DECEMBER 2020 # 71

In My View Feature Best Practice NextGen The benefits of 3D printing How far have we come Top tips for E&L Reviewing setbacks and for biopharma against COVID-19? analysis successes in gene therapy

10 24 – 31 36 – 39 46 – 49

The Innovation Awards 2020

Celebrating 2020’s top pharma development and manufacturing technologies

14 – 21

www.themedicinemaker.com Do You Want to Learn More About monoclonal Antibody Production?

Today’s bioprocess professionals need to stay on top of many things: Scale-up parameters and equipment capabilities, control strategies and automation, validation requirements and docu- mentation to name a few. New fields of applications like stem cell technology are evolving into powerful tools of the future.

Become a bioprocessing. Join us at www.eppendorf.com/bioprocess

Eppendorf® and the Eppendorf Brand Design are registered trademarks of Eppendorf AG, Germany. www.eppendorf.com /bioprocess All rights reserved, including graphics and images. Copyright © 2020 by Eppendorf AG. Is it Time to Reevaluate Our Priorities? The COVID-19 vaccines demonstrate what’s possible Editorial when disease is tackled as a genuine priority

he whole research and development community is working hard to bring us that [COVID-19] breakthrough sooner rather than later,” wrote TStephanie Sutton in her November editorial (1). And here we are, just one month later, with not one but three breakthroughs. Pfizer (2) and Moderna (3) are both claiming around 95 percent efficacy in their vaccine studies, involving 44,000 and 30,000 volunteers respectively. And then we had AstraZeneca and the University of Oxford announcing that their vaccine, which should be cheaper and easier to distribute than the aforementioned mRNA approaches, is 70 percent effective (4). In a serendipitous turn, some volunteers were mistakenly given shots half the planned strength, References which turned out to be more effective than the original dose – 1. S Sutton, “Beyond the Storm,” The 90 percent as compared to the original 60 percent (hence the 70 Medicine Maker (2020). Available at: headline figure – and an additional dose of controversy). https://bit.ly/2VkGAJq It’s important to not get carried away – however desperate we 2. Pfizer, “Pfizer and BioNTech Conclude all are to see the back of this pandemic. As Peter Doshi writes Phase 3 Study of COVID-19 Vaccine in the BMJ (5), we don’t know about the vaccines’ ability to save Candidate, Meeting All Primary Efficacy lives, prevent infection, the efficacy in important subgroups, or Endpoints” (2020). Available at: https://bit. the performance at three, six or 12 months. But if (and that’s a ly/3mnKX1X big if) we now have the means to beat COVID-19 in the near 3. Moderna, “Moderna’s COVID-19 Vaccine future, the industry has managed to accomplish a feat that would Candidate Meets its Primary Efficacy ordinarily take years – even decades. How was this possible? Endpoint in the First Interim Analysis of the And are there any lessons we could apply to other diseases? Phase 3 COVE Study” (2020). Available at: SARS-CoV-2 may be, as Stat News pointed out (6), an https://bit.ly/33uKX9a easier target for potential vaccines than other pathogens. But 4. AstraZeneca, “AZD1222 vaccine met a major factor has to be money. Both the funding received by primary efficacy endpoint in preventing companies developing vaccines (close to a billion dollars from COVID-19” (2020). Available at: https:// the US government in Moderna’s case), and the prospect of bit.ly/36naZgA huge financial rewards should they succeed – a combination 5. BMJ, “Peter Doshi: Pfizer and Moderna’s of state and market incentives. “95% effective” vaccines—let’s be cautious As a global society, we must ask ourselves a big question: and first see the full data” (2020). Available Are we really prioritizing medicine? We might not think of at: https://bit.ly/37gemVG cancer or Alzheimer’s as “emergencies” (unless we are directly 6. Stat News, “‘A huge experiment’: How the affected) – but they have a combined economic impact that world made so much progress on a Covid-19 must surely exceed that of COVID-19 – especially over the vaccine so fast” (2020). Available at: https:// course of decades. Though we couldn’t go after one disease bit.ly/39tpy3S at the expense of all others (consider the hidden death toll of the pandemic), perhaps we could achieve remarkable things, if governments – with the support of the general population – made tackling diseases a genuine priority.

James Strachan Deputy Editor

www.themedicinemaker.com Contents

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In My View

10 3D printing is far more than just a “cool” technology when it 14 comes to biopharma, according to Klas Marteleur

12 David Jones says that quality control must evolve with 03 Editorial Upfront modernized approaches to meet Is it Time to Reevaluate our today’s challenges Priorities? by James Strachan 06 The latest news, views, and research – including the use of microbes to enhance On The Cover Cover immunotherapy efficacy, Features pharma’s advertising push, Ending 2020 on a high: and sustainability in the 14 The Innovation Awards 2020 celebrating the annual biopharma cold chain. Celebrating the groundbreaking Innovation Awards drug development and manufacturing technologies released in 2020 ISSUE 71 - DECEMBER 2020

Feel free to contact any one of us: [email protected] Content Team Editor - Stephanie Sutton Charlotte Barker (Associate Content Director) Kirstie Anderson (Commercial Editor) James Strachan (Deputy Editor) Maryam Mahdi (Associate Editor) Commercial Team Associate Publisher - Helen Conygham Helen Johnson (Business Development Manager) Stacy Gaines (Business Development Manager, North America) Design Team Head of Design - Marc Bird Hannah Ennis (Senior Designer) Charlotte Brittain (Designer)

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 – Brice Agamemnon CRM & Compliance CRM & Compliance Manager - Tracey Nicholls Hayley Atiz (CRM Assistant) Commercial Support Team Internal Systems Manager - Jody Fryett Dan Marr (Campaign Reporting Analyst) Commercial Services Commercial Service and Social Media Manager- Matt Everett Kevin O’Donnell (Marketing Executive) Alice Daniels-Wright (Video Project Manager) 42 Jess Lines (Video and Project Support Coordinator) Lindsey Vickers (Sales Support Project Manager) Jennifer Bradley (Sales Support Coordinator) Marketing Team 24 COVID-19: Cutting Marketing Manager - Katy Pearson Jo Baylay (Marketing Executive) Through the Noise NextGen Accounts Team Looking over the astonishing Kerri Benson (Accounts Assistant) Emily Scragg (Accounts Apprentice) COVID-19 research that has 42 Putting Sleeping Sickness taken place over the last 12 months to Bed Human Resources Human Resource Manager - Tara Higby How Sanofi and the Drugs for Management Team Neglected Diseases initiative Chief Executive Officer - Andy Davies Chief Operating Officer- Tracey Peers are working to tackle sleeping Senior Vice President (North America) Reports sickness once and for all - Fedra Pavlou Financial Director - Phil Dale Commercial Director - Richard Hodson 23 Speeding Up the Development 46 Gene Therapy: The Rocky Content Director - Rich Whitworth of Purification Methods Road to Success Change of address [email protected] Reviewing the setbacks and Hayley Atiz, The Medicine Maker, Texere Publishing Limited, Booths Park 1, Chelford Road, Knutsford, Cheshire, WA16 8GS, UK 32 Up to the Challenge successes of gene therapy – and General enquiries what may lie ahead for the field www.texerepublishing.com | [email protected] +44 (0) 1565 745 200 | [email protected]

Distribution: The Medicine Maker (ISSN 2055-8201), is published monthly by Texere Publishing Limited, Booths Park 1, Chelford Road, Knutsford, Cheshire, WA16 8GS, Best Practice UK. Single copy sales £15 (plus postage, cost available on request [email protected]). Non-qualified annual Sitting Down With subscription cost is £110 plus postage 36 Extracting Sense From Reprints & Permissions – [email protected] The copyright in the materials contained in this publication and the E&L Science 50 Elaine O’Hara, Chief typographical arrangement of this publication belongs to Texere Publishing Limited. No person may copy, modify, transmit, distribute, display, An update on the latest Commercial Officer, Sanofi reproduce, publish, licence or create works from any part of this material or typographical arrangement, or otherwise use it, for any public or commercial guidance and science around Pasteur, US (Swiftwater, PA) use without the prior written consent of Texere Publishing Limited. The names, publication titles, logos, images and presentation style appearing extractables and leachables in this publication which identify Texere Publishing Limited and/or its products and services, including but without limitation Texere and The Medicine Maker are proprietary marks of Texere Publishing Limited. Nothing contained in this publication shall be deemed to confer on any person any licence or right on the part of Texere Publishing Limited with respect to any such name, title, logo, image or style. 6 Upfront Upfront

Research Trends Bacterial Boost Innovation Can microbes enhance the efficacy of immunotherapy?

Why don’t immunotherapies work for everyone? The answer isn’t entirely clear – but new research published in Science sheds some light (1). According to Lukas Mager, a senior postdoctoral researcher at the University of Calgary and first author of the paper, specific bacteria in the gut microbiome play a significant role in the success of immunotherapies in treating certain cancers. “Immune checkpoint blockade (ICB) treatment is used with great success increased the antitumor capacities of T ICB-enhancing bacteria in sufficient in some tumors, but not all cancer cells in multiple tumor types, including quantities over time. patients respond due to primary – and colorectal and bladder cancer, as well The researchers are also investigating later secondary – resistance to these as melanoma. the microbiomes of tumors themselves. therapies,” Mager says. “Recent studies Looking forward, the team hopes “Recent work has shown that tumors have have shown that the efficacy of ICB to translate their ICB-enhancing their own distinct microbiomes (2). We therapy depends on specific bacteria, microbes to the clinic, but Mager sees have also observed differences between the but it remains unclear how they elicit challenges ahead. “We and others have fecal- and tumor-associated microbiome. this enhanced response.” identified several different bacteria and Arguably, these tumor-infiltrating bacteria Mager and his colleagues decided a metabolite that could be used as an will have a strong impact on local tumor to investigate the role gut microbes ICB-adjuvant treatment in clinics. immunity,” says Mager. He expects future play in ICB treatment efficacy and However, it remains to be seen which trials to examine the likely intimate found that certain bacteria produced bacterium or mix of bacteria is most relationship between these bacteria and a metabolite called inosine, which efficient and safe in humans.” Further the immune system. enhances the effect of immunotherapies to this, the mode of application will in cancer. In mice, inosine – together likely require optimization to overcome References with proinflammatory stimuli and colonization resistance in patients and 1. L Mager et al., Science, 369, 1481 (2020). checkpoint blockade immunotherapy – to allow for the stable integration of 2. D Nejman et al., Science, 368, 973 (2020).

INFOGRAPHIC Key findings How important is sustainability to your business?  Sustainability is a talking 8% Neither 3% Unimportant Green Progress point but green initiatives important are not widely formalized nor unimportant  Sustainability is already A report on biopharma cold a factor in cold chain chain reveals green goals for a decision making more sustainable future  Expectations are high for recyclable cold chain 23% packaging materials and Important energy-efficient shippers 66% Very important Upfront 7

BUSINESS IN BRIEF

Criminal charges, drug pricing, and upgraded headquarters… What’s new Full PowPowerwer in business? for 2021 • Purdue Pharma pleaded guilty to three charges concerning will support the company’s Nominations for The Medicine its role in the supply of R&D and manufacturing Maker Power List will close on OxyContin, bringing an end needs, and will accommodate January 25 to its civil case with the US an additional 12,000 members Department of Justice. The of staff. The Medicine Maker 2021 Power List will charges included two counts • A collaboration between Gavi, be published in April to celebrate the great of conspiracy to violate the The Vaccine Alliance, and the minds and personalities that contribute to the Federal Anti-Kickback Statute International Organization for development of new medicines – including – a law that prevents the Migration pledges to provide small molecules, biopharmaceuticals, and exchange of items or services vaccinations for those affected advanced medicines. Nominations can be for reward referrals – and one by emergency or humanitarian submitted using the quick form at http:// count of dual-object conspiracy crises, and encourage tmm.txp.to/pl2021-noms. to defraud the US. companies to consider those Who is eligible? You can nominate • Most Favoured Nation, a drug who may otherwise be anyone involved in the development or pricing policy, was set into missed in their COVID-19 manufacture of new medicinal products – motion in late November by responses. “Children from and we invite nominations from all corners President Donald Trump. The migrant, refugee, and displaced of the industry including big pharma, pricing model is expected to populations are too often startups, research institutes, societies, lower the cost of 50 prescription overlooked when it comes regulators, NPOs, academia and more. medicines in line with the to basic health care. This We want to celebrate the diverse talent prices paid by Europe’s obviously becomes all the and experience that makes the pharma wealthiest nations. The policy more important as we plan to industry tick – please join us! will come into effect on January roll out COVID-19 vaccines 1, 2021. worldwide; we cannot allow For inspiration or reference, the 2020 • In line with a new 15-year these populations to miss Power List can found at: www. plan, Roche’s Genentech is out on what could be one of themedicinemaker.com/power-list/2020 expected to almost double its our best routes out of this headquarters space to 9 million pandemic,” said Gavi’s CEO, Questions? Email stephanie.sutton@ square feet. The upgraded sites Seth Berkley, in a statement. texerepublishing.com

How frequently does How likely are you in the Driving factors sustainability factor into future to use energy-efficient your cold chain purchasing packaging?  Preserve the planet decisions?  Reduce waste 5% Never 19% Neither  Strengthen brand preference 9% Rarely likely nor and outperform peers unlikely Source: 1. Pelican BioThermal, “2020 45% Biopharma Cold Chain Logistics Always 81% Highly Sustainability Survey,” (2020). 41% likely or likely Sometimes Available at https://bit.ly/3lmtXZE 8 Upfront

pandemics have shaped responses to millions of masks because it didn’t think Pandemic the COVID-19 crisis. The conversation they would be needed. The masks were involved Pieter Neels, Chair of the purchased over a decade ago because of Preparedness Human Vaccine Committee of the fears of an influenza epidemic. However, International Alliance for Biological Neels adds that we “simply could not What have we learned from Standardization; Marco Cavaleri, Head imagine that the next pandemic would the pandemics of the past? of Office, Biological Health Threats and be on the same level as the Spanish flu.” Experts give their view in a vaccines strategy at EMA; Rebecca Cox, But it’s not all bad news. When it video discussion Professor of Medical Virology and Head comes to vaccine manufacture, processes of the Influenza Centre at the University have certainly changed drastically over Why was the world so unprepared for of Bergen and Haukeland University the last century – emphasized by the fact a coronavirus pandemic? Long before Hospital, Norway; and Daniel Hoft, that the industry has been able to create 2020, scientific experts, the WHO, and Professor of Internal Medicine at St new vaccines for COVID-19 in such a even the World Bank pointed out that Louis University Schoolol of short space of time. coronaviruses could be problematic. Medicine, USA. In some ways, we were perhaps lulled “We were not prepared Wildfire,W Neels, and into a false sense of security by recent because the previous the other participants epidemics and pandemics. SARS and SARS and MERS discuss these topics MERS did not spread extensively across pandemics were far and more in the the globe, and the 2009 H1N1 crisis was from our bedside,” video roundtable considered mild in comparison to 1918’s said Neels. “The – available for Spanish flu. 2009 H1N1 free at http:// “We took our eye off the ball – crisis was judged tmm.txp.to/ possibly in 2008 when funding for a mild influenza, vaccineroundtable betacoronaviridae took a nosedive so why should because we went into an economic we have all these crash,” says Adrian Wildfire, Director, measures in place Scientific and Business Strategy for such a pandemic?” at hVIVO, a clinical development As an example of services business. complacency, before the Wildfire recently moderated a COVID-19 crisis broke roundtable discussion for The Medicine out, Belgium destroyed Maker focusing on how previous a strategic stockpile of

• innovative leadership in the industry you do science the right way, you never Topping the Charts • respectful treatment of staff really fail. You either succeed or learn • social responsibility something more valuable,” he said in a Celebrating pharma’s best • loyalty statement (1). employers • a work culture that aligns with staff’s personal values The full list can be found here What makes a good pharmaceutical https://bit.ly/3nogIZ7. employer? Science asked over 7,000 people Regeneron ranked top of the opinion poll – this question in its annual ‘Top Employer’ a victory that the company’s executive vice- Reference survey to determine the ingredients president, Drew Murphy, puts down to a 1. AG Levine, “2020’s Top Employers: Rapid required for a positive work culture. For science-first approach. “Our commercial response to COVID-19, diversity, and 2020, five key characteristics emerged as people don’t tell our researchers what to innovation” (2020). Available at having significant importance to employees: do. The scientists set the agenda. And if https://bit.ly/3nogIZ7. Upfront 9

IMAGE OF THE MONTH The Advertising Push

How has pharma’s ad spending changed in 2020?

