APRIL 2021 # 74

Upfront In My View NextGen Sitting Down With The risk profile of Analyzing capsids for Unit-level traceability of Johannes Khinast – the only pharma-grade whey gene therapy glass containers science is good science

07 12 38 – 42 50 – 51

www.themedicinemaker.com Value beyond the vial

When you have questions, we have answers.

When evaluating your product against a reference standard, questions arise. Give yourself a cushion of confidence.

When you need expert advice or are seeking a training course to help you with our reference standards, you’ll always have access to answers when you need them — with USP.

Move forward with more confidence: Contact USP. 1-301-881-0666 | usp.org/chemical-medicines A Roadmap for Access We must secure sustainable markets to ensure patient Editorial access to generic and biosimilar medicines

he pandemic has presented a unique challenge to healthcare systems and infrastructure, including the generic drug supply chain. Generic drug Tmanufacturers have met this challenge, ensuring a stable supply of life-saving medicines for patients throughout the pandemic. However, the long-term sustainability of the generic and emerging biosimilars medicines market faces threats. Policymakers should consider and address the unique challenges facing generics and biosimilars to maintain long-term access to cost savings for patients. In its latest paper, Securing Sustainable Markets, the Association for Accessible Medicines (AAM) announced a series of policy proposals intended to ensure patient access to lower-cost medicines (1). Generic drugs face competitive imbalances in the market, such as a highly consolidated drug purchasing system controlled by a few major organizations, combined with ill-advised government policies. These policies have historically led to high rates of price deflation and low reimbursement, sometimes driving manufacturers out of the market. For example, Medicaid imposes an inflation penalty that penalizes generic manufacturers who experience price variability due to fluctuation in purchasing patterns. And consider this: the growing categories of specialty and complex generics and biosimilars offer critical new savings Reference opportunities for patients, along with financial sustainability for 1. AAM, “Securing Sustainable Markets,” manufacturers; however, patient adoption of such new, lower-cost (2021). Available at www.secureourmeds. alternatives is unfortunately hindered by government and payer org/securing-sustainable-markets policies that perversely reward the use of high-cost brands over lower-priced generic or biosimilar competitors. Policies such as the brand drug Coverage Gap Discount Program and the use of brand drug rebate traps encourage plans to restrict patient access to generics or biosimilars in favor of higher-cost brands. Note that Medicare Part D formularies are slower in covering newly approved first generics compared with commercial health plans, in spite of the lower cost of generics. Similarly, Medicare Part B reimbursement policies discourage biosimilar adoption, even though biosimilars are 30 percent less expensive (on average) than reference brand-name biologics. As more FDA-authorized COVID-19 vaccines are distributed and administered, we’ll all be hoping for a speedy rebound from the pandemic. Certainly, generics will have played a key role as a bridge to those vaccines. AAM calls for updated government policies that value generic and biosimilar competition, do not penalize continued production of older commoditized generics, and create opportunities for future patient savings.

Craig Burton Vice President, Policy at the Association for Accessible Medicines

www.themedicinemaker.com Contents

48

09

In My View 20 12 We need better analytical techniques that can tell us what is happening inside our capsids for gene therapy, says 03 Guest Editorial Upfront Lori Stansberry A Roadmap for Access, by Craig Burton 06 The latest news, views and 14 According to Jason Lacombe, research – including guidance secure digital technology is more on whey and lactose-derived essential than ever before in On The Cover Cover excipients, a technique for today’s world of remote working lowering chromatography costs Celebrating The Medicine Maker in bioprocessing, and the true 16 Karen Fallen believes that DNA 2021 Power List effectiveness of traditional manufacturers need to pick up medicine the pace if they want to take part in the genetic medicine revolution ISSUE 74 - APRIL 2021

Feel free to contact any one of us: 38 [email protected] Content Team Editor - Stephanie Sutton James Strachan (Deputy Editor) Maryam Mahdi (Associate Editor) Commercial Team Publisher - Helen Conyngham 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) Jess Lines (Video and Project Support Coordinator) Lindsey Vickers (Sales Support Project Manager) FeatureFeature Marketing Team Marketing Manager - Katy Pearson Jo Baylay (Marketing Executive) 20 The 22021021 P owoPowererr L isiListt Accounts Team We celcelebrateebbratee thethe toptop Kerri Benson (Accounts Assistant) inspirationalinspirationan l anandd iniinfluentialfluuential Emily Scragg (Accounts Apprentice)

professionals across three Human Resources categories of medicine 48 Hello World! Human Resource Manager - Tara Higby Management Team making: small molecules, We round up the hottest topics Chief Executive Officer - Andy Davies biopharmaceuticals, and that have been seen in the cell Chief Operating Officer- Tracey Peers Senior Vice President (North America) advanced medicine and gene therapy field over the - Fedra Pavlou Financial Director - Phil Dale course of the last month Commercial Director - Richard Hodson Content Director - Rich Whitworth

NextGen Report 38 Raising the Bar(code) Change of address [email protected] Stevanato’s Tod Urquhart has 18 Filling: How to Find the Hayley Atiz, The Medicine Maker, Texere Publishing Limited, Booths Park 1, Chelford Road, Knutsford, Cheshire, WA16 8GS, UK taken a lead role in a draft ISPE Right Setup General enquiries Discussion Paper on traceability www.texerepublishing.com | [email protected] +44 (0) 1565 745 200 | [email protected] of glass containers; he tells us Distribution: The Medicine Maker (ISSN 2055-8201), why it is so important is published monthly by Texere Publishing Limited, Booths Park 1, Chelford Road, Knutsford, Cheshire, WA16 8GS, Sitting Down With UK. Single copy sales £15 (plus postage, cost available on request [email protected]). Non-qualified annual 44 A Smaller Piece of PiE subscription cost is £110 plus postage There are growing concerns 50 Johannes Khinast, CEO Reprints & Permissions – [email protected] The copyright in the materials contained in this publication and the about API levels in wastewater, and Scientific Director of the typographical arrangement of this publication belongs to Texere Publishing Limited. No person may copy, modify, transmit, distribute, display, but pharma manufacturers can Research Center for reproduce, publish, licence or create works from any part of this material or typographical arrangement, or otherwise use it, for any public or commercial manage these – with the right Pharmaceutical Engineering use without the prior written consent of Texere Publishing Limited. The names, publication titles, logos, images and presentation style appearing processes in place (RCPE), Graz, Austria 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 A Little Less Innovation Conventional

Researchers prove the effectiveness of traditional herbal medicines against neglected tropical diseases

Can traditional medicines be standardized to help create affordable drug access in low- and middle- income countries? Dorcas Osei-Safo Researchers at the University of Ghana, certainly think so and have published data that indicates how herbal preparations are thought to have few adverse effects. So far, only one active extract has can be successfully used for the treatment With the aim of improving access, Osei- been subject to complete bioassay of neglected diseases (NTDs) like Safo and her colleagues decided to explore fractionation. The remaining identified schistosomiasis (snail fever), onchocerciasis whether these plant-based medicines could active extracts are currently under (river blindness), and lymphatic filariasis make a difference to patient care. investigation. “We hope to come up (elephantiasis) (1). After screening multiple plant and solvent with a couple of promising compounds “The use of traditional medicines as combinations, the team found 15 dried herb that could be further developed into therapeutic agents is generally not accepted extracts that were effective against their potential drugs,” says Osei-Safo. But the by pharma,” says Dorcas Osei-Safo, associate target NTD – but they also discovered team’s goals are not limited to molecular professor and researcher at the University something unexpected. “Though the isolation of traditional medicines for of Ghana. “There are grave concerns about extracts certainly demonstrated different pharmaceutical development; they are the lack of established evidence of safety levels of activity against their target disease, also exploring how they can develop and efficacy, as well as data on dosage, good many of them were more effective against standard protocols to ensure the manufacturing practices, quality control, other tested NTDs – much to our surprise!” safety and effectiveness of the original and standardization.” says Osei-Safo. The majority were most traditional medicine. However, Osei-Safo explains that, active against Trypanosoma brucei brucei, among the Ghanaian public, traditional a parasite that causes sleeping sickness. Reference medicines are widely used – particularly The researchers believe the findings 1. EB Twumasi et al., PLOS Negl Trop Dis, 14, in rural areas – as they are cost-effective suggest that traditional medicines deserve 12 (2020). DOI: 10.1371/journal. alternatives to conventional medicines and further exploration. pntd.0008919

INFOGRAPHIC

Manufacturing sites Inspections at home and abroad Beating the Number of US inspections Number of foreign inspections 26% 1000 Backlog 800 USA 600

How well has the FDA managed 400 its inspections at home and 74% 200 abroad during the pandemic? ROW 0 2016 2017 2018 2019 Upfront 7

The Whey BUSINESS IN BRIEF of Things Manufacturing mishaps, improper practices, and regulatory New guidance outlines the recommendations… What’s new in safety of animal-derived business? excipients

• The US Department them to move between Responding to regulators’ calls for of Health and Human manufacturing areas without clearer guidance on the risks of excipients Services has stripped having to remove their sterile to patient health, the International Emergent BioSolutions of gowning. This led to the Pharmaceutical Excipient Council its responsibilities for the improper disposal of uniforms (IPEC) Federation has published a manufacture of COVID-19 in biohazard bins. In the letter, position paper outlining the safety of vaccines and handed over Kerner said, “I am troubled by the lactose-derived excipient whey (1). A production to J&J. The move many aspects of this matter. natural polymer, whey is used in various comes after the CMO’s I urge the agency to closely oral dosage forms for its drug-binding Baltimore-based plant, examine compliance issues capabilities – but some regulatory Bayview, was found to have like these.” authorities consider ingredients from mixed up two ingredients • The MHRA and EMA have human or animal sources to have high used in the AstraZeneca and concluded investigations into chemical and biological risks when J&J COVID-19 vaccines – the use of the AstraZeneca incorporated into oral preparations. resulting in the production of COVID-19 vaccine. The IPEC argues that the risk profile of 15 million botched doses. vaccine has recently come pharmaceutical-grade whey is low because • A letter penned by the White under public scrutiny as it is sourced from lactose manufactured House’s Special Counsel, cases of rare blood clots were to GMP standards. Historically, the Henry J. Kerner, outlines reported after administration. excipient has also proven to be nontoxic claims from a former FDA The EU regulator argues that with a good safety profile. The council employee and whistleblower, the benefits of use outweigh now hopes that this classification will who alleges that regulatory the risks given the low number “result in fewer dossier requirements misconduct led to several of reported cases. However, for lactose when applying for marketing inspections being improperly the MHRA has recommended authorizations” – making medicines that downgraded and violations that alternative vaccines are contain it more readily available. overlooked. The whistleblower used in people under the age claims that employees soiled of 30. Other countries will use Reference themselves rather than take alternative vaccines in those 1. IPEC Federation (2021). Available at https:// bathroom breaks, allowing under the age of 50. bit.ly/3d3H6nA.

COVID-19 Consequences Barriers to inspection Never inspected 60% Not inspected in five years fewer Highest risk remaining sites inspections took place in 2020 than  Availability of overseas the two years inspectors 13% 6% 14% previous  Differences in inspection 27% 17% 59% procedure in the US and abroad 51% 43% Language barriers 70% 

Source United States Government Accountability Office, “FDA’s Future 2020 2021 2022 Estimated Inspection Plans Need to Address Issues Presented by COVID-19 Backlog” (2021). Available at https://bit.ly/3rOTGx5. 8 Upfront

Protecting the Vulnerable

How do COVID-19 vaccines impact at-risk patients?

