, it sometimes takes a crisis to reveal where the cracks are. And the bigger the crisis, the more cracks we find.

James Strachan Deputy Editor

www.themedicinemaker.com Contents

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03 Editorial Upfront In My View Fragile Pharma? by James Strachan 06 The latest news, views 10 Eric von Hofe believes that the and research – including a drug fastest route to a COVID-19 combination to mend broken vaccine is through synthetic On The Cover Cover bones faster, a stem cell cure for solutions HIV, and why the EMA is Celebrating the most influential offering free scientific advice for 11 China provides enormous people in the pharma industry companies working on opportunities, but companies COVID-19 treatments must keep track of the and vaccines “regulatory rapids,” says Matthias Bucerius ISSUE 64 - APRIL 2020

Feel free to contact any one of us: [email protected] Content Team Editor - Stephanie Sutton Kirstie Anderson (Commercial Editor) James Strachan (Deputy Editor) Maryam Mahdi (Associate Editor) Commercial Team Associate Publisher - Helen Conygham Helen Johnson (Business Development Manager) Sarah Griffith (Business Development Manager, North America) Kevin Vlad (Business Development Executive, North America) Design Team Head of Design - Marc Bird Hannah Ennis (Senior Designer) Charlotte Brittain (Designer) 08 Digital Team Digital Team Lead - David Roberts Peter Bartley (Digital Producer Web/Email) Abygail Bradley (Digital Producer Web/App) Audience Team Audience Growth Strategy Manager Feature Reports – Brice Agamemnon CRM & Compliance CRM & Compliance Manager - Tracey Nicholls 16 The Power List 2020 14 The Rise of Liquid Hayley Atiz (CRM Assistant) We celebrate the finest Nanoparticles Commercial Support Team Internal Systems Manager - Jody Fryett medicine makers in the Dan Marr (Campaign Reporting Analyst), industry across three categories: 49 The Glass Quality You Seek Jennifer Bradley (Production Assistant), Lindsey Vickers (Project Manager - Webinars) Biopharmaceuticals, Advanced Does Exist Events Team Medicine, and Small Molecules Events Manager - Alice Daniels-Wright Jess Lines (Events Coordinator) Marketing Team Marketing Manager - Katy Pearson Sitting Down With Jo Baylay (Marketing Executive) Kevin O'Donnell (Marketing & Events Executive) NextGen Matt Everett (Social Media Manager) 50 Stephen Tindal, Director, Joe Box (Social Media and Marketing Assistant) 36 Fast-Farming Pharma Science & Technology, Catalent Accounts Team Kerri Benson (Accounts Assistant) Find out why one company is Pharma Solutions, Swindon Emily Scragg (Accounts Apprentice)

using plants to accelerate the Human Resources manufacture and scale up of Human Resource Manager - Tara Higby new vaccines Management Team Chief Executive Officer - Andy Davies Chief Operating Officer- Tracey Peers Senior Vice President (North America) 40 Advanced Medicine: - Fedra Pavlou Replicating the mAb Financial Director - Phil Dale Commercial Director - Richard Hodson Success Story Content Director - Rich Whitworth What lessons has the industry learned from monoclonal Change of address [email protected] antibodies and how can these Hayley Atiz, The Medicine Maker, Texere Publishing Limited, be applied to cell and gene Booths Park 1, Chelford Road, Knutsford, Cheshire, WA16 8GS, UK General enquiries therapies? www.texerepublishing.com | [email protected] +44 (0) 1565 745 200 | [email protected]

Distribution: The Medicine Maker (ISSN 2055-8201), 44 The Bumpy Road to a is published monthly by Texere Publishing Limited, Booths Park 1, Chelford Road, Knutsford, Cheshire, WA16 8GS, Cytomegalovirus Vaccine UK. Single copy sales £15 (plus postage, cost available on request [email protected]). Non-qualified annual Cytomegalovirus infects most subscription cost is £110 plus postage people during their lifetime, but Reprints & Permissions – [email protected] The opinions presented within this publication are those of the authors it’s taken decades for vaccines to and do not reflect the opinions of The Medicine Maker or its publishers, Texere Publishing. Authors are required to disclose any relevant be developed – and there is still 50 financial arrangements, which are presented at the end of each article, where relevant. © 2020 Texere Publishing Limited. All rights room for improvement reserved. Reproduction in whole or in parts is prohibited. 6 Upfront SPECIAL SERIES Advanced Medicine Upfront

Research Trends Hot Topics at Innovation CAR-TCR 2020

Clinical trial confusion, off- the-shelf cell therapy, 24-hour CAR-T, and more

In what may have been one of the last advanced therapy meetings to go ahead for some time, delegates met in London in late February for CAR-TCR. A central theme was the difficulty of conducting clinical trials in Europe compared with the US and China. Dolores Schendel, Medigene, pulled no punches during the first panel discussion of the event, telling the audience that Medigene needed nine academic centers The concerns were reflected in the be to supply the cells needed for such – not the expected three – for a “small figures presented by Pippa Gledhil therapies... phase I trial” in Germany, as well as a from Beacon Intel (see our infographic Elsewhere, Omar Ali, Visiting “crackerjack” team of lawyers. Schendel below) who reported that there were Lecturer at the University of suggested that the German situation was more than five times as many CAR- Portsmouth and Former Adviser to a microcosm for the whole of Europe, as TCR developers in China and the US NICE, spoke about the growth of different apheresis sites in Germany are compared with Europe. innovative reimbursement payment regulated by the different states. In terms of other hot topics at the models. Here, according to Ali, it is the Andre Choulika, CEO of Cellectis, also conference, off-the-shelf cell therapy was US that is falling behind because, even compared the experience of filing a patent certainly one – Choulika claimed that if insurers can get their heads around in the US to France. “On the US side you 2020 will be the “year of the allogeneic” the price, there is ambiguity over who had, like, 10 questions. On the French – as well as TCRs for solid tumors and pays when hospitals need more money side, you had 16 pages of questions,” he 24-hour CAR T. But for some allogeneic for administration. “Is it the patient? said. “It took us 18 months to do this and therapies, there may only be a handful Is it the government? Is it the insurer? when you’re a small biotech company you’re (perhaps less than 50) donors worldwide. You’re driving an electric car with no burning cash every month.” Enter the “super donor,” whose job it will charge points,” he said.

INFOGRAPHIC What are American therapies in Peeking into companies up to? development An the CGT Pipeline More than increase of

Intel shows a rise in cell in and gene therapy diseases development currently for rare development in the US, treated diseases being diseases since 2018 with China not far behind with CGT explored Upfront 7

to a staggering $2.4 billion and ADVANCED involves approximately 60,000 Bug Therapy MEDICINE IN BRIEF patients annually, paying up to $40,000 per treatment. The society Cancer patients have responded Tackling solid tumors with macrophages, a has seen an increase in unproven to a live biotherapeutic– stem cell cure for HIV, and travel bans… therapies for COVID-19 and is checkpoint inhibitor combo for What’s new in advanced medicine? taking a stand. “Most importantly, the first time these ‘treatments’ produced with • A proof-of-concept paper has no evidence can be even more 4D Pharma, based in the shown that it is possible to dangerous to the immediate health UK, has partnered with genetically engineer macrophages of patients and their communities,” Merck Sharp & Dohme to kill solid tumors in both said Laertis Ikonomou. to deliver anti-PD-1 mouse models and human • A major concern for the cell and therapy, Keytruda, in samples. UPenn researchers gene therapy industry is getting combination with a live were able to overcome the cells’ around the travel bans that are biotherapeutic to patients innate resistance to gene transfer cropping up in response to the with advanced malignancies. with a chimeric adenoviral coronavirus pandemic. The good The additional interim clinical vector. In addition to expressing news: Novartis reportedly says data showed two partial responses with CAR, the process transformed it has found alternate methods evidence of tumor shrinkage; one patient the macrophages into highly to ship Kymriah following whose disease isn’t progressing or regressing, inflammatory cells that could resist disruption to passenger flight evidence of increased tumor-infiltrating tumor co-option and stimulate the services from Europe. lymphocytes following treatment, and no rest of the immune system. • Researchers have used stem cell drug-related serious adverse events. • According to ISCT, the unproven transplantation in combination “Our approach is to take a single strain cell therapy market is worth up with chemotherapy to cure the of bacteria from the human microbiome second-ever patient of HIV. and understand how it interacts with the The first patient to be cured immune system. Regarding the strain used nine years ago in Berlin received in this study, we believe the flagellin protein total body irradiation and two is responsible for the increased immune rounds of stem cell transplant activity, which facilitates the activity of the from a donor who carried the checkpoint inhibitor,” says Duncan Peyton, resistant CCR5Δ32/Δ32 gene, CEO of 4D pharma. “What’s interesting whereas the “London patient” is that the two patients in which we saw a only underwent one round of response had already received and didn’t transplant, a less intensive cocktail respond to checkpoint-inhibitor therapy of chemotherapy drugs, and no before taking Keytruda in combination total body irradiation. with the live biotherapeutic, MRx0518.”

A snapshot of thehe global CAR-CA Global distribution of There are 2282 CAR/TCR TCR landscape:pe: commonmmon targets CAR T Developers trials in China,ChChihin which makesmak upp 22%22% 250 CD19 268 of the totaltootal 200

150

100 MSLN CD22 (in solid 49 CD20 tumors) 50 37 33 Allogeneic 19 0 US: 57 Europe: 9 China:na 47

Sources www.themedicinemaker.comwwwww.themedicineemmakaker.coomm PhRMA, “Medicines in Development 2020 Update: Cell and Gene Therapy” (2020). Beacon Targeted Therapies, “Our Highlights from CAR-TCR Europe 2020) (2020). 8 Upfront

The Battle Against the Brain-Eating Amoeba

How can nanoparticles be used to prevent deaths caused by unicellular organisms?

Unicellular organisms like Naegleria fowleri with diseases caused by the amoeba are type of protist pathogen that causes brain are generally harmless. However, the rising, particularly in developing countries. infection. The novel compounds alone, organism is known by another – far more Now, researchers at the American University as well as in combination with silver ominous – name: “brain eating amoeba.” of Sharjah, United Arab Emirates, have nanoparticles, showed potent effects. N. fowleri typically eat bacteria, but if designed novel compounds which, when They also tested the cytopathogenicity introduced into humans via nostrils (usually combined with silver nanoparticles, show and cytotoxicity of the compounds against via contaminated water during swimming, promise in killing the amoeba. amoeba-mediated damage of the human ablution, bathing, nasal irrigation etc.) they “Currently available antimicrobials can keratinocytes, which resulted in the can use brains as a food source. N. fowleri cause severe systemic side effects, such as reduced viability of both pathogens. is attracted to the chemicals that neurons nephrotoxicity, as they are administered Siddiqui and Naveed Ahmed Khan, produce when communicating with one intravenously. And that’s one of the another researcher from the American another, and will travel through the nose reasons why the mortality rate for these University of Sharjah, now plan to and olfactory nerve before reaching the diseases is more than 95 percent,” says commence further studies to develop a better brain, where it can cause infections like Ruqaiyyah Siddiqui. understanding of the precise molecular primary amoebic meningoencephalitis Siddiqui and her colleagues tested pathways the parasites use to cause disease, (which causes inflammation and a variety of quinazolinones and their with a view to seeking drug targets. destruction of the brain and its linings) and derivatives in vitro as their antiamoebic granulomatous amoebic encephalitis (a rare effects had not previously been tested. Reference but usually fatal CNS disease). They found that these compounds elicited 1. R Siddiqui, “Aryl quinazolinone derivatives as Though such incidences are fortunately amoebicidal effects against N. fowleri novel therapeutic agents against brain-eating rare, morbidity and mortality rates associated and Balamuthia mandrillaris, another amoebae”, ACS Chem. Neurosci, (2020).

and strengthens weakened bones. When over the age of 60 die within a year of Sticks and injected, the anabolic agents selectively suffering from this type of fracture (1). accumulate on bone fracture surfaces where But Novosteo also has plans to explore Stones... they promote rapid healing. The research the future use of the drug for other team also believes that the localization applications, including dental implants An injectable drug could help of the bone-building drug combinationn asas wellwell as hheadead anandd fafacialcic al fractures.fractures. heal broken bones faster at fracture sites will reduce the collaterall toxicity that would occur if the agents weree ReferenceReferrence Novosteo, a spinout from Purdue to circulate throughout the body. 1.1. P Purdueurduee University,UUniversity, “Injectable“Injejectaable drugdrd ug forr fasterfaf ster University, has developed a targeted drug The company initially intends to focuss healinghealing oofffb bboneone ffracturesractures ppreparesrepareara s fforor cliclinicalninicall combination, NOV004, which reportedly its use of the product on hip fracturess trials”trials” ((2020).2020). AvailablAvailablee aat:tt: hthtthhttp://bit.p://bit. helps accelerate the repair of bone fractures in the elderly, as one in three adultss ly/2xaRFUk.ly/2xaRFUFUUk. Upfront 9

IMAGE OF THE MONTH Pro Bononnoo AdviceAdvice

The EMA is offeringffffering scientists freee adaadvicevice oonn thethhe development ofo therapeuticstherapeutu ics to treat COVID-19D-19

Developers of potentialtenential ththerapeuticserapeuticcs or vaccines for COVID-19OVID-19 hhaveave been invited to contactt thethe EMAEMA as soon as possible to take advantagedvdvantantage of the full fee waiver the agency iis offering for fast-tracked scientific advice applications. The agency will identify products mature enough to benefit from the fast-track advice service, which includes preliminary informal comments, feedback on development programs, as well as guidance on best methods, study designs, Do You See What I See? and the efficacy and safety of The rise of augmented reality in the pharma industry. IMA Active is using products. augmented reality for assistance in case of malfunctioning machines. In addition Credit: IMA Active to the fast- track scientific Would you like your photo featured in Image of the Month? advice service, Send it to [email protected] the EMA also reminds drug companies that it has several other measures that can speed up the development QUOTE of the month of pertinent medicines, including the PRIME scheme (originally launched to enhance support for the development of medicines that target “Society needs to know it can count on the biopharmaceutical an unmet medical need), accelerated industry to work to rapidly bring forward therapies, assessment, and conditional vaccines and diagnostics that protect humankind from marketing authorization procedures. The EMA is also working this escalating pandemic and prepare the industry to better closely with other international respond to future global health crises”. regulatory bodies to identify effective therapeutics with prophylactic effects. Thomas Cueni, IFPMA Director General. Read more at: https://bit.ly/2wC34fZ Further details are available at: https://bit.ly/2UtZ3ne

www.themedicinemaker.comwww.themedicinemaker.com 10  In My View In My View Experts from across the world share a single Coronavirus: strongly held opinion A Synthetic or key idea. Solution

What’s the fastest route to a COVID-19 vaccine?