The COVID-19 pandemic is adding additional momentum to the digital revolution in pharma. Now more than ever before, companies are becoming reliant on digital tools to facilitate their everyday activities – and the sector’s approach to advertising is no exception. According to a report published by eMarketer, pharma’s digital ad spending is projected to increase by 14.2 percent this year to an estimated US$9.53 billion. COVID-19 awareness campaigns and marketing for products related A Tight Grip to safety and testing are cited as some of the key factors for this growth. Researchers at Johns Hopkins Medicine have developed micro drug delivery devices Although pharma is bolstering called theragrippers that cling to the gut when exposed to the internal temperatures its mobile advertising capacity – of the body – in a similar manner to parasitic worms! with almost 58 percent of spending Credit: Johns Hopkins University https://bit.ly/3nrqfi9 targeting the mobile platforms – it still falls short of the 68 percent Would you like your photo featured in Image of the Month? average across other industries. Send it to [email protected] It will be interesting to see how spending patterns continue to shift as the pandemic evolves.

Read the full report: QUOTE of the month https://bit.ly/3eVx48j.

“The best possible position we could be in is where we have four or five or six of these vaccines available in the year 2021. The competition here isn’t one of the other companies. It is the virus.” Alex Gorsky, Chairman and CEO at Johnson & Johnson at a virtual Detroit Economic Club conference. 10  In My View In My View Experts from across the world share a single 3D Printing strongly held opinion Unleashed or key idea.

Additive manufacturing is so much more than just “cool” technology; it holds great promise for the biopharma industry

By Klas Marteleur, a Principal Mechanical Engineer at Cytiva, Uppsala, Sweden

Additive manufacturing – or 3D printing – is the process of creating a physical object layer by layer, using different materials, such as stainless steel, titanium or nylon. 3D-printed components find their way into diverse products, including jet engines, cars, and the productivity per square meter to handle more materials. This work and bioprocess instruments. Until will improve. Imagine the innovation will continue but, for the components recently, 3D printing was primarily that could take place thanks to this needed in life sciences products, post used in product design departments increased design freedom. processing is equally important. to quickly create prototypes for testing Additive manufacturing will also There are many different 3D purposes during development. Thanks help the biopharma industry reach its printing technologies and, depending to advances in printing technologies, sustainability goals faster. Reducing on the application, the resulting parts manufactured (printed) components material usage has a ripple effect. Lighter will require different types of post- are equal to, if not better than, those components require lighter frames or processing. For example, if you print produced by conventional technologies; chassis to carry the components, and complex components, such as a manifold in short, 3D printers are now ready to consolidation of components will lead of a chromatography system, in stainless be used to improve end products. to smaller instruments that require less steel, you’ll end up with rough surfaces In my view, the benefits of 3D space in the clean rooms. For example, directly from the printer. For use in a printing technology are significant. chromatography instruments with life science product, the component Products will be smaller, lighter, and many components and long lengths must have those surfaces polished – more optimized for the task; studies of piping could be reduced in size. A conducted here at Cytiva have shown smaller and lighter instrument will that we can use 80 percent less material also reduce the climate impact from in some stainless-steel components transportation, and reduce the amount “So what’s the using 3D printing! We can save even of chemicals needed to clean and more material if we can consolidate maintain the instrument. holdup? Why isn’t several components into one (and we So what’s the holdup? Why isn’t the often can). By consolidating parts industry making greater use of 3D the industry and reducing the number of joints printing? To answer that, I need to go in a bioprocess instrument, quality into more technical detail. Until now, making greater use can also be improved and the risk of the focus has been on the 3D printing leakage reduced. It follows, then, that machines themselves: making them of 3D printing?” every instrument will be reduced in size better, faster, more accurate, and able in a life science product. It is important to have full control over the complete “There are many manufacturing process – from the raw material that goes into the 3D printer to different 3D the final post-processing and assembly steps – to ensure no harmful substances printing are able to leach into, destroy, or SAVE THE DATE FOR THE contaminate the customer process. technologies and, To maintain full control, we decided 2021 PDA to invest in essential technologies, depending on the including 3D printers and post- processing equipment. ANNUAL application, the The biggest threat to a wider implementation of additive MEETING! resulting part will manufacturing in the life sciences space is that we tend to stop challenging the require different way we do things today. If we just 3D print whatever designs we have today, NEW NEW NEW types of post- little is won. For example, a simple FORMAT PRICING WAYS TO sheet metal bracket can easily be made CONNECT processing.” by bending a piece of sheet metal the Dive into exciting interactive traditional way, so 3D printing makes sessions and tracks especially no sense. Instead, we need to rethink designed for early career especially those areas in direct contact and redesign components and systems professionals, manufacturing with the process contact – to improve to unleash the power of 3D printing. We leaders, and technical experts/ cleanability and reduce the risk of need to continue developing standards scientists, all offered in a fully cross contamination and bioburden. It and technologies in parallel, while digital format for easy access from is important to have control over each focusing on what is important and not anywhere in the world. step in this manufacturing process to discarding new solutions just because understand how they affect the result. they might look different. Of course, Come away with tangible, practical When it comes to the cleanliness we must never compromise on quality. solutions to improve your operations of surfaces, the definition of “clean” There are many opportunities with and your standing within your depends on who you ask. If you ask a 3D printing, but there are no quick company! child if she washed her hands carefully wins and plenty of challenges to Stay tuned for more information on before dinner and you watch her during overcome. Stamina, long-term vision, the intriguing lineup of sessions, the process, you might have a different and the freedom to creatively challenge speakers, and networking activities. opinion. And that does not necessarily assumptions are all necessary to reach mean that the child didn’t try to clean the goal. Naturally, an area with Register early to take advantage of her hands; more likely, it is that you this much potential benefits from XLIQSWXWMKRMƼGERXHMWGSYRXW have more experience and knowledge collaboration; working with customers For more information and to about what it takes to clean hands and academia is crucial when it comes register, visit pda.org/2021annual properly. It is similar in the 3D-printing to understanding the real needs and industry. opportunities. There are many good print shops By identifying pain points in existing that can 3D print the physical part – products and then researching and PRESENTED VIRTUALLY and some that can even post-process developing new technologies to 15-17 MARCH it so it looks good, but there are not address those issues directly, I believe many that actually understand the we can realize the next generation of EXHIBITION: 15-17 MARCH requirements on a part that will end up biopharma equipment. #PDAannual ’s DIAMO DA ND P A G N N N I I T V A E R R

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Y C 12  In My View

where drugs move through an integrated QC system. The adoption of an automated A Brave New production workflow, without hold approach for QC can also accelerate times between steps. The FDA calls the validation in terms of environmental World of Quality conversion to continuous approaches a monitoring, bioburden, and water systems. “challenging but worthwhile transition Integration of automated systems also Quality control must (4).” While both batch and continuous eliminates the need for incubators and evolve to meet progress manufacturing are subject to the same peripheral equipment, further reducing in biopharmaceutical QC standards, however, monitoring is the time required for validation. manufacturing more frequent and must be automated In addition to supporting new strategies, in continuous manufacturing facilities to such as continuous processes and modular By David Jones, Director of Technical keep pace with production. facilities, rapid and automated QC Marketing and Industry Affairs at Rapid With continuous flow processes, processes also enable wider adoption of Micro Biosystems the more rapid the turnaround of digitization, where sensors and chemical environmental monitoring and in- testing methods are placed along the Biologics are expected to reach 50 percent process testing, the better – these tests manufacturing line. As QC data come of market share of all therapeutics within will identify a process that is going out off the line, operators can respond more 10 years (1) and, as a consequence, demand of control and enable a quicker response. rapidly to process deviations. Automated for biologics manufacturing is at risk of In addition, many of the raw materials QC processes provide an electronic output growing faster than capacity (2). Companies used in the manufacture of biologics are of data and can deliver a real-time display are now actively streamlining processes to expensive, and the ability to rapidly detect of conditions within the manufacturing run more activities in parallel, executing contamination will help reduce the risk of facility, identifying possible hotspots of manufacturing development, scale-up, lost investment. contamination with greater agility. and validation of processes and clinical The use of modular cleanroom Conventional methods of lots much earlier in the value chain, and production facilities also benefits from manufacturing will continue to evolve – increasing capacity to keep up with demand. rapid, automated QC processes. In and drug manufacturers will embrace new They are also exploring new manufacturing contrast to conventional facilities that technologies and workflows capable of approaches, such as continuous processing require significant capital outlay and long delivering gains in speed, efficiency, and and modular manufacturing. construction times, modular facilities are capacity, while preserving quality and data These activities will contribute to a complete, turnkey units that are designed, integrity. But if we, as an industry, are truly brave new world of medicine making, validated and assembled off-site. Skid- aiming for improved speed, patient safety, but we also need modernized approaches mounted platforms in these facilities and reduced business risk in the years to to quality control (QC). To keep pace enable reconfiguration and upgrades come, then we cannot neglect innovation and with accelerated and streamlined without the costs and time requirements implementation of modern QC approaches. manufacturing, QC processes must of major renovations. The environmental be faster, highly automated, support monitoring strategy can be identified References confident decision-making, and ensure before the installation of the facility, further 1. IQVIA, “Disruption and maturity: The next complete data integrity. The FDA has accelerating deployment. This process phase of biologics” (2017). Available at https:// highlighted the importance of improved includes the determination of high and bit.ly/2XmMNpw. QC and stated that increased investment low-risk contamination areas, the possible 2. Biospace, “CPhI Annual Report predicts Europe in manufacturing quality is a critical step impact on the process, and identification to surpass the USA in biologic manufacturing towards minimizing disruptions in the of where to test and how. Automated QC capacity by 2023” (2019). Available at https:// supply of drugs (3). systems for environmental monitoring bit.ly/30oY5eO. A critical cornerstone of QC is and in-process testing can further increase 3. FDA, “To Help Reduce Drug Shortages, We environmental monitoring and in-process the flexibility of modular manufacturing. Need Manufacturers to Sell Quality — Not Just testing for microbial contamination. These systems can be integrated into Medicine” (2020). Available at https://bit. Current processes to detect microbial manufacturing, eliminating the need for ly/3k6gl4m. contamination are time- and labor- a separate QC module. In this scenario, 4. FDA, “Modernizing the Way Drugs Are Made: intensive; we need faster, better technology. trained members of the manufacturing A Transition to Continuous Manufacturing” Consider continuous manufacturing staff can feed samples into the automated (2017). Available at https://bit.ly/2D5cpQZ. Advancing the race for a COVID-19 Vaccine Faster vaccine research & production Our experience and solution portfolio can help customers at all stages of vaccine development, from discovery and testing to large scale manufacturing against the novel SARS-CoV-2 outbreak.

Learn More. www.sartorius.com/covid19 CELEBRATING THE MOST IMPRESSIVE DRUG DEVELOPMENT AND MANUFACTURING TECHNOLOGIES OF THE LAST 12 MONTHS

Welcome to the 2020 edition of a long-standing tradition at The Medicine Maker: The Innovation Awards! Here, we celebrate the top technologies released over the course of the year. (Nominations were collected via an online form available at www.themedicinemaker.com during 2020).

But which technology is truly the most innovative? Well, only you, our readers, can decide!

Go to http://tmm.txp.to/2020/innovationwinner to vote for your top pick. Please note: voting will close on March 3, 2020, and we’ll publish the development story behind the grand winner in a 2021 edition of The Medicine Maker.