COVID-19 vaccinations have begun worldwide, but how effective will they be for at-risk groups, such as immunocompromised patients? Researchers from several British academic institutions have launched a trial, OCTAVE, to better understand how current iterations of COVID-19 vaccines will impact vulnerable populations (1). According to Pam Kearns, Professor associated immune dysregulation, or their dose and who live with end-stage kidney of Clinical Paediatric Oncology at the use of immune-modifying medications,” disease, liver disease, some forms of cancer, University of Birmingham, and Director Kearns says. “Trials that evaluated the immune-mediated rheumatic diseases, or of both the Cancer Research UK efficacy of the SARS-CoV-2 vaccines a history of solid organ transplant. Clinical Trials Unit and the Institute of predominantly recruit individuals without The team is not short of volunteers. Cancer and Genomic Sciences, studies chronic diseases. Therefore, we do not “Trial inboxes have been inundated with over the last 12 months have shown know the effectiveness of the immune hundreds of messages from patients highly wide variation in immunocompromised response and its durability in patients with committed to helping us find the answers patients’ responses to COVID-19. These impaired immune systems.” to our questions. Though not all are patients’ vulnerability to the virus Through the OCTAVE trial, the eligible, we aim to disseminate our results increases the importance of vaccination, collaborative team will evaluate immune to inform the wider public as soon as they but their conditions also make them responses to COVID-19 vaccines, are available,” says Kearns. more likely to exhibit altered immune including the BioNTech/Pfizer, Oxford/ responses to the vaccines. AstraZeneca, and Moderna vaccines. The Reference “Their response to the virus can be team aims to recruit unvaccinated patients, 1. University of Birmingham (2021). Available at: attributed to their underlying disease, its as well as those who have received their first https://bit.ly/3vTvTyB.

their accessibility. “Every year, individuals method used for plasma processing to the Lowering and insurance companies spend upwards development of antibody drugs (1). The team of US$100 billion on antibodies, with costs added zinc chloride and polyethylene glycol Chromatography to treat a single patient often exceeding to separate a target antibody in solution $50,000,” said Andrew Zydney, Bayard D. – a cheaper, time-effective alternative to Costs Kunkle Chair, and professor of chemical conventional practices. This progress has engineering at Penn State, in a statement (1) left the team hoping that the process can An old technique – . The reason? Affinity chromatography, the be scaled up to help patients access these resurrected and repurposed process used to separate a desired antibody medicines at affordable prices. for modern bioprocessing from a solution, relies on chromatography columns that can cost up to $10 million each. Reference Though useful in the treatment of various Aiming to lower the cost of these much- 1. AL Zydney et al, Biotechnology Progress chronic illnesses, the price of many needed medicines, Zydney and his colleagues (2020). Available at: https://doi.org/10.1002/ monoclonal antibodies negatively impacts applied a 70-year-old protein purification btpr.3082. Upfront 9

IMAGE OF THE MONTH

In Silico Insight

A report shows the benefits of synthetic data for clinical trials

A report published by Accenture and Phesi shows that synthetic data can help drive faster, more efficient clinical trials. According to the document, AI systems that Benchtop Buddy analyze electronic medical records and track patient outcomes allow Helping to accelerate drug manufacturing, a benchtop robot developed for new data on trial protocols by collaborators at Clemson University and Nephron Pharmaceuticals is put to use and results to be generated easily. for the fill and finish of sterile syringes. However, the collaborators also https://bit.ly/3civA8r Credit: Clemson University point out that there are barriers to implementation. Often, pharma Would you like your photo featured in Image of the Month? companies do not have access to Send it to [email protected] data from varied sources and can also refuse to share the data they generate with others, preventing accurate statistical analysis. “Once the availability of data QUOTE of the month is addressed, an investment into technology, skills, and leadership is a must,” the report states. “Pharma companies need to do more to “We are at a critical point in human history. We now have the tools to identify and adopt advanced dramatically reduce or eliminate the risk of future epidemics and pandemics. technologies to work with the data We must invest now in the vaccines and biologic countermeasures that we needed for in-silico clinical trials. need, while linking these investments with commitments to equitable access.” R&D leaders will have to be bold in defining their next steps.” Richard Hachett, Chief Executive Officer, CEPI https://bit.ly/2OCpeHY Read the full report at https://accntu.re/31u91HX

www.themedicinemaker.comwww.themedicinemaker.com 10 Upfront

manufacturing partnership agreement products, with orders totalling over Fit for with Lilly back in May 2020 to address US$1.5 billion (1.8 trillion KRW) in the the urgent demand for COVID-19 first half of 2020 alone – a 150 percent the Future treatments worldwide. Despite the increase over our total revenue last year. global challenges of securing stable We catch up with Samsung supply amid the pandemic, we were How did you shorten the tech transfer Biologics about easing tech able to manufacture and deliver an initial timeline with Lilly? transfers and preparing supply of APIs within five months of Thanks to the close communication plants for the future contract signing, as well as reduce the and coordination between our two timeline for tech transfer to less than teams’ technical, quality, supply chain, Since its founding, Samsung Biologics three months. This was all possible and regulatory experts, we reduced the has gone from strength to strength. because of great collaboration between tech transfer timeline from six months Recently, the company partnered us and Lilly. to three. Biopharmaceutical technology with Eli Lilly to help boost Lilly’s transfer requires careful planning COVID-19 antibody manufacturing How has demand for manufacturing and evaluation to meet the scale-up capacity. Samsung is also building a capacity changed since the pandemic and GMP manufacture timelines. “Super Plant” that will incorporate began? Specifically, we believe the timing of automation and emerging technologies. Even before COVID-19, we’d seen facility fit and gap assessments is critical We caught up with James Choi, Senior an increasing trend in the demand to the success of the technology transfer, VP and Head of Marketing and Investor for biomedicines manufacturing. The as well as to avoid unexpected risks and Relations from Samsung Biologics, to pandemic has definitely intensified delays to the manufacturing schedule. get more details. this demand. We’ve signed numerous contracts with global biopharma Samsung Biologics has also started What’s the background between Lilly companies to manufacture a variety of work on Plant 4 – why is it dubbed and Samsung Biologics? drugs, including COVID-19 treatment “Super Plant”? We entered into a long-term candidates and expanded biologics Plant 4 will be the world’s largest Upfront 11

biopharmaceutical manufacturing technologies. For our new Plant 4, facility of its kind, with a total of 256,000 and across our existing plants, we have L manufacturing capacity. Upon begun a digital transformation initiative completion, our company is expected to enable real-time client access to their to be accountable for one-third of the quality records and documentation total global bio-CMO manufacturing while ensuring client confidentiality capacity, offering a combined sum of and security. Our systems are fully 620,000 L from our site in Incheon, implemented with data integrity and South Korea. cybersecurity, and Samsung Biologics We chose a modular design to allow is the first CDMO to be ISO 27001 flexibility for certain parts of the plant certified across all of our existing plants. to begin manufacturing activities It’s also imperative that manufacturing by the end of 2022, with the goal of facilities are equipped to cater to clients’ commencing full operations in 2023. needs and support them throughout the drug development process. Our What do you think is important to Super Plant will provide a full range ensure any new facility is truly fit for of CDMO processes for a complete the future? one-stop service, including early-stage Now, more than ever, it’s vital for development capabilities and large-scale biopharmaceutical companies to commercial manufacturing with a full evolve digitally through innovative QC lab. 12  In My View In My View Experts from across the world share a single What’s in Your strongly held opinion Capsids? or key idea.

Are your capsids full, half full, or empty? We need better analytical techniques to tell us the answers to these crucial questions in the development of gene therapies.

By Lori Stansberry, Senior BioPharma Marketing Manager at Thermo Fisher Scientific

It’s just over 30 years since the first approved gene therapy procedure was performed – and I’m sure we’re all amazed at how the field has progressed since then. The FDA expects approvals for cell and gene therapy products to reach around 20 per year by 2025 (1). A key component enabling the growth of the field of gene therapy is recombinant adeno-associated virus (AAV) vectors. There have been three recombinant AAV-based gene therapies approved for commercial use so far (2), and there include viral potency, identity, laboratory, including transmission are hundreds of active clinical trials quantity, process residuals (i.e., Triton electron microscopy (TEM), analytical worldwide for a variety of diseases. and deoxiribonuclease), aggregation, ultracentrifugation (AUC), charge As development of gene therapies empty capsids, capsid protein content, detection mass spectrometry, and UV increases, there is a growing demand and product safety. To meet purity spectrophotometry. The two main for accurate and efficient techniques requirements the proportion of empty, methods are TEM and AUC. TEM for characterizing AAV vectors. Many partial, and full AAV capsids must be involves a sample vitrified by rapid existing methods for analyzing AAV determined. Unsurprisingly, full capsids freezing to preserve the structure of a vectors, particularly for determining are required for therapeutic efficacy; biological specimen. When imaged, the full/empty capsid ratio, are empty capsids, which do not contain there is a clear difference in structure labor-intensive and time consuming. genetic material, or partial capsids, between full and empty particles. Analytical methods using anion which contain only a fragment of the The AUC method distinguishes and exchange (AEX) chromatography, genetic material, are simply by-products quantifies the different AAV capsids however, are supporting the analysis of AAV production and can negatively either by density (sedimentation of AAV capsids and could be a key impact product efficacy and safety – equilibrium) or mass (sedimentation technology for further advancing potentially producing adverse reactions, velocity). gene therapies. such as an immunogenic response in As AAVs are relative newcomers Viral vector characterization is the patient. in gene therapy, the industry has not essential for assuring product quality. There are various analytical methods yet decided upon the most effective Critical quality attributes (CQAs) for characterizing capsid levels in the method of analysis. Certainly, existing #CHROMATO methods for determining the full/empty ratio of AAV capsids have limitations; for example, TEM provides direct GRAPHY visualization and counting of the empty and full particles, but quantification heavily relies on image quality and EXPERTS field selection. And although AUC has excellent resolution and is highly accurate, it often requires a dedicated facility and specially trained analysts, who must spend hours on data interpretation. Moreover, AUC also consumes hundreds of microliters of valuable samples. In short, TEM and AUC are both low throughput – and neither is readily scalable. In my view, AEX chromatography is a useful technique for the analytical toolbox. When genetic material is encapsulated in the capsid, the surface Efficiently purify and characterize your antibody fragments charge on the particle changes. This physiochemical difference between full Reduce the capturing costs by up to 80 % with TOYOPEARL® AF-rProtein L-650F resin and empty capsids makes them ideal Increase speed and improve resolution of your analysis with TSKgel® UP-SW columns TM for analysis with AEX chromatography Get deeper insight into your samples with LenS3 MALS detector methods. AAVs are also small (20-25 Discuss with a chromatography expert and identify the best set of tools for your challenge: nm) and suitable for both traditional and bit.ly/ABfragments monolithic columns. The AEX chromatography method requires only several microliters of material – clearly a real benefit when gene therapy samples are so precious. Furthermore, no sample preparation is have learned they need to search across cost-effective way of speeding up needed, which simplifies the analysis multiple column chemistries to find the product development and reducing time and increases throughput. solution that provides the best resolution to market. Historically, use of the AEX method for empty/ full capsid separation. for separation of empty, full, and Right now, AUC provides the better References partial capsid was less than optimal resolution, but I believe that ongoing 1. FDA, “Statement from FDA Commissioner due to analysts narrowly exploring developments with AEX column Scott Gottlieb, M.D. and Peter Marks, M.D., anion exchange column chemistries. chemistries and chromatography Ph.D., Director of the Center for Biologics For example, a user may begin method systems make it a technology to watch Evaluation and Research on new policies to development with a column that for the future. Chromatography systems advance development of safe and effective cell would be recommended for nucleotide are already up and running in the QC and gene therapies,” (2019). Available at analysis because this would work well environment for other processes and https://bit.ly/3ryl9mp for characterizing genetic material specialist expertise is not needed. 2. FDA, “Chemistry, Manufacturing, and inside the AAV. However, this same Also, chromatography lends itself well Control (CMC) Information for Human Gene column chemistry may not be best to automation opportunities, opening Therapy Investigational New Drug suited to separate empty, partial, and the door for high-throughput capsid Applications (INDs),” (2020). Available at full capsids. Today, chromatographers analysis, ultimately providing a more https://bit.ly/3t728b6