By Eric von Hofe, CSO at NuGenerex Immuno-Oncology, USA

The novel coronavirus appears to be less severe in terms of mortality than SARS or avian influenza, averaging about two percent, but it is far more infectious. If too many people contract the virus at once, healthcare systems will not be able to cope with the sudden demand. After the initial wave of infections, there’s a good chance that the virus will not go away entirely, and will re-emerge at a later date. There’s also the possibility that the virus could mutate into an even more virulent strain. Lastly, it is clear from the emergence of a number of pandemic and potentially pandemic viruses over the last 15 years – from SARS and bird flu to Ebola – that COVID-19 will not be A much faster approach is to take the last. In short, the need for a vaccine protein fragments from the virus and use to address these threats could not be those to stimulate the immune system. “There are basically more pressing. These can be manufactured synthetically For the past 20 years, I’ve been and do not need to be produced in four novel involved in developing immunotherapies any biological system, meaning large for cancer as well as infectious disease. quantities can be produced quickly. An approaches being We first began exploring the use of our advantage of our approach is that we synthetic peptide technology around modify the peptides, so that they are sure taken: DNA, RNA 15 years ago when SARS and the avian to be recognized by critical components influenza virus emerged. With avian of the immune system. and recombinant influenza, in particular, it was nearly Previously, we conducted a clinical impossible to develop a traditional study with our modified avian influenza protein vaccines, vaccine where you could simply grow peptides, with promising results. We’ve large quantities of inactivated virus also found that there’s an overlap and our synthetic because the virus would destroy between the H1N1 swine flu and avian the biological systems needed to flu in terms of the peptides usable as modified peptide manufacture the vaccine. Even if this a vaccine. The result of these studies were successful, developing a traditional is that we have identified a process approach.” vaccine is time consuming. whereby we can, in a relatively short In My View  11

period of time (roughly three to five up. Unfortunately, this means that we, vaccines, and our synthetic modified months), identify peptides that could as an industry dependent on funding peptide approach. Trials have started be used to immunize people. to make advances, are hampered with an RNA vaccine being developed There is an 80 percent homology from following through as efficiently by Moderna. While promising, there between the novel coronavirus and as possible in terms of learning what are currently no RNA vaccines on the SARS. We’re currently working with it takes to quickly develop a useful market. We believe that the synthetic another company that specializes in vaccine for a novel agent. It is clear now approach will be the fastest way identifying active peptides usable as that the coronavirus is different. It is to a vaccine but acknowledge that, a vaccine to see if there’s an overlap already having a significant impact on with unprecedented investment in between the peptides we identified in healthcare systems and economies and vaccine development, we may also see SARS and those in SARS-CoV-2. In may well never go away. some success using more traditional addition, computer algorithms have I recall that, during the avian flu approaches. The main advantage we have improved significantly in being able outbreak, President George Bush is the excellent safety record of peptides to predict active peptides just from Jr announced that the US Federal in general and our modified peptides in the genetic sequence of the virus. The Government would put $3 billion into particular. But it is not at all unlikely final step is to then take blood cells research. It seems inevitable that there that some of these novel approaches will from people who have recovered from will be significantly more funding for be combined. coronavirus and see if they recognize coronavirus, given the effect it is already One thing is for sure: we must not these vaccine peptides. If they do, this having. This time, I believe we will see a forget the lessons that will be learned is good confirmation that they will make more concerted and sustained effort to over the next year or two because it a useful vaccine. develop an effective vaccine, as well as a is inevitable that we will experience With any infectious disease outbreak, more significant investment in pandemic something like the new coronavirus there is generally a great deal of initial preparedness. again. We must take the learnings interest and funding from governments, In terms of where we’re at regarding from this period and apply them more particularly if there’s the potential for a potential vaccine, there are basically effectively in the future. My only hope high mortality, until the pandemic four novel approaches being taken: is that we do not have to do too much passes – and then the funding dries DNA, RNA and recombinant protein more learning the hard way.

but over the past five years, things Riding China’s have changed. Chinese biopharma companies have cropped up and we’re Regulatory seeing an increasing number of global companies investing in China. Rapids Foreign companies, however, can sometimes struggle to navigate the The Chinese market presents country’s regulatory landscape, which a major opportunity for has undergone significant changes over pharma companies, but the past two decades. Here, I will focus spending time and money on the regulation of excipients, which, on keeping track of its despite a recent shift towards Western quickly shifting regulations standards, is still quite unique (1). – as recent changes in the With the world’s largest (aging) It wasn’t until the turn of the century excipients field have shown – population, China provides an enormous that Chinese regulators first stated is key to success opportunity for pharmaceutical in article 11 of the Pharmaceutical companies. Traditionally, the Chinese Administration Law that excipients By Matthias Bucerius, Head of Actives pharma market has focused on the should meet certain requirements for & Formulation, Merck manufacture of small molecule APIs, medical use. But the general wording

www.themedicinemaker.com 12  In My View

led to inconsistencies, with some usage information must be included. those that are not included in these provinces regulating excipients as Moreover, detailed information on documents. APIs and others not regulating them the manufacturing process is required, It’s no surprise that a major challenge at all. Then, in 2005, the Chinese FDA together with a list of equipment and for companies looking to take advantage introduced a pharma excipient dossier, process validation data. Lastly, the of China’s emerging biopharma which proposed excipient registration dossier must include quality control industry is the rapid pace at which according to the same process as APIs. specifications with descriptions of the regulations change. For example, when And that meant they would be reviewed analytical methods and validation. the co-review process was introduced in by the Center of Drug Evaluation 2017, there was no transition time; to (CDE) for import and novel excipients, this day, many excipient manufacturers and by the local CFDA for excipients lack the technical dossiers needed for described in the Chinese Pharmacopeia successful registration. As a result, (ChP). But even this was more of a “Detailed many drug manufacturers cannot general principle, with execution and yet register their products in China. adherence often varying. information on the Another major challenge is that the Roughly 10 years later, the Chinese Chinese Pharmacopeia has not yet State Council initiated substantial manufacturing been fully harmonized with other reforms for drug approval processes. international compendia, forcing global In 2017, this culminated with the process is required, pharmaceutical companies to perform “co-review” or joint review approach. additional comparisons of methods and Now, the excipient manufacturer (and together with a list cross-validation checks. no longer the drug manufacturer) is the Regulatory developments – and first party to submit an application of an of equipment and the rise of China’s technology and excipient. The excipient manufacturer biopharma industries – have shifted then issues a letter of authorization process validation public opinion: China is no longer (LOA) with the registration number viewed simply as a location for cheap to the pharmaceutical manufacturer data.” manufacturing. To successfully invest who uses the respective excipient. The in China, companies should employ pharmaceutical manufacturer then the same focus on quality as they would includes the LOA in its dossier when in Germany, the US, or Japan. The applying for marketing authorization The level of detail required for the fast-growing Chinese pharmaceutical for drugs on the Chinese market. registration dossier is based on the market is highly attractive and holds It was a big change. And although excipient classification as revised tremendous potential. the overall quality framework has by the National Medical Products Success requires the investment of dramatically improved over the past 10 Administration (NMPA, formerly time and money – and an ability to years (and is much more comparable to CFDA) in July 2019. Excipients are understand and navigate China’s rapidly quality systems and standards that we classified into products with or without evolving regulatory environment. see in the West), the co-review process a history of use in approved drugs. Overcoming the remaining challenges can be difficult for companies to get The latter comprises completely new is both rewarding and feasible. And their heads around. molecules, as well as molecules with given that the Chinese market is now When submitting an application simple changes to their structure or poised to become even more open, through the co-review process, a changed route of administration. the potential value for international excipient manufacturers must compile Products with a history of use are, pharmaceutical companies can a comprehensive dossier to the Chinese in turn, divided into two groups of only increase. authorities for all the excipients they excipients. The first group includes want to commercialize in China. those excipients that are included in Reference General information on the company the Chinese Pharmacopoeia or the 1. Merck, “Chinese Excipient Regulation – a and the excipient itself, such as its name, pharmacopoeias of the EU, the US, Globally Unique Challenge” (2019). structure, characteristics, approval and UK or Japan. The second group includes Available at: https://bit.ly/2U6YUo6 pda.org/global-event-calendar

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Quality and Regulations JUUNE 2020

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2020 9-11 June Quality and Regulations Conference Virtual Conference 22-23 June Virus Forum Virtual Conference 24-25 June Advanced Therapy Medicinal Products Virtual Conference 8-9 September Medical Devices and Digital Healthcare Madrid, Spain 22-23 September BioManufacturing Dublin, Ireland 24 September Pharmaceutical Freeze Drying Technology Dublin, Ireland 19-20 October Visual Inspection Forum Berlin, Germany The Hague, 20-21 October Aseptic Animal Health The Netherlands 2021 The Universe of Pre-Filled Syringes 5-6 October Gothenburg, Sweden and injection Devices 14  Sponsored Feature

TheThe RRise of Lipid NanoparticlesN

Lipid nanoparticles (LNPs) are typically seen as a niche approach to formulation, but with more complex molecules filling company pipelines, is it time for LNPs to finally shine? Rahul Keswani and Benjamin King are formulators at Exelead specializing in early stage LNP development. We asked for their take on the current market for LNPs.