And, of course, the Innovation Awards will be back in 2021! Nominations will open in late Spring 2021. Sign up for our newsletter via the website to keep updated. Feature  15

3D-PRINTED TOOL PROTOTYPING SERVICE

A prototyping service that creates test products using 3D printing technology

Maruho Hatsujyo Innovations BIO4C This 3D printing service can create PROCESSPAD sample blister cavities to help determine the most suitable options ADHEREIT Data collection, visualization, for particular medicines in terms 360 BASE AND and analytics software for of stability, childproofing, and ADHEREIT 360 bioprocessing material limits for filming/lidding. CLIP The results are almost identical to Merck final production, potentially saving A connected solution for time and money compared with improving adherence in Bio4C ProcessPad is a browser-based traditional metal tooling prototypes. patients with auto-injectors software platform for bioprocess After all, production tooling for monitoring, lifecycle management, blister machines is expensive – Noble and Aptar Pharma reporting, investigations, and hence the need to get it right at the continued process verification. The design stage. Historically, tooling AdhereIT can integrate with self- software combines process data lead times were measured in weeks; injection devices to support patients from different sources – including Maruho Hatsujyo Innovations with initial onboarding and ongoing batch records, quality control results, claims that it can create 3D printed adherence to therapeutic treatments. standard databases, QMS, MES, blister prototypes in days. The base and clip provide visual, LIMS, and data historians – into audio,audio, andand haptic feedback during a single, integrated data source. It the injectiinjectiono process to guide dosing also features out-of-the-box data success. EncryptedE data is then visualization and analysis tools to transferredtransferred to a smartphone app, help scientists understand, explore, whichwhich also incorporates patient and analyze their data. The data resources,r such as training can also easily be shared across videos, injection geographies and organizational reminders, and drug structures with operators, CMOs, reorder notifications. and decision-makers. Data can be shared According to Merck, without a with healthcare structured process data management providers to track tool, bioprocessing scientists can patient performance spend over 80 percent of their time tthroughh a dashboard, hunting and gathering data and providingproviding real-worldr data to support only 20 percent on analysis. Bio4C ongoing therapeutic programs. ProcessPad was developed to help Aggregated,Aggregat anonymized data improve data analysis, facilitate can also be made available to quicker release of quarantined lots pharmaceuticalpharmaceu companies to help under investigation, and improve addressaddress popoor adherence. productivity and process monitoring.

www.themedicinemaker.com 16  Feature

BLAZAR PLATFORM CERELLA

Multiplexed degenerate PCR-based platform for Artificial intelligence technology for active detecting viral contamination learning in drug discovery

Merck Optibrium

The Blazar Platform expands the ability of conventional Unlike many other AI platforms for drug discovery, PCR. Degenerate primers are designed to target conserved Cerella is directly deployed by customers – enabled by a protein motifs within viral families and multiplexing combination of on-premises software and cloud computing. allows for coverage across hundreds of viruses. In addition, The technology uses a peer-reviewed adaptive learning detection identifies the contaminating virus through sizing method, and directly connects with a corporate compound and sequence, facilitating faster investigation. GMP level database to automatically update models when necessary. viral screening can be achieved in one week. Among other features, Cerella can “fill in” missing The ability to screen biopharma products and their data to highlight high-quality comcompounds,pounds, raw materials faster could be of significant interest to to identify experimentalntal the industry. Faster viral screening can help biologic outliers (to draw attention to manufacturers reduce costs by accelerating the production experimental errors, unexpectedted process. According to Merck, the Blazar Rodent Virus structure-activity relationships,ps, Panel is already helping the industry by reducing the time and false negatives) and ttoo required for cell line characterization from around three apply virtual screening acrossss months to just four weeks, which should allow therapies multiple endpoints to target thehe to enter the clinic faster. best compounds for synthesis.s. FeatureFeature  17

GPEX BOOST TECHNOLOGY

Cell line expression technology for improving titers and cell-specific productivity

Catalent Biologics J.T.BAKER GPEx Boost builds on the company’s BAKERBOND GPEx technology with enhanced PROCHIEVA benefits, including up to 10 g/l titer LABCONSOL for standard mAbs (up from 7 g/l for A recombinant protein A GPEx), up to four-fold higher titers in affinity chromatography Software to automate and difficult-to-express proteins, reduced resin for purifying antibodies coordinate lab equipment ammonia build-up to improve cell growth and viability, and fewer process Avantor H.E.L Group steps. The increased efficiency could lead to the use of smaller bioreactors Protein A chromatography is a proven labCONSOL can act as a single point (providing a greater number of downstream purification step in of control for around 140 separate facility fit options) or a reduction in manufacturing mAbs, but there remains control applications and over 900 the number of manufacturing batches a need to reduce total purification device drivers. The engine can capture necessary (potentially increasing costs, while improving purity and up to 100 data points per second. production scheduling). yield. Bakerbond PROchievA is a The developers say the software was The cost of goods sold can be high-performance protein A resin that based on feedback from scientists high for biologics, but improved uses a proprietary ligand to achieve about wanting their teams to do the titers can help reduce costs during dynamic binding capacity for mAbs “right” experiments rather than the development and commercial stages. and improved purification results in “easy” experiments. The software Catalent Biologics claims that, Fc-Fusion proteins and other emerging aims to make the right experiments based on expression data, GPEx molecules. The resin is compatible with as straightforward as possible, and Boost can significantly reduce the current manufacturing standards to includes drag and drop experimental development batch costs for mAbs ensure continuity in workflow processes setup capabilities and real-time and recombinant proteins. and compliance protocols. data display capabilities that can be configured to user needs. Suitable for use in controlling potentially hazardous reactions, labCONSOL also includes multiple layers of warning and safety controls to protect both the user and the studied reactions.

www.themedicinemaker.com 18  Feature

NEVOLINE UPSTREAM PLATFORM

An automated solution for intensified upstream viral manufacturing

Univercells Technologies

This integrated and automated upstream manufacturing platform is suitable for multiple viral applications, such as gene therapy and vaccine production. It enables intensified OMNITOP processing by chaining unit operations, SAMPLE TUBES such as culture, virus production, ADJUSTABLE clarification, concentration, VOLUME ORBITRAPORBITRAP dilution, and conditioning to deliver SAMPLING EEXPLORISXPLO RIS concentrated, clarified bulk product. SYSTEM (AVSS) 22404 0 MAMASSSS Single-use assemblies can be selected SSPECTROMETERPEC TRO METER to accommodate different process A single-use aseptic sampling configurations, enabling sequential, product for bioprocessing High-resolutionHigh-resolution mass continuous, or parallel processing for spectrometerttfdi for diverse time and footprint optimization. Avantor small- and large- molecule The NevoLine Upstream platform applications has been designed for rapid deployment Every drop is vital in cell and to overcome capacity and timeline gene therapy production, but Thermo Fisher Scientific constraints. At the core, the scale-X poor sampling methods can nitro structured fixed-bed bioreactor have a detrimental effect on the Orbitrap Exploris 240 further expands provides up to 600 m² of growth surface volume yield in any biopharma on the Orbitrap Exploris platform to for high viral productivity, making manufacturing process. Traditional provide mass accuracy, sensitivity, parallel processing at commercial- open process sampling methods, and resolving power for both small- scale possible in a 3 m² module. The which use an open bottle, conical and large-molecule applications, high capacity, low footprint platform is tube, or other container, can risk irrespective of complexity or dynamic controlled by a centralized automation contamination. The OmniTop range, while minimizing time-to- system with pre-defined process Sample Tubes AVSS standardizes results. The system uses the company’s recipes and in-line parameter control the sampling process and enables AcquireX intelligent data acquisition for batch-to-batch consistency. technicians to aseptically collect the workflow to enable automation, exact amount of media required for while positive/negative mode routine sampling – and it is suitable switching enables comprehensive for a variety of products, including sample coverage and fast scan speeds. mAbs, vaccines, gene therapies, Regardless of application or sample and cell therapies. When used as complexity, the system is designed to part of scale-up and commercial provide high-resolution accurate-mass manufacturing processes, it can mass spec data that can be trusted. potentially help minimize waste, Instrument setup is facilitated by reduce risk of contamination, and one-click calibration and ready-to-use increase end product yield. method templates. Feature  19

SERIALIZED PRODUCT INTELLIGENCE (SPI)

Cloud-based analytics application that uses serialization data to offer supply chain visibility

TraceLink

Built on TraceLink’s Opus Digital Network Platform, SPI allows companies to monitor, aggregate, and analyze serialization data, with a view to using that information to improve supply chains and on-time delivery of medicines. Users can examine the journey of each serial number to accelerate root cause analysis of internal and CMO operational issues, including reconciling all shipments and deliveries. It is also possible to compare operational events with regulatory reports to verify accuracy or to troubleshoot – and view compliance failures to drill down into root causes. Additional features include the ability to reconcile serial numbers and monitor commissioned lots. SPI can be deployed quickly within QX ONE DROPLET DIGITAL PCR existing TraceLink serialization SYSTEM systems. Finally, the ability to review messages and search audit trails are Multiplexed digital PCR system planned for a future release.

Bio-Rad Laboratories

Bio-Rad’s Droplet Digital PCR (ddPCR) technology can be used for the absolute quantification of target DNA and RNA via the generation and thermal cycling of thousands of nanoliter droplets. The QX ONE ddPCR system integrates the components of a standard ddPCR workflow, including droplet generation, thermal cycling, droplet reading, and analysis into one platform. The system features walk-away automation, reduced cost per sample, and the ability to optimize processes with a new multiplex supermix, and compatibility with existing supermixes. And, of course, it can be used with the company’s QX ONE software.

www.themedicinemaker.com 20  Feature

SMARTSMART COCONTAINERNTAINER

ContainersContainners laser-markedlaser-marked with data-matrix codeco to enenableable tratraceabilityceability and induindustrystry 4.0 standardsstanddards in fill-fill-and-finishand-finish

SchottSchoottt PhaPharmaceuticalrmaceutical SystemsSystems

A laser is used to melt a datadata-matrix-code-matrix onto the container thethe momomentment it is manufactumanufactured,re allowing each vial to be tracedtraced throughout the filfill-finish-processl- and beyond. The code withstands all followingfo fill-and-finish steps and thethe marking prprocessoce reduces particle contamination by avoidingavoiding additionaladditio substances for the application of the code.code. SmartSmart ContainerCo ensures each container is matched with thethe righti content, cap, label, and secondary packaging based on the data stored in the system, and the containers can also help automate reject management and line clearance by collecting line performance data of the entire fill-and-finish process. In particular, the containers are well suited for lyophilizationlyophilization as the data matrix allows the exact ppositionosition of each container to be tracked duriduringng freeze drying.drying. The data can then be used to “map”“map” the the prprocessocess to to find find specific defects. SOTERIARXSO

On-doseOn authentication technology that allows solidso dose medicines to be tracked from the manufacturerm to the patient

ColorconCo

SoteriaRxSot involves embedding micro tags into Colorcon’s OpadryOp film coatings. The taggants are undetectable to the human eye, but can be quickly authenticated by in- fieldfiel portable devices. Effectively, the pill, itself, becomes a bbarcode, meaning that authenticity can be confirmed by pharma companies – or patients – even without the productpro packaging. CounterfeitC drugs are a major problem. Traceability and securitysec measures focused only at the packaging level are not always enough to protect patients. Medicines made withwit on-dose taggants can be authenticated throughout the supplysup chain and are almost impossible for counterfeiters to replicate. The digitalization of medicines could be a majorma step forward in the fight against unauthorized and illegitimateille pharmaceutical production, and an opportunity for regulators and industry to safeguard patients and improveimp supply chain efficiency. VANQUISH CORE HIGH- PERFORMANCE LIQUID CHROMATOGRAPHY (HPLC) SYSTEM

High-performance liquid chromatography systems for routine pharmaceutical laboratories

Thermo Fisher Scientific VAYA RAMAN Pharmaceutical QA/QC testing laboratories are expected to Spatially offset handheld deliver precise and timely results. spectrometer for raw VIP LASER DRILL However, analytical scientists are materials ID verification + NIR often required to run methods on a diverse range of instrumentation, Agilent Technologies Tablet laser drilling machine which presents challenges, especially with near-infrared and vision when integrating new systems into Vaya is a handheld system that uses inspection for controlled- existing infrastructure. Vanquish spatially offset Raman spectroscopy release pharmaceutical Core HPLC Systems are suitable for for raw material identity verification products routine testing and quality control in pharmaceutical warehouses. The workflows, designed to deliver on-time technology can be used by non- Ackley Machine Corporation results, simplify method transfer, and spectroscopists to verify incoming integrate with leading chromatography solid and liquid raw materials – The VIP Laser Drill + NIR data system software platforms. through either transparent or non- incorporates near-infrared Downtime is also reduced via a transparent containers (including spectroscopy alongside precision solvent monitor (which automatically colored plastics, sacks, and amber CO2 laser drilling and vision tracks and determines mobile phase glass), with a simple ‘Pass/Fail’ answer. inspection for the production of consumption and waste accumulation There is no need for sampling and osmotic drugs. The machine uses to prevent the systems from running the rapid result means that testing is NIR inspection to verify a tablet’s dry or from waste overflowing) and reduced from days to hours compared enteric coating prior to laser drilling continuous background monitoring of with conventional identification sub-millimeter sized apertures into system health. solutions for raw materials. modified-release products to achieve Methods for new materials the desired dissolution rate and drug are developed via an intuitive release profile. Vision inspection wizard, with the user guided then confirms each aperture, while through material and container a patented fail-safe rejection system spectroscopic evaluation, method separates tablets with membrane development, and pharmacopeia- defects from those with drill defects based identification method for further analysis. validation. Method assessment and The system has an output rate of spectral advisor features also allow up to 60,000 products per hour, a users to develop robust methods by small footprint, multiple recipe strengthening and challenging the management, and quick removal method prior to deployment. change parts.