www.themedicinemaker.com 14  In My View

pre-COVID-19, their suppliers were platform, and seamlessly collaborate Jumping into adamant that they had to always supply a and communicate with all parties physical document. The document would involved in the audit. the Digital need to be printed, physically signed, Although digitization is new scanned, and then returned. Now, many to pharma, it is not new to other World employees are working remotely and not industries. Many companies elsewhere all have access to printers and scanners; have embraced digital technology, and In today’s world of home as a result, companies have been forced software companies have spent decades working and remote business to adopt new software and platforms that developing flexible and agile platforms. operations, secure digital allow business to continue as normal. Operating in a GxP environment such technologies are more In the pharmaceutical and life as pharma means that industry agnostic essential than ever. Pharma sciences industry, traveling to a software platforms are required to be can no longer sit on the supplier or partner site to perform an validated before going live. The speed sidelines. audit has also changed, with regulators required to adopt new technology and market authorization holders because of COVID-19 has meant that performing these critical assessments pharma-specific software platforms virtually. In line with recent EMA, that provide validation out of the box FDA, and MHRA guidance, both are taking center stage. parties involved in the virtual audit We don’t know how long the have had to put digital solutions in pandemic will last for but, even after place. Gone are the days when you it has ended, we will not return to the could take the auditors to a boardroom old ways of working. Many companies and present them with endless boxes of are satisfied with flexible working and paper documents to prove compliance. will allow this to continue – and there Instead, companies have rolled out are costs to be saved; downsizing office new software tools allowing them to space, for example. But digitization share electronic documents, such as, is not just about enabling remote SOPs, training materials, and quality working. In my view, digital tools allow documentation directly in a software for significantly improved efficiency and cross-company collaboration. Relying on emails and non-validation file sharing tools for collaborating with your partners leads to poor document “Gone are the days visibility, versioning issues, delays, lost information, and poor cybersecurity. By Jason Lacombe, Chief Executive when you could One of the most common tools for Officer of Veratrak sharing documentation is email, but take the auditors to emails are a popular entry port for COVID-19 has accelerated digital cyber attacks, such as PDF malware. adoption of new technologies moving a boardroom and What looks like an uploaded PDF pharmaceutical and life sciences in one’s inbox can carry malicious companies away from paper-based present them with JavaScript code; once an employee processes and towards electronic data opens the attached PDF, it comprises capture. Rightly or wrongly, many endless boxes of the entire network. In recent years, pharma companies have traditionally a number of pharmaceutical entities, preferred paper-based systems for paper documents to including Merck, Dr. Reddy’s, recording and sharing data, which has and even the EMA, have been hit exposed inefficiencies. For example, prove compliance.” with cyberattacks. one customer explained to me how, One of the digital technologies In My View  15

integrity when documents are being we’ve seen an increase in companies “We don’t know shared. Using a blockchain architecture looking into blockchain technology to underlie all external exchange of data – as well as other digital solutions how long the and documentation across your supply to product their IT infrastructure as chain significantly reduces the risk more organizations share sensitive GxP pandemic will last of cyber attack on your organization. information regularly outside their Blockchain is a distributed ledger. A four walls. but, even after ledger is just a way of record-keeping. It As a result of COVID-19 accelerating is a reliable way of keeping transactional the use of digital technologies across the it has ended, we information and understanding who pharma industry, I hope that companies has performed an action, such as who will be more proactive when it comes will not return to has uploaded something, downloaded to adopting new technology in the something, or reviewed something. future. By piloting a new process and the old ways of Instead of a single ledger with a single technology like blockchain in parallel point of failure, there are multiple with a current process, you can measure working.” ledgers that are continuously updated. efficiency gains and other benefits more To compromise the entire distributed readily. Once you have the results at ledger, you need to take over the the end of a pilot, you can build a I am most excited by is distributed majority of ledgers within the network business case for full implementation ledger technology – often known as – and that’s close to impossible. With more easily and begin scaling up this blockchain – because it ensures data so many people working from home, new technology.

Contract Manufacturing Excellence

Experts in Viral Vector (AAV, adenovirus and lentiviral vectors) and Plasmid DNA (non-GMP, High Quality and GMP) manufacturing for pre-clinical, clinical and commercial supply.

Visit our website to find out more and take a virtual tour: www.cobrabio.com

www.themedicinemaker.com Cobra Biologics is part of the Cognate BioServices family 16  In My View

ground for these new technologies and is Riding the expected to result in tremendous industry growth. The number of indications that “The demand for (Nucleo)Tidal could benefit from this advancement is vast, including a wide range of infectious millions (or Wave diseases. Moderna, for instance, is working on mRNA programs for HIV, flu, and the billions) of doses of DNA manufacturers must pick Nipah virus. There is also a lot of activity up the pace to support the in the oncology space. these pioneering genetic medicine revolution The demand for millions (or billions) of doses of these pioneering vaccines vaccines sparks the sparks the question of how we can deliver genetic medicines at scale. We have seen question of how we regulators working to significantly shorter timeframes, and large-scale collaborations can deliver genetic have been announced worldwide, with big pharma working with biotechs medicines at scale.” and CDMOs to combine strengths, expertise, skills, and technologies. There has been considerable financial challenges for the rapid, scalable response investment from both big pharma and required in a pandemic situation, and governments, including the Biomedical DNA production has, therefore, become Advanced Research and Development a significant bottleneck. One approach Authority (BARDA), Defense Advanced (and my company’s approach) to solving Research Projects Agency (DARPA), and these challenges is to use synthetic By Karen Fallen, Chief Executive Officer of Coalition for Epidemic Preparedness DNA manufacturing, which enables Touchlight DNA Services Innovations (CEPI) programs, which have significantly accelerated production, rapid provided major support for the industry. scale-up, greater reliability, and lower The genetic medicine sector is booming. Manufacturers are also committing to capital and costs. Before the pandemic hit, research and sizable capacity expansions to meet the We must remember that, when compared commercialization of cell and gene growing needs. Despite all these efforts, with the rapidly maturing genetic therapies (CGTs) was advancing at however, we are already seeing how fragile medicine industry, DNA manufacture pace and, despite slight disruption in the supply chains are, with major players is still in its infancy. If we are to support 2020, the market is still expected to reporting delays in delivery, primarily due the growing sector, we must embrace new reach US$13.23 billion by 2023 (1). to production issues. approaches and technologies, maintain But COVID-19 has also highlighted Genetic medicines, such as nucleic focus, and commitment to improving the immense potential of other genetic acid vaccines and cell and gene therapies, the supply chain, and continue funding medicines, specifically prophylactic are heavily reliant on a sufficient and beyond the pandemic. Collaborations vaccines. The exceptional circumstances adequate supply of DNA. With the will also be crucial for future success. over the past year have accelerated remarkable expansion of both fields, the We must ensure that we make the most the emergence of novel nucleic acid demand for DNA today is extraordinary. of the current momentum by working vaccine technologies, and motivated Unfortunately, conventional plasmid together on the advancement of genetic development and manufacture at an DNA manufacturing technologies are medicine manufacture. unprecedented scale. The first mRNA not well suited for rapid scale-up. E. vaccine ever approved for human use coli fermentation is slow, expensive, Reference is already being distributed by the and limited by a lack of capacity. Batch 1. Research and Market, “Cell and Gene Therapy millions, and a second generation of failures are not uncommon, and antibiotic Global Market Report 2020-30: COVID-19 DNA vaccines is also in the pipeline. resistance genes can be present in the final Growth and Change” Available at https://bit. The pandemic has been a proving product. These factors bring significant ly/3s6pYTW.

TMM House.indd 1 07/12/2020 21:24 Enjoying your monthly copy of The Medicine Maker? Want the full experience? Join your peers today at themedicinemaker.com/register

Register online and you will get:

 access to all of our articles, including online exclusives  a monthly print or digital magazine (or both – your choice!)  a weekly newsletter covering the top trends and topics in drug development and manufacture  a community of over 112,000 medicine makers across the world

TMM House.indd 1 07/12/2020 21:24 18  Sponsored Feature

Filling: How to Find the Right Setup

Ready-to-use containers for sterile injectables can significantly improve total costs of ownership for pharmaceutical companies *MKYVI:EPYIWXVIEQWJSVXVEHMXMSREPERH689½PPMRK By Robert Linder PMOIP]8LIWIXVIRHWVIUYMVILMKL¾I\MFMPMX] produced and transported to the Pharmaceutical operations are optimized which can be provided by pre-washed, pre- pharmaceutical manufacturer, where to produce high quality drugs reliably over a sterilized standardized RTU containers. XLI]EVIJIHMRXSXLI½PPMRKPMRI[EWLIH period of decades. Introducing innovations However, there are cases where a switch dried, and depyrogenated to ensure the into manufacturing can lead to long-term from traditional to RTU containers is containers are safe and sterile, ready for risks, so any necessary changes demand not economically feasible. To account for XLI½PPERH½RMWLTVSGIWW%WEPPGSRXEMRIV thorough consideration. In particular, this added complexity, we must gain a types have different dimensions, separate medical safety and economic viability have thorough and holistic understanding of all ½PPMRK PMRIW EVI VIUYMVIH MR MRHMZMHYEP to be analyzed in parallel when choosing the options and parameters. GPIERVSSQW JSV ZMEPW TVI½PPIH W]VMRKIW primary packaging and the corresponding (PFS), and cartridges. This translates into ½PP ERH ½RMWL GSRGITX %WWIWWMRK XSXEP RTU vs traditional containers higher initial investments, greater operating cost of ownership is a good approach to Unlike traditional solutions, RTU containers GSWXWERHVIHYGIH¾I\MFMPMX]-REHHMXMSR gauge the economic viability of a project come washed, depyrogenated, and the glass-to-glass contact throughout the that spans several years, particularly when sterilized, which means they can go straight process carries a risk of defects, breakage, choosing between ready-to-use (RTU) MRXSXLI½PPMRKSTIVEXMSRIPMQMREXMRKQER] and particle generation. and traditional containers. SCHOTT has steps for pharma companies (see Figure With RTU containers, the value developed a straightforward model to help 1). The containers are delivered in a nest- stream is forward integrated to reduce GYWXSQIVWWIPIGXXLIMHIEP½PPMRKWIXYTJSV ERHXYFGSR½KYVEXMSR[LMGLEPWSTVIZIRXW GSQTPI\MX]ERHQE\MQM^I¾I\MFMPMX]JSV their operation – based on an analysis of glass-to-glass contact, and reduces defects, the pharmaceutical company, as all the the total costs of ownership. such as scratches, breakage, and particles. GSRXEMRIVWJIHMRXSXLI½PPMRKPMRILEZI 8LIRIWXERHXYFGSRGITX[EW½VWX already gone through a standardized, Exploring the trends HIZIPSTIHJSV689TVI½PPIHW]VMRKIWERH validated and cost-optimized washing The pharmaceutical industry is at a pivot has been the industry standard for around and sterilization procedure. Because point. Of the more than 4500 injectable 30 years. Today, SCHOTT offers the whole the SCHOTT iQ® platform is built on drugs in the pipeline, approximately range of primary packaging containers compliance with all relevant industry 80 percent are biologics (1). These are in its SCHOTT iQ® platform within a standards, the different container formats mainly targeted towards smaller patient harmonized and standardized secondary GERFI½PPIHSREWMRKPI½PPMRKPMRI[LMGL populations, addressing rare diseases or packaging. Pursuing a single, standard WMKRM½GERXP]VIHYGIWXLIMRMXMEPMRZIWXQIRX enabling a more patient-centric therapy. QIXLSHSJ½PPMRKEPPS[WQERYJEGXYVIVWXS in machinery and cleanroom capacity. %X XLI WEQI XMQI XLI QSVI VETMH QE\MQM^IXLIYXMPM^EXMSRSJIEGL½PPMRKPMRI market entry of biosimilars increases the  %RHXLEXPIEHWXSKVIEXIV¾I\MFMPMX] Counting costs impor tance of drug life cycle management. which is further enhanced through Economic viability is best assessed by Batch sizes are getting smaller, changeovers MRGVIEWMRKP]¾I\MFPIQEGLMRIGSRGITXW looking at the total cost of ownership, SR½PPERH½RMWLPMRIWEVIFIGSQMRKQSVI 8LIXVEHMXMSREPZEPYIWXVIEQJSV½PPMRK which includes all initial and recurring frequent, and adaptations in primary pharmaceutical containers is relatively costs throughout the whole project packaging container formats are more straightforward. Glass containers are PMJIXMQI *SV ½PPERH½RMWL STIVEXMSRW MR Sponsored Feature  19

• Where will the factory be? • How long is the project duration? • Which and how many containers of HMJJIVIRXX]TIW[MPPFI½PPIH# • Which machines will be used? • How many shifts will be in operation? • Will it be a small batch or campaign production?