Why are LNPs so compelling for in the 1970s. LNPs can be seen as a new than the industry is typically used to! But certain drug molecules? generation of liposomes that have a more this is where companies like Exelead come Many of today’s drug molecules are small complex internal lipid architecture with in. We do the heavy lifting to help clients molecules and biologics, but increasingly low or minimal internal aqueous presence VIETXLIFIRI½XWSJ024JSVQYPEXMSRW there is a move beyond traditional XLEXMW[IPPWYMXIHXSWXEFPIERHIJ½GMIRX to create effective oligonucleotide-based biopharmaceuticals to more specialized encapsulation of various genetic payloads. QIHMGMRIW;I½RHXLEXGPMIRXWEVISJXIR and complex therapies. These include TPIEWERXP]WYVTVMWIHEXXLI¾I\MFMPMX]XLIWI oligonucleotides ņ including RNA, mRNA, Are companies reluctant to use LNPs? platforms can offer. For example, the siRNA, and even DNA-based molecules LNPs are not the go-to formulation library of lipid excipients that can be used ņ that can trigger an effect at the genetic approach for routine pharmaceutical in these formulations is sizeable, and it is level to combat disease. As one example, development; they are better suited to growing rapidly with the current interest in a drug molecule could include siRNA to highly complex APIs, such as those based oligonucleotide-based therapies. inhibit expression from messenger RNA on oligonucleotides or products requiring (mRNA) in cells to enable therapeutic YRMUYIFMSHMWXVMFYXMSRTVS½PIWSVHIPMZIVMRK What are the main challenges of working activity. Drug products are also being multiple payloads. These types of therapies with LNP formulations? developed that deliver mRNA to a cell to are appearing more frequently in drug Synthesizing nanoparticles is a complex provide expression of therapeutic proteins. development pipelines as companies focus process, and requires a different sort of LNPs are receiving increasing attention in more on identifying druggable targets at formulation expertise compared to traditional the industry because of their ability to act as the genetic level. Because of this growing ½PP½RMWLEGXMZMXMIWJSVTEVIRXIVEPTVSHYGXW drug carriers for these complex but highly activity, the LNP market is set to expand where the API is essentially combined with promising therapeutics. Oligonucleotides WMKRM½GERXP]MRXLIGSQMRK]IEVW8LIQEMR a mixture of buffer and excipient ingredients. are susceptible to degradation in the body, advantages of LNPs are improved stability With LNPs, you need a good understanding but LNPs provide a stable matrix for the ERHHIPMZIV]IJ½GMIRG]JSVSPMKSRYGPISXMHI SJI\EGXP]LS[XSQM\XLIQSPIGYPIW ¾S[ drug molecule to reside in. They can also APIs. Simply put, the API is much less rates, temperatures, composition, and facilitate entry into target cells. likely to degrade before it can deliver its GSQTSRIRXVEXMSWEVIEPPGVYGMEPXSMR¾YIRGI One common misconception is that therapeutic effect because it is protected JSVQEXMSRSJXLIRERSTEVXMGPIWERHIJ½GMIRXP] liposomes and LNPs are interchangeable by the by the LNP. Moreover, the LNP can encapsulate the API. terms. They are similar ņ and both can be FIWTIGM½GEPP]XEVKIXIHYWMRKGYWXSQM^IH 3XLIV GLEPPIRKIW VIPEXI XS ½PXIVEFMPMX] effective for drug delivery ņbut liposomes ligands attached to its surface. and stability. LNP formulations need careful are simpler vesicular formulations made Drug developers can be wary of LNPs STXMQM^EXMSRSJXLI½PXVEXMSRXSEGLMIZILMKL up of a mostly aqueous interior core. because of the perceived complexity ņ and ¾Y\ERHXLVSYKLTYX[LMPIEPWSQEMRXEMRMRK Liposomes for drug delivery were developed they are certainly more involved formulations the nanoparticulate morphology. While there is always an option to synthesize the What is your advice for companies What other expertise does Exelead formulation in an aseptic environment, interested in pursuing LNP formulations? bring to LNP development? the process becomes very challenging Our guiding principle, and advice to any Nanomedicinal formulations require and expensive. Again, developing a good company, is to always consider scalability from careful attention to detail, comprehensive understanding of the design space, and how the very start. Clients often come to us with expertise and complementary teams design variables impact product attributes a product in the early stages of development to design and manufacture successful such as encapsulation, nanoparticle diameter, that they wish to scale up, but it’s clear they products. Exelead’s primary expertise and formulation stability can help set you up have not fully considered its feasibility. It is is in parenteral drug products focused JSVWYGGIWWEXWXIVMPI½PXVEXMSREW[IPP never too early in your development process on LNP/liposomal formulations and It is also worth noting that LNPs demand to start thinking about paths to scale-up. PEGylated (polyethylene glycol) extra attention in the supply chain in terms We would even go so far as to recommend formulations. of getting all of the different raw materials looking at developing with unit operations We have more than 150 employees ready at the same time – and made to cGMP that are scaled down from manufacturing from diverse backgrounds and areas of standards. However, the growing interest scales to bench scales rather than developing expertise, and we offer end-to-end and investment in oligonucleotides has led EFIRGLWGEPITVSGIWWERHXV]MRKXS½XMRXS solutions to our customers ņ from XSWMKRM½GERXP]QSVIVIWIEVGLMRXLIEVIE¯ manufacturing scale after-the-fact. pre-clinical development through including how to make and modify LNPs. At Exelead, we’ve been working with LNPs commercial supply, from project Often, just changing a few ingredients can for years, so we have the technology and management to stability testing. PIEHXSIRSVQSYWFIRI½XW8LIEHHMXMSREP expertise to improve the LNP formulation We offer considerable support for know-how and development to optimize process, and develop a more scalable format. nanoparticle formulation development these variables are well worth the effort. We’ve been able to form the same particles and optimization, using lipids, polymers Oligonucleotides are becoming a go-to seen in the client’s early stage process using a and other traditional ingredients. approach to tackling disease, and LNPs go much more scalable method, such as in-line Currently, the pharmaceutical industry hand in hand with them, ensuring that the mixing (a simple ratio matrix mixing involving is seeing an explosive growth in the FIWXXLIVETIYXMGFIRI½XGYVVIRXP]TSWWMFPI the right ingredients, pH and temperature) or, oligonucleotide market, particularly with reaches the precise location where it is in some cases, extrusion (although the latter hard-to-treat diseases. Our development most effective. When these processes can is not typically suitable for oligonucleotides, teams can help scale up manufacturing be made scalable and easily transferable to which tend to be shear sensitive). We can help processes to support commercial many different kinds of products, it becomes clients with formulation development wherein production, and our in-house analytical clear that the technology is becoming truly we can suggest lipid choices and potential capabilities involve the whole spectrum relevant, and more important to the overall vendors based on desired pharmacological of specialized assays for the lipids, particle pharmaceutical market. And that’s where performance, develop these formulations at size and surface charge, residual solvents, we are with LNPs right now. bench-scale volumes (<20 ml) rapidly within and APIs required to release a product. %JXIV]IEVWSJ6 (XLI½VWXWM62%FEWIH a short time-frame and provide a bank of By offering end-to-end solutions, a therapy, patisiran, was approved in the US potential candidate formulations for use in dedicated team with deep expertise in 2018 for the treatment of a rare form of their screening assays. When we execute and a robust cold chain, Exelead clients hereditary peripheral nerve disease – and it these pseudo-high-throughput approaches can expect to reduce supply chain risks uses an LNP formulation. The drug inhibits to development, we are able to present a ERHTVSGIIH[MXLGSR½HIRGI;MXLSYV the expression of an abnormal protein by panel of options to a client who can then QYPXMHIGEHILMWXSV]ERHTVS½GMIRG] interfering with the segment of RNA that WIPIGXEGERHMHEXIFEWIHSRJYP½PPQIRXSJ with complex formulations, Exelead is GVIEXIWMX4EXMWMVERMWNYWXXLI½VWXETTVSZIH their desired quality attributes. We also use uniquely poised to support clients who drug; many more oligonucleotides using XERKIRXMEP¾S[½PXVEXMSRXSVIQSZISVKERMG wish to bring exciting new treatments LNPs are in pipelines and clinical trials. solvents, which is a low-cost unit operation. to the clinic and market.

www.exeleadbiopharma.com 16 Feature

CELEBRATING THE GREAT MINDS THAT BRING US INNOVATION IN SMALL MOLECULES, BIOPHARMACEUTICALS, AND ADVANCED MEDICINE

2020 has proven to be a challenging year for humanity: volcanic eruptions, bushfires, floods, storms, the melting of glaciers, and the emergence of COVID-19, which has brought much of the world to a standstill. Against this backdrop, putting together The Medicine Maker’s annual Power List has been a surreal experience. How can we prepare for a celebration of pharmaceutical development and manufacturing when it seems as if the world is falling apart around us? At times like this, we believe it is even more important to recognize the many people working hard to improve our world. The professionals highlighted here are driving the industry forward and saving lives by developing new medicines. And some of these professionals will also be lending a helping hand in bringing COVID-19 vaccines and treatments to market as soon as possible.

For 2020, we present the top 20 inspirational medicine makers in three different categories: Biopharmaceuticals (page 17), Advanced Medicine (page 22), and Small Molecules (page 28).

By Stephanie Sutton, James Strachan, and Maryam Mahdi 17 BIOPHARMACEUTICALS Feature Top 20

ROBERT BRADWAY Roundtable on Cancer, a non-profit CHAIR AND organization of executives CHIEF EXECUTIVE that focuses on solutions OFFICER AT AMGEN to cancer treatment and prevention, and Prior to Amgen, a member of the Bradway was a American Heart managing director Association CEO at Morgan Stanley in Roundtable. London. He joined Amgen and the Amgen in 2006, Amgen Foundation becoming Chair in 2013 recently committed and CEO in 2010. He $12.5 million to support is also the chair of the CEO COVID-19 relief efforts.

RICK BRIGHT nation’s health security and pandemic DIRECTOR AT THE BIOMEDICAL response posture,” he says. ADVANCED RESEARCH AND Bright is currently working to DEVELOPMENT AUTHORIT implement a strategy for improved HAL BASEMAN (BARDA); AND DEPUTY pandemic response capabilities CHIEF OPERATING OFFICER ASSISTANT SECRETARY IN THE throughout the SARS-CoV-2 pandemic. AT VALSOURCE OFFICE OF THE ASSISTANT SECRETARY FOR PREPAREDNESS “Given the relatively slow pace of AND RESPONSE AT THE US innovation in biopharmaceutical DEPARTMENT OF HEALTH AND manufacturing technology, our industry HUMAN SERVICES needs to consider more effective ways to employ innovative methods and Bright is an expert on immunology technologies. We need to recognize and influenza – and previously where traditional methods and ways served as Director of the Influenza may no longer be the best. We need to and Emerging Infectious Diseases identify where innovation can improve Division in BARDA. “While I was at the manufacturing process and quality the CDC, I developed a rapid screening assurance. Then, we must use this tool to assess antiviral drug resistance information as motivation to work with in influenza viruses. Using the tool, suppliers and regulators to develop and I discovered that all circulating implement those technologies. This influenza viruses were resistant to recognition that there will likely be a the world’s most used influenza need for inclusion of new technology antiviral drug. This led to CDC should be addressed in the plans for guidance change on the use of influenza manufacturing processes and facilities antiviral drugs. As BARDA director, I – even and especially where that new changed the USG strategy to drive and technology may not be apparent.” incorporate innovation to improve our

www.themedicinemaker.com KENNETH C. FRAZIER CHAIR AND CHIEF EXECUTIVE OFFICER AT MERCK SHARP & DOHME

Frazier started out as a lawyer and taught trial advocacy in South Africa. He joined MSD’s public affairs division as a general DARIO CAMPANA counsel in 19921992 andand MRS. LEE KONG CHIAN CHAIR became CCEOEO in IN ADVANCED CELLULAR 2011. Full-yearll-year THERAPY AND PROFESSOR, 2019 globalo b a l DEPARTMENT OF PAEDIATRICS, sales forr thethe AT THE NATIONAL UNIVERSITY company wewerere OF SINGAPORE $46.8 billion,on, uupp MIKE GRIPPO by 11 percentcent SENIOR VICE PRESIDENT, “The defining event of my career was comparedd STRATEGY & CORPORATE discovering a passion for translational with 2018. AT CATALENT PHARMA research during my laboratory training. SOLUTIONS Subsequently, there was guidance from a multitude of indirect mentors, and “The cost and complexity of bringing inspiration from patients.” a biologic to market can be daunting, especially when the ‘burn rate’ of small biotech companies can exceed JACKIE HUNTER BenevolentAI is using artificial intelligence $250,000 per week, and 9 out of 10 CHIEF EXECUTIVE OFFICER technology to transform the way medicines drugs in clinical trials never make it to AT BENEVOLENTBIO; AND are discovered and brought to market. market. By providing integrated, end- CE OF CLINICAL AND Jackie Hunter has extensive experience in to-end solutions, we help customers STRATEGIC PARTNERSHIPS the industry and was previously responsible overcome development hurdles. It’s AT BENEVOLENTAI for developing GSK’s external innovation more important than ever that we strategy, as well as the concept of the demonstrate advantage at every stage, Stevenage Bioscience Catalyst. In 2010, and save innovators the costs and she was awarded a CBE in the Queen’s delays of negotiating with multiple Birthday Honours list in the UK for contractors, and the complexity and Services to the Pharmaceutical Industry. risks of handoffs and tech transfers.”

JUSTIN HANES LEWIS J. ORT PROFESSOR OF OPHTHALMOLOGY AT JOHN HOPKINS UNIVERSITY

“If I could do one thing to improve the positive impact of drug development and the biopharma industry, it would be to dramatically increase funding for basic medical science, starting with the National Institutes of Health in the US and its counterparts throughout the world, filling the pipelines of existing companies, and leading to the creation of hundreds of startups with more effective new drugs and vaccines.” RICHARD JOHNSON PRESIDENT AND CHIEF EXECUTIVE OFFICER AT THE PARENTERAL DRUG ASSOCIATION (PDA)

Johnson joined the PDA as President in 2009, following a 30-year career in the pharma industry, which included 20 years as an active PDA volunteer and member. MAIK JORNITZ Early in his career, he took on international PRESIDENT AND CHIEF assignments, which he says changed his EXECUTIVE OFFICER AT perspective and prepared him for the G-CON globalization of the industry. “Right now, our industry has dual “Joining the PDA turned out to be responsibilities in the fight a huge turning point for my career. against the COVID-19 It opened up a large network of global pandemic: one, peers for me; peers I can learn continuing the supply from and that I can tap into the of critical medications experience of when needed and vice while dealing versa. Moreover, it is a joy to work with supply chain together with this group of experts interruptions, personnel to support our industry, regulators, absenteeism, and societal and suppliers. I have learned that impacts; and two, rapidly when we all work together, we can developing and evaluating treatments accomplish phenomenal benefits MARIA JOSÉ ALONSO and vaccines to combat COVID-19.” for our industry and patients. Right PROFESSOR OF now, there are new therapies – in BIOPHARMACEUTICS some instances, cures – entering late- AND PHARMACEUTICAL stage development phases rapidly, TECHNOLOGY AT THE KIRAN MAZUMDAR- and showing extremely encouraging UNIVERSITY OF SANTIAGO SHAW signs. Patients who could not be DE COMPOSTELA CHAIR AND MANAGING helped in the past have a good DIRECTOR, BIOCON chance of treatment and survival. “A defining moment for me was my This is extremely motivating!” postdoctoral training with Robert Although initially intending to be Langer at MIT, who introduced me brewmaster, Mazumdar-Shaw set up an to the global health area of research. entrepreneurial biotechnology company in This impacted my career and opened India in the 1970s. Since then, Biocon has RINO RAPPUOLI the door for collaborations with the grown to become a globally recognized CHIEF SCIENTIST AND Bill and Melinda Gates Foundation company and Mazumdar-Shaw has HEAD, EXTERNAL R&D AT and the World Health Organization.” received numerous awards and honors. In GLAXOSMITHKLINE Maria José Alonso’s lab has November 2019, she received a Lifetime pioneered numerous discoveries Achievement Award from the Indian Rappuoli is considered one of the world ’s in nanomedicinesnes and she is Council of MedicaMedical Research for leading vaccine experts. He was involved also a past presidentsident ooff tthehe outstandingoutstanding acachievementh in in the development of CRM197 used Controlled Releaseease SocietSociety.y. hhealthcareealthcare andand contributionc to in H. influenzae, N. meningitidis, She believes ththatat ddrugrug thethe societysociety at large.la and pneumococcus vaccines, and has development coulduld imimproveprove also introduced several novel scientific if academic researchesrches adoadoptpt concepts – genetic detoxification a more “rational aapproachpproach (1987), cellular microbiology (1996), towards unmet needs reverse vaccinology (2000) and the and criteriaa to pangenome (2005). He is now involved ensure quality and in collaborations focusing on a vaccine reproducibility”. for COVID-19.