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C u t t i n g T h r o u g h t h e NOISE

LOOKING BACK ON 12 MONTHS OF COVID-19 RESEARCH

By Stephanie Sutton

There’s no sugarcoating it: COVID-19 has been a disaster. happening and to identify the most important research taking Almost 1.5 million global deaths, as of early December, 64.5 place. The task is complicated by media companies who pick million cases, and economies and livelihoods in tatters. Beyond and choose which science to report on. And when they do the direct toll, the disease has affected many other aspects of report on science, it may be skewed or overhyped. All of this health; for example, preventing patients from accessing elective adds to some serious online noise. How do you find out what surgeries or treatments for other diseases and conditions. really matters in the race to understand and fight COVID-19? Scientists have scrambled (and are still scrambling) to The COVID-19 Curator is run by my colleague, Michael understand more about coronaviruses and COVID-19 – and Schubert, Editor of The Pathologist – a sister publication to The if there is one good thing to come out of the pandemic, it’s Medicine Maker. Every week, the Texere Publishing editorial how it has inspired so much research and collaboration. The team sift through and share the latest research on COVID-19, pharmaceutical industry – viewed by some as a slow, lumbering leaving Michael, Rich Whitworth (Content Director of Texere behemoth – has demonstrated incredible speed, flexibility, and Publishing) and I to review and select the most novel or high determination. Vaccine development typically takes years, but, impact efforts. The output? The COVID-19 Curator – you can at the time of going to print, we are at the start of the first wave sign up for free: www.texerenewsletters.com/covid19newsletter of approvals after just ten (admittedly long) months. For this feature, I’ve gone back through 11 months of news The WHO has compiled a database of global literature on and our 36-issue strong archive to bring you a helicopter view COVID-19, which includes more than 30,000 papers. Such of our fight against COVID-19. In a nutshell: though we still a vast amount of scientific research – in such a short time have a long way to go, there are many reasons to feel positive – is incredible, but it can be hard to keep track of what is as we move into 2021!

www.themedicinemaker.com PART I: CHARTING PROGRESSESS OVER TIME

JANUARY FEBRUARY

Whole genome of WHO officially chooses the name “COVID-19” 2019-nCoV sequenced NIH begins clinical trial of remdesivir European Commission launches European Commission issues statement on EU response: request for research proposals for “According to the information provided by the national authorities, COVID-19OVID 19 there is a strong overall level of preparedness with countries having response measures in place to provide treatment for the cases in the EU and to mitigate any further transmission within and into the EU.” (https://bit.ly/3kElkIw)

JUNE

Eli Lilly launches trial of LY-CoV555 antibody isolated from blood of COVID-19 patient Systematic review and meta-analysis of all available evidence highlights benefits of physical distancing, masks, and eye protection in community and healthcare settings (https://bit.ly/38RA3hk) FDA revokes authorization for chloroquine and hydroxychloroquine UK government authorizes dexamethasone Gilead’s Phase III remdesivir trial shows that hospitalized patients in the five-day remdesivir group are 65% more likely to show clinical improvement by day 11 than those receiving standard care

JULY

Commentary emphasizes benefits of voluntary human infection models for COVID-19 – with strict controls in place – and offers practical considerations (https://bit.ly/2IO4A4n) Remdesivir receives conditional marketing approval from EMA Japan approves dexamethasone EMA says it will review study results on dexamethasone Pfizer and BioNTech select lead mRNA vaccine candidate – after studying four opoptionstions

DECEMBER NOVEMBER

UK MHRA grants temporary Regeneron told to modify trial of REGN-COV2 authorization to Pfizer/BioNTech FDA issues EUA for Eli Lilly’s bamlanivimab vaccine Pfizer and BioNTech claim vaccine efficacy is 95% Moderna says efficacy of mRNA-1273 is 94.5% Interim data of Sputnik V suggests 92% efficacy; later increased to 95% efficacy GSK and Medicago commence phase II/III study of CoVLP vaccine Synairgen’s inhaled formulation of Interferon-beta-1a, SNG001, passes small phase II study AstraZeneca’s Calquence (acalabrutinib) fails phase II trial AstraZeneca and the University of Oxford announce interim results for vaccine; efficacy is up to 90% Feature 27

MARCHH APRIL

The WHO declared COVID-19 a pandemic Early results from Gilead receives orphan drug designation for remdesivir in the US different studies suggest Phase I study of Moderna’s mRNA vaccine mRNA-1273 begins hydroxychloroquine, lopinavir/ Pfizer and BionTech announce co-development partnership for mRNA vaccines ritonoavir, and umifenovir are all FDA issues Emergency Use Authorization for hydroxychloroquine ineffective at treating COVID-19 FDA criticized for treating COVID-19 as a rare disease (https://bit.ly/2Helkla) (https://bit.ly/2H8RluJ); Gilead withdraws orphan drug designation European Commission By end of March, FDA had granted 20 EUAs for COVID-19 tests calls for partners to join Exscalate4Cov project, which will use supercomputers to screen databases of active molecules MAY Gilead highlights promising results from phase III FDA issues Emergency Use Authorization for remdesivir remdesivir trial Japan approves remdesivir AstraZeneca and the University Operation Warp Speed announced in US of Oxford announce agreement FDA grants fast track designation to Moderna’s mRNA-1273 for vaccine ChAdOx1 nCoV-19 WHO and Costa Rica launch Technology Access Pool (AZD 1222) FDA research team review all clinical and research findings to date and compile key immunological events that existing drugs could target (https://bit.ly/2IM8bjZ)

AUGUST SEPTEMBER

FDA issues EUA for convalescent plasma EMA endorses use of for hospitalized COVID-19 patients dexamethasone Russia approves Sputnik V vaccine Regeneron’s experimental drug Gilead submits NDA to FDA for remdesivir REGN-COV2 added to UK’s Gavi, CEPI and WHO launch RECOVERY trial COVAX initiative Trial of Fujifilm’s approved Corona Accelerated R&D in Europe Avigan anti-influenza tablets meet consortium launched primary endpoint

OCTOBER

Sanofi and GSK commence phase I/II trial of adjuvanted recombinant protein vaccine Clinical trials for Eli Lilly’s Ly-CoV555 treatment and J&J’s JNJ-78436735 vaccine paused due to safety concerns Remdesivir, hydroxychloroquine, lopinavir/ritonavir, and interferon found to have little or no effect on overall mortality, need for ventilation, and hospital stay duration in WHO Solidarity Trial FDA approves remdesivir Results from phase I/II trial of Sinopharm’s BBIBP-CorV vaccine suggest it is safe and well tolerated PLACID trial in India shows convalescent plasma ineffective in preventing progression to severe COVID-19 or all- cause mortality (https://bit.ly/3kzuhTL) 28 Feature

P A R T I I : FRONTRUNNING VACCINES

P F I Z E R A N D MODERNA A S T R A Z E N E C A BIONTECH AND THE Candidate: mRNA-1273 UNIVERSITY Candidate: BNT162b2 Type: mRNA vaccine OF OXFORD,UK Type: mRNA vaccine Notes: Candidate: ChAdOx1 nCoV-19 (AZD1222) Notes: • Can be stored at 2-8 °C for 30 days Type: adenovirus vector vaccine • Requires two doses • Shipping and long-term storage • Vaccine must be stored at around require temperatures of -20 °C Notes: -70 °C • No dilution or special handling • Expected to require storage around • Companies expect to produce up to required at vaccination site 2-8 °C 50 million vaccine doses globally • Developed in collaboration with • EMA has commenced rolling in 2020 and up to 1.3 billion doses NIH and BARDA review of the vaccine in 2021 • Trial was suspended in September • Companies originally investigated Primary efficacy analysis of the but resumed quickly four vaccine candidates before phase III COVE study of the selecting BNT162b2 vaccine involved 30,000 participants This vaccine is expected to be cheaper and 196 cases of COVID-19 – of and easier to distribute than the Pfizer Vaccine has demonstrated efficacy of 95 which 30 cases were severe. Vaccine or Moderna mRNA vaccines. However, percent in a phase III study. The study efficacy against COVID-19 was questions have been asked about the enrolled over 43,000 participants. 170 94.1 percent and 100 percent against vaccine’s efficacy. A report from the trial confirmed cases of COVID-19 were severe COVID-19. FDA has told the seems to suggest overall efficacy of 70 evaluated; 162 cases in the placebo company that a meeting is expected percent, a lower efficacy of 62 percent, group versus 8 in the vaccine group. around December 17 to discuss the and a high of 90 percent. During the The vaccine was approved for use in the regulatory submission for an EUA. trial, some participants received 1.5 UK in early December. doses in error, which seems to correlate with the higher efficacy. Regulators were informed of the error and agreed that the trial could proceed.

A D D I T I O N A L K E Y CONTENDERS: Sanofi and GlaxoSmithKline: phase I/II trial of adjuvanted recombinant protein-based vaccine commenced in October Janssen: JNJ-78436725 (also known as Ad26.COV2.S) is a single dose adenovirus vector vaccine based on the same GSK and Medicago: phase II/III study commencing of CoVLP, technology (AdVac) used in Janssen’s Ebola vaccine, and which is composed of recombinant spike glycoprotein expressed investigational HIV, RSV, and Zika vaccine candidates. A as virus-like particles phase III trial is underway. Sinovac: inactivated vaccine undergoing phase I/II trials; Novavax: NVXCoV2373 nanoparticle vaccine has commenced recent death in trial not attributed to vaccine phase III and been granted FDA Fast Track designation Gamaleya Research Institute of Epidemiology and Microbiology: Sanofi and Translate Bio: mRNA vaccine induced high antibody Sputnik 5 is already approved for distribution in Russia; Russia levels in preclinical studies says vaccine has 92% efficacy PART III: KEY RESEARCH FINDINGS including chronic Our understanding of COVID-19 continues to evolve, but kidney disease, scientific ping-pong has been a key theme – with significant which triples risk, as back and forth and contradictory findings in several areas. well as cancer, diabetes, heart conditions, and hypertension, COMPLICATED KIDS all of which show significant effects. Early on, it was suggested that children are less vulnerable Surprisingly, a study showed that asthma to the effects of COVID-19. However, scientists soon learnt sufferers’ risk of severe disease or death from that children may present with different symptoms, show COVID-19 is not increased compared with the characteristic imaging findings, and must be included in clinical general population. trials for the disease. Researchers have also claimed that children Five biomarkers – IL-6, D-dimer, CRP, LDH, and actually carry a high viral load and can transmit the disease with ferritin – may predict which COVID-19 patients are at great efficiency – which is why there have been calls for high- higher risk of severe disease. Elevated levels are associated with quality testing and tracing for schools. Asymptomatic SARS- ICU admission, ventilation, and death. Tests have also been CoV-2 may be particularly prevalent in children. It is generally developed that offer insight into which patients are most likely accepted that children tend to get COVID-19 less often than to suffer severe disease or death from COVID-19. Airway cell adults and have less severe symptoms. However, children infected immune analysis can identify patients at higher risk of severe with SARS-CoV-2 can experience catastrophic inflammation disease, whereas red cell distribution width is highly correlated – and it may be possible for them to sustain significant heart with mortality. damage. Discussions around exactly how susceptible children are to COVID-19 continue to take place. THE DRUGS DON’T WORK? LONGEVITY OF Hydroxychloroquine received early attention and emergency IMMUNITY use authorization from the FDA – which was revoked in June. Studies seem divided on the longevity of antibody-based However, some scientists continued to believe that the potential immunity to COVID-19, with some new studies revealing of hydroxychloroquine was still worth exploring. In November, that robust neutralizing antibodies persist for months. For further studies emerged showing that hydroxychloroquine example, a survey of almost 6,000 patients finds SARS-CoV-2 does not benefit adults hospitalized with COVID-19. In a antibodies persist for at least five months, suggesting possibility statement, James P. Kiley, director, Division of Lung Diseases of lasting immunity after infection. Other studies, however, at the US National Heart, Lung, and Blood Institute, said, have shown significant drops in population antibody positivity. “We hope this clear result will help practitioners make But the outlook is bright for T cell immunity – with researchers informed treatment decisions and researchers continue their showing long-lasting SARS-CoV-2-specific T cell immunity efforts pursuing other possible safe and effective treatments in recovered SARS and COVID-19 patients, and uninfected for patients suffering with this disease.” individuals. It is possible for a recovered COVID-19 patient to Although the case seems closed for hydroxychloroquine, be reinfected, but this area is not yet well understood. what about remdesivir? Remdesivir also received significant Would herd immunity ever be possible? Research into attention early on – and approval in around 50 countries. transmission dynamics suggests that a herd immunity Gilead has claimed that the trials have proceeded well, showing strategy for COVID-19 management requires extremely benefit in hospitalized COVID-19 patients compared with sensitive and responsive fine-tuning, rendering it impractical placebo and standard treatment, and reducing mortality by 70 for real-world situations. percent in patients on low-flow oxygen. And yet the WHO’s SOLIDARITY trial found that remdesivir, as well as several RISK FACTORS other treatment options, had little or no effect on overall By linking routine health data to records of severely ill patients, mortality, need for ventilation, and hospital stay duration. researchers have sought to quantify clinical risk factors linked to Gilead has described the SOLIDARITY data as “inconsistent.” death from COVID-19. A meta-analysis revealed pre-existing conditions that may increase risk of COVID-19 mortality, See references and further reading online at tmm.txp.to/1220/covid19

www.themedicinemaker.comwww.themedic THE PANDEMIC DIARIES

Stephanie Sutton, Editor of Rich Whitworth, Content Director of As 2020 draws to a close with The Medicine Maker and “a curator” Texere Publishing and “a curator” on The positive news of vaccines with (almost on The COVID-19 Curator COVID-19 Curator unbelievably!) high efficacy – for many a light at the end of a very long, dark, and At the start of 2020, I was naïve about SARS-CoV-2 – or rather its devastating unsettling tunnel, I look forward to an what COVID-19 really meant. This direct and indirect effects – certainly even slightly more normal 2021. isn’t the first time I’ve written about a never crossed my worried mind in 2019 pandemic. Back in 2005/2006, there were (despite subconsciously knowing that Michael Schubert, Editor of The Pathologist fears about H5N1 and significant media the risk was always there; if SARS and and “The Curator” of The COVID-19 Curator attention, but the pandemic (thankfully) MERS weren’t warning shots across the never materialized. bow, I don’t know what were). In the spring of 2020, I was engaged And then in 2009 came swine flu. I Welcoming my daughter into the in online science outreach (somewhat remember reporting on the deaths and world in the year 2020 (hello, Mirajane!) presciently, as it turned out!). I hosted cases in a weekly newsletter that I was has not been easy. Explaining to my regular science chats with school-aged responsible for at the time. The numbers three-year-old son (hello, Gray!) why children, fielding questions on everything were high, but the situation never felt out he could not see “Grandma Buttons” or from “how can a spider bite give you of control. A bottle of communal hand play with friends has not been easy. But, superpowers?” to “how can we cure cancer?” sanitizer appeared in the office – but most of course, I fully recognize the triviality As March rolled on, though, the people didn’t use it. of such personal struggles when viewed questions changed. “What is the When COVID-19 began to appear in in full COVID-19 context. At the pandemic?” “Do we have a cure for the headlines, I wrongly assumed it was another same time, I think it is important to coronavirus?” “Can people die from the flu we’d weather through. Even people remember that – COVID-19 or not – coronavirus?” Tough questions to answer directly involved in the pharma industry did certain populations around the world for any crowd – let alone schoolchildren. not appreciate the severity of COVID-19 in are in a continual battle against deadly And the answers to those questions January. One anonymous individual I spoke (though sometimes preventable or changed, too. Initially, there was a lot with explained that someone had mentioned curable) diseases. Perspective can be a of reassurance. The phrase “like a bad COVID-19 at a briefing in January – not powerful tool. cold or a flu” made frequent appearances. because they felt it was dangerous, but just Being part of the team behind The Unfortunately, for nearly 1.5 million as a “point of interest”. COVID-19 Curator has not only people, COVID-19 was far worse than For me, the biggest shock was how quickly kept me abreast of the breakthroughs, any cold or flu they had ever encountered. the situation escalated. At the start of March, the big questions, and the failures (all And that’s just the death toll; our ability I attended a fitting for my wedding dress – important) – it has also kept me sane. to track and count those who suffer long- frankly without a care in the world. A few I’ve marveled at the speed of science and term consequences lags far behind. days later, Italy went into lockdown. Two how it collides with clumsy politics. I This is the “new normal” – a world in weeks later, the UK followed suit. would have been amused by the regular which we stay indoors, wear masks when Fortunately, scientific progress has been “ping pong” (as Steph like to call it) had we venture beyond our thresholds, wash staggering – despite the aforementioned it not been over such serious matters. and sanitize our hands every time we touch concerns, controversies, and questions. It And I’ve been utterly impressed by the something unfamiliar, and anxiously track is incredible to think that we already have seemingly unending sense of collective reports on vaccine candidates. results from three highly promising vaccine determination. When one well of hope Will a vaccine change the world? candidates – and even approval in the UK. ran dry, researchers in industry and Undoubtedly. Will we return to our “old But given that vaccine development typically academia had dug three more. normal?” Only time will tell – but the takes many years, it’s understandable that It’s hard to talk about silver linings when tremendous efforts of scientific, medical, many people both inside and outside faced with such a high and increasing and pharmaceutical professionals globally of the industry may experience vaccine death toll. But I welcome the growing have not gone unnoticed. As results and hesitancy. Vaccine take up needs to be high understanding that we need adequate regulatory approvals roll in, we’ll slowly see to stall COVID-19 – so the industry has resources (funding) to tackle global the world to come take shape – but it can a responsibility to reassure everyone that problems. I also welcome the broadening only happen with appropriate oversight, speed has not compromised safety or quality acceptance that any solutions to this global open conversation, and a culture of shared standards. problem must be accessible to all. scientific success. PART IV: RESEARCH CONCERNS