With these inputs and database values for the different cost positions, the total cost of ownership can be modeled for different growth scenarios. Figure 2 shows 8EFPI'SWXX]TIWERHMQTEGXSJGSWXTSWMXMSRWSJXVEHMXMSREPERH689½PPMRK an exemplary case calculated using this model. The project, starting in 2021 with an initial investment of around US$2 million, is modeled with a linear growth (solid line) and an exponential growth (dashed line). It can be seen that for both growth scenarios, ½PPMRKSRP]689GSQTSRIRXWMWGLIETIVEX the end of the 10-year project timeframe. 8LIIGSRSQMGEHZERXEKISJ½PPMRK689 containers can be par tly attributed to the higher costs associated with the need to FY]QYPXMTPI½PPMRKPMRIWJSVXLIHMJJIVIRX container types and greater cleanroom space requirement. *MKYVI+VS[XLWGIREVMSWJSVXSXEPGSWXWSJS[RIVWLMTJSVXVEHMXMSREP½PPMRKERHVIEH]XSYWI½PPMRK (IGMHMRKSRE½PPERH½RMWLGSRGITXXLEX Note that this case is illustrative only. RIIHWXSFIIGSRSQMGEPP]FIRI½GMEPJSV several years or even decades is becoming the pharmaceutical industry, SCHOTT ½PPMRKXLIMQTEGXSJXLIMRHMZMHYEPGSWX more challenging, with new container options developed a straightforward model and positions becomes apparent. Though entering the market and the increased need calculated the total cost of ownership for ½PPMRKXVEHMXMSREPGSRXEMRIVWMWEWWSGMEXIH JSV¾I\MFMPMX]0SSOMRKEXXLIXSXEPGSWXSJ different scenarios using RTU and traditional with lower expenses for primary packaging, ownership helps obtain a clear picture of containers. The model allows us to guide 689½PPMRKSJJIVWEHZERXEKIWSJRSHMVIGX the machine and container combination GYWXSQIVWXS½RHXLIVMKLXTEGOEKMRK costs for washing and sterilization, as well that facilitates operation throughout the GSR½KYVEXMSRJSVXLIMVFYWMRIWWGEWI as lower costs associated with the risk of PMJIXMQISJXLITVSNIGX%RH7',388´W SCHOTT’s model is based on the typical glass breakage and cosmetic rejects caused straightforward TCO model – based on costs that occur during a pharmaceutical by glass-to-glass contact. Similarly, fewer extensive knowhow of an industry leader ½PPERH½RMWLSTIVEXMSREWPMWXIHMR8EFPI personnel are needed to operate the – helps you come to a sound conclusion. %PPGETMXEPI\TIRHMXYVIW '%4)< EVI LMKLIVEYXSQEXIH689½PPMRKPMRIW taken into account, with a depreciation rate Dr Robert Linder is Product Manager appropriate to the project lifetime, such as Building the business case at Schott XLIGSWXSJXLI½PPMRKPMRIERHXLI[EWLIV ;LIRXV]MRKXSHIGMHI[LMGL½PPMRK and setting up the cleanroom space. The strategy to follow, all costs have to be References recurring operational expenses are also carefully balanced against each other. 1. GlobalData, 12/2020 included, such as primary packaging or In SCHOTT’s TCO model, the above- 2. European Pharmaceutical Manufacturer, labor costs. By comparing typical relative mentioned costs are determined based “Money talks,” (2014). Available at values between traditional and RTU on several simple questions: www.epmmagazine.com/money-talks

www.schott.com/pharma Welcome to our annual celebration of the great and inspirational minds that contribute to the development and manufacture of medicines, including small molecules, biopharmaceuticals, and advanced therapies By Stephanie Sutton, James Strachan, and Maryam Mahdi

Putting together last year’s Power List was learned many lessons in terms of securing medicines to combat COVID-19. The a surreal experience; at the time, we were supply chains, adapting operations to suit industry has genuinely outdone itself. And just getting to grips with how COVID-19 social distancing, and working faster than alongside interventions against COVID-19, was affecting the world and changing our ever before to research and develop new others in the industry continue to work everyday lives. We faced a very uncertain therapeutic options for a new virus. tirelessly to address other crucial areas. future – especially as we all knew that new The pandemic is not over – and won’t For 2021, we present the top 20 vaccine and drug development typically be for some time – but there are reasons to inspirational medicine makers in three takes around ten years. feel optimistic. Effective vaccines have been different categories: Small Molecules Now in 2021, lockdowns remain in approved by various regulators for emergency (page 21), Biopharmaceuticals (page 26), place in many countries and the death toll use, existing drugs are being repurposed to and Advanced Medicine (page 32). continues to rise; approaching 3 million as help patients with severe COVID-19, and of early April 2021. Severe lessons have been new drug development is vibrant. Small Want to share this list with a colleague? learned by governments that failed to respect molecules, biopharmaceuticals, and even cell It can be accessed online for free at https:// the dangers of the virus. And pharma too has therapies are all being explored as potential themedicinemaker.com/power-list/2021 Feature 21 SMALL MOLECULES Top 20

ROSS T. BURN adoption by healthcare providers. CEO AT CATSCI LTD Small molecule therapeutics will always play a key role in combating After completing his PhD in 2007, diseases due to their relative Ross joined AstraZeneca as a Senior affordability, greener profile, and well- Analytical Chemist in process R&D. understood development processes. Burn helped launch CatSci Ltd in 2011 Additionally, with advances in and became its Chief Executive chemistry, the industry can Officer in 2015. “Even though uncover new molecular new therapeutic modalities entities with unprecedented are on the rise, there are target activity that can be still limitations to their manufactured at a speed efficacy, scalability, patient and cost not feasible 10 tolerability, and wider years ago.”

KELLY CHIBALE Development Research Unit at UCT, NEVILLE ISDELL CHAIR IN and the Founder and Director of the AFRICAN-CENTRIC DRUG UCT Drug Discovery and Development DISCOVERY & DEVELOPMENT Centre (H3D). In 2018, he was AND SOUTH AFRICA RESEARCH recognized by Fortune magazine as CHAIR IN DRUG DISCOVERY one of the World’s 50 Greatest Leaders PHIL S. BARAN and, in 2019, he was named as one of the PROFESSOR AT SCRIPPS Chibale is a Professor of Organic 100 Most Influential Africans by New RESEARCH Chemistry at the University of Cape African magazine. Town (UCT). He is also a Full Member Baran has received numerous awards and of the UCT Institute of Infectious “I hope to continue to develop preclinical accolades for his contributions to both Disease & Molecular Medicine, a tools that will facilitate prioritization of industry and academia. His ambition Tier 1 South Africa Research Chair in small molecules during their chemical is to contribute to the development of Drug Discovery, founding Director of (lead) optimization phase based on their organic chemistry by educating students, the South African Medical Research predicted pharmacological profile in inventing new tools and strategies, and Council (SAMRC) Drug Discovery & African patients.” using these new technologies in the pharmaceutical space to accelerate the development of small and large molecule medicines. “The use of biologics and oligonucleotide based therapies will continue to grow in popularity (for good reason) but, when the same outcome can be achieved using orally bioavailable small molecule therapies, those are almost always preferable from the standpoint of cost, simplicity, and worldwide availability.” PAOLO COLOMBO EMERITUS PROFESSOR AT THE UNIVERSITY OF PARMA

Colombo joined the University of Parma, Italy, in 1986. His interest in drug delivery research focuses on oral, transdermal, and inhalation products. He has patented over 40 different drug delivery systems, JOHN CHIMINSKI many of which have become registered CHAIR AND CEO AT CATALENT products. He is also the Chief Executive Officer of PlumeStars and Fellow In the more than 20 years Chiminski of AAPS, AIMBE, and CRS. “My has spent at Catalent, he has personal opinion is that the lesson of overseen the company’s strategy to COVID-19 has to be capitalized on and help accelerate the small molecule not forgotten, because similar diseases development process and improve and pandemic situations, coming from clinical outcomes. “We want to power our global lifestyle, could be repeated.” the innovation and growth of the life science industry by becoming its ATHENA leading development and commercial COUNTOURIOTIS partner. To do that, we have built PRESIDENT AND CEO our team and capabilities to be in AT TURNING POINT the best position to help innovators THERAPEUTICS with development expertise, delivery technologies, and the right-scale Countouriotis’ experience manufacturing platforms to bring includes large and small molecule more of these programs to patients.” therapeutics in hematologic and solid tumor indications, with multiple regulatory approvals in the US and Europe. In 2018, Countouriotis joined Turning Point Therapeutics’ board of directors and also became the company’s President and Chief Executive Officer. She also serves on the board of directors of Iovance Biotherapeutics and Passage Bio.

“The speedy development of COVID-19 vaccines may provide a template for some drug development projects. Though that approach won’t apply in all settings, ‘speed’ is an attribute we value and recognize at Turning WILL DOWNIE impact of COVID-19 on pharma, he Point. We see it as our duty to CEO AT VECTURA responded, “Often, out of a crisis, great bring differentiated therapies to things happen. This is clearly a moment patients as rapidly as possible, Downie has over 30 years of industry in time where the world has faced one of which leads us to think creatively experience and joined Vectura as its biggest challenges, with the pharma and collaboratively with regulatory CEO in November 2019 – helping the industry playing a central role in fighting agencies about important topics company implement its strategic change the pandemic. I truly believe we will like trial design.” from an inhaled therapy development look back on COVID-19 as a seminal company to CDMO in the inhalation moment – a time where the impossible field. When asked to comment on the was made possible.” ALISON HOLMES PROFESSOR OF INFECTIOUS DISEASES AT IMPERIAL COLLEGE LONDON

Holmes is also a Fellow of the Academy of Medical Sciences and an NIHR Senior Investigator. She leads a multidisciplinary research group and collaborates with international organizations to help improve the pharmaceutical industry’s response to JOHANNES KHINAST antibiotic-resistant infections. She is also PROFESSOR OF the President of the International Society PHARMACEUTICAL for Infectious Diseases – a body established ENGINEERING AT to support a range of stakeholders in the GRAZ UNIVERSITY OF management and prevention of infectious TECHNOLOGY AND CEO disease outbreaks. AT RCPE

Khinast has almost 300 publications in refereed journals and 10 patents registered under his name, and has worked with numerous pharmaceutical companies as an advisor for the implementation of novel drug formulations. “Pharma will look back on COVID-19 as a game- changer that hopefully brought back API production to Europe. We will be better prepared to face another health crisis in the future by reacting faster and making EDWARD rapidly invented drugs accessible HAEGGSTRÖM for a large number of people CEO AT NANOFORM around the world.”

In 2015, Haeggström commercialized the nanoparticle engineering platform he developed with Jouko Yliruusi, quality generic medicines to international Acting Professor at the University of aid organizations, having exported to Helsinki, Finland. This marked the more than 120 countries worldwide since beginning of Nanoform. Haeggström its inception. is also a professor at Helsinki University Outside of Morningside, Kotecha and Head of the Electronics Research regularly advises businesses and Laboratory within the Department of government departments. He is a Physics. When asked about his future NIK KOTECHA Department for International Trade aims, he responded, “My ambition CHAIRMAN OF MORNINGSIDE (DIT) Export Champion, a CBI Regional is to continue pushing the progress PHARMACEUTICALS LTD Councillor, and a Board Member for of nanoparticle engineering on a the British Generic Manufacturers global scale. By furthering the reach A self-made entrepreneur, Kotecha Association (BGMA). In 2017, Kotecha of our small molecule and biologics established generic medicines manufacturer set up the Randal Charitable Foundation, nanoforming technologies, we can and supplier Morningside Pharmaceuticals which works to ensure that grants reach provide promising therapies with a from a home garage in the 1990s. Since charities helping individual people in need route to market and improve existing then, Morningside has grown to be one of of assistance and has directly led to more therapies.” the leading UK suppliers of a wide range of than 145,000 lives being saved so far.

www.themedicinemaker.com 24 Feature

M. N. V. RAVI KUMAR PROFESSOR AT THE UNIVERSITY OF ALABAMA IN TUSCALOOSA

Kumar’s lab develops non-competitive receptor targeting carrier systems for oral drug delivery applications in human health and disease. Their rational design of biodegradable polyesters with tunable ligand-receptor stoichiometry has enabled the clinical translation of small molecule drugs with otherwise poor oral bioavailability. “I am confident that our technologies will not only facilitate drug repurposing, but also minimize attrition rates when applied early in drug discovery programs. The majority of human conditions remain safely, efficaciously, and economically managed with traditional pharmaceuticals, especially when novel formulations are considered. Small molecule drugs remain a central plank of academic-industry innovation and are here to stay.”