www.themedicinemaker.com 20 Feature

MELINDA RICHTER MIKE REA GLOBAL HEAD OF JLABS CHIEF EXECUTIVE OFFICER, IDEA PHARMA AT JOHNSON & JOHNSON INNOVATION Mike Rea says that the biggest course change in his career was leaving a job because he didn’t agree with “Improving access to medicines starts their strategy. Without that, he’d never have started with shortening the amount of time IDEA Pharma - a consultancy focusing on path- it takes to get a therapeutic into the to-market design strategies. When it comes to hands of the patient or consumer. improving biopharma development, Rea believes Typically, that process can take up to that less managerialism, combined with organizations ten years anda millions or even billions taking more of the right kinds of risk in early-phase ofof dolladollars.r This has to change!” development, would improve decision quality. BeforeBefore joiningjo JLABS, Richter was thethe FoFounderun and CEO of Prescience International,Internat which was dedicated toto acceleratingaccel research to the LUC-ALAIN SAVOY patient.patient. RichterR created the company GLOBAL HEAD OF BIOLOGICSCS – LIFELIFE afterafter a medicalm emergency left her SCIENCES AT SGS qquestioningu the efficiency of the current healthcare Luc-Alain Savoy was the managinganaging system. In her current director of M-Scan SA, whichwhich role, she supports the focused on protein characterization,ation, innovation community by bioanalysis, and impuritiess in creating capital-efficient identification and quantificationtion commercialization before it was sold to SGS in 2010.010. models that help early- “Joining SGS Life Sciences gavegave stage companies. me the opportunity to conveyey mymy ideas and values to a larger audiencedience of biopharma decision-makers,” hhee ssays.ays. For the future, he is passionatete CARLO TONIATTI about access to medicine CHIEF SCIENTIFIC OFFICER AT IRBM – and hopes to see more affordable biological drugs “I envisage that a major breakthrough being made available to in drug development will come from the whole population. technological advancements. In particular, the more extensive generation and use of big data originating from preclinical and JAMES N. THOMAS and using innovative technologies to clinical studies, combined with a more EVP, GLOBAL HEAD OF meet the needs of patients. In 2014, comprehensive application of artificial BIOTHERAPEUTICS AND he co-founded and became CEO of intelligence-enabled solutions. This will PRESIDENT OF US OPERATIONS Just Biotherapeutics, with a focus on cover all the steps of drug discovery and AT JUST - EVOTEC BIOLOGICS expanding global access to biologics, development, from the initial target and is now continuing this journey at identification to clinical trial design and Over the course of his career, Thomas Just-Evotec Biologics. data interpretation.” has contributed to the advancement of many important therapeutics including Activase, Vectibix, Enbrel, Prolia/Xgeva and Repatha, as well as numerous biosimilar programs. Thomas has built teams, departments, and functions passionate about creating MIKE VANDIVER SENIOR VICE PRESIDENT OF BIOTHERAPEUTIC OPERATIONS AT JUST - EVOTEC BIOLOGICS

Vandiver has over 30 years of biopharmaceutical process development and manufacturing experience. At Just Biotherapeutics, he led efforts to bring the company’s clinical GMP facility online. Now at Just - Evotec Biologics,g, Vandiver is leadingg effortsefforts toto bring the company’sny’s firsfirstt North American JJ.POD.POD clinical and commercialmercial biomanufacturing facilitfacilityy online. He says thathat one of the defining momentsoments of his career was whenwhen he started to empowerrh hisis staffstaff and learned just howw creative, innovative, and mmotivatedotivated they could be.

EMMA WALMSLEY Patient-focused CHIEF EXECUTIVE OFFICER AT GLAXOSMITHKLINE

Walmsley first joined GSK in 2010, initially working for the drug delivery devices Consumer Healthcare, Europe, division. She became CEO in April 2017. 2019 was seen as a strong year for the company, with an increase in group sales, eight filings, six positive pivotal trial results, and four priority assets moving to phase II/III. Drug Delivery Devices Innovative developments Customized solutions  ſ0./*( -ſ ſ()0!/0-$)"

www.nemera.net [email protected] • Phone: +33 (0)4 74 94 06 54 ADVANCED MEDICINE Top 20

VERED CAPLAN CHIEF EXECUTIVE OFFICER MASSIMO DOMINICI AT ORGENESIS ASSOCIATE PROFESSOR OF MEDICAL ONCOLOGY AT THE Orgenesis is building a network of hospitals UNIVERSITY HOSPITAL OF around the world called point of care MODENA AND REGGIO EMILIA (POCare), which are equipped to develop and process cell and gene therapies. “My ultimate vision is “Instead of frantically searching allogeneic cell production for ways to turn a few chosen centralized within large- USMAN “OZ” AZAM therapies into off-the-shelf scale manufacturing PRESIDENT AND CHIEF products and generate quick models, where the last EXECUTIVE OFFICER AT profits for mammoth biotech steps of cell product TMUNITY THERAPEUTICS companies ruled by the reconstitution/ ruthless demands of short- manufacturing are As head of cell and gene therapy at term economic and performed at the Novartis between 2014 andd 2016, stock market mark hospital level, in a solvent/ Azam was part of the teamam that pressures,pressures our solute model – as we already brought the first CAR T celll therapy therapy cchallengehallen is to see with chemotherapy agents. to market. Before that, he heldd various aadvancedvance towards a This would require a chain of trust science, regulatory and commercialmercial more ddecentralized between pharma and caregivers roles at Aspreva, J&J and GSKGSK — healthcarehealthc integrated and must be facilitated by novel originally training as an obstetriciantetrician industryindust – a truly culture technologies, breakthrough and gynecologist. At Tmunity,y, Azam consconsumer-basedu cryobiology innovations, new is focused on bringing the next-xt- industry.”in packaging and dedicated infusion generation of T cell therapies systems.” to market.

JENNIFER DOUDNA PROFESSOR OF BIOCHEMISTRY, BIOPHYSICS AND STRUCTURALBIOLOGY AT THE UNIVERSITY OF CALIFORNIA, BERKELEY

Early in her career, Doudna’s lab determined some of the first crystal structures of RNA and RNA-protein complexes. In 2012, she rose to fame after co-discovering the revolutionary gene editing technology, CRISPR-Cas9. She later co-founded Caribou to commercialize the technology. Recently, Doudna’s team created a COVID-19 diagnostic lab from scratch, with the capability to process more than 1,000 patient samples per day. MIGUEL FORTE CHIEF EXECUTIVE OFFICER AT BONE THERAPEUTICS

“Advanced therapies represent a real opportunity for long-term effect and even cures for many currently unmet medical needs. I believe we will progressively increase our capacity to cost-effectively and consistently produce advanced therapies. More than 10 years ago when I started my involvement with cell therapy, the field was delivering promise, but today we all agree it is delivering value. Tomorrow it will provide cures that are unthinkable even today!”

KURT GUNTER CHIEF MEDICAL OFFICER AT KUUR THERAPEUTICS

Kurt Gunter has an expansive history in advanced medicine, spanning many roles. After starting his career as a physician, he went into regulation – becoming deputy RACHEL HAURWITZ director of the FDA’s cellular and gene CHIEF EXECUTIVE OFFICER AT therapy division in 1988. Then, after heading CARIBOU BIOSCIENCES up stem cell processing at the Children’s National Medical Center, he took several Haurwitz has a research background in leadership positions in industry (including CRISPR-Cas biology and holds several Transkaryotic, ViaCell and Hospira). He is patents covering CRISPR-derived an active member of many societies, and has technologies. She co-founded Caribou served as President of ISCT. in 2012 and Intellia Therapeutics in 2014, both of which are developing genome editing therapies.pies. Late DENG HONGKUI eventually becoming research director of the in 2019, Caribouaribou CHANGJIANG PROFESSOR, THE stem cell company ViaCell in Cambridge, published a paperpaper BOYA CHAIR PROFESSOR, AND Massachusetts. He then went back to showing that ttheirheir DIRECTOR OF THE INSTITUTE OF China after being awarded the prestigious type I CRISPR-SPR- STEM CELL RESEARCH AT Changjiang Professorship. In 2017, he and Cas platform,orm, PEKING UNIVERSITY Chen Hu engineered resistance to HIV in FokI-Cascade,e, can mice using CRISPR gene editing, and for be used to performform In 1989, Deng Hongkui left China for the first time used the technique on an genome editingting the US, working on HIV at New York AIDS patient – demonstrating the safety with highh University before switching to stem cells – of CRISPR for humans. precision.

CARL H. JUNE RICHARD W. VAGUE PROFESSOR IN IMMUNOTHERAPY AT THE UNIVERSITY OF PENNSYLVANIA

Carl June’s research was pivotal to the development of CAR T cell therapy. In 2018, he was named as one of Time Magazine’s most influential people. QUEENIE JANG His entry was written by Emily CHIEF EXECUTIVE OFFICER AT Whitehead, aged 12, who was the first THE INTERNATIONAL SOCIETY patient to receive CAR T cell therapy PETER MARKS FOR CELL AND GENE THERAPY six years earlier. “Dr. June is my hero! DIRECTOR OF THE CENTER FOR (ISCT) He saved myy family.”family. BIOLOGICS EVALUATION AND Recently, June RESEARCH AT THE FDA Jang thinks the emergence of the and his teamm at advanced medicine field is akin to UPenn showedwed During his wide-ranging career, Peter evolution from analogue to digital that CRISPR-PR- Marks has been involved in practicing platforms in the IT sector. She also edited immunemune internal medicine and clinical science believes that cost-of-goods optimization cells can surviveurvive with Brigham and Women’s Hospital is key to broad healthcare adoption after being infusednfused in Boston, academic medicine at Yale of ATMPs. “This will create higher into cancer patients.patients. (where he led the adult leukemia service), demand for technical expertise to pharmaceutical drug development, execute on product development plans and most recently, regulation. As as the CGT sector rapidly expands. head director of CBER, Peter plays Therefore, training and development a pivotal role in the development to populate this highly skilled CGT and commercialization of advanced workforce will become critical to fuel medicines in the US. growth of the sector.”

BRUCE LEVINE ANTONIOS MIKOS BARBARA AND EDWARD NETTER PROFESSOR IN CANCER GENE PROFESSOR AND DIRECTOR THERAPY AT THE UNIVERSITY OF PENNSYLVANIA OF THE CENTER FOR ENGINEERING COMPLEX As ISCT’sISCTs president elect, LevineLevin has been vocal about the need TISSUES AT RICE UNIVERSITY to address the talent bottlenecbottleneckk in advanced medicine. “There is a critical shortage of talent at aall levels, from technicians “A major obstacle for tissue andand developmentdevelopment scientisscientists,t manufacturing and engineering is the translation analytics staff, to clinicclinical expertise in the of biological discoveries managementmanagement ooff cecellll anandd ggenee patients,” he says. into regenerative “There is a hugehuge needneed forfor more cell and gene medicine solutions for specificspecific education prograprogramsm as scientific and the treatment of patients,” clinicalclinical developmentdevelopment hhasas ooutpaced the training says Mikos. His vision ofof new proprofessionalsfessionals to memeete the demand.” Levine for advanced medicine alsoalso asksasks howhow reguregulationslations aandn policies can be revised focuses on the development and adaptedadapted to allow the advaadvancementn of cells and engineered of biomaterials to enable engineers, cellscells producingproducing medicines. “F“Foro countries that have a limited scientists, and clinicians to work regulatoryregulatory frameworkframework in pplacelace fforor advanced therapies, what is the collaboratively to create viable tissues bestbest model of flexibiliflexibilityty tha thatt protects patients while allowing and organs. “I am confident that the investigation andand subsequent approvals based on convergence of sciences will address the best scientificsci and clinical evidence to some of society’s toughest healthcare proceed?”procee he asks. problems.” Feature 25

RODGER NOVAK CO-FOUNDER AND PRESIDENT AT CRISPR THERAPEUTICS

Novak is one of the three co-founders QASIM RAFIQ of CRISPR Therapeutics, which aims ASSOCIATE PROFESSOR IN CELL AND GENE THERAPY to treat diseases using CRISPR/Cas9 BIOPROCESS ENGINEERING AT UNIVERSITY COLLEGE LONDON gene editing technology. In 2019, the company announced positive “As a biochemical engineer by training, I would expect the delivery of cell interim safety and efficacy data in and gene therapies to be underpinned by robust and scalable bioprocesses their ongoing CTX001 clinical and innovative manufacturing technologies. To ensure the sector’s continued trials, a CRISPR/Cas9 therapy growth, it is now at a critical juncture where it needs to demonstrate sustained for ŷ-thalassemia and sickle cell value and commercial viability. This can only be achieved through improved disease, as well as advancing their standardized, scalable and robust manufacturing processes. In brief, advanced first allogeneic CAR T cell therapy therapies need to be industrialized.” targeting CD19+ malignancies.