INSUFFICIENT TRIALS Early on in the pandemic, the EMA raised concerns about the number of stand-alone COVID-19 trials with few participants – This lack of sustained and called for resources to be pooled into larger, multi-arm trials. research prevents us from There have also been concerns about whether clinical understanding and responding trials for COVID-19 vaccines and treatments are suitably rapidly to new outbreaks such as incorporating volunteers from diverse ethnic and age groups. COVID-19. Independent of the outcome Some researchers say that remdesivir studies have failed to of the current outbreak, measures should be provide equal representation (1); others have reported that taken to encourage sustained research in the field. older adults are in danger of being excluded from around 50 Meanwhile, an analysis of COVID-19 publications percent of COVID-19 treatment clinical trials and 100 percent has shown that basic microbiological research on SARS- of vaccine trials (2). CoV-2 is lacking (7). Though perhaps understandable during a pandemic, this relative lack of lab-based studies is unique MOVING TOO FAST in research of other coronaviruses. Although the speed of action against COVID-19 is to be admired, questions have been posed: how could moving too POLITICS AT PLAY fast prove harmful? For example, Douglas R. Green wrote an An opinion piece has also proposed FDA reforms to improve editorial in Science Advances, warning against speedy vaccine Emergency Use Authorization and drug approval processes development at the expense of safety, highlighting evidence in light of recent problems and controversies surrounding for potential ADE in SARS-CoV-2 (3). hydroxychloroquine, which had emergency approval revoked Writing for the BMJ, Katrina Bramstedt raised concerns only a few months after issue (8). about substandard research (4): “No research team is exempt More controversy surrounded the FDA’s approval of from the pressures and speed at which COVID-19 research remdesivir, with scientists raising concerns that the drug is occurring. And this can increase the risk of honest error as may be ineffective and questioning why the FDA did not well as misconduct. To date, 33 papers have been identified consult external experts before issuing the approval. Some have as unsuitable for public use and either retracted, withdrawn, suggested the approval may have been politically motivated (9). or noted with concern.” In another BMJ article, Els Torreele explained how rapid References vaccine development may lead to substandard first efforts that 1. DB Chastain et al., NEJM, 383:e59 (2020). DOI: 10.1056/ harm health, undermine public confidence in science, and NEJMp2021971 squander financial resources that could otherwise be used 2. The Medicine Maker, “Don’t Exclude the Aged,” (2020). Available at to produce genuinely effective products (5). “By setting the https://bit.ly/3mBPtKm performance bar far lower in COVID-19 vaccine development 3. DR Green, Science Advances (2020). DOI: 10.1126/Sciadv.abc7428 than what would otherwise be acceptable for a new vaccine, we 4. KA Bramstedt, Journal of Medical Ethics, 46 (2020). DOI: 10.1136/ are also unwittingly redefining the very concept of a vaccine medethics-2020-106494 – from a long-term effective preventive public health tool to 5. E Torreele, TheBMJOpinion, “The rush to create a covid-19 vaccine may do what could amount to a population-wide suboptimal chronic more harm than good,” (2020. Available at https://bit.ly/33DE4lM treatment.” 6. D Kagan, J Moran-Gilad, M Fire, Giga in Science, 9 (2020). DOI: 10.1093/gigascience/giaa085 SUSTAINING 7. A Doanvo et al., Patterns (2020). DOI: 10.1016/j.patter.2020.100123 RESEARCH 8. K Thomson, H Nachlis, JAMA, 324 (2020). DOI: 10.1001/ According to Dima Kagen, Jacob Moran-Gilad, and Michael jama.2020.16253 Fire, research volumes tend to skyrocket after a coronavirus 9. Science, “The ‘very, very bad look’ of remdesivir, the first FDA-approved outbreak, but then drop precipitously after containment (6). COVID-19 drug,” (2020). Available at https://bit.ly/33DEM2q

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Up to the Challenge As bioprocess technologies advance and drug markets evolve, new issues continually arise. How can manufacturers avoid the headaches? Ma Sha and Kamal Rashid (www.cbetalbany.com) Developing a new bioprocess is rarely straightforward – and optimizing an existing acid depletion. Similarly, manufacturers He also says that cutting corners in bioprocess is often no easier. And so it should optimize impeller RPM and heat equipment selection could result in significant helps when manufacturers can work with transfer consistency throughout the negative impacts. To avoid expensive instrumentation suppliers who are familiar reactor volume; remember that each instrumentation mistakes, ask vendors for with the problems they face; indeed, the cell line responds differently to mixing, data demonstrating the suitability of their shared understanding can benefit both aeration, and oxygen mass transfer. And to equipment for your process. “The best parties. But what kind of challenges does fully capture upstream yield improvements, companies will have data from both in- the industry face, and how should they consider investing in advanced downstream house research and independent studies,” be addressed? Kamal Rashid (Founding process instrumentation; after all, legacy says Rashid, before citing Eppendorf as an Director, Center for Biopharmaceutical systems are often inefficient. Finally, exemplar. “Their scientists are rigorous Education & Training CBET, Albany College maintain strict controls throughout the – they follow the data wherever it leads of Pharmacy & Health Sciences, USA) and process to avoid contamination-related them.” Being data-driven has enabled Ma Sha (Head of Bioprocess Applications, batch failures. Meeting all these demands? Eppendorf to continuously improve its Eppendorf, USA) are well-positioned to Well, says Rashid, that also requires key technology portfolio, to the great benefit answer these questions. personnel to be regularly re-trained. of the biomanufacturing industry. How do Eppendorf’s scientists see things? The fundamentals The new hurdles Yield maximization, says Rashid, is an The plethora of new products entering The Eppendorf way enduring challenge. “Yield is a function development, including bi-specific Sha agrees with Rashid’s analysis, and of cell viability and productivity – its antibodies, antibody fragments, and describes how “data-driven rigor” is part maximization requires both excellent antibody drug conjugates, bring their of Eppendorf’s culture. “From its inception, cloning technique and optimized media.” own specific scale-up challenges; Eppendorf Bioprocess Applications has Top tips include establishing where in for example, bi-specific antibody reacted to the evolving needs of industry the cell cycle the product is expressed manufacture is complicated by difficulties by developing advanced expertise and (G1 or G2), as it may be possible to in the reproducible production of heavy novel applications. When customers asked elongate the relevant phase – even a 1–2 and light chains, Rashid noted. More us to demonstrate antibody production hour extension can appreciably increase fundamentally, the entire sector is being in addition to cell expansion, we brought productivity. Rashid also emphasizes the affected by COVID-19; as Rashid says: in a biosimilar CHO cell line, valued at importance of understanding the entire “The industry must now develop the $300,000, with high hmAb expression process, from cell-line design onwards. capability to rapidly produce stockpiles yield and standardized our CHO cell “Don’t design your process on the basis of vaccines and antiviral drugs.” A feat applications to include hmAb production.” of unverified assumptions – every cell that will require exploitation of advanced Today, for every new product, Eppendorf line is different,” says Rashid. Accordingly, instrumentation. “Getting this provides a corresponding CHO Rashid advises monitoring and optimizing wrong could cause costly cell bioreactor application reactor conditions with regard to key batch failures and limit note; examples include CHO metabolic pathways, and assessing the supply for patients,” fed-batch culture for the productivity consequences of any amino says Rashid. new SciVario twin Monoclonal Antibody Production QEWW XVERWJIV GSIJ½GMIRXW /LE  ERH maintaining constant P/V scale-up – which controllercontroller and ttheh is to say, maintaining constant impeller Methods (3) ',3GYPXYVI[SVO¾S[',3GYPXYVI[SVO¾ TS[IVTIVYRMXZSPYQI 4: ²3RXLEX scale-up applicationapplication note latter point, Eppendorf has now published • &EXGL JSVXLIJSVXLGSQMRK&MS*PS4MPSX7GEPIJSVXLIJSVXLGSQMRK&MS*PS4MPS multiple applications dealing with constant • %PPRYXVMIRXWWYTTPMIHMR 7MRKPI9WI&MSVIEGXSV 79& GSRXVSPPIV P/V scale-up and released many vessel initial base medium 7LEEPWSIQTLEWM^IWXLIX[S[E]¾S[SJ TS[IVRYQFIVW ZEPYIWVIUYMVIH[LIR • Lower productivity information, recognizing that Eppendorf’s HIZIPSTMRKWGEPIYTTVSGIWWIW  • *IHFEXGL success is partly due to its ability to learn %RHXLIMRHYWXV][MPPWSSRFIRI½XJVSQ • Nutrients are added to from the customer. “Our collaboration )TTIRHSVJ´WRI[GSRXVSPPIV&MS*PS  in-process medium, to with customers who were ahead of MXW±7GEPIYT%WWMWX²JIEXYVIYWIWEFYMPX avoid depletion XLIGYVZIMRQMGVSGEVVMIVERH*MFVE in constant P/V algorithm to automatically • ,MKLIVTVSHYGXMZMX] cel® packed-bed Vero cell culture for calculate agitation and gassing set-points • 4IVJYWMSR vaccine production resulted in vaccine- RIIHIHJSVGSRWXERXQ%F]MIPHMRHMJJIVIRX • *VIWLQIHMYQMW related Vero cell application notes – ZIWWIPWM^IW6IQEVOEFP]XLI&MS*PS continuously circulated and industry-wide dissemination of this [MPPEPWSTVSZMHI7GEPIYT%WWMWXJSVRSR through growing culture, RI[I\TIVXMWI  ² Eppendorf bioreactors. “It’s just another allowing simultaneous But Eppendorf’s determination to FIRI½XJSVSYVGYWXSQIVW²WE]W7LE removal of waste, supply of solve customer problems goes much ±%PSRK[MXLSYVETTPMGEXMSRRSXIWSYV nutrients, and harvesting further than producing application notes. system makes it simple to maintain cell of product. “Customers developing cell therapies KVS[XLTVS½PIWERHERXMFSH]TVSHYGXMSR • ,MKLIWXTVSHYGXMZMX] needed products for stem cell cultivation,” yields, all the way from 3 L bench scale to says Sha. “So Eppendorf developed 0TMPSXWGEPI² ±4IVJYWMSRKMZIWLMKLIVQ%F]MIPHWXLER stirred-tank bioreactor applications for FEXGLSVJIHFEXGLFYXWEGVM½GIWXLI large volume stem cell culture.” Similarly, Closing remarks simplicity desired in a manufacturing customers’ pursuit of exosome therapy “Process optimization at bench, pilot, environment.” – Ma Sha led to Eppendorf’s development of a new and production scale is critical for stem cell application note for exosome biomanufacturing success and requires production – and customer interest in EHZERGIHMRWXVYQIRXEXMSR²WE]W6EWLMH EPXIVREXMZIWXS',3GIPPFEWIHERXMFSH] But adoption of novel technology can production resulted in Eppendorf itself pose challenges for manufacturers; HIZIPSTMRKXLI½VWXFMSVIEGXSVJSVMRWMXY vendor support is therefore critical. References Pichia-based production of full-length, *SVXYREXIP])TTIRHSVJ&MSTVSGIWWMWRSX 1. <,ERERH17LE±,MKL(IRWMX]:IVS'IPP LYQER ERXMFSH] *G [MXL LYQERM^IH just another bioreactor manufacturer; it 4IVJYWMSR'YPXYVIMR&MS&09®T7MRKPI9WI glycosylation. “When customers SJJIVWGYWXSQIVWRSXSRP]XLIFIRI½XSJ :IWWIPW²)TTIRHSVJ%TTPMGEXMSR2SXI started exploring Pichia-based human over one hundred application notes and  %ZEMPEFPIEXLXXTWXIVPMITTIRHSVJ antibody production as a potential future industry publications, but also the problem- ETTPMGEXMSRRSXI VITPEGIQIRXSJ',3TPEXJSVQ[I[IVI solving capabilities of two bioprocess 2. 1(SVGIYWIXEP±'SQTEVMRK'YPXYVI right there with them,” says Sha. application labs with PhD-level expertise. 1IXLSHWMR1SRSGPSREP%RXMFSH]4VSHYGXMSR It is perhaps unsurprising then that the -RWLSVXGYWXSQIVWIVZMGIVIQEMRW½VWX &EXGL*IH&EXGLERH4IVJYWMSR²&MS4VSGIWW industry frequently asks Sha’s team for ERHJSVIQSWXMR)TTIRHSVJ´WGYPXYVI%RH -RXRP  %ZEMPEFPIEXLXXTWFMX EWWMWXERGI[MXLTVSHYGXMSRTVSFPIQW% Sha invites all interested parties to contact P]QN/(OR GSQQSRMWWYI7LEWE]WMW',3GYPXYVI )TTIRHSVJVIKEVHMRKXSXLIMVWTIGM½GRIIHW  <,ERERH17LE±)EW]4IVJYWMSRSJ scale-up, where it is critical to maintain “Eppendorf Bioprocess strives to become %RGLSVEKIHITIRHIRX'IPP'YPXYVIYWMRKER XLI GIPP KVS[XL TVS½PIW ERH ERXMFSH] the expert partner of choice in antibody )TTIRHSVJ:IWWIPIUYMTTIH[MXLTIRHSVJ:IWWIPIUYMTTIH[MXL yields achieved at bench scale. “Strategies production, vaccine, and stem cecellll cuculturelture 1MGVSGEVVMIV7TMR*MPXIV²)TTIRHSVJ1MGVSGEVVMIV7TMR*MPXIV²)TTIRHSVJ include keeping tip speed constant across markets and we are determinedermined to meemeett %TTPMGEXMSR2SXI  %ZEMPEFPIEX%TT%T%TTTPMGP EXMSR2SXI  %%ZEME PEFP PIEX bioreactors, matching oxygen volumetric customer needs at the highestghest level.level.”” LXXTWXIVPMWTMR½PXIVERLXLXXLXXXTTWXIVPMWTMR½PXIVER