ANDREW MOORE NIGEL LANGLEY GENERAL MANAGER AT PFIZER GLOBAL TECHNOLOGY CENTREONE DIRECTOR AT BASF

Moore joined Pfizer CentreOne during Langley has written over 100 scientific the COVID-19 pandemic. But with over publications and co-edited two books. 18 years of leadership experience, Moore He is also an adjunct professor at the was unphased by the change. He says, University of Mississippi and a Fellow “The pharmaceutical industry will look of the UK’s Royal Society of Chemistry. back at this historic period as the catalyst In 2018, he was awarded the Industry that propelled us to do things differently Research Achievement Award in and collaborate in ways not seen before. We Excipient Technology by the IPEC found ways to be more innovative because Foundation. He has been a member we worked closely together to find solutions of the Executive Committee at IPEC faster and overcome challenges at a time of Americas since 2010 and is currently unprecedented need. This was often achieved Chair Elect. He is also helping to lead despite working remotely and conducting the Novel Excipients Initiative for IPEC meetings virtually. There are many lessons Americas in collaboration with the IQ learned throughout this experience, some of Pharma Consortium. “I have a passion which we haven’t even realized today.” and interest in innovation especially in the area of pharmaceutical excipients. I am hopeful that, in the coming years, ROBERT S. LANGER Sciences, and the National Academy excipient innovation will become a key DAVID H. KOCH INSTITUTE of Inventors. He has also served on the driver in the pharmaceutical industry, PROFESSOR AT THE FDA’s Science Board from 1999 to 2002. in both biologics and small molecule MASSACHUSETTS INSTITUTE OF drug development. Without the TECHNOLOGY opportunity to develop new excipients that have been specifically designed Arguably one of the most prolific to help address current and future inventors in all of medicine and with formulation challenges – for example, over 1,300 issued and pending patents, in improving the stability of biologics Langer’s work has impacted many lives. and in the area of poorly soluble small He holds 34 honorary doctorates and has molecules – these challenges will been elected to the National Academy remain unmet and, as a consequence, of Medicine, the National Academy of optimal medicines will not be available Engineering, the National Academy of to the patient.” MATTHEW TODD PROFESSOR OF DRUG DISCOVERY AT UNIVERSITY COLLEGE LONDON

Todd founded and currently leads various open-source drug discovery consortia, including Open Source Malaria, Open Source Antibiotics, and JOHN TALLEY MycetOS. These focus on ways that CHIEF SCIENTIFIC OFFICER AT open science can accelerate the discovery EUCLISES PHARMACEUTICALS of new medicines: all data and ideas are freely shared, anyone may participate, Talley joined Euclises Pharmaceuticals and there are no patents. His research in 2011 and has co-invented several interests span drug discovery and the marketed drugs. He also serves as development of new synthetic methods. FAITH OSIER Partner and Vice President-Chemistry GROUP LEADER, MALARIA at Emmyon, advising on the “Small molecules can be VACCINE DEVELOPMENT AT identification of new chemical entities. tremendously powerful, effective, KEMRI – WELLCOME, KENYA “My ambition in the near future is to safe, inexpensive, and (because of AND VISITING PROFESSOR continue to be actively engaged in their simplicity) ‘democratisable’ OF IMMUNOLOGY AT OXFORD drug discovery research programs. I in that lots of laboratories can be UNIVERSITY would love to have access to laboratory involved in their optimization. We facilities for hands-on experimental need every weapon available if we are Osier’s work focuses primarily on the research because I thoroughly enjoy it.” to combat disease more effectively.” eradication of malaria and is currently exploring the possibility of developing a vaccine against the disease. She is also the President of the International Union MARTIN VAN TRIESTE been damaged in recent years. We are of Immunological Societies, and oversees PRESIDENT AND CEO AT CIVICA in the biotechnology century. We will the FAIS Legacy Project, which aims to RX look back and say we learned more train 1000 African immunologists over about human biology, how our DNA 10 years. Under Van Trieste’s leadership, Civica impacts the effectiveness of treatments, has expanded its membership to and how we can design drugs to target include more than 50 health systems a specific disease. As a result, we will across the US and has delivered more all benefit from cures and not just G.V. PRASAD than 40 essential medications for treatments for chronic conditions.” CO-CHAIRMAN AND hospitals, 11 of which are being used MANAGING DIRECTOR to treat COVID-19 patients. Most AT DR. REDDY’S recently, Civica began providing its LABORATORIES medicines to the US Department of Veterans Affairs and the US Prasad has played a key role in Dr. Reddy’s Department of Defense. During the operations since the company’s inception. A peak of COVID-19 outbreaks in the firm believer in sustainable manufacturing, US, Van Trieste led efforts to deliver he leads initiatives on the adoption of green 2.1 million containers of Civica technologies and processes. Most recently, medicines to the country’s Strategic he was declared a Regional Honoree for National Stockpile. the 2020 YPO Global Impact Award, was conferred the V. Krishnamurthy “It was satisfying to see how the Award for Excellence by the Centre for pharmaceutical industry responded Organizational Development in 2019, quickly, collaboratively and effectively and received The Boundary Breaker at the in response to COVID-19 – and CEO Awards in 2018. improved our reputation, which has

www.themedicinemaker.com BIOPHARMACEUTICALS Top 20

the complexities of manufacturing drug products during a time of pandemic related-restrictions, has uncovered areas where there are opportunities for improvement. This includes: risk- and science-based regulatory decision making to help companies and regulators prioritize and evaluate alternative and better means to control drug manufacturing processes; manufacturing supply reliability to ensure essential materials are available; expansion RICK BRIGHT of capability to provide production SENIOR VICE PRESIDENT, lines for the manufacture of essential PANDEMIC PREVENTION drug products; technical resources & RESPONSE, HEALTH to develop and implement drug INITIATIVE AT THE HAL BASEMAN product manufacturing methods and ROCKEFELLER FOUNDATION CHIEF OPERATING OFFICER AT technologies; and harmonization, VALSOURCE modernization, and understanding Bright joined The Rockefeller of post-approval change procedures Foundation in March 2021 to lead “The global pandemic has resulted and requirements to provide the the development of the Foundation’s in the need to accelerate the most valuable information needed pandemic data and action platform, development, approval, and for the expansion of drug product which will help prevent future distribution of COVID-19 related manufacturing output and reduce pandemics by identifying and products. This need, combined with barriers to that expansion.” responding to the earliest alerts of a disease outbreak and stopping it in the first 100 days. He has extensive experience in global public health KAREN FLYNN patients as quickly as possible. This and most recently served the US PRESIDENT, BIOLOGICS & CHIEF unprecedented sharing of knowledge Department of Health and Human COMMERCIAL OFFICER AT has paved the way to find solutions.” Services as the Deputy Assistant CATALENT Secretary for Preparedness and Response, and Director of the Prior to joining Catalent, Flynn served esteemed Biomedical Advanced as the Senior Vice President and Research and Development Chief Commercial Officer of West Authority (BARDA). Bright Pharmaceutical Services. “One of the resigned from government service lessons learned from the pandemic in protest against the Trump is that the partnerships between administration’s approach to public and private entities, spanning handling the COVID-19 pandemic, academia, government, and non- specifically over the level of political profit organizations, and even between interference in science and the spread companies that would traditionally of inaccurate information that he compete, have been hugely beneficial said was “dangerous, reckless and in getting vaccines and therapies to causing lives to be lost.” KENNETH C. FRAZIER CHAIRMAN OF THE BOARD AND CEO AT MERCK SHARP & DOHME

Frazier started out as a lawyer and has taught trial advocacy in South Africa. He joined MSD’s public affairs division as a general counsel in 1992, and became CEO in 2011. He will retire from the role of CEO as of June 30, 2021, but will continue to serve as an executive chairman on the board of directions for a transition period. “It has been a privilege to serve as Merck’s CEO for the past decade and to work with the most dedicated and talented employees and management team in the industry,” Frazier said in a company statement.

JUSTIN HANES JACKIE HUNTER LEWIS J. ORT PROFESSOR OF BOARD DIRECTOR AT OPHTHALMOLOGY AT JOHN BENEVOLENTAI HOPKINS UNIVERSITY; AND DIRECTOR AT THE CENTER Hunter has over thirty years of experience FOR NANOMEDICINE in the bioscience research sector, working across academia and industry, including MAIK JORNITZ “The most defining moments of my leading neurology and gastrointestinal drug PRESIDENT AND CEO AT career involve the many people who discovery and early clinical development for G-CON MANUFACTURING have influenced my thinking, and GlaxoSmithKline. with whom I have worked to create “For me, it is always exciting and new methods to make drugs safer “BenevolentAI leverages machine encouraging to see new therapies being and more effective. Big problems are learning to help scientists view and developed, especially fighting against rarely solved by individuals. Thus, reason across all of the world’s available cancer, but nowadays also rare diseases, my most defining moments include: biomedical information to solve complex which had no treatment options in the meeting my mentors, including Robert drug discovery challenges. Last year, past. Treatments against cancers are Langer of MIT, and Henry Brem the company identified baricitinib as a now becoming a targeted approach, and Drew Pardoll of Johns Hopkins; treatment for COVID-19, which later instead of affecting the patient’s entire the opportunity to work with scores won FDA approval for use in hospitalized body. In other cases, patients who had of amazing students, postdoctoral patients. Post-pandemic, we should no chance of survival now see hope fellows, and colleagues at Johns expect industry conversations to revolve that their disease may be treated. These Hopkins; the vision of the Wilmer Eye around how we use AI to improve future inspiring treatment steps forward make Institute led by Peter J. McDonnell health systems and revolutionize the drug me want to work harder to find the to start a center of excellence focused discovery process. Another topic that will manufacturing and process solutions to on the intersection of medicine and dominate the industry post-COVID is how support such efforts. The COVID-19 nanotechnology, and being asked to we improve and unblock approval processes pandemic and the incredible speed at be its founding director; and support for future therapies and vaccines. We have which vaccines have been developed from the generous philanthropists seen how approvals can be expedited with highlight an urgency for much-needed and investors who have catalyzed our rolling data reviews and large data trials solutions. We as an industry have discoveries, allowed many of them in the pandemic, and, as a result, come a long way for the to be tested in human clinical trials, we have witnessed huge scientific better of the patient – and I and helped maximize the good our leaps in vaccine development.” find this very motivating.” inventions can do for humanity.”

www.themedicinemaker.com

JEAN-PAUL KRESS CEO AT MORPHOSYS

“One lesson from COVID-19 is the idea that scientists in industry, academia, and government can coordinate activities better and work more openly together to rapidly MARIA JOSÉ ALONSO develop transformational medicines in PROFESSOR AT THE the future. Such collaborations should UNIVERSITY OF SANTIAGO have impacts far beyond pandemics to DE COMPOSTELA CIMUS provide patients with better treatments RESEARCH INSTITUTE for life-threatening diseases such as cancer. At MorphoSys, we’ve Alonso’s lab has pioneered numerous learned that including innovative discoveries in nanomedicines and she is clinical strategies with real-world also a past president of the Controlled evidence studies and pursuing Release Society. She has coordinated accelerated pathways for breakthrough research consortia financed by the medicines can lead to accelerated drug WHO, the Gates Foundation, development and approval.” and the European Commission, NEIL KUMAR and is the author of almost 300 Since joining MorphoSys as CEO in FOUNDER AND CEO AT scientific contributions. For Alonso, September 2019, Kress has strategically BRIDGEBIO PHARMA biotechnology, nanotechnology, and repositioned the company from an artificial intelligence will drive the antibody technology provider to a Prior to founding BridgeBio in 2015, future of the pharma industry. commercial-stage biopharma company. Kumar served as a principal at Third Rock Ventures, the interim vice president of business development at MyoKardia, and an associate principal at McKinsey & Company. “What are the most exciting technologies that will drive the future of pharma? There are so many! To start, technologies that help us better interrogate genetics and link DNA sequence to RNA transcription and protein translation, through more sensitive transcriptomics (single cell and bulk) and quantitative mass spectrometry proteomics. Second, we have more EMMANUEL LIGNER and better quality datasets of human PRESIDENT AND CEO AT CYTIVA; GROUP EXECUTIVE AT DANAHER mutations which help us identify BIOTECHNOLOGY GROUP new, causal pathogenic variants in different populations. Third, we have Ligner has been the President and CEO of Cytiva since July 2017, when it was known made rapid progress on technologies as GE Healthcare Life Sciences. like cryo-EM and CRISPR screens to understand the effect of mutations on “I’m excited about the development of new modalities. It’s amazing to see years protein structure, cellular function and of research and development come to fruition with mRNA technologies and cell systems dysregulation. The confluence therapies finally reaching patients. We must continue investing in automation and of these technologies promises digital technologies that will help accelerate the development and manufacture of better medicines to patients faster in these novel therapeutics, so we can reach as many patients as possible.” the future.” Feature 29