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qualicaps.com 26 Feature

CLAUDIA ZYLBERBERG JOHN ROSSI CHIEF EXECUTIVE OFFICER AT DIRECTOR OF TRANSLATIONAL AKRON BIOTECHNOLOGY SCIENCES AT KITE PHARMA Zylberberg is concerned about the lack of “I believe in my heart of hearts that closed or automated systems in cell and we are going to use off-the-shelf gene therapy. “The closing of systems will progenitor stem cells engineered to provide opportunities to manufacture in target cancer cells and overcome the different environments, such as hospitals, tumor microenvironment. Off-the- and will enhance the capability to scale- shelf therapies will reduce costs and out many of these autologous therapies. increase access to a great number DOLORES SCHENDEL Right now, you would need a CMO of patients. It will take time, but CHIEF EXECUTIVE OFFICER to manufacture them, but a closed it’s where we are headed – Kite has AND CHIEF SCIENTIFIC OFFICER system would allow you to manufacture an active program in that area. It AT MEDIGENE anywhere. The logistics,ggl globally,obally, ofof thesethese is also crucial that we continue to therapies is also one of thehe biggestbiggest pieces invest in academic science that seeks Schendel has been a member of the of the puzzle.” Akron hhasas responded further advances. Kite is sponsoring German Research Foundation, German to the COVID-19 epidemicpidemic by numerous studies, providing Cancer Aid and the European offering its biomolecules,ules, sucsuchh funding and samples to some Research Council, and as interferons and otherher novelnovel of the best and brightest developed her interest in formulations, to be furthefurtherr in the field. We hope tumor immunology while investigated. “These will hhopefullyopefully that governments working at the Sloan- be used to create solutionsns for around the world will Kettering Institute in early stages of infectionon continue to invest in New York. In 2019, and advance initiativeses basic research that Medigene commenced a that we’ve proposedd is ultimately going phase I/II trial of its first both independently andd to drive these next TCR-T immunotherapy in collaboration withh generation therapies.” against several blood cancers. others.”

JAMES THOMSON INVESTIGATOR, REGENERATIVE BIOLOGY AT THE MORGRIDGE INSTITUTE FOR RESEARCH

James Thomson is a developmental biologist well known for his pioneering work isolating and culturing human embryonic stem cells in 1998, and developing human pluripotent stem cells from adult skin cells in 2007. He co-founded Cellular Dynamics International (now part of Fujifilm) in 2004 to commercialize human-induced pluripotent stem cells for drug discovery and toxicity testing. In 2019, the Thomson Lab at Morgridge found a better way to grow smooth muscle cells from pluripotent stem cells. SHINYA YAMANAKA DIRECTOR AND PROFESSOR AT THE CENTER FOR IPS CELL RESEARCH AND APPLICATION (CIRA) AT KYOTO UNIVERSITY

Shinya Yamanaka believes the number one obstacle for advanced therapies is time and cost. “It could take decades and hundreds of millions of dollars to bring a breakthrough in basic research to patients,” he says. “How to survive this long and costly journey is the biggest hurdle.” Yamanaka believes the current goal in his field of regenerative medicine is to reactivate patients’ own regenerating potentials by small molecules or other means, without transplanting cells from outside.

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www.lbbohle.com SMALL MOLECULES Top 20

PHIL BARAN PROFESSOR AT SCRIPPS RESEARCH

Phil Baran has received numerous awards and accolades for his contributions to both industry and academia. He has worked at the Scripps Research Institute since 2003 and says he is most inspired by his “former mentors, students and postdoctoral collaborators”, as well as entrepreneur Elon Musk. His research interests include the organic synthesis of complex molecules with minimal labor and material costs. KELLY CHIBALE NEVILLE ISDELL CHAIR IN AFRICAN-CENTRIC MINZHANG CHEN THOMAS CECH DRUG DISCOVERY & CHIEF EXECUTIVE OFFICER DISTINGUISHED PROFESSOR AT DEVELOPMENT AND SOUTH AT WUXI STA, A WUXI APPTEC UNIVERSITY OF COLORADO, BOULDER AFRICA RESEARCH CHAIR COMPANY IN DRUG DISCOVERY AT In 1989, Thomas won the Nobel Prize in H3D, DRUG DISCOVERY AND “I think the next ‘big thing’ for the small Chemistry along with his colleague, Sidney DEVELOPMENT CENTRE AT THE molecules field is how our industry will Altman, for their discovery of the catalytic UNIVERSITY OF CAPE TOWN continue to strive towards more solutions properties of RNA. Thomas is currently and getting treatments to patients faster. an Investigator with the Howard Hughes As director and founder of H3D, a Undoubtedly, we have made great strides Medical Institute, and also a Distinguished research and development project in this, but the incorporation of new Professor at the University of Colorado and at the University of Cape Town, technologies and fully-integrated Director of the university’s Chibale is dedicated to dispelling afro outsourcing, from discovery to BioFrontiers Institute. His pessimism – the idea that Africa has commercial production, will lab discovered an enzyme, nothing to contribute to the global drastically reduce timelines. TERT (telomerase economy. Chibale’s research focuses This could make the difference reverse transcriptase), on delivering treatment options for between a healthcare product’s which is part of the tuberculosis and malaria that are both success or its failure. We must process of restoring safe and affordable. continue to help innovators improve telomeres after they are “I believe polypharmacology will both rates of productivity shortened during go a long way to address and delay the and attrition – that’s cell division. emergence of drug resistance arising where I see the next big from mutations in a single target. It revolution occurring, will also have the added advantage of and contract benefiting patients by minimizing the manufacturers pill burden and cost associated with have a central combination drug regimens which role to play.” currently require two or more small molecules that inhibit different single targets to be combined.” PAOLO COLOMBO EMERITUS PROFESSOR AT THE EDWARD UNIVERSITY OF PARMA HAEGGSTRÖM CHIEF EXECUTIVE OFFICER Paolo Colombo AT NANOFORM joined the University of In 2015, Edward Haeggström Parma in 1986. commercialized the His strong nanoparticle engineering interest in platform he developed with drug delivery Jouko Yliruusi, Acting research, Professor at the University of particularly oral, Helsinki, with the launch of transdermal and Nanoform. The company offers inhalation delivery, API particle-size reduction services have led him to patent over 40 and won the CPhI Award for different drug delivery systems, many of Formulation in 2019. Haeggström which have become registered products. is also a professor at Helsinki Colombo is also on the editorial board University and Head of the of several pharmaceutical publications Electronics Research Laboratory and is a member of the American within the Department of Association of Pharmaceutical Scientists Physics. “I have alwaysalways been inspiredd bbyy Frederick Sangernger JOHN CHIMINSKI and John Bardeen.een. CHAIR AND CHIEF EXECUTIVE OFFICER They are theo nlonlyy AT CATALENT PHARMA SOLUTIONS people who have wwonon a Nobel Prize inn tthehe “Despite the rise in biologic-based medicines, we cannot forget the vital role that small same category ttwicewice molecule drugs continue to play in the treatment of so many conditions. These drugs, – Frederick Sangerger for however, are now often more complex than ever and bring new challenges to drug Chemistry andnd developers and formulators, especially in the areas of bioavailability, differentiation John Bardeen and patient centricity. The future lies in finding new ways to formulate and deliver for Physics,” complex molecules, and in designing dose forms that are effective and that foster he says. patient acceptance.”

ALISON HOLMES JOHANNES KHINAST PROFESSOR OF INFECTIOUS DISEASES PROFESSOR OF AT IMPERIAL COLLEGE LONDON PHARMACEUTICAL ENGINEERING AT GRAZ Alison Holmes’ long-standing UNIVERSITY OF TECHNOLOGY interest in antimicrobial resistance has been a driving force in her career. Johannes Khinast has worked with She is also a Fellow of the Academy numerous pharmaceutical companies of Medical Sciences and an NIHR as an advisor for the implementation Senior Investigator. Holmes leads of novel drug formulations. As the a multidisciplinary research scientific director of the Research Center pharmaceutical engineering and group and collaborates with Pharmaceutical Engineering, Graz, chiral catalysis have led him international organizations Austria, he works with multidisciplinary to patent several products to help improve the teams to develop advanced medicines related to pharmaceutical pharmaceutical industry’s and continuous processes. His interests in manufacturing. response to antibiotic- resistant infections.

www.themedicinemaker.com 30 Feature ROBERT LANGER DAVID H. KOCH INSTITUTE PROFESSOR AT MIT

STEVEN M. KLOSK The most cited engineer in history and PRESIDENT AND CHIEF EXECUTIVE OFFICER one of the most prolific inventors in all AT CAMBREX CORPORATION of medicine, Langer has nearly 1,300 issued and pending patents, many of “I believe that the next big thing for small molecules is which have been licensed or sublicensed actually an old thing, and that is the speed that clinical to over 350 pharma, chemical, biotech and candidates can progress through the development medical device companies. He has been process, and specifically the acceleration of the speed honored with over 200 major scientific from IND to NDA. This touches areas of process awards, including the United States improvements such as the use of quality by design, as National Medal of Science, and the well as the use of different technological concepts. One 2002 Charles Starkrk Draper such method is the use of continuous flow chemistry where Prize (often consideredered the applicable in the process, and Cambrex is working with customers equivalent of the NobelNobel to use this technology for general chemistry processing to exploit the Prize for engineers).eers). advantages it offers.” He has also foundedded a number of biopharmaharma companies, includinguding Moderna Therapeutics,peutics, NIGELNI LANGLEY which is currently workingorking GGLOBALLO TECHNOLOGY DIRECTOR, PHARMA on a COVID-19 SOLSOLUTIONS AT BASF CORPORATION vaccine.

“COVID-19“CO has certainly changed the world and has sadly shownshow how vulnerable we all are without an effective treatment forfo this infectious disease. I am truly impressed by the FAITH OSIER commitment and collaboration that is occurring within PRINCIPAL INVESTIGATOR the pharmaceutical industry to help tackle this disease AT KEMRI-WELLCOME TRUST both by investigating the repurposing of existing drugs RESEARCH PROGRAM; AND as well as accelerating a new effective vaccine. There is PROFESSOR OF MALARIA a common target that the whole industry is working IMMUNOLOGY AT on , one where collaboration is center stage.” UNIVERSITY OF OXFORD

For her research into the mechanisms of immunity against Plasmodium falciparum, DUJUAN LU shown promise in treating COVID-19 Osier has won multiple awards. As a E&L MANAGER/GLOBAL patients. The majority of new drug trained physician, Osier has specialized in LEADER AT SGS LIFE application approvals by FDA pediatrics in both Kenya and the UK. In SCIENCES areare ststillill forfor smallsmall molecules.m 2014, she was awarded the Young African ThereThere areare alsoalso trtremendous Scientist Award by EVIMalaR, and won “Although biologicalological drugs amountsamounts of ANDA the Merle A Sande Health Leadership have been risingg stars in the appapprovalsrovals fofor generic Award and the Royal Society Pfizer Award. industry, smallll molecule drudrugs,gs, wwhichh are drugs remain essentialessential fforor mainly forfor common the majority off treatments smallsmall moleculem for patients aroundaround the medicinesmedicine rather world. For example,ample, momostst thanthan bbiosimilars.”iosim antiviral drugsgs are small molecules, includingncluding remdesivir, tthehe novel antivirall drug that has MARTYN POLIAKOFF RESEARCH PROFESSOR OF CHEMISTRY AT THE UNIVERSITY OF NOTTINGHAM

Martyn Poliakoff is a chemist whose work focuses on fundamental chemistry and the development of environmentally friendly processes and materials. Throughout his career, he has received several accolades including a CBE in 2008. In 2019, he won the James T. Grady-James H. Stack Award for Interpreting Chemistry for the Public by the American Chemical Society. Poliakoff has also held senior positions G.V. PRASAD within many organizations dedicated to CO-CHAIR AND MANAGING DIRECTOR AT DR REDDY’S chemical research. He was named both Foreign Secretary and After becoming CEO in 1990, Prasad led the global expansion of Dr Vice-President of the Royal Reddy’s, especially in developed markets. He is also passionate about Society in 2011, and held sustainable manufacturing and business practices. He leads the company’s the position for five years. sustainability initiatives including the adoption of green technologies He was also appointed and processes. He was a Regional Honoree for the 2020 YPO Global Honorary Professor at Impact Award, received the V. Krishnamurthy Award for Excellence by Beijing University of the Centre for Organizational Development in 2019, and was designated Chemical Technology in 2018. The Boundary Breaker at the CEO Awards in 2018.

www.theanalyticalscientist.com 32 Feature

MARTIN VAN TRIESTE NIKLAS SANDLER PRESIDENT AND CHIEF CHIEF TECHNOLOGY OFFICER EXECUTIVE OFFICER AT AT NANOFORM CIVICA RX

Niklas Sandler has extensive experience Martin Van Trieste is the president of in both industry and academia, Civica Rx, a company founded in 2018 particularly within the fields of in response to drug shortages and high pharmaceutical product development prices. Prior to setting up the company, and material science. Alongside his role he held positions in the Parenteral Drug as chief technology officer at Nanoform, Association and was a special advisor he is also a professor at Åbo Akademi MATTHEW TODD to FDAzilla. “From a professional University, with over 100 published CHAIR OF DRUG DISCOVERY AT perspective, I recognize now more papers in several pharmaceutical UNIVERSITY COLLEGE LONDON than ever the importance of using my journals. He has a strong interest in the experience and expertise to help improve ways that small molecules can be used Todd founded and leads the Open the safety and availability to bolster new technologies. Source Malaria and Open Source of vital medicines for “Small molecules are still a crucial part Mycetoma consortia, which focus on patients. I feel a deep of development pipelines and cover many the ways open science can be used responsibility to give therapeutic areas. New technologies, to accelerate research. His research back and influence including nanotechnology, will interests include the development of improvements to the boost the potential of these new ways to make molecules, pharmaceutical supply molecules to create future particularly how to make chain in innovative ways therapies. Also, old chiral molecules with – and that is incredibly treatments will benefit new catalysts. He is also fulfilling.” from technologies on the editorial boards that improve drug of several publications performance and including Nature provide life cycle Scientific Reports and extension opportunities PLoS One. for existing drugs.”