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36-3936-39 ExtractingExtracting Sense FroFromm E&LE&L Science MarkMark JJordiordi of Jordi LaLabsbs gives the lowdownlowdown on EE&L&L sciscience,ence, incincludingluding newnew guidancesguidances rereleasedleased in 2020 aandnd whatwhat to dodo ifif youyou findfind ununknownsknowns thatthat cannotcannot bbee iidentifieddentified 36 Best Practice

changes in the landscape of available Chapters under revision include Extracting guidance. A partial list of the current US USP <661>, <661.1>, <661.2>, <1661> Pharmacopeia (USP) chapters that provide – December 1, 2025 is the scheduled Sense From E&L guidance include: implementation date for these revisions. Though the USP chapters provide E&L Science • <87> Biological Reactivity Tests, significant guidance, other sources of in Vitro guidance also exist, such as the Product Mark Jordi, President of Jordi • <88> Biological Reactivity Tests, Quality Research Institute (PQRI) Labs, discusses the latest in in Vivo recommendations on orally inhaled and extractables and leachables • <381> Elastomeric Closure for nasal drug products (OINDP): “Safety science, including changes in Injections Threshold and Best Practices for Extractables the regulatory landscape and • <232> Elemental Impurities - Limits and Leachables in Orally Inhaled and Nasal recent advances in methods • <233> Elemental Impurities - Drug Products.” PQRI is also working on for the identification and Procedures another document specific to parenteral and quantitation of leachables • <661> Plastic Packaging Systems and ophthalmic drug products. Their Materials of Construction Meanwhile, the BioPhorum Operation Give us the quick lowdown on E&L… • <661.1> Plastic Materials of Group (BPOG) has published a revised Leachables are substances that come Construction document this year entitled “Extractables from – or “leach” out of – pharmaceutical • <661.2> Plastic Packaging Systems Testing of Polymeric Single-use Components packaging or manufacturing components for Pharmaceutical Use used in Biopharmaceutical Manufacturing,” and enter the drug product, resulting in • <1031> The Biocompatibility of which streamlines their testing patient exposure. Leachables can also Materials Used in Drug Containers, recommendations. There is also ISO 18562, stem from medical devices and transfer Medical Devices and Implants “Biocompatibility evaluation of breathing to the patient through contact with • <1661> Evaluation of Plastic gas pathways in healthcare applications,” and the medical device, either directly or Packaging Systems for ICH has provided guidance applicable to indirectly. Extractables are substances that Pharmaceutical Use ad Their E&L as a part of Q3C Residual Solvents are observed to extract under laboratory Materials of Construction and Q3D: Elemental Impurities. In July conditions. Put another way, extractables • <1663> Assessment of Extractables 2020, ICH also released a concept paper are the components that may come out of Associated with Pharmaceutical describing a new proposed guidance, Q3E, a medical product, while leachables are Packaging/Delivery Systems entitled “Guideline for Extractables and compounds that do come out. • <1664> Assessment of Drug Leachables (E&L)” (2). This discussion has E&L analysis for drug products is required Product Leachables Associated with not included the EU guidance documents, by regulators, including the FDA: Pharmaceutical Packaging/Delivery but I think it’s clear that the guidance for “Drug product containers and Systems E&L of pharmaceutical products is rich and closures shall not be reactive, continues to expand. additive, or absorptive so as Two additional USP In my opinion, the biggest news this to alter the safety, identity, chapters are also in year for E&L was the release of the much- strength, quality or purity development: <665> Plastic anticipated ISO 10993-18:2020 medical of the drug beyond the Materials, Components, device guidance, which became an FDA official or established and Systems Used in recognized consensus standard. This requirements”(1). The goal the Manufacturing of document provides a much greater degree of E&L analysis is to protect Pharmaceutical Drug Products of clarity surrounding best practices for patient safety and support drug and Biopharmaceutical Drug E&L analysis of medical devices. and device manufacturers by identifying Substances and Products, and <1665> The document begins with a general toxic leachables before they reach the patient. Characterization of Plastic Materials, description of the chemical characterization Components and Systems Used in the process. It then details the role and methods What guidance exists for E&L analyses? Manufacturing of Pharmaceutical Drug for obtaining information on the materials 2020 has been an exciting year in the world Products and Biopharmaceutical Drug of construction, and for conducting of E&L analysis because of significant Substances and Products. compositional profiling as a starting point Best Practice 37

for E&L analysis. The document then provides an overview of the E&L process, with guidance for assessing worst-case chemical release, establishing the analytical evaluation threshold (AET), and estimating chemical release using extractables studies and determining the actual release by subsequent leachables assessments. The next significant section provides recommendations for the chemical characterization process, including selection of analytical techniques, the role of structural composition analysis, analytical methods and their qualification, and even reporting practices. It is then further supplemented with no less than seven A thorough understanding of the product importance of information about the annexes, providing an in-depth discussion should include information on each of the materials of construction, it would be on topics ranging from general principles materials of construction, such as the identities natural to conclude that E&L analysis is of chemical characterization, extraction of each polymer and its additives package. essentially a targeted exercise; that is to say, theory, qualification of analytical methods, This should also include the proportion of the process could be reduced to analyzing a and calculation of the analytical evaluation each material and its physical state (surface targeted list of expected extractables to see threshold (AET). This document also area and topography), along with the which ones actually leach from the product. includes a great series of flow charts geometric distribution of the materials in the However, there is a problem with this idea. summarizing the chemical characterization finished article. Information on any expected The history of recalls due to toxic leachables process. It is by far the most comprehensive processing residues is also helpful, and the does not support the contention that all guidance for medical devices to date. potential effects of sterilization should also be leachables are predictable. Consider for considered. Finally, it is advisable to consider instance the Eprex recall due to unexpected Can you tell us more about the if any of the materials of construction are dialkylphenol disulfide compounds importance of understanding “materials likely to have constituents from the cohort from rubber stoppers (4). Though these of construction?” of concern (3). Given the importance of this compounds were related to a known Actually, the first step in conducting a information for informing an E&L study, it constituent, the nature of these degradation proper E&L analysis is the determination begs the question: how is this information products was not anticipated. Alternatively, of the materials of construction and product determined? The supplier is generally the consider the recall of breast implants due configuration. This information is essential primary source for information about the to tainted industrial grade silicones with for several reasons. First, it establishes the materials of construction, but in cases where unexpected impurities (5). These examples theoretical worst-case chemical release; the supplier is either unable or unwilling show that in many cases harmful leachables in other words, which configuration to provide comprehensive information that lead to recalls (and hence, true safety of the product will release the most then compositional testing is the next concerns) are not adequately predictable leachables. Second, it informs all of the best alternative. based on the expected chemistry of the data interpretation that will occur in any medical product under study. subsequent E&L studies. Over many years Should leachables and extractables The detection phase of an E&L analysis of practicing E&L analysis – and seeing analysis be a targeted or untargeted is intrinsically a screening process. Is many thousands of extractable compounds screening exercise? this screening for known or unknown – I’ve found that most extractables and The process of extractables and leachables components? I would submit that the leachables can be logically related to one of analysis can be broadly summarized true answer is both. Proper practice of the materials of construction. For this reason, in three steps: detection (determining E&L screening includes both targeted it is important that the chemists interpreting which compounds are above the AET), and untargeted analyses. It should begin E&L data have a clear picture of the material identification, and quantification. Based with a review of material chemistry and composition and configuration. on the above discussion regarding the consideration of what extractables are

www.themedicinemaker.com 38 BestBest PPracticeraccttice

signal is not observed in the initial LC-MS screening, it does not mean that identification by mass spectrometry is impossible. The use of high sensitivity QTOF instruments provide a greater opportunity to detect poorly ionizable species, while obtaining high mass accuracy and fragmentation data. This data is well suited to the task of identification. Our laboratories use both GC-QTOF-MS and LC-QTOF-MS (Agilent Technologies) instruments for this purpose. It is also often true that a compound not initially detected by MS can still be successfully analyzed using a more likely to be observed. If the material review presence of chromophores, and non- concentrated extract or an alternative means indicates the potential for toxic leachables volatility). This method is paired with the of ionization. For instance, if electrospray then a targeted approach is highly advisable. use of a dual detection gas chromatography ionization was used in the initial analysis, However, if no specific safety concerns are (GC) system to aid in detection of volatile a second analysis can be conducted with raised during material review, then E&L and semi-volatile species using electron atmospheric chemical pressure ionization, analysis reverts to what is essentially an ionization and flame ionization. Headspace or atmospheric pressure photo ionization, untargeted analysis. There is little value in GC-MS and inductively coupled plasma resulting in accurate mass information that targeted approaches for compounds that are (ICP)-MS are applied for very volatile ultimately leads to an identification. expected to be of low toxicological concern. compounds (typically residual solvents) A robust database of E&Ls also greatly Instead, the main goal at this stage is and elemental impurities respectively. aids in obtaining identifications due to the reliable detection of those compounds that This combination of methods provides ability to use retention time matching. In are unexpected but of significant toxicity, comprehensive coverage for expected and our laboratories, we have combined more or those which are of moderate toxicity unexpected impurities. A recent publication than 15 years of analytical data from a wide but which are at such high levels as to be showed that the six analytical signals (five variety of medical products, building what significant toxicologically. LC or GC detectors with LC-MS in I believe is one of the most comprehensive Put simply, a properly protective positive and negative mode) allowed for up databases in the industry with more extractables screening approach needs to 97 percent positive detection at the AET than 5,000 compounds. We use this to be capable of detecting untargeted for a broadly constituted database of organic internal database along with the Agilent’s extractables and leachables. To accomplish extractables (6). The approach increases Masshunter Extractables and Leachables this, our laboratories have designed a the assurance that no toxic leachables will personal compound database and library strategy called the multidetector approach, be missed during the early extractables to help identify unknown extractables. It which is intended to provide a universal screening work, increasing confidence that allows us to combine two or more means means for detection of unexpected E&Ls. no unwanted discoveries will be made later of identification – retention time and The approach uses a combination of in the product development lifecycle. mass spectral database matching – which chromatographic methods and detectors, increases the identification confidence level allowing detection of a very wide range of What should you do if you find to “Confident” as per USP <1663>. extractables. We use a triple detection liquid unknowns that cannot be identified? If these approaches do not prove adequate, chromatography (LC) system, including a Based on USP <1663>, each identified then additional work using fraction collection quadrupole time of flight mass spectrometer extractable should be assigned a rating of is often the best alternative. The goal of this (QTOF-MS) coupled with an ultraviolet “Tentative,” “Confident,” or “Confirmed.” work is to isolate the unknown for further detector (UV), and a charged aerosol But one frequently asked question is: identification. The process typically starts detector (CAD) – all combined in a single “What do I do if I find a leachable or by creating a more concentrated form of analytical instrument (QTOF-LCMS-UV- extractable using a detector that does not the unknown, which may be accomplished CAD) for detection of compounds based on provide identification information, such through an exaggerated extraction or sample three independent properties (ionizability, as the UV, CAD or FID?” In general, if a concentration. Once the component is Best Practice 39