RINO RAPPUOLI CHIEF SCIENTIST AND HEAD OF EXTERNAL R&D AT GLAXOSMITHKLINE

Considered one of the world’s leading vaccine experts, Rappuoli was involved in the development of CRM197 used in H. influenzae, N. meningitidis, and pneumococcus vaccines, and has introduced several novel scientific concepts. He is also actively involved in research and development. Rappuoli and a team of Italian scientists at the Monoclonal Antibody Discovery Lab have been conducting extensive work on SARS-CoV-2 and recently demonstrated three mutations that allow the virus to evade the polyclonal antibody response of highly neutralizing convalescent plasma. MIKE REA CEO AT IDEA PHARMA

Rea is building off the applied innovation platform of IDEA and the lessons of the Pharmaceutical Invention and Innovation Index to launch Protodigm – an alternative research organization that brings a constellation of technology to the ODE (options, decisions, evidence) challenge to deliver disruptive development approaches.

“There is so much amazing technology that could support pharma that is not reaching into development because companies are stuck on what worked last year versus what could work next year. One huge area is drug delivery – from what is druggable, to what is soluble, to how it can be delivered to its target. So much can be unlocked by thinking differently early.”

Mazumdar-Shaw is seen as a pioneering “A positive outcome of the pandemic biotech entrepreneur, a healthcare is the global commitment to collective visionary, a global influencer, and a surveillance and pandemic prevention philanthropist. She is the recipient of two and preparedness. At long last, of India’s highest civilian honours: the healthcare investment is likely to see Padma Shri and Padma Bhushan. She has a sharp increase across the world. also received many other accolades from Moreover, the crisis has brought to the overseas. She serves on the board of MIT, fore a host of complex issues around KIRAN MAZUMDAR- Pure-Tech Health, Infosys, and Narayana drug pricing and distribution, as SHAW Health, and holds key positions in various well as a number of social and other EXECUTIVE CHAIRPERSON AT industry, educational, government, and inequalities that are now demanding BIOCON AND BIOCON BIOLOGICS professional bodies globally. close attention.”

www.themedicinemaker.com 30 Feature

MELINDA RICHTER GLOBAL HEAD OF JLABS AT JOHNSON & JOHNSON INNOVATION

Before joining JLABS, Richter was the Founder and CEO of Prescience International, which was dedicated to accelerating research to the patient. Richter created the company after a medical emergency left her questioning the efficiency of the current healthcarecare system. system. In her current role, she supports the innovation communitymmunity by creating capital-efficient commercialization dmodelsels t hthatat help early-stage companies. She is also Board Chairir of the California Life Sciences Association and a board memberember of BIO’s Technology Transfer Committee.

“COVID-19 accelerated trends in the healthcare industrytry which have and will continue to create more value for everyone. We’ve seen parallel processing in drug development accelerate time to market for life- enhancing, life-saving therapies; collaboration across companies, borders, and types of organizations to meet an urgent health security threat; an increased focus on health equity and diverse clinical trials to bring more potential solutions to people who’ve had marginalized care; and more options to get and GIL ROTH cover virtual care outside of traditional institutional PRESIDENT AT THE PHARMA offerings. I feel the crisis of COVID-19 demanded & BIOPHARMA OUTSOURCING creativity, generosity, empathy and pure determination, ASSOCIATION and each of us played our part.” Roth founded PBOA in 2014 to give a voice to the CDMO sector in regulatory, legislative and business matters. During JAMES N. and is now continuing this journey at the pandemic, he helped connect the THOMAS Just - Evotec Biologics. federal government and other parties with EVP, GLOBAL CDMOs to develop and manufacture HEAD OF “How can we accelerate drug treatments and vaccines. Alongside his BIOTHERAPEUTICS development projects of the future? work with the pharma industry, he also AND PRESIDENT OF US Through systematic, vertically integrated runs a cultural podcast called The Virtual OPERATIONS AT JUST - EVOTEC modality platforms bound together Memories Show. BIOLOGICS and defined through a common data pool. Acceleration requires prediction, “Post-pandemic, the industry – and Over the course of his career, Thomas and the machine learning and AI tools governments across the world – will has contributed to the advancement that are available or emerging will be have to answer major questions about of many important therapeutics capable of doing this if the right data pharma supply chains. Our members including Activase, Vectibix, Enbrel, are captured and registered. A data-rich have risen to the challenge of helping Prolia/Xgeva, and Repatha, as well systems approach should go as far back develop and manufacture vaccines as numerous biosimilar programs. into the discovery process as possible to and therapeutics for COVID-19 Thomas is passionate about creating capture improvements to speed, cost, while maintaining supply of their and using innovative technologies to quality, number of clinical experiments clients’ non-COVID products, but it meet the needs of patients. In 2014, and ultimately clinical success rates. This remains to be seen how manufacturing he co-founded and became CEO of approach will not only accelerate drug infrastructure will change to Just Biotherapeutics, with a focus on development, but reduce R&D costs accommodate the potential for more expanding global access to biologics, and, ultimately, improve patient access.” global vaccination programs.” JAN VAN DE WINKEL Feature 31 PRESIDENT AND CEO AT GENMAB

After co-founding Genmab and serving as President, Research and Development and Chief Scientific Officer, van de Winkel was appointed President and Chief Executive Officer in 2010. Under his leadership, Genmab has created three antibody medicines that all received Breakthrough Therapy Designations from the FDA and are now commercialized by partners: Darzalex, a backbone therapy for multiple myeloma, commercialized by Janssen; Kesimpta by Novartis; and Tepezza by Horizon Therapeutics.

“We believe that partnerships and collaborations are foundational to accelerate innovation and bring medicines to patients as quickly as possible. It takes an innovation ecosystem with partnerships between biotech and big pharma, academia, research institutes, data sciences companies or medical electronics companies to catalyze break-through innovation.”

MIKE VANDIVER EMMA WALMSLEY SENIOR VICE PRESIDENT OF CEO AT GLAXOSMITHKLINE BIOTHERAPEUTIC OPERATIONS AT JUST - EVOTEC BIOLOGICS Walmsley first joined GSK in 2010, initially working for the Consumer Healthcare, Europe, division. She became CEO in April 2017. The company missed a key Vandiver has over 30 years of internal profit goal in 2020 due to the impact of the pandemic, but still performed biopharmaceutical process development well. Recently, the company announced promising results from a phase III trial and manufacturing experience. At Just with Vir Biotechnology for a monoclonal antibody to treat COVID-19. Biotherapeutics, he led efforts to bring the company’s clinical GMP facility, online. Now at Just - Evotec Biologics, Vandiver is leading efforts to bring the company’s first North American J.POD clinical and commercial biomanufacturing facility online. When considering the most exciting technologies that will drive the future of the industry, Vandiver says: “Deployable and portable biologics manufacturing is gaining more momentum as a result of the pandemic. Assurance of regional supply and rapid response will fuel further development of the enabling technologies. This future may be closer than we think.”

www.themedicinemaker.com ADVANCED MEDICINE Top 20

USMAN “OZ” AZAM PRESIDENT AND CEO AT TMUNITY THERAPEUTICS

As head of cell and gene therapy at Novartis between 2014 and 2016, Azam was part of the team that brought the first CAR T cell therapy to market. Before that, he held various science, regulatory and commercial roles at Aspreva, J&J and GSK, but originally trained as an obstetrician and gynecologist. At Tmunity, Azam is focused on bringing the next-generation of T cell therapies to market. He is also on the board of directors for the Alliance for Regenerative Medicine.

VERED CAPLAN CEO AT ORGENESIS

Orgenesis recently announced several collaborations with international institutions, including Johns Hopkins University and the University of California, Davis, both of which joined the company’s POCare network. Caplan says, “We as an industry must invest in building the frameworks that will allow scientists to translate CATHERINE BOLLARD large-scale patient-specific products as their advancements to industrial DIRECTOR AT THE CHILDREN’S more cell therapies are getting approval products. It’s not enough to make NATIONAL RESEARCH (for example, the latest approval of the these therapies available, we must INSTITUTE; AND PROFESSOR Bristol Myers Squibb BCMA-CAR make them available for all that OF PEDIATRICS AT GEORGE T cell product for myeloma). Looking need them.” WASHINGTON UNIVERSITY to the future, cell-based therapies will She likens the industry to the early not be sustainable with a purely patient- days of computers. “We are building “The success of the mRNA vaccine specific centralized manufacturing model more sophisticated hardware (cell and technology for COVID-19, I believe, has and, therefore, the field must move into gene processing systems) that in turn huge implications for the cancer vaccine the development of off-the-shelf cell drives more software development field and, ultimately, for combination therapies. The success of off-the-shelf (the molecular biological pathways vaccine and cell therapy approaches virus-specific T cells is especially exciting by which we manipulate cellular for cancer and virus infections. But because it has the potential to be the systems) that again requires more the biggest challenge remains the platform for other antigen specific and advanced hardware. We can only centralized manufacturing model for CAR T cell therapies.” imagine what the future holds.” MASSIMO DOMINICI PROFESSOR AT THE UNIVERSITY HOSPITAL OF MODENA AND REGGIO EMILIA; AND SCIENTIFIC FOUNDER OF JENNIFER DOUDNA RIGENERAND LI KA SHING CHANCELLOR’S PROFESSOR OF BIOMEDICAL “COVID-19 has led to challenges with SCIENCE AT UNIVERSITY OF clinical trials; almost 1500 trials have CALIFORNIA, BERKELEY reported delays due to the pandemic. This is particularly true for phase I studies. For Along with Emmanuelle Charpentier, those, almost half of the trials that have MIGUEL FORTE a Director at the Max Planck Institute been delayed have had a special impact CEO AT BONE for Infection Biology in Berlin, Doudna in oncology. Considering that cell and THERAPEUTICS played an instrumental role in the gene therapies have their big fraction of development of CRISPR-Cas9. The investigations in that phase, this could “The development of vaccines pair were the first to suggest that the have a relevant impact on the field. The for COVID-19 came about at technology could be used for gene big challenge – but also opportunity – for lighting speed because of the editing. For her contribution to the the industry is how to adapt to the current alignment of a global need, cell and gene field, Doudna was the and possibly enduring situation and how regulatory support, and political co-winner of the 2020 Nobel Prize for to conceive new ways to conduct trials, will. Extensive scientific chemistry. Her current research focuses accounting for regulatory frameworks, collaboration and focus to address on RNA-guided gene regulation. new technologies, and new needs.” a significant unmet medical need is an important lesson to extrapolate to the field of cell and gene therapies, where it is FABIAN GERLINGHAUS in the cell therapy field struggle to key to collaborate and combine CO-FOUNDER AND CEO AT treat a few thousand patients per emerging technologies to deliver CELLARES year because of the lack of scalable what we know is bringing manufacturing technologies. But I’m enormous value to patients with “The biggest challenge commercial cell most excited about the creation of still unmanageable conditions.” therapy developers are facing is their true end-to-end automation of cell inability to scale manufacturing to meet therapy manufacturing platforms as Forte believes the main challenge patient demand. The one-dose-at-a- they’ll help accelerate access to life- for the industry in 2021 is access. time approach is highly labor-intensive, saving cell therapies by resolving this “The field explodes with enabling failure prone, and extremely difficult manufacturing bottleneck. At Cellares, technologies but the objective to scale with manual methods. For we believe the industry must move should always be to deliver the example, to produce 10,000 patient beyond ‘semi-automated’ processes, and value to patients.” doses, one needs to run 10,000 separate toward the adoption of true automation. He is also excited about the manufacturing processes – each of This is critical to de-risking the increasing “professionalization” which takes weeks and includes around manufacturing process, reducing costs, of biology: “Instead of cells 50 manual processing steps and and the risk of manufacturing learning ‘on the job,’ they will be 80 hours of touch time. This failures, enabling cell administered already primed for is a logistical nightmare; therapy companies to tolerance, allogenicity, and for even the most treat significantly larger optimization of the therapeutic pioneering companies patient populations.” effect.”

www.themedicinemaker.com 34 Feature

RACHEL HAURWITZ PRESIDENT AND CEO AT CARIBOU BIOSCIENCES

Haurwitz co-founded Caribou Biosciences in 2011 with Nobel Prize winner Jennifer Doudna and other CRISPR scientists. Caribou is a clinical-stage company developing an internal pipeline of off-the-shelf genome-edited CAR-T and CAR-NK cell therapies for oncology. In 2014, she was named by Forbes Magazine to the “30 Under 30” list in Science and Healthcare, and in 2016, Fortune Magazine added her to the “40 Under 40” list of the most influential young people in business. In 2018, the Association for Women in Science recognized Haurwitz with the annual Next Generation Award. She also serves on the board of directors of the Biotechnology Organization (BIO).