JOYL SILVA GENERAL MANAGER AT PFIZER CENTREONE

“I am excited to deliver on the innovative promise that small molecules are expected to bring to key therapeutic areas. The growth of highly potent APIs and the combined use of small molecules with ADCs represents an exciting opportunity for pharma and gives patients hope. Given the evolving potency and complexity, the life science sector will continue to demand that we work alongside other areas of industry to deliver new specialized technologies so that targeted precision medicine is available when patients need it most.” Wait a minute. What? Pfizer offers API supply and CDMO services?

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36-39 Fast-Farming Pharma One company is planning to use plants to speed up the manufacture of a potential COVID-19 vaccine.

40-42 Advanced Medicine: replicating the mAb Success Story We have learned much from mAb manufacturing – and this experience can help us to optimize the processes for advanced therapies.

44-48 The Bumpy Road to a Cytomegalovirus Vaccine What technologies in the pipeline could help boost the development of a CMV vaccine? 36 NextGen

Just producing an immune response Fast-Farming is relatively easy, but producing an immune response that is protective and Pharma durable is not. In addition, the vaccine candidate must not produce a harmful How plants could speed up immune response that might cause vaccine manufacture to tackle unwanted side-effects, or potentially the COVID-19 pandemic even make a person more susceptible to viral infection – an effect referred to At the start of April 2020, the global as “antibody-dependent enhancement.” number of confirmed COVID-19 cases This was a serious problem in past was rapidly approaching 1.5 million; attempts to develop a safe and effective the death toll: over 80,000. And these vaccine against Dengue fever. numbers will likely have changed We felt a responsibility to take a substantially since the publication proactive role in the response to SARS- of this article. A vaccine is urgently CoV-2, especially as our FastPharming needed. Pharma companies are facility was purpose-built for just this scrambling into action with vaccine kind of scenario. We’ve made our candidates and early trials, but drug advanced manufacturing systems development will take time. Some available as a CDMO, while at the same companies, however, are taking a time developing our own proprietary different approach by introducing vaccine candidates. technologies that could help with Not every company has the appropriate research or manufacturing. As just one enabling technologies and capabilities, but example, iBio is hoping its technology there are definitely roles for big pharma One thing that this pandemic has can help accelerate manufacturing and companies to play in this response. absolutely made clear, however, is that scale up for a potential vaccine. The This can be by directly supporting the there is a crucial need for governments company is developing a new vaccine efforts of companies pursuing vaccines to proactively provide funding to ensure for COVID-19 and has partnered and therapeutics for SARS-CoV-2, or that we develop robust, sustainable with Beijing CC-Pharming to test the simply ensuring that there are no critical response capabilities so that we are vaccine in China. The vaccine will be interruptions in the supply chains of any collectively better prepared to respond produced using iBio’s FastPharming necessary medicines. to future pandemics. system – a manufacturing technology that uses plants for rapid scale-up. We Why must research teams consider speak with Robert Erwin (President) manufacturability even at the early and Sylvain Marcel (Vice President of “Just producing an stages of development? Protein Expression Sciences) from iBio A vaccine must be administered to large to find out more. immune response is numbers of people at a reasonable cost to be effective in preventing disease spread What are the challenges when it relatively easy, but within populations. To be practical, the comes to developing a vaccine for a vaccine must be priced affordably and new virus, such as SARS-CoV-2? producing an obviously produced in large quantities. There are challenges to developing any Any inefficiencies in the manufacturing safe and effective vaccine, but even more immune response process – or stability and storage so once an outbreak has already begun. problems with the vaccine – will extend First, a scientific team must determine that is protective the time required for production and which and how many targets to focus raise the cost. An excellent vaccine on to create vaccine candidates that will and durable is not.” design that cannot be turned into produce a protective immune response. high-quality, finished pharmaceutical

NextGen 39

As part of the DARPA Blue Angel of hydroponically-grown plants. H1N1 program, the facility was designed Pharmaceutical proteins accumulate and built to manufacture kilogram in the leaves as the plants grow over quantities of recombinant proteins within a period of 4 to 7 days, and the leaves months versus the historically longer are then harvested. The protein is time frames needed for more traditional isolated, purified, and formulated into systems. Its rapid launch to production the desired drug or vaccine product. has been designed specifically for medical The plant we use is a relative of the countermeasure responses. tobacco plant. Plant-based production saves months in initial setup time compared with traditional pharma manufacturing “During a methods, and there is no need for expensive, labor-intensive, cell-line pandemic, having development. The risks and delays associated with manufacturing scale- the ability to up are also reduced – it’s easy to grow more plants. In addition, the protein for rapidly scale up, pharmaceutical use obtained during the research stage is highly comparable to with confidence, the protein obtained at the commercial scale. During a pandemic, having the is invaluable.” ability to rapidly scale, with confidence, is invaluable.

How and why did you partner with product at a reasonable cost is not worth Today, iBio’s site in Bryan/College Beijing CC-Pharming? much in practical terms. In addition, Station, Texas, is among the largest We began working with CC-Pharming scalability and ready access to large cGMP-compliant biotherapeutic back in 2018, with an initial focus scale production is critical, as the time production facilities in the world for on an anticancer antibody and the required to build a production facility the production of recombinant protein design of processes and facilities that meets regulatory compliance for a in N. benthamiana, with a capacity to for manufacturing in China. The vaccine takes years. produce bulk clinical protein at the original agreement was written in scale of 0.5–1 kg per month, or 15–30 the expectation that iBio and CC- What’s the story behind the million doses/month (at 30 μg/dose). Pharming would eventually select FastPharming facility? And how did the The site is equipped with automated additional product candidates for joint Defense Advanced Research Projects hydroponics and vertical farming development and commercialization. Agency (DARPA) get involved? systems for the production of a wide When it became clear in mid-to-late iBio’s FastPharming facility was array of biological medicines. January that the new coronavirus was originally constructed in 2010 with going to be a problem, the companies funding from the Defense Advanced Why did you choose to focus on agreed to work together to design, Research Projects Agency (DARPA), plant-based production? produce and test vaccine candidates. part of the US Department of Defense, Unlike traditional cell-culture We plan to have CC-Pharming test which was exploring a range of bioprocesses that are performed in our proprietary vaccine candidates technologies that could enable faster stainless-steel or single-use bioreactors, in China. We will soon enter the responses to outbreaks. Plant-based the FastPharming system uses plants as in vivo testing phase with one or expression technology won out, and the bioreactors. The gene or genes encoding more candidates, and expect further facility was one of three commercial sites the protein or proteins of interest are evaluation and development to occur comprising the “Blue Angel” initiative. temporarily transfected into the leaves in both the US and in China.

www.themedicinemaker.com 40 NextGen SPECIAL SERIES Advanced Medicine

the production of viral vectors. Relatively like Kite Pharma, which was purchased Advanced few cell and gene therapies have been by Gilead, and Juno Therapeutics, later commercialized so far – and prices are high, purchased by Celgene. When it comes to Medicine: reflecting the increased development and the gene therapy side, there are many small manufacturing challenges. There is a long gene therapy companies that have been Replicating the way to go before the industry can say it has struggling along for years, but 2013 saw truly optimized the processes for bringing investors really stand up and take notice of mAb Success these advanced therapies to market. Clive these, too. Today, there is a phenomenal Glover, Director, Cell and Gene Therapy, amount of investment going into both cell Story and Rene Gantier, Director Biotech therapy manufacturing and gene therapy Process Research & Development, both manufacturing. According to estimates, What lessons has the industry from Pall, review the progress so far and around $22 billion in capital funding was learned from the manufacture assess how manufacturing can be improved committed to the industry in 2018, which of monoclonal antibodies? for viral vectors. is a 30 percent increase on the funding And how can these help us received in 2017. face the challenges presented What cell and gene therapy milestones Rene Gantier: This is a big moment for by viral vector production for have we passed in recent years? the sector, especially for gene therapy, cell and gene therapies? Clive Glover: Well, there have been exciting which has been waiting a long time. The approvals and some amazing results money pouring into the field means that The rise of monoclonal antibodies (and coming from the clinic. One key milestone companies can start to tackle the challenges other important biopharmaceuticals) that stands out to me in particular, is the associated with industrialization and has taught the industry much in terms deal signed between Novartis and the figure out how we safely bring these of how to successfully manipulate and University of Pennsylvania in 2013 because therapies to as many patients as possible. manufacture living cells to achieve the it really kicked off the CAR-T field and desired yields and properties. But the next put advanced medicine in the spotlight The gene therapy sector has suffered from stage of evolution for drug manufacturers is for big pharma and investors. And then hype in the past. What’s different now? far more complicated and tends to require we saw the beginnings of companies Glover: Safety issues almost killed the gene therapytherapy industryin in the early 2000s, but whatwhat has changed since then is the safety profileprofile oft the viruses being used. For gene- modifiedmodified ccell therapies, the next generation of lentivirlentivirallen vectors being used today have a high safsafetyaf profile. Many patients have recentlyrecently beenbe treated with CAR-T therapy andaand we hhaven’ta seen issues with insertional mutagenesis,muutagene which was a problem with earliereaarrlier gegenerationsn of gene therapy. Over onn thethe viralvirir gene therapy side of things, therethere hashah s also been a recent switch away fromffrromo adenovirusaded n to adeno-associated virus, whichwhich hashah much lower immunogenicity andand a higherhih gh safety profile. Gantier:Gaantieier: We also know much more about thethhe sciencesc behind these therapies. WhenW you compare what is going ono in the gene therapy field to what we’ve seen in the past for monoclonal antibodies (mAbs), there are obvious parallels. The early days for mAbs #CHROMATO were a little shaky, but as science in the area improved, so too did safety. We now know how to modify genes to obtain different proteins of interest with the correct GRAPHY mutation, and how to humanize the mAbs to reduce the risk of immunotoxicity and EXPERTS immunogenicity. The industry succeeded in overcoming the challenges for mAbs so there is no reason why we cannot do the same for gene therapies.

Cell and gene therapies are often grouped together under “advanced medicines”, but how do manufacturing and scale up approaches differ between the two? Glover: For mAbs, the manufacturing process is a fairly uniform process. In contrast, the significant number of extra SIMPLIFY YOUR CHROMATOGRAPHIC PROCESS DEVELOPMENT FOR BIOMOLECULES steps and workflows that can be used for cell and gene therapies add complexity. The Short delivery times - all common Tosoh chromatography media on stock two most common workflows for advanced Reliability - reproducible packing medicines are viral vectors and CAR-T. Scalability - same conditions from lab to process scale At a very high level, the viral vector The new SkillPakTM 1 and 5 mL pre-packed columns are designed for fast method development, workflow bears a resemblance to the mAb resin screening, or sample concentration for biomolecules. Enquire today about additional workflow, as a single batch can serve many information and a set of columns for your upcoming process! bit.ly/SkillPak patients. To make more viral vectors and serve more patients, you need to scale up your process, which can become less complex and less expensive as a result. A lot of the unit operations, at a high level, look similar to the mAb process, but when you get into the detail of those operations, industry can adapt and customize some sustainable on a commercial scale. One of they are very different. When it comes to standard bioprocessing techniques for viral the key challenges is being able to move cell processing, the manufacture of CAR-T vectors, but we also need new approaches. from a scale-out approach to a scale-up therapies is autologous; one batch equals one Patients can’t wait so borrowing tools from approach. The technique used so far, patient. If you want to make more therapies, traditional biopharma manufacturing is mostly on the upstream side or the cell you need to scale out and increase the okay for now, but it’s not going to see culture side where the virus is produced, number of batches without increasing the the industry through to cost effective, relies on scale out. But multiplying the risk of mix up or cross contamination – and optimized industrialization. number of cell culture devices to increase that makes manufacturing complicated. the volume of manufacturing takes up And expensive. What are the biggest manufacturing a large manufacturing footprint and Gantier: The workflows for cell and gene challenges for viral vectors? contributes to costs. However, bioreactors therapies are different, but one thing in Gantier: Many of the manufacturing optimized for viral vector production have common for gene therapies and many processes for cell or gene therapies are now become available, allowing companies cell therapies is the need for viral vectors. developed in hospitals and academic labs. to scale up rather than scale out. Producing and purifying viral vectors Not only are they produced under non- Downstream, ultra-centrifugation is is challenging and has proven to be a GMP conditions, but they also require probably the best way to obtain the purest major bottleneck for manufacturers. The additional work and optimization to be virus, but it is not a scalable process that can