purified, other chromatographic methods accurate surrogate standard quantitations of analyzing the drug matrix. Development and detectors can be applied to aid in will also remain a hot topic, especially for of robust methods for quantitation of identification or, alternatively, traditionally exaggerated extractions of complex medical multiple leachables within a complex drug non-chromatographic methods, such as products where a large number of species matrix requires significant expertise. The NMR and FTIR, can be applied. In some need to be simultaneously quantified and addition of biological components, such as instances, unknown peaks are actually formal quantitation is impractical. proteins, or polymeric surfactants also adds compounds already observed by another I expect rapid change specifically in the additional challenges in sample preparation. chromatographic method, but for which a requirements for E&L for medical devices, It is essential that the laboratory has the correlation has not yet been established. As but also for combination products. This trend experience and the necessary analytical tools an example, fraction collecting an unknown will be primarily driven by the release of the to deal with the increasing complexity. peak detected in LC-UV and subjecting ISO 10993-18 guidance, which includes E&L analysis remains an essential part of it to GC-QTOF-MS could provide an changes to the extraction process, such as ensuring medical product safety. It answers identification that allows correlation between an emphasis on exhaustive extractions for the big picture question, “What comes out the two approaches. Alternatively, analysis all permanent contact devices and a firm of the drug packaging or medical device by pyrolysis MS or any of a host of specialty emphasis on using three solvent extraction that could adversely affect the patient?” The techniques can be brought to bear to aid in studies (polar, mid-polar, non-polar). Though complexity of medical products and the identification once a compound is purified. this may have been best practice in the past, difficulty of the objective means that the In this way, an identity can be reached for today it is essential for most submissions. In industry standard practice to E&L is likely essentially any compound. the last two years, a much greater emphasis to continue to evolve as discoveries and on quality controls has emerged. Triplicate innovations are made in analytical chemistry. Where do you see the future of E&L analyses are now widely used to gauge I feel certain that E&L will remain an heading? overall analytical precision. A consistent interesting, exciting, and challenging field E&L work has the difficult objective of requirement for spiking studies as a means of study for many years to come! trying to detect, identify, and quantify to prove the recovery of chemically relevant any species that leaches or extracts from a compounds during sample preparation is now References medical product. The complexity of the array widely cited. There is also greater scrutiny 1. US FDA, “Code of Federal Regulations Title 21,” of different medical products, their materials regarding aspects such as surrogate standard (2019). Available at https://bit.ly/3kn0Wwx of construction, and the development of selection, number of surrogate standards, 2. ICH, “Final Concept Paper: ICH Q3E: Guideline novel materials means that the universe of and confirmation of quantitative accuracy for Extractables and Leachables (E&L),” (2020). potential E&L is large and ever expanding. through mass balance between NVR Available at https://bit.ly/35jqHas Developing methods suitable for the results and results from chromatographic 3. ICH, “M7(R1) Assessment and Control of DNA detection of this universe of extractables methods. Even highly technical details, such Reactive (Mutagenic) Impurities in remains a daunting analytical goal and, in our as selection of an appropriate uncertainty Pharmaceuticals To Limit Potential Carcinogenic labs, has been answered by the development factor in the AET calculation, are frequently Risk: Guidance for Industry,” (2018). Available at of multidetector systems. We believe that discussed and questioned. Overall, there https://bit.ly/37zlQEU the application of more detection methods has been a significant increase in regulatory 4. J Pang et al., “Recognition and Identification of will become more standard as a greater scrutiny of chemical characterization data UV-absorbing Leachables in EPREX Pre-filled understanding of the limitations of only LC- and a greater emphasis on quality control. Syringes: An Unexpected Occurrence at a MS/GC-MS detection approaches becomes Moving into the future, we see this trend of Formulation–Component Interface,” PDA journal, apparent. No single chromatographic increasing quality requirements continuing 61, 423-432 (2007). PMID: 18410043 detector can detect all analytes. – especially for medical devices. 5. Reuters, “France, UK issue clashing advice on breast Obtaining “Confident” or “Confirmed” At the same time, we also see a growing implants,” (2011). Available at https://reut. identifications also requires significant complexity in drug formulations, which rs/2FVKILO. analytical expertise, including the is driving the need for more advanced 6. MA Jordi et al., “Reducing relative response factor development of large databases. I believe instrumentation and more skilled method variation using a multidetector system for the future of E&L identification will be development. Biologics and drug products extractables and leachables (E&L) analysis to dependent on the development of very large containing significant amounts of non- mitigate the need for uncertainty factors,” J. Pharm. and comprehensive commercial databases that aqueous components increase the extracting Biomed. Anal., 186, 1-14 (2020). doi. allow for confident identifications. Obtaining power of the drug product and the complexity org/10.1016/j.jpba.2020.113334.

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2021 PDA EUROPE HIGHLIGHTS

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2021 Highlights EU 210x266.indd 1 04.12.20 10:06 NextGen R&D pipeline New technology Future trends

42-44 Putting Sleeping Sickness to Bed Sanofi and the Drugs for Neglected Diseases initiative explain the story behind a new medicine for sleeping sickness: acoziborole

46-49 Gene Therapy: The Rocky Road to Success Gene therapies today receive enormous attention but their rise to success has not been an easy one. Alexandra Brinkman looks back over the field. Credit: Neil Brandvold-DNDi Neil Credit: 42 NextGen

Tropical Diseases at Sanofi Global Health. the 10-day treatment received a positive Putting Sleeping “The disease is also considered endemic in scientific opinion from the European 36 sub-Saharan African countries, where Medicines Agency and was granted Sickness to Bed around 60 million people are estimated to market authorization to treat patients be at some level of risk of HAT – primarily in the Democratic Republic of Congo How can we eradicate this those living in poor, rural, and remote parts (DRC). Though the partners believe the fatal tropical disease once and of East, West, and Central Africa, where rollout of the drug was “successful,” the for all? health infrastructure is poor or nonexistent.” 10-day commitment to treatment could Sanofi and DNDi are co-developing a be difficult for patients in the most remote In 1990, serious inequalities in global drug – acoziborole – to treat HAT that, areas – a single dose would be ideal for R&D were highlighted in a report once approved, will be distributed at them. Acoziborole, on the other hand, is penned by The Commission on Health no cost to patients or governments (3). a single-dose treatment and the partners Research for Development. According “Acoziborole was identified by researchers hope that it can be used alongside a rapid to the independent healthcare body, from the University of San Francisco along diagnostic test, which would simplify the the world’s poorest nations accounted with our biotech partners at Anacor and process even further. for up to 90 percent of the global Scynexis,” says Antoine Tarral, Head of Unfortunately, says Tarral, “HAT is disease burden – but only 10 percent of the HAT Clinical Program at the DNDi. complicated to diagnose because many research was geared toward treating the “We selected the compound for our symptoms displayed by patients are conditions that caused such significant lead optimization program and received nonspecific and accurate tests require skilled morbidity and mortality (1). Three new chemical entity status in 2009.” personnel.” In many disease-endemic areas, decades have passed since these findings The compound is the first new chemical staff simply aren’t available in the numbers were first published, and the international entity from DNDi ‘s lead optimization needed to effectively diagnose the patient community has made strong efforts to programme to enter clinical development. population, resulting in many detrimental address the disparity that exists between Though several medicines already existed, diagnostic delays. Despite these challenges, healthcare systems and to find solutions the discovery of acoziborole marked the he remains optimistic. “Current tests rely to the treatment of neglected diseases. start of a new approach to HAT treatment. on the detection of parasites in patient Today, many companies have aligned “Until 2009, treatments for sleeping sickness cerebrospinal fluid as well as white blood themselves with the WHO’s Neglected were toxic and complex. They included an cell counts. We don’t have the molecular Tropical Disease (NTD) Roadmap 2030 arsenic derivative called melarsoprol that biomarkers necessary for an improved, to “respond to NTDs over the next decade brought about such severe pain when easy-to-use test, but we are optimistic that (2).” And, to that end, Sanofi has been administered that it was known by patients the industry will create reliable options in working with the Drugs for Neglected as ‘fire in the veins.’ Devastatingly, it killed the future.” Diseases initiative (DNDi) on a new one in 20 people,” says Neau. And though Acoziborole is currently undergoing treatment for sleeping sickness – also these toxic treatments were replaced by phase II/III trials in the DRC and Guinea known as human African trypanosomiasis the safer combination therapy nifurtimox- and is being tested against some of the most (HAT). Transmitted by the tsetse fly, the eflornithine (NECT), it too was imperfect common strains of the disease. “Recruiting condition is characterized by the entry of – hampered by logistical concerns in remote patients was challenging,” says Tarral. a parasite, Trypanosoma brucei, into the regions and the need for trained nursing “Given the aforementioned diagnostic host’s bloodstream, lymphatic system, staff for administration and hospitalization challenges, finding people with confirmed and eventually central nervous system. for patients. cases and robust documentation to allow The first stage of the disease causes their participation in trials wasn’t easy. lymph node enlargement, fever, and A new era in HAT R&D We also had to ensure that they could be headache; the second results in serious Before collaborating on acoziborole, DNDi screened and tested close to their homes.” neurological changes, including sensory and Sanofi worked together on fexinidazole Beyond recruitment, the DNDi also disturbances, poor coordination, and errati – the first all-oral treatment for HAT, needed to build some of the infrastructure sleeping patterns. which made it easier for patients to avoid the necessary for the trials to take place. “To “Without prompt diagnosis and challenges of systematic hospitalization and allow investigators to work in the best treatment, sleeping sickness is usually fatal,” lumbar puncture associated with NECT. possible conditions, we were involved in says Philippe Neau, Head of Neglected Clinical studies began in 2009. In 2018, the reconstruction of labs, hospitals, and Credit: Neil Brandvold-DNDi Therapeutic Altruism The result was the Pan African Tsetse of HAT as a public health issue by aligning and Trypanosomiasis Eradication our objectives with the WHO’s goals and With Phillipe Neau Campaign (PATTEC). Another key freely supplying drugs to ensure that all alliance was the formation in 2001 of a patients can access appropriate treatment. Devastating HAT epidemics have long-standing public-private partnership We also develop new therapeutic options occurred throughout the 20th century with Sanofi, which would make it through alliances with partners like but, following the neglect of control possible to distribute vital drugs to DNDi, Bristol-Myers-Squibb, and Bayer efforts implemented until the 1960s, treat HAT and other NTDs in endemic Healthcare. the 1990s saw a dramatic resurgence of areas free of charge. The partnership also In 2021, we will celebrate the 20th the disease. The WHO reported almost provided funds to support screening and anniversary of our collaboration with 40,000 new cases in 1998 but estimated surveillance reports, improve treatment the WHO. We are deeply proud of all that approximately 300 000 cases were centers, train local health workers, initiatives this partnership has led to. undiagnosed and untreated (1). In and create research and development Since 2001, the number of HAT cases response, the WHO passed a resolution programs for new treatments. has dropped by 97 percent, more than 40 in 1997 to raise awareness of the disease, At Sanofi, we cemented our commitment million people have been screened, and promote access to diagnosis and treatment, to the goal of eliminating HAT by signing over 210,000 patients have been treated. and strengthen control and surveillance. the London Declaration on Neglected But the disease is still killing people – so In July 2000, the WHO intensified Tropical Diseases in 2012. The declaration we must maintain these efforts until we efforts to achieve these goals by forming focused on the commitment of a range of put an end to the disease once and for all. global alliances with United Nations actors from the public and private sectors agencies (under the Program Against to control or eliminate 10 infectious Reference African Trypanosomiasis, PAAT), diseases (including HAT) that affect 1. WHO, “Trypanosomiasis, human African national governments (under NSSCPs), the world’s poorest populations. In this (sleeping sickness)” (2020). Available at and the Organization of African Unity. context, we contributed to the elimination https://bit.ly/3ncHNhU.

pharmacies. We really wanted to witness considerations that will help the drug reach smaller companies and biotechs can step in. the project’s success,” says Tarral. as many affected people as possible.” They have the capacity to focus more time The supply chain for acoziborole will be and resources and can work collaboratively An easy-access future managed by the Sanofi-WHO partnership. with larger companies to make a difference.” Although acoziborole hasn’t yet completed With support from Médecins Sans But no one organization, government, or its trials or received a regulatory green light, Frontières, the company will ship the drug company can effect lasting change alone. the partners have made plans for Sanofi from its warehouse in France to Kinshasa, “It is essential we work together to ensure to handle its manufacture, supply, and DRC. “Once the medicines reach their optimal use of resources as well as to explore distribution – for free. destination, they will be distributed to and implement innovative strategies for a Sanofi has a long-term partnership patients in the field through the National future in which stronger local accountability program with the WHO to combat several Sleeping Sickness Control Program,” says is a reality,” says Neau. “Importantly, we NTDs, through which it provides drug Neau. “We have years of experience in must all remain committed to improving donations and financial support. Neau the distribution of NECT and know how access to healthcare for the most vulnerable says, “Historically, we’ve contributed to this cumbersome and difficult it is to ship and people in low- and middle-income partnership with medications for patients store the drug. With fexinidazole today and countries.” with sleeping sickness. We also support acoziborole tomorrow (if approved), the capacity-building and patient screening logistical challenges will be significantly References through yearly contributions. Acoziborole simplified due to the medicine’s oral form.” 1. WHO, “Diseases of poverty and the 10/90 Gap” should be no different.” The partners believe they are well on (2004). Available at https://bit.ly/2Ssj7Ez. Tarral adds that the project also received their way to eliminating HAT in line with 2. WHO, “Introduction to NTD 2030 Roadmap” early support from several donors. “The Bill the WHO’s 2030 goal. But is the industry (2020). Available at https://bit.ly/2I1mb8V. & Melinda Gates Foundation, among a doing enough to address the wider problems 3. DNDi, “Innovative single-dose oral sleeping broad range of industry partners, offered NTDs cause? “We can all do a bit more,” sickness treatment to be co-developed by Sanofi and donations early on that helped drive the says Tarral. “It’s difficult for big pharma to DNDi partnership” (2020). Available at https:// project. Sanofi has also made logistical invest in NTD research and that’s where bit.ly/34FEFDB. Draw on our experience to get on the fast track through production

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caused by mutations in both copies of highlighting the challenges and successes Gene Therapy: the RPE65 gene. of the field. The concept of gene therapy was officially The Rocky Road established back in 1972. And although Setbacks and successes gene therapy is considered a relatively According to the Gartner hype cycle, a to Success new area of therapy, the field can be dated graphical representation depicting the even further back to 1928, when Frederick maturity of novel technologies, gene therapy A rapid review of gene Griffith first described the transforming reached its peak of inflated expectation in therapy’s rise – and a quick principle. By 1968, Rogers and Pfuderer the mid-1990s. This inflated expectation glimpse into the future performed the first proof-of-concept viral was paralleled by a rapid rise in clinical trial mediated gene transfer. Fast-forwarding activity and the publication of early proof-of- By Alexandra Brinkman to 2003, China became the first country concept studies for genetic conditions, such to approve a gene therapy for clinical use. as adenosine-deaminase deficiency (ADA- The manipulation of genes to treat By 2009, the first successful phase III trial SCID). It had been clear from the start that disease once seemed only to be the basis of a gene therapy had occurred in the EU gene therapy had potential, however, focus for an average science fiction novel. And and in 2012, the EMA recommended the needed to be given to the basic science of if your story restored an individual’s first gene therapy product for approval. gene transfer and its respective technologies. vision by using a virus to replace a Following on from this success, the FDA Following this peak of excitement, mutant version of a gene with a healthy approved Luxturna, the first gene therapy the field descended into the “trough of one, you might have a best seller on for an inherited disease, in 2017 (1). disillusionment” following the death of Jesse your hands. But we all now know that However, the road for gene therapy has Gelsinger during a clinical trial for ornithine this is not fiction; it is a description of not been smooth. Here, I look at genetically transcarbamylase (OTC) deficiency (2). Luxturna, the first FDA-approved gene driven non-oncology indications, based on Consequently, concerns over the future therapy for an inherited retinal disease data from Beacon Targeted Therapies, of gene therapy were raised – and further

Figure 1. Vector distribution based on the number of active drugs within gene therapy. Source: Beacon Target Therapies, October 2020. NextGen 47

25 30%

25% 20

20% 15 responses to the wild-type virus that the

15% vector is engineered from, or the transgene

10 CAGR Plot product itself, can interfere with therapeutic

Number of Trials 10% efficacy if not identified and managed

5 optimally. It is, therefore, important for 5% the field to gain a better understanding of