DENG HONGKUI CHANGJIANG PROFESSOR, THE BOYA CHAIR PROFESSOR, AND DIRECTOR OF THE INSTITUTE OF STEM CELL RESEARCH AT PEKING UNIVERSITY BRUCE LEVINE In 1989, Hongkui left China for the US, working on HIV at New York University BARBARA AND EDWARD NETTER before switching to stem cells – eventually becoming research director of the PROFESSOR IN CANCER GENE stem cell company ViaCell in Cambridge, Massachusetts. He then went back to THERAPY AT THE UNIVERSITY OF China after being awarded the prestigious Changjiang Professorship. In 2017, he PENNSYLVANIA and Chen Hu engineered resistance to HIV in mice using CRISPR gene editing, and for the first time used the technique on an AIDS patient – demonstrating Levine believes the success of COVID-19 the safety of CRISPR for humans. vaccine development carries lessons for cell and gene therapy by validating the benefit of long-term investment in research. “Additionally, the importance of a robust QUEENIE JANG $20 billion in 2020, more than supply chain has gained wide acceptance CEO AT ISCT doubling the amount raised in 2019 during mass vaccination campaigns,” he (according to the ARM State says. “In particular, the investment and “Specializedd trainingtraining of the Industry, JanJan 2021). knowledge gained implementing large scale and developmentment ThereThere wwillill conticontinue to cold chain logistics will carry lasting benefits to populate thethe bebe hugehuge demanddeman for a for future delivery of cell and gene therapies.” highly skilledd cell skilledskilled anandd qqualifiedu Levine is looking forward to and gene therapyerapy workforceworkforce toto improvements both in viral vector workforce remainsemains developdevelop anandd deliver manufacturing, and viral-free methods an essential thesethese therapies,thera of gene delivery. “We will continue to see task to enablele requiringrequiring the implementation of multicomponent the continueded strategicstrategic genetic engineering strategies to enhance growth of thehe investmentinvestmen from cell function. As a positive ripple effect of sector. Despiteite the all stastakeholderskeh the pandemic and the lipid nanoparticles pandemic, cellell and in the sector.”s and RNA breakthroughs, look for gene gene companiesnies delivery and combination vaccine strategies raised almostst with advanced cell and gene therapies.” Feature 35

CARL H. JUNE PETER MARKS RICHARD W. VAGUE DIRECTOR AT THE FDA CENTER PROFESSOR IN FOR BIOLOGICS EVALUATION AND IMMUNOTHERAPY AT RESEARCH THE UNIVERSITY OF PENNSYLVANIA Over the past 12 months, Marks has played a pivotal role at the FDA in ensuring June is credited for the development that COVID-19 vaccines are both safe of CART T therapy, which he and effective. Weighing in on how the first began to work on in pandemic may impact cell and gene the late 1980s. Today, therapy, he says, “The holistic approach his research involves the to product development, simultaneously discovery of new CARs focusing on manufacturing challenges for a variety of disease and clinical development combined with indications. In 2020, June increased sponsor-agency interactions became an elected member could potentially propel cell and gene of both the American therapy product development forward the treatment of human disease, which Philosophical Society more rapidly.” he thinks could be a “game-changer,” and the National For the future, he is most excited about as well as the application of advanced Academy of Sciences. the application of genome editing with manufacturing technologies to cell and base editors or similar technologies to gene therapy production.

MARC MARTINELL CO-FOUNDER AND CEO AT MINORYX

Martinell co-founded Minoryx to provide therapeutic options to patients of orphan diseases with no alternatives. The company recently presented results from its phase II/ III ADVANCE study, showing that leriglitazone reduced progression of cerebral lesions and myelopathy symptoms in adrenomyeloneuropathy patients. Martinell has previously worked for Crystax Pharmaceuticals and Oryzon Genomics, where he managed several research projects and led the team in charge of target selection, structural biology, computational chemistry, and hit ID through a fragment-based approach. According to Martinell, the biggest challenge the industry faces this year is uncertainty.

www.themedicinemaker.com 36 Feature

BENJAMINBENJA L. OAKES CO-FOUNDERCO-FO PRESIDENT, AND CEO AT SCRIBE THERAPEUTICS

Oakes has contributed to over 25 publications and patent applications across synthetic biology, molecular engineering, CRISPR, and zinc finger-based genetic modification. He received a PhD in Molecular and Cellular Biology from the University of California, Berkeley, in 2017, where he worked in the Doudna Lab and Savage Lab developing CRISPR-Cas9 molecules with enhanced characteristics. Scribe Therapeutics was spun out of the Doudna lab in 2018.

JAMES THOMSON AMY RONNEBERG INVESTIGATOR, CEO AT BE THE MATCH REGENERATIVE BIOLOGY AT THE MORGRIDGE INSTITUTE With an extensive history of leadership, FOR RESEARCH AT THE Ronneburg has worked across a variety UNIVERSITY OF WISCONSIN, of sectors but joined Be The Match MADISON in 2013 as Chief Financial Officer. She assumed the position of Chief Thomson is a developmental biologist Executive Officer in 2020, and oversees well known for his pioneering work more than 1,300 professionals and isolating and culturing human 3,000 volunteers who help manage the embryonic stem cells in 1998, and organization’s stem cell registry for the developing human pluripotent stem development of novel cell therapies. cells from adult skin cells in 2007. In Around the same time that Ronneberg 2004, he founded Cellular Dynamics joined the company as CFO, she was International to investigate the potential diagnosed with cancer. She is now of human-induced pluripotent stem cells cancer free. In a statement, she said, for drug discovery and toxicity testing. “As a cancer survivor, I have personally The company has since been acquired felt what many other cancer patients by Fujifilm. Thomson has been the and their loved ones encounter every recipient of many prizes and accolades day. My experience, the patients we during his career, including the King serve, and our outstanding, dedicated Faisal International Prize and the employees are my motivation.” Albany Medical Center Prize in 2011. Feature 37

EVELINA VÅGESJÖ CO-FOUNDER AND CEO AT ILYA PHARMA

“The development of immunotherapies for oncology has been fantastic. I think the time is now for immunotherapies in other medical indications, steering the different immune cell subtypes to perform whatever tasks are needed – be it reducing fibrosis, increasing regeneration, fighting bacteria more efficiently, regulating blood pressure, or preserving organ function. With ILP-technology, we can use chemokines as therapeutics in a way that works well, is cost efficient, and has scalable manufacturing and a sustainable supply chain, by expressing them from lactic acid bacteria.”

SHINYA YAMANAKA CLAUDIA ZYLBERBERG to support this new therapeutic DIRECTOR AND PROFESSOR CEO AT AKRON BIOTECH modality (i.e., delivery systems AT THE CENTER FOR IPS CELL and manufacturing schemes). RESEARCH AND APPLICATION “We’ve passed the eras of small Moreover, regulators globally were (CIRA); AND REPRESENTATIVE molecules, chemistries, proteins challenged to understand the value DIRECTOR OF THE CIRA (such as biologics and monoclonal and opportunity to create solutions FOUNDATION antibodies) – now, it’s nucleic acids’ in a fast and efficient way without time to shine. By utilizing cellular compromising safety. We gained Yamanaka is a world-renowned stem machinery to redirect and recreate lots of general knowledge about cell expert. He won the Nobel Prize in the destiny of our own cells, these RNA and adenoviruses, and the Physiology or Medicine in 2012 alongside powerful moieties can create more global educational factor on these John Gurdon for the discovery that mature opportunities than ever in the novel therapeutic vaccines will cells can be converted to stem cells, but he therapeutic arena and beyond. A create a more open environment of has also won numerous other awards and fascinating future is opening ahead acceptance for new remedies using prizes. Discovering the medical applications of us. The global pandemic and RNA and DNA.” of induced pluripotent stem cells has been worldwide pressure for a vaccine a major focus for Yamanaka since he first gave RNA the chance to show what reprogrammed human cells in 2007. More it can do, if positioned properly. recently, the CiRA Foundation has been After years of trials around how involved in COVID-19 research to use this molecule in several by creating induced pluripotent applications, the opening came by stem cells from the blood way of COVID-19 vaccines. We of recovered COVID-19 have now expanded our toolbox and patients and making created a new therapeutic solution for them available to research complex problems in short timelines. institutions worldwide for free. With this comes growth in areas 38 NextGen

NextGen R&D pipeline New technology Raising the Future trends Bar(code) Track and trace barcodes must appear on secondary packaging, but are here benefits to applying similar codes to parenteral containers?

By Stephanie Sutton

When thinking of traceability in the learn more about the benefits of applying a Although adding a unique identifier to pharma industry, most of you will unique identifier to glass containers. glass parenteral containers could offer many immediately think of serialization benefits for manufacturers, it is not easy to regulations, such as the Drug Supply Why did you become interested in the mark glass packaging. Glass is glossy and Chain Security Act (DSCSA) or the EU idea of unit-level traceability for glass non-absorbent, and the containers also tend Falsified Medicines Directive (FMD), containers? to be very small and have curved surfaces. which mandate the use of 2D matrix There has been a lot of focus on In short, it is far more complicated than codes to be applied to each individual pharmaceutical secondary packaging – adding a barcode to secondary packaging pack of pharmaceuticals (among other and I think the industry breathed a huge of prescription medicines. obligations). However, there is also room sigh of relief when it met the mandates for At Stevanato Group, we looked at for traceability to be used in other ways the DSCSA and FMD. Compliance with the idea of marking containers with a to benefit pharmaceutical manufacturers. traceability initiatives has cost companies laser solution, but it was rejected because For example, applying unique product hundreds of millions of euros/dollars. I have the technology could potentially create identifiers to glass containers could help been working in serialization for well over a micro-cracks in the glass. We looked at prevent mix ups and allow manufacturers decade and I was interested in how we could various other printing technologies – and greater visibility into where problems are take the concept of traceability further and someone told me that they had the need occurring in the fill and finish process. deliver more value for the industry. completely covered. But when I looked The ISPE has published a Discussion Most traceability solutions only apply to at their idea, it would have reduced our Paper on the unique identification of the secondary packaging. Once a product output per machine by around 50 percent. primary containers to drive product is removed from that packaging, the The industry would not want to absorb traceability and quality (1). The paper traceability is lost. Glass containers usually that cost – and we did not want to reduce outlines the current implementation have a label on the container but it can still our capacity so significantly. After that, we of unique container identification be damaged. Putting the finished product started to consider other technologies and technology in parenteral manufacturing inside a secondary box is also the last step and looked at nine different solutions. In the lines, including potential solutions, and provides no traceability on the manufacturing discussion paper, several key characteristics provides a summary of the challenges line. If a barcode were to be applied to glass are described for a marking process: that technology developers face when it pharmaceutical containers prior to fill- comes to developing and implementing finish, it would allow tracking throughout • It should be a digital process capable identification solutions in process lines. the filling and sterilization processes, which of managing high speed serial Tod Urquhart, Product Manager and could help identify problems or issues within numbers and barcodes. Core Team Leader at Stevanato Group, the process, enable faster root cause analysis, • Must have no impact on container has taken a lead role when it comes to and, ultimately, help companies improve integrity or glass mechanical drafting the paper. We spoke with him to their processes and save money. properties.