www.themedicinemaker.com 42 NextGen

be implemented in a GMP, industrialized What recent technology (or upcoming environment. There has been a great technology) are you excited about? “Companies need to deal of discussion in the industry about Glover: My answer is going to sound rather chromatography-type techniques for viral self-serving, but I’m really proud of our evaluate new vectors – an enormous topic unto itself. I iCELLis bioreactor, which was used to think everybody is very much aligned in commercialize Novartis’ Zolgensma gene technologies – and terms of implementing chromatography therapy for spinal muscular atrophy. The techniques, but how we go about this is therapy requires a fairly high dose of virus keep an eye on another question. For example, protein per patient and we worked closely with the A is the chromatography workhorse for developers of the therapy so that this could emerging mAbs but will never be suitable for viral be achieved. The developers even told us vectors. Companies are now exploring that, without this bioreactor, it wouldn’t approaches – and alternative ligands. have been possible to commercialize the therapy quickly. It emphasizes how then optimize their How can companies ensure therapies are important technological innovation is in as cost effective as possible? ensuring that these advanced medicines processes and Gantier: There are many factors that can be brought to patients. contribute to high drug costs. Technology Gantier: Continuous bioprocessing equipment.” companies can certainly help in reducing is being explored for mAbs – and, in the cost of manufacturing by developing time, the great deal of effort going into new technologies that optimize the process development could pass onto viral vector associated with many of the most well- as much as possible and deliver high yields. manufacturing. Viruses are very fragile used assays – in some cases up to two We don’t know exactly what percentage and it’s very difficult to recover the active weeks. If you are trying to optimize a of a therapy’s price tag is attributed to virus at the end of the process. The process particular manufacturing process when manufacturing, but it will be higher than also takes a long time. Intensification via your assay has such a long turnaround mAbs. We do know that producing a a continuous process could reduce process time, it complicates and slows down 200-L batch of viral vectors (based on a times and improve recovery rates, allowing the whole process. There are industry 200-L bioreactor) costs several hundreds the industry to significantly increase the groups and experts working to improve of thousands of dollars – and the resulting number of doses that can be made and the quality and accuracy of analytics, and batch will most likely yield less than 10 supplied to patients. when we start to see progress, I think doses for an indication like Duchenne we’ll see a real acceleration in improving muscular dystrophy. What big changes would boost the manufacturing processes. Glover: Process development is production of cell and gene therapies? Gantier: Another big change on the key. Companies need to evaluate Glover: For me, it’s analytics. We already processing side would be the ability to new technologies – and keep an eye have a good starting point in the cell and produce viral vectors without relying on emerging approaches – and then gene therapy field with the increasing on a transfection process. Right now, optimize their processes and equipment. science and innovations in manufacturing the process is cumbersome, and the Cell and gene therapies are moving fast technologies, but what is holding us back science is not completely controlled. and benefitting from reduced approval is the poor quality of analytics associated We rely on plasmid DNA to go into times and specialized clinical studies, with viral vectors. If you are trying to the cell to produce the virus. Imagine but this also means you have less time for optimize a process and improve yields modified or engineered cells that could process development. For mAbs, it takes by 20 to 30 percent, but the error bar produce viruses by themselves without around 8.5 years to go from preclinical to associated with the analytical assay you any external manipulation... Going back commercialization. For gene therapies, are using is plus or minus 50 percent, then to the mAb story, the creation of cell it’s around 6.5 years. Given the added you have a problem. And these numbers lines made an enormous difference to complexity of these therapies, we have are fairly usual in this particular industry the industry and the amounts of drugs something of a conundrum when it right now. that could be produced. Imagine what we comes to finding the time for process In addition to very large error bars, could achieve if we could do the same for development. there are also long turnaround times viral vector manufacturing. ARE YOU LOOKING FOR EXPERTS IN

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The Bumpy Pentamer Complex (gH/gL/UL 128/UL 130/UL131A) Road to a Tegument Cytomegalovirus Glycoprotein B (gB)

Vaccine Lipid Envelope

The development of a Nucleocapsid cytomegalovirus vaccine has been 50 years in the making. Double Stranded DNA Are there any technologies in the pipeline that could 150-200nm prompt a breakthrough?

By Andy Lane Figure 1. A diagram of a cytomegalovirus virion, with key proteins labelled.

To say that cytomegalovirus (CMV) is body’s natural ability to respond quickly childhood disorders, such as Down common would be an understatement. to infection, the majority of those syndrome (5), and takes the top The virus, which belongs to the infected with CMV are asymptomatic, spot for infectious hearing loss in Herpesviridae family, infects the though some may present with mild children worldwide (7). majority of people over the course of symptoms, including fever, sore throat • Recipients of donated organs their lifetime, making it one of the and fatigue. and stem cell transplants. CMV most ubiquitous human pathogens is also a threat to the recipients in the world (1, 2). And yet general The case for a CMV vaccine of solid organ or hematopoietic awareness of CMV and its impact on Though the majority of CMV infections stem cell transplants during human health (particularly the risk of are often benign and of little concern, immunosuppressive therapy. congenital infection) is relatively poor. the virus poses a significant risk to those These infections can occur due CMV has one of the largest viral who struggle to mount an effective to the presence of CMV in genomes known to man and is composed immune response – a problem that the transplanted organ, viral of hundreds of proteins (see Figure 1). It occurs predominantly in two groups: reactivation in the recipient’s tissue, exists as a variety of interrelated strains, or primary infection in seronegative both within the environment and those • The pregnant mother and fetus. If a recipients. Transplant-acquired it infects (3). new or reactivated CMV infection infections can cause conditions, Though we don’t yet have a full picture occurs during pregnancy, the virus such as hepatitis, pneumonia and of how CMV is transmitted, the virus can be transmitted to the placenta viremia (1) – all of which increase appears to spread via a range of human and establish a congenital infection the likelihood of transplant bodily fluids, including urine, saliva, in the developing fetus (cCMV). rejection and graft-versus-host blood and tears. Once inside the body, Here, it can wreak havoc on an disease. The incidence of CMV it invades a remarkably broad range of infant’s developing nervous system infection among transplant recipients cell types to mold cellular functions (5), causing irreversible defects is remarkably common, with 20– that support its replication. Fortunately, that range from hearing loss, to 70 percent of recipients acquiring the immune system typically responds impaired organ growth and learning an infection in the first year post- quickly, and drives the virus into a disabilities (6). The magnitude of transplant (1), making it one of latent state, where it remains dormant cCMV is significant, affecting the most common complications throughout a person’s life and waits for approximately double the number of affecting the survival of transplant more favorable conditions (4). Given the children living with better-known recipients worldwide (8). NextGen 45

Despite its significant burden, no drastically improving patient survival effective countermeasures are currently and procedure success rates. in place to protect those at risk, with “Much like the No licensed vaccines are currently only basic screening or behavioral available, but researchers haven’t been measures, such as hand hygiene, rubella vaccine, a sitting idle; the development of CMV available (7). And while antiviral vaccines has been ongoing for nearly therapies have been invaluable, they are novel vaccine for 50 years (9). Major impediments limited by toxicity and the continual to the development of a suitable emergence of viral resistance. CMV could protect vaccine have likely been down to poor Much like the rubella vaccine, a general awareness of the virus and its novel vaccine for CMV could protect mothers and their immunological complexity. However, mothers and their developing infants the acknowledgement of the clinical from CMV. Similarly, a vaccine for developing infants significance of CMV in recent years transplant recipients would avoid the has stimulated a surge in funding and need for expensive antiviral treatments from CMV.” research interest. that are limited in efficacy and duration,

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The current pipeline Attenuated vaccines Attenuated vaccines are created by reducing the virulence of a pathogen, while still keeping them viable. They have the potential to be one of the most effective ways of vaccinating against CMV, as they can mimic a natural infection (10). The 1990s saw the development of the first attenuated vaccines – a new generation of so-called transgenic disabled infectious single cycle (DISC) strains (see Figure 2) (11). These are live viruses with selective gene deletions in their membrane proteins that allowed them to assemble after their first infection cycle, but which were unable to infect successive cells (12). By expressing only a limited subset of the viral proteome, DISCs can be Figure 2. Diagram illustrating DISC, subunit and mRNA vaccines. 1) In vitro (left), Shield-1 propagated under controlled conditions ligand is added to cell culture alongside V160 formulation. This stabilizes the replication complex that allow for their production in vitro, and allows the virus to proliferate; in vivo (right), no Shield-1 ligand is present, which causes but cannot replicate in vivo, preventing destabilization of the replication complex and prevents viral assembly. 2) The adjuvant MF59 is latent infection (13). comprised of squalene, surrounded by surfactants and formulated with subunit antigens. 3) A lipid The current DISC frontrunner is nanoparticle fuses with cell membranes to release 6 mRNAs into the target cell cytoplasm. The Merck’s V160 strain, which includes mRNAs are translated by host cell machinery to produce antigens that can be detected by the rapamycin-binding protein (RBP) immune system. insertion. In vivo, RBPs are rapidly degraded to prevent viral replication. their development) and are used to trigger vaccinated within one year of giving DISC strains such as these have an immune response and stimulate birth, with acceptable adverse events effectively mitigated the concerns of acquired immunity against the pathogens (17). This landmark study was the first viral replication and latency, and could, from which they are derived. The protein to demonstrate efficacy in preventing in theory, elicit the full repertoire of responsible for mediating CMV’s entry primary CMV infection, and was antibody and T-cell responses of a to human cells and the dominant followed three months later by a phase natural infection. However, considering target of the body’s humoral response II in transplant recipients that showed that natural CMV infections can fail to is glycoprotein B (gB) – a homotrimeric significantly reduced viremia and length provide the immunity required to prevent envelope protein that has seen of antiviral therapy required (18). a secondary infection, it remains unclear considerable development as an antigen A glance over the literature makes if these vaccines will offer sufficient in subunit vaccines. Formulated with it clear that no major breakthroughs protection. Merck’s recent phase I trials Novartis’ proprietary MF59 adjuvant, gB with gB subunit vaccines have taken have shown good tolerance (14) and a has shown some promising early results place since. A likely reason for this was phase II study of 2,100 women, aged by a range of vaccine developers and has the realization that CMV’s pentamer 16–35 is now underway, with results arguably advanced the furthest to date in complex is also a key target for expected in 2021 (15). clinical trials (16). neutralizing antibodies and would be In a 2007–2010 phase II trial of required in formulations (19). Combined Subunit vaccines postpartum women, Sanofi Pasteur’s with the fact that gB has reached only Subunit vaccines (see Figure 2) are gB/MF59 formulation demonstrated 50 percent efficacy, and that the immune created using fragments of pathogens 50 percent efficacy against primary responses to gB and pentamer stimulate (typically surface proteins are used for CMV infection in seronegative women protection in different cell types, it is NextGen 47

making it the first mRNA vaccine for Though this must have made vaccine an infectious disease to enter a phase II design feel like a shot in the dark for “A slightly clinical trial. Moreover, plans are already researchers in the past, emerging data in place for a phase III in 2021, which is now starting to paint a more detailed disconcerting will evaluate efficacy in up to 8,000 picture. A vaccine will need to stimulate women of childbearing age. both the humoral and cell-mediated consideration is that Though attenuated, subunit and RNA immune responses, as anti-CMV vaccines are demonstrating varying levels antibodies have been shown to prevent we still don’t fully of success in the clinic, there are a wide transmission and minimize clinical range of other vaccine strategies beyond manifestations, while T-cells are likely understand how the scope of this article, including involved in suppressing viral replication peptide, DNA and vectored vaccines, and prevent reactivation of infection (2, protective all of which present viable options for 23). Further research is necessary to tackling CMV. provide a clearer picture that defines immunity is the correlates of protection. What next? Immunization is also challenged by conferred by natural It’s clear that the industry has made the fact that natural infection with significant advances in our understanding CMV is only partially protective and infection with of CMV in recent years, with a range of does not prevent placental transmission emerging technologies that could soon of the virus (24, 25). And that means CMV.” see a breakthrough. However, to develop vaccine candidates will need to an effective vaccine that can prevent provide protection exceeding that of both in utero and transplant-associated natural infection (8), and may make likely that an effective vaccine will need infections, some key challenges will the prospects for traditional vaccines to consist of both proteins (20). need to be addressed. somewhat limited (26). A slightly disconcerting consideration An ongoing challenge in biologic RNA Vaccine is that we still don’t fully understand manufacturing has been the need to A recent entrant to the CMV race is how protective immunity is conferred maintain homogenous cell lines that Moderna, which has been developing by natural infection with CMV (13). can be scaled to yield vaccines of a novel messenger RNA technologies since their founding in 2010. Unlike protein-based vaccines, Moderna’s mRNA-1647 formulation uses mRNA pda.ororg/EU/QU/QR20R202020 to instruct the host’s cells to produce antigens on-site, making manufacture 2020 PDA EUROPE and administration far simpler (21). The formulation comprises a lipid nanoparticle, that contains six separate Quality and mRNAs, collectively encoding five of the pentamer complex subunits and gB. Earlier this year, Moderna released Regulations some promising phase I trial data (22). Results showed good toleration and no severe adverse events after a three-dose Conference schedule, and boosting of neutralizing antibody titers in both seronegative and PDA EUROPE seropositive participants; 10-fold and VIRTUAL EVENTS 20–40-fold, respectively (23). Moderna LIVE | INTERACTIVE | ONLINE are now taking their vaccine forward, 9-11 JUNE 2020 YOU WILL BE GIVEN THE OPPORTUNITY TO CONNECT TO THE PRESENTATIONS FROM YOUR HOME-OFFICE VIA CONFERENCING TECHNOLOGY WITH AN INTERACTIVE COMPONENT!