0 0% the different viral and non-viral platforms 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 used so that immunogenicity can be Trial Start Year minimized. Currently, the AAV vector is A the most frequently used delivery system based on the number of active drugs, but also contains the greatest immunogenicity challenges (see Figure 1). Outside of AAV vectors, there are further novel vectors being Metabolic Disorders created to help evade the immune response – and the clear innovation occurring in Kidney Disorders the non-viral delivery space can help to Eye Disorders overcome the immunogenicity problems seen with AAV vectors (4). Cardiovascular Diseases A key challenge inherent to immunogenicity is our ability to measure Blood Disorders and predict the immune response. A lack of Lung Disorders standardization of regulatory protocols for assays and immune prediction levels – or, Diabetes put another way, what level of an immune 0 5 10 15 20 25 response is acceptable – have created Number of Trials B problems. Patient stratification, as defined by the amount of neutralizing antibodies Figure 2. Clinical growth and disease variation within RNAi therapies. A) The number of trials present, can be one alternative to help mitigate evaluating RNAi therapies initiated per year since 2010 and the compound annual growth rate immunogenicity. It can then be decided (CAGR) of 28 percent. B) Distribution of trials across disease indications, with at least five clinical which patients are enrolled onto trials as part trials using RNAi therapies. Source: Beacon Targeted Therapies, October 2020. of the inclusion criteria (for example, anti- adenovirus antibodies). Another strategy complicated by an increasing awareness of of enlightenment” and into a “plateau of being used to help prevent immunogenicity the challenges that would be encountered, productivity.” As a result, we’ve seen greater is immunosuppression/patient conditioning. including vector-induced immune response innovation in strategies addressing editing Though the strategy reduces unwanted (immunogenicity) and decreased financial and vector technology, and the creation of immune responses to the gene therapy, there investment. To overcome one (possibly both) more biotechnology companies dedicated are still questions around its use; specifically, of these challenges, researchers have focused to gene therapy development – backed with are immunosuppressants suitable for long on improving their understanding of disease substantial financial investment. term use? Furthermore, efficacy of the gene pathophysiology to develop safer and more We should not become blinded by the therapy can potentially be compromised by efficient vectors. success gene therapy is having. The field is use of immunosuppressants. Standardization The research has resulted in recent clinical young and dynamic, but still faces challenges of immunosuppression protocols, such as successes for inherited orphan diseases around transduction efficiency, clinical inclusion/exclusion of use, would need to from the treatment of Leber’s congenital trial endpoints, and, most significantly, be better defined. And yet, though these amaurosis to the EMA approving immunogenicity. As AAV vectors can be are hurdles to be addressed, they have not Glybera in 2012 for lipoprotein lipase administered directly to the patient, the stopped gene therapy from being validated as deficiency (3). These successes are driving likelihood of a host immune response a therapeutic approach – and that is reflected the field up what is known as the “slope is high. Additionally, any pre-existing in the present-day landscape.

www.themedicinemaker.com 48 NextGen

Consequently, an influx of data is predicted 18 in the coming years. Looking at the number

16 of phase III trials expected to be completed over the next five years, we can expect to 14  Zinc Finger Nuclease see new approvals for both classical gene TriMix 12 1 TANGO therapy and RNA-based approaches.   SynCon® 10 Alnylam Pharmaceuticals is leading the  STARR™   Optogenetics way with three assets in phase III, but it will 8  ! OliPass PNA Technology be exciting to see who will ultimately win Number of Trials  1 miQURE™ silencing technology 6  GalXC™ the race for the next approval (see Figure 4).     Exon-skipping Technology 4     According to the ARM 2020 report (6),  DNAzyme    CRISPR/Cas9 this year (even taking into consideration 2           COVID-19), is on track to be a record-    0 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 breaking year for regenerative medicine and Trial Start Year advanced therapy financings. Therapeutic developers raised more in the first half of Figure 3. Number of clinical trials initiated each year in the last decade versus editing technology. 2020 than in all of 2019 (US$10.7 billion Source: Beacon Targeted Therapies, October 2020. in the first half of the fiscal year 2020 versus $9.8 billion total in 2019). This year will Changing approaches technology of choice – transforming likely provide the best year on record for The discovery of RNAi enabled a shift biomedical science. cell and gene therapy financings ($13.5 from only focusing on gene augmentation CRISPR/Cas9 started receiving billion total), with developers having and replacement to also focusing on attention in 2012 as an editing technique, already raised nearly 80 percent of the full- downregulation of genes – namely, mutant and the first clinical trials were initiated in year total seen in cell and gene therapy variants that can result in a therapeutic 2017 (see Figure 3). The tool was pioneered financings in 2018. Investors will no doubt effect on disease pathogenesis. This shift by Emmanuelle Charpentier and Jennifer appreciate the robust pipeline that each of is reflected by recent approvals, such as Doudna, who received the 2020 Nobel the gene therapy therapeutic classes offers; Givosiran in 2019 and Patisiranin in 2018, Prize in Chemistry. Proprietary editing however, it is important to appreciate that, as well as the increasing number of RNAi technologies are now rapidly being due to the immaturity of the field, there are clinical trials over the last decade (CAGR developed across the industry; for example, a significant number of companies at the of 28 percent) for a variety of disease UniQure’s miQURE silencing technology preclinical stage – and there will be both indications (see Figure 2). Some of the first and CRISPR/OMNI. significant winners and losers. clinical therapies using small‐interfering It is also important to note the impact RNA (siRNA) were for diseases of the And the future? that COVID-19 is still having on the liver, as siRNA sequences were initially Although there have been setbacks, the field. The increased number of INDs filed developed to target hepatocytes. Examples ultimate success of gene therapy has been within cell and gene therapy, and a shift in of this type of therapy include treatments driven by improvements in both nonviral focus towards COVID-19 therapeutics and for transthyretin‐mediated amyloidosis and and viral vectors. Though the majority of vaccines, has placed an additional burden complement‐mediated diseases (5). assets still use viral vectors, the increasing on the FDA and led to delays. For example, In recent years, gene editing has also diversity of the field is reflected in the Sarepta Therapeutics’ asset SRP-9001 for taken off. Gene editing tools offer a more number of nonviral assets (46 in total) Duchenne muscular dystrophy (DMD) elegant and precise method of treating that have entered the clinic for both ex has seen a delay in its clinical trial. While genetic diseases. There have been efforts vivo and in vivo gene therapy. Some of giving late notice, the FDA has requested on this front through ex vivo homologous these technologies include vectors, such an additional potency assay for the release recombination, TALENS, and Zinc Finger as cationic lipids, plasmids, and peptide of SRP-9001 prior to dosing, resulting in Nucleases (ZFNs). However, clustered nanoparticles. trial delay. During these unprecedented regularly interspersed short palindromic Based on analysis from Beacon Gene times, it is likely that we will see more repeats (CRISPR)/Crispr‐associated Therapy, 88 trials are expected to be trials delayed while the FDA tries to keep protein 9 (Cas9) has become the editing completed in 2021, with 70 trials in 2022. the pace with both the increasing number NextGen 49

100

90

80

70 60 of gene therapy IND applications and 50 the impact of COVID-19 on trial and

40 drug development. Number of Trials Undoubtedly, the path for gene therapies 30 has been rocky. The field has seen significant 20 setbacks, from understanding disease 10 pathology to safety and immunogenicity 0 concerns, but these hurdles have pushed the field to pursue improved technologies, Trial Completion Year and the variety of delivery and editing A technologies available today offers a perspective on how challenging it is to tackle certain diseases. With several assets

14 already successfully approved and more seeking approval, the approach of the field 12 has been validated; next, we expect to see a domino effect of approvals driven by the 10   increased influx of data, IND filings, and  8 
  new technologies being implemented.  
  6 



  Alexandra Brinkman is a Gene 



  Number of Trials 
  Therapy Research Analyst at Beacon 4   

  Targeted Therapies 
 
 
  2 References 0 2020 2021 2022 2023 2024 2025 1. AM Keeler, MK ElMallah, TR Flotte, Trial Completion Year B “Gene Therapy 2017: Progress and Future Directions,” Clin. Transl. Sci., 10, 242-248 (2017). PMID: 28383804

*Ionis Pharmaceuticals has 2. S Raper et al., “ Fatal systemic inflammatory Weill Medical College of Cornell University   5 of its 14 assets in response syndrome in a ornithine transcarbamylase Great Ormond Street Hospital for Children   co-development with Biogen (4 in phase I and 1 deficient patient following adenoviral gene Arrowhead Pharmaceuticals    in phase I/II) transfer” (2003). Available at: Applied Genetic Technologies Corporation  

Imperial College London   https://bit.ly/3kunJpm

University of Pennsylvania  3. L Bryant et al., “Lessons learned from the clinical

Sarepta Therapeutics    development and market authorization of Alnylam Pharmaceuticals Inc.    Glybera”.(2013). Available at Moderna Therapeutics    https://bit.ly/2UJLqQd Inovio Pharmaceuticals   4. F Mingozzi, KA High, “Immune responses to University of Oxford   AAV vectors: overcoming barriers to successful gene Shenzhen Geno-Immune Medical Institute  

*Ionis Pharmaceuticals    therapy,” Blood, 122, 23-36 (2013). PMID: 0 2 4 6 8 10 12 14 16 23596044 Phase 1 Phase 1/2 Phase 2 Phase 2/3 Phase 3 Phase 4 Early Phase 1 Unknown C 5. J Baruteau et al., “Gene therapy for monogenic liver diseases: clinical successes, current challenges Figure 4: The Future of Gene Therapy. A) Number of gene therapy trials completed versus and future prospects,” J. Inherit. Metab. Dis., 40, completion year B) Distribution of phase 3 trials coming to completion in the next five years broken 497-517 (2017). PMID: 28567541 down by completion year and therapeutic class C) Developer with at least five active gene therapy 6. Alliance for Regenerative Medicine, “Innovation assets broken down by total number of therapies and highest phase of development. Source: Beacon in the Time of COVID-19” (2020). Available at Targeted Therapies, October 2020. https://bit.ly/3ozzLkq.

www.themedicinemaker.com In the Face of Crisis

Sitting Down With… Elaine O’Hara, Chief Commercial Officer, Sanofi Pasteur, US (Swiftwater, PA) Sitting Down With  51

How were you introduced to industry? demand, a rapid turnaround is a must. It’s powerful when you have a boss who I moved to the US for my Master’s degree The structured timeline requires a lot of encourages you to go in a certain direction in Business Administration at St. Joseph’s dedication, patience, and attention to detail. I and helps you grow. University in Philadelphia. After completing wanted to be in that kind of environment and Outside the industry, one of my current my studies, I joined Accenture – called was fortunate enough to join the company heroes is Anthony Fauci. He has been Anderson at the time – for a consulting in 2017. Today, I lead Sanofi Pasteur’s North incredible at toeing the line with respect to role. Serendipitously, I was involved in a America commercial operations. what’s important regarding COVID-19. project that helped get Astra Merck off the He’s also under incredible pressure, but he’s ground. The newly formed enterprise had a How has the COVID-19 pandemic spent years fighting for medical excellence great pipeline of drugs and was launching affected you? and has a vast knowledge of pandemics, Prilosec, a treatment for acid reflux. I really Before the pandemic began, we all met face- epidemics and health crises. I appreciate enjoyed working with the company and to-face. It was normal for me to sit down the work he is doing and the way he has decided to leave the consulting world behind. with my team and plan our commercial continued to promote the scientific messages Since then, I’ve had the opportunity to work activities – designing strategies for the year required to deal with the pandemic. on many product launches. The journey has and assessing vaccine needs across North been tremendous! America. That has now drastically changed. Are you optimistic about the future? Remote interactions have become our new At Sanofi Pasteur, we’re developing our What makes pharma so interesting? reality and, though it was a shock to begin own COVID-19 vaccine and – as our It’s the opportunity to intervene in public with, it soon became the norm. Our sales CEO put it – it’s very interesting to health. Though working in the industry representatives, for example, adapted very work on a vaccine with the world’s eyes may not be as exciting as the emergency quickly. Though they had previously met on you. Internationally, people will have room – and is certainly not as high- with customers in physical locations, Zoom questions about our progress. How will paced – I’d argue that it is still incredibly became an integral part of their continued this vaccine come to market? How will it rewarding. Many people live with chronic client relationships. Beyond this, we’re on be distributed? Who will receive it? diseases whose management requires a track to meet many of the goals we had We’ll be able to provide more answers consistent effort on the patient’s part. I’ve set at the beginning of the year. We’ve as the situation changes. I think this will been fortunate enough to contribute to the developed adaptive vaccination solutions help the general public develop a stronger development of a variety of interventions that help healthcare providers immunize understanding of pharmaceutical products and witness the advances the industry has the patients reluctant to physically enter the and how they are produced and delivered to made and continues to make – positively doctor’s office – they were concerned with the market. Conversely, there’s the potential impacting lives across the globe. exposure to the coronavirus. However, in for skepticism because of the speed at which But, ultimately, it’s the fact that pharma a year like the one we’ve had, no one wants this kind of vaccine is moving through the allows us to rally around the causes that to see other vaccine preventable diseases clinical pipeline. That’s something the really matter. The COVID-19 pandemic cropping up. And so, it was important for us pharmaceutical industry will have to continue is one example that demonstrates how to develop solutions that supported HCPs to address. We have very good processes in invested we are in protecting patients – to continue to administer all those other place to ensure product safety and efficacy – but companies across the industry are also vaccines that protect against diseases like but now, more than ever before, we must be working to treat everything from CNS influenza and meningitis, these vaccines can able to prove that to patients. disorders to antimicrobial diseases. It’s be administered anywhere – even through All this being said, the public’s knowledge something we can all be proud of. the window of your car in a parking lot. of – and trust in – the pharmaceutical This approach helps ensure that as many industry is better than it was in the past. Why Sanofi? people as possible are properly protected Until perhaps a year ago, most people didn’t Years before I joined Sanofi, I had already against viral and bacterial infections. have a clear understanding of what vaccine developed an interest in the company’s manufacturing looked like. I’m pleased that work. It had an extensive vaccine portfolio, Which industry figures have we’re now at a pivotal moment where we can but what stood out to me the most were inspired you? educate our community and reduce vaccine its influenza products. Once strains are I’ve been fortunate in that most individuals fear. This will help us build stronger bonds identified, the manufacturing of relevant I’ve reported to throughout my career have with the people we aim to serve, which can vaccines has to begin. To meet public been very helpful and given great advice. only be described as a positive step forward.

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