2020 QR_133x98mm.indd 1 07.04.20 10:52 48 NextGen

high enough purity for use in humans. 7437-7442 (2019). Cytomegalovirus Vaccine (V160) in Healthy mRNA technologies, such as Moderna’s, 3. A Ross et al., “Mixed Infection and Strain Women 16 to 35 Years of Age (V160-002)” are entirely cell-free and avoid the need Diversity in Congenital Cytomegalovirus (2019). Available at: http://bit.ly/399hItc. for complex manufacturing processes, Infection”, J Infect Dis, 204(7), 1003-1007 16. TM Fu et al., “Progress on Pursuit of Human which would make these strategies (2011). Cytomegalovirus Vaccines for Prevention of much more practical for real-world use. 4. NB Knipeet al., “Fields Virology”, Wolters Congenital Infection and Disease”, Vaccine, However, it has yet to be seen whether Kluwer Health, 1-3091 (2007). 32(22), 2525-2533 (2014). mRNA vaccines are able to consistently 5. MC Cheeran et al., “Neuropathogenesis of 17. NIAID, “Recombinant CMV gB Vaccine in elicit potent and long-lasting immune Congenital Cytomegalovirus Infection: Disease Postpartum Women” (2011). Available at: responses to CMV. Mechanisms and Prospects for Intervention”, http://bit.ly/2PvwjHR. Another serious consideration: how Clin Microbiol Rev, 22(1), 99-126 (2009). 18. NIAD, “CMV Glycoprotein B Vaccine in to practically evaluate efficacy in trials. 6. SC Dollard et al., “New Estimates of the Allograft Recipients” (2011). Available at: cCMV is fairly rare at the population Prevalence of Neurological and Sensory http://bit.ly/39eaNiI. level (about 1 in 150 pregnancies) and Sequelae and Mortality Associated With 19. F Wussow et al. “Human Cytomegalovirus occurs in mostly vulnerable patient Congenital Cytomegalovirus Infection”, Rev Vaccine Based on the Envelope gH/gL populations. In practice, this requires Med Virol, 17(5), 355-363 (2007). Pentamer Complex”, PLoS Pathog, 10(11), large patient samples in resource- 7. SB Boppana et al. “Congenital (2014). limited populations, which may deter Cytomegalovirus Infection: Clinical Outcome”, 20. F Rieder and C Steininger, “Cytomegalovirus more risk-averse developers. Likewise, Clin Infect Dis, 57, S178-S181 (2013). vaccine: phase II clinical trial results”, Clin determining practical endpoints can be 8. DJ Diamondet al. “A fifty-year odyssey: Microbiol Infect, 20(Supplement 5), 95-102 a headache when you consider that viral Prospects for a cytomegalovirus vaccine in (2014). transmission, prevention of maternal transplant and congenital infection”, Expert 21. C Zhang et al. “Advances in mRNA Vaccines infection, blocking of cross-placental Rev Vaccines, 17(10), 889-911 (2018). for Infectious Diseases”, Front Immunol, transmission, reduction in congenital 9. SA Plotkin “The history of vaccination against 10(594), (2019). infection in infants, transplant cytomegalovirus”, Med Microbiol Immun, 22. Moderna, “Moderna Announces Additional survivability, and reduction in antiviral 204(3), 247-254 (2015). Positive Phase 1 Data from Cytomegalovirus treatment are all clinically relevant (27). 10. KY Choi et al., “A Novel Non-Replication- (CMV) Vaccine (mRNA-1647) and First Despite these challenges, the industry Competent Cytomegalovirus Capsid Mutant Participant Dosed in Phase 2 Study” (2020), remains optimistic. Successful phase Vaccine Strategy Is Effective in Reducing Available at: http://bit.ly/2T7s1bK. III trials from vaccine front-runners, Congenital Infection”, J Virol, 90(17), 23. AW Sylwester et al. “Broadly targeted human such as V160 and mRNA-1647, could 7902-7919 (2016). cytomegalovirus-specific CD4+ and CD8+ T clear the path to market in the coming 11. DM Koelle and L Corey, “Recent Progress in cells dominate the memory compartments of years. And though the road towards a Herpes Simplex Virus Immunobiology and exposed subjects”, J Exp Med, 202(5), CMV vaccine has been long and bumpy, Vaccine Research”, Clin Microbiol Rev, 16(1), 673-685, (2005). encouraging results from a wide scope of 96-113 (2003). 24. CL Rosa and DJ Diamond “The immune vaccine types suggests that we’re getting 12. MJ Reddehase,“Cytomegaloviruses: From response to human CMV”, Future Medicine, closer to a future where CMV poses Molecular Pathogenesis to Intervention”, 7(3), 279-293, (2012). less of a risk to those most vulnerable Caister Academic Price, 1-464 (2013). 25. KM Bialas and SR Permar, “The March to infection. 13. T M Fu et al.“Progress on Pursuit of Human towards a Vaccine for Congenital CMV: Cytomegalovirus Vaccines for Prevention of Rationale and Models”, PLoS Pathog, 12(2), Andy Lane is Commercial Director at The Congenital Infection and Disease”, Vaccine, (2016). Native Antigen Company 32(22), 2525-2533 (2014). 26. RF Pass et al. “Vaccine Prevention of 14. Merck Sharp & Dohme Corp., “Safety and Maternal Cytomegalovirus Infection”, New References Immunogenicity of the Human Engl J Med, 360(12), 1191-1199, (2009). 1. X Cui, CM snapper, “Development of novel Cytomegalovirus (CMV) Vaccine (V160) in 27. CS Nelson et al., (2018). “A new era in vaccines against human cytomegalovirus”, Healthy Japanese Men (V160-003)” (2019), cytomegalovirus vaccinology: considerations for Hum Vacc Immunother, 2673-2683 (2019). Available at: http://bit.ly/387J4OY rational design of next-generation vaccines to 2. SA Plotkin, SB Boppana, “Vaccination against 15. Merck Sharp & Dohme Corp., “Safety, prevent congenital cytomegalovirus infection”, the human cytomegalovirus,” Vaccine, 37(50), Tolerability, and Efficacy of the Human NPJ Vaccines, 3(38), (2018). SponsoredSpSponnsosorered FeatureFeFeaatture  494

intervene, increasing the potential for The Glass contamination (1). Often, pharma manufacturers don’t Quality You Seek realize that these problems can be reduced or avoided. Background glass Does Exist particles, for example, are considered the “norm” since they are created as vials rub Quality advocates Glass is an indispensable EKEMRWXSRIERSXLIVSRXLI½PPMRKPMRI The FDA has continued to raise primary packaging material When one pharma company switched concerns with the quality of conventional for pharma, but alongside the from borosilicate glass to Corning’s Valor® glass packaging through both advisory and many benefits of conventional Glass during a line trial, they assumed their other communications (3). Moreover, FDA glass are disadvantages, such as particle monitoring equipment was broken has supported – through its Emerging breakages, delamination, and glass FIGEYWIXLITEVXMGPIGSYRXWMRXLI½PPMRK Technology Program – advancement of particulates. It doesn’t have to be environment dropped to such low levels. new glass packaging technologies, like this way. Recent glass innovations They hadn’t realized it was possible to Valor Glass, with the potential to improve can make a big difference. reduce particle counts so much simply by drug product quality. Traditionally, glass changing the glass! manufacturers have been seen as “just &]6SFIVX7GLEYX7GMIRXM½G(MVIGXSVJSV There are many glass suppliers who suppliers” to pharma manufacturers, with Corning Pharmaceutical Technologies highlight the processes used to make prices based on the cost of materials and the glass, and how, for example, they manufacturing process. But there have been Everyday objects, such as a glass jar, a reduce the potential for defects. In some negative consequences related to glass bottle or even a car window, tend to many instances, the solutions only quality issues, such as drug recalls resulting be made from an easy-to-melt glass address one problem – one solution from delamination, or from glass particles in composition that is fairly inexpensive to tackles delamination, another reduces XLIHVYKGSRXEMRIV4SSV½PPMRKPMRIIJ½GMIRG] manufacture. As a result, the glass can extractables and leachables, and a due to jamming vials or breakages can also have poor chemical durability – after all, third might focus on machinability. In add to manufacturing costs. These issues can you don’t need high chemical durability contrast, Corning’s Valor Glass has been be reduced with the right glass containers. for soda. But this “everyday” glass is not developed as a holistic glass solution that A product like Valor Glass may cost a little suitable for pharmaceutical use. For a minimizes as many problems as possible more than conventional borosilicate glass, pharmaceutical product, impurities from – simultaneously. but it will improve manufacturing by resulting the primary packaging can cause problems To create Valor Glass, Corning’s R&D in fewer problems that could lead to delays, – such as contamination, degradation of team took a Quality by Design approach. drug shortage or potential recalls – a win for the APIs, or even pH shifts. Glass for 8LI] MHIRXM½IH XLI VSSX GEYWIW SJ both manufacturers and patients. pharmaceutical use must have excellent problems like delamination and breakage At Corning, solving tough customer chemical durability to keep the drug and used materials science to optimize problems is what we do. We do our best product stable for as long as possible. This the glass composition. For example, the work when we have the opportunity to durability can be achieved by increasing root cause of delamination was traced partner for innovation. the aluminum oxide in the glass or by to the evaporation and condensation keeping the silica content of the glass high. of boron from borosilicate glass during References 4LEVQEGIYXMGEP ½PPMRK PMRIW TVSGIWW the tube-to-vial converting process. 1. CL Timmons et al., “Particulate Generation hundreds of vials a minute, creating glass- The resulting boron-free composition Mechanisms during Bulk Filling and Mitigation via to-glass frictive contact that leads to SJ :EPSV +PEWW WTIGM½GEPP] IPMQMREXIW New Glass Vial,” PDA J Pharm Sci and Tech, scratches and breakage. It can also lead to delamination and gives the glass low 71, 379 (2017). small glass particles and cause down-time. extractable concentrations (2). The 2. RA Schaut et al., “A New Glass Option for The underlying cause of these challenges low friction external surface keeps it Parenteral Packaging,” PDA J Pharm Sci and Tech, is that conventional borosilicate glass vials inherently strong and damage resistant, 68, 533 (2014). LEZIELMKLGSIJ½GMIRXSJJVMGXMSRWYVJEGI moves smoothly through manufacturing 3. FDA, “Summary of Recent Findings Related to increasing their predisposition to jam. In lines, and can reduce peak particle counts Glass Delamination,” (2018). Available at this situation the operators may have to by up to 96 percent. https://bit.ly/2UhJJtQ

www.corning.com The Forensic Troubleshooter Sitting Down With... Stephen Tindal, Director, Science & Technology, Catalent Pharma Solutions, Swindon. Sitting Down With  51

If you weren’t a scientist, what would facility to another, and could not get significantly fewer products) were you be? some of the batches to run correctly influencing monographs that affected When I was at school, I toyed with despite using the same equipment. our work. I stepped up to try and correct the idea of being a comedy actor! But After manufacturing, I moved to a the imbalance – and it was a fantastic throughout my career, people have formulation role. This gave me further experience. If you’re prepared to roll told me that I would have been a good opportunity to grow and learn, and over your sleeves up and get involved, you teacher. I’m not sure I would personally the next few years I spent less energy fixing can make a difference. But you can’t have chosen a teaching career, but issues, and more energy on putting in place just think about your own company; you perhaps it would have chosen me if I a “right-first-time” methodology. need to think about what is best for the hadn’t focused on science. industry overall. I chose to study chemistry and What are your proudest achievements? analytical science at university. For a At Catalent’s Somerset site in New Jersey, Why is it so valuable to gain experience time, I had wanted to be a policeman, we commercialized several products. It outside of your own company? but I decided to fight crime in a different was crucial to be able to flag up potential Two things are important in way by becoming a forensic scientist. manufacturing issues early enough for development. One of them is diversity After I graduated, however, I found them to be fixed before validating the of thought; getting as many different that I couldn’t really afford to leave home process – I’m proud of the part that I opinions about a project on the table and survive on the starting salary of a played in fixing any possible problems as possible – and preferably at the forensic scientist. I’d like to believe that before they affected the business. beginning. If you come across unforeseen the forensic science industry lost out on Over the last few years, I have been issues later on in a project, I believe it a great scientist that day and they really asked to write chapters on soft capsules proves there wasn’t enough diversity of should review their starting salaries… for several publications, including thought early on. Instead, I decided on a career in the Encyclopedia of Pharmaceutical The second is being able to define a water analysis. I went to an interview Technolog y and Aulton’s Pharmaceutical continuous strategy to deliver projects in Swindon, UK. Next door, there was Sciences, which are used to educate successfully. Working outside your own also a job in quality control going at RP students and others. Aulton was the same company gives you both diversity of Scherer and I ended up taking the QC book that I was given as a student to learn opinion and a better sense of when you job. Actually, it all turned out rather well! about the pharmaceutics part of my course! have the right strategy. It was really nice to be recognized as an Sometimes, even when people think And how was your first foray into expert in the field and to give something there is a better way of doing something, the industry? back to the next generation. no one wants to change – finding a new At the time, the company wanted a solution is extra work. But if you have graduate with a fresh perspective to look You’ve also been involved with the US other experiences you can draw on, you at their testing laboratory and solve some Pharmacopeia... can show the benefits of the future state: of the problems they were experiencing I was on an advisory panel. The more “I’ve seen how other companies approach with ageing methods. That really suited I thought about it, the more I realized this problem. Let’s try it this way…” me because I liked mysteries and solving that it was a terrific thing to get involved All that said, you don’t necessarily problems (hence my original forensic with. After monographs are drafted, need to move companies to gain interest!). However, I didn’t enjoy QC they are released for people to comment diversity of thought, especially in a larger all that much. Ultimately, a lot of the on; if you’re not paying attention, it’s company like Catalent. My advice is to problems went back to people, and easy to miss the review window and then talk to people – both inside and outside although I made friends in high places you have to live with the consequences your own department, unit or company. by solving problems, I also made a few of what was finally published. There is turnover in any company and enemies on the bench. The work was also Catalent makes more than 7,000 there are always new people. Invite too repetitive and it wasn’t the place for products, and I’d say there have been them for a coffee. Ask them about their me. But then I had the opportunity to instances when we should have had job and what they did before. There is move into process development – where a seat at the table when it came to always an opportunity to share common there were more mysteries to solve. The monograph negotiations. People experiences and maybe learn something company had recently moved from one from smaller companies (and making new that will help you in the future.

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