• Must not be impacted by or impact containers as “vanilla glass.” All the stamp associated with the point at which a on sterilization processes. containers are identical and they move at container has been filled. If contamination • Must have minimal impact on high speed throughout the line. If there is is found, you can check the identity of the manufacturing lines (such as filling, a problem with, for example, particulates containers that were in the machine during inspection, etc.) being present, the container will be rejected. the period of concern and use a defined • Must be readable with standard However, when it is in the reject chute you segregation policy based on real data. serialization cameras. do not know which container has been Once the batch is complete on a filling rejected for particulates, for example, or for line, pharma companies must also ensure How can manufacturers benefit from a container closure integrity issue container there is a complete reconciliation of the applying unique identifiers to parenteral without thoroughly examining the process, to prevent the potential for a mix containers? container and conducting an investigation. up when a different filling process begins. In a PDA survey (cited in the ISPE Unique container identification provides The reconciliation process is laborious; if discussion paper), respondents cited a variety individual container visibility in the key 100,000 containers go into the machine of considerations that would inspire them manufacturing processes. there must be a complete count to check to build a business case for implementing One challenge with filling lines is that that 100,000 containers came out! By unit-level traceability of glass containers: batch release documentation may not be marking individual containers, the whole limiting batch segregation, avoiding mix completed until two or three weeks after process can be automated. You know exactly ups in the filling process, reject analysis the product has been filled. If a problem which containers entered the machine and inspection greater traceability in the event is identified, manufacturers must ascertain once you know which containers have been of a product recall, segregation of drugs the filled product that has been impacted rejected, you’ll know if any containers are in the market, automating reconciliation, and this is not an easy task. As such, it missing – and potentially still in the line. racking, improving clinical trial monitoring, is common for manufacturers to over Traceability gives individual container and increasing efficiency, such as overall segregate or even write off the entire batch. visibility in the line. You will know the date equipment effectiveness. But if each container has a unique and time each container was filled, which I like to refer to unmarked glass identifier there will be a date and time pump was used, and how long it took – and NextGen 41

this insight could be used to improve the Distribution and Filling Inspection Packing process overall. In the same way, unique drug delivery containers can be used in the automated Reject cause Ensuring each inspection process. Today, when a defect Limited tracking due to final pack Traceability in the is detected it is difficult to determine the segregation of container contains the case of a product reason a container was rejected without quality issues production correct filled recall additional manual intervention. Unit level deviations containers traceability will indicate which container Segregation of was rejected and why, thus helping with Reject analysis by Mix-up avoidance Association of problematic process improvement and reconciliation. type to facilitate of filled containers to marketed drugs There are also benefits beyond detailed root containers secondary pack due to filled manufacturing. Traceability is incredibly cause analysis product useful during a product recall. I was Segregation of working at a pharmaceutical distribution Reject cause problematic company in Asia during a product recall, tracking due to marketed drugs and that is when it really hit home how filling deviations important serialization is. Keeping due to containers track of the status of the recall was very Automate batch challenging. We had no idea where the reconciliation affected products had gone. Which doctor, clinic, or pharmacy had them? Or were Table 1: Benefits of unit-level traceability for glass containers they already in somebody’s medicines cabinet? It seemed an impossible task. unique identification for parenteral drug companies, including LifeBee, Eli Lilly, containers. At that time, it was not on Novartis, Groninger, Optima, Seidenader, How did you get involved with the PDA anyone’s radar and so understanding the Vetter, Alexion, Alfasigma, CIM Pharma, and the ISPE? concept and why it may be important was a ISPE, and Janssen-Cilag. In 2016, I went to a PDA meeting in Venice challenge! But, in time, the PDA began to I believe that the solution for unit-level and started talking about the concept of understand the potential benefits and they traceability cannot just come from one have been very supportive by conducting supplier. Stevanato Group is not the only surveys of their members to get viewpoints supplier to our customers – they will also on traceability. In one of their surveys, they be working with our competitors, as well “One challenge asked if their members would consider as equipment providers. The challenge using unique containers; 68 percent of requires a multi-ended strategy and work with filling lines is respondents said yes, which was a ringing from different parties to make it successful. endorsement to what we were doing! A working group was set up with that batch release In 2019, I started looking at different the initial aim of creating a discussion standard agencies to see if they could offer document that could be used for documentation support because the pharma industry is implementing unique identification of driven by standards! I went to a few primary glass containers. Because of may not be different organizations. One of them the pandemic, nobody was traveling so told me that it would be much easier to we were able to have our weekly group completed until get support if I was from a big pharma meetings with everyone attending – and company; but, as I was from a supplier it allowed us to work quickly and consider two or three weeks company, it may be more difficult! the viewpoints of pharma manufacturers, But the ISPE stepped up and offered filling line manufacturers, inspection after the product their support. They have been incredibly machine manufacturers, and so on. helpful. Other people showed their There is a lot of detail in the document, has been filled.” support too and we have authors on the and it outlines how to go about discussion paper from many different implementation. The whole point of a

www.themedicinemaker.com 42 NextGen

sterilization, for example, there are (L4) system that works at a corporate level different processes depending on to create and manage the unique serial “In my view, there whether you are using a ready-to- numbers throughout the life of the product use syringe, or vial. The temperature Also discussed in the paper is nest/ are three key things difference and effect on the container container aggregation – which I think will can be significant depending on the be a novelty to the industry. I proposed with serialization: process. We wanted to apply the same the idea because it will make it easier marking process and methodology to to potentially implement this unique readability, all containers. We had to go away and identifier approach on existing filling think about how that would work and lines. Most syringe filling machines use readability, and make sure it was suitable for all the a nest during the filling process. When different processes that might be used. reading the code on a syringe, you’ll readability.” We tested many different approaches! need to remove the syringe from the For the discussion paper, we agreed nest, ensure that it is facing the camera that the preferred method should be and that any systems do not affect the standard is to make something easy, not a digital printing process and that the sterility and validation of the process. just for pharma manufacturers but also inks must be able to withstand process Product aggregation is a process that for suppliers like us. It is about creating temperatures. Standard inks can be can overcome these issues by creating an a level playing field and understanding destroyed by sterilization temperatures, electronic parent and child relationship how we can all work together. From the so inorganic inks are better. Laser between the container and the nest. The very start, the aim has been to develop an systems can also be considered, but exact process for this is described in the open-source solution that can be used by as mentioned previously, they can paper for those who want the details… the industry through a licensing model. potentially impact on the container so this needs to be carefully considered. What are the next steps? What were the considerations around In my view, there are three key things There are huge benefits to introducing where to place the barcode? with serialization: readability, readability, this concept and the ISPE has been very We had a lot of conversations about this and readability. If you cannot read the code supportive. in the working group. We did some tests then it is all pointless, so the code needs To conclude, I would like to point you using our process to test the best place for to be able to withstand all steps of the fill- to the purpose of the ISPE document – to the barcodes in terms of readability and not finish process – as well as other tests, such obtain your feedback on four areas: creating defects in the container. When as stability tests – and still be readable. discussing 0.5 mL syringes, a group of At Stevanato Group, our solution 1. Have all your potential use cases engineers from one pharma company said is a digital process that prints a GS1 been covered? If not, what has been that they did not want the code anywhere ECC 200 2D data matrix barcode on missed? on the body because it would prevent the the container after the forming process 2. What are the perceived challenges of detection of particulates during inspection. and immediately inspects it against a implementing this solution? They wanted the code on the plunger, but I standard – rejecting it if necessary. That 3. If there are challenges, how can they strongly advised against that because it is the way, we know the code will be readable as be overcome? plunger that guarantees drug sterility during it passes through the rest of the line and 4. What additional discussion or data is the shelf life. We eventually agreed it should process steps internally and externally. needed for this to become the basis be placed on the body. The discussion paper You would not believe how many grey of a standard for the industry? states the recommended place to apply the hairs I have from developing this process. code, depending on whether you are using It is not easy to get such a small barcode We eagerly anticipate your feedback! a syringe, cartridge, or vial. onto a glass container and ensure that it is readable in all circumstances. Reference How will the barcodes be applied in As for the software requirements, 1. ISPE, “Unique Identification on Primary practice? we followed traditional serialization Containers to Drive Product Traceability & To answer this, I need to take a step architecture. We have a Level 3 (L3) Quality,” (2021). Available at https://bit. back and look at the processes. For system that runs on the line, and a Level 4 ly/3eRJekB. EVERIC® care

EVVERERICC® ccaree. Nextt-generrattioon vials..

SCSCHOH TTT AG,G, Phaarmaceutiicaal Syyststemms,s, wwww.w schotttt.ccomom/p/ harmr a 44 NextGen

A Smaller Piece of PiE How can manufacturers reduce the presence of pharmaceutical ingredients in the environment?

By Jonathan Rhone

The presence of pharmaceuticals in the Regulatory disparities the FDA unless the action qualifies environment (known as PiE) has become a One of the main drivers of the problem is for exclusion. Environmental Risk global issue, with trace levels of APIs now a lack of regulation. There are more than Assessments (ERAs), as defined by the widespread in rivers, lakes, groundwater, 10,000 pharmaceutical manufacturing EMA, have tighter requirements. For and, in some cases, drinking water plants worldwide, with 80 percent of all example, the EMA’s aquatic environment worldwide. According to the WHO, we APIs manufactured in India and China. concentration threshold for exclusion are now facing one of the most pressing However, standards and reporting is 0.01 μg/L. But even if the expected health threats in modern times (1). As requirements are poorly-defined, which environmental concentration is lower concerns grow, many in the pharma creates an environment where practices than the threshold, manufacturers still industry are beginning to re-evaluate vary significantly – not only on a national need to complete the next phase of their practices. But the challenge we must scale but internationally. In short, it is ERA if there is an expectation that the contend with is far from straightforward; difficult to fully ascertain the extent of drug could affect the reproduction of rather it is a multifaceted puzzle that the problem. vertebrates or lower animals. requires some background and context to That said, some regulatory guidelines Unfortunately, most drugs approved accurately address. do provide limited help. For example, prior to October 2005 (when the APIs reach wastewater through environmental risk assessment standards guidelines first came into effect) have multiple pathways – significant routes for APIs are built into new drug not been subject to these evaluations. include human and animal excretion approvals by the FDA and the EMA. There are several draft recommendations and the disposal of unused medicines Though the intent of such guidelines currently being considered by the EMA by consumers. However, manufacturing is to address the environmental impact to not only bring these older generic effluent is another clearly identifiable from normal prescribed use rather than drugs into the ERA framework but also point source pathway. Notably, such actual manufacturing processes, they to enhance the overall ERA requirements discharge can lead to localized hot have been applied to manufacturing to further mitigate the potential impact spots downstream of manufacturing effluent in many cases. For the US, this on the environment and public health. plants, which pose higher risks for means that Environmental Assessments It is also important to note that, though aquatic organisms in the receiving (EAs) must be submitted as part of most the regulatory framework for GMP was water. A high-profile example is in the applications for new drugs, marketing developed to provide rigorous guidelines Hyderabad pharmaceutical cluster, where approval for existing applications, and for pharmaceutical product quality and Swedish researchers found that large for various other actions defined by safety, it was never intended to include volumes of surface and groundwater environmental criteria. And that means US were contaminated by antibiotic APIs and EU inspectors are unable to influence (2). Ciprofloxacin was measured at up to or control manufacturing discharge at 10,000 μg/L in rivers and 6,500 μg/L in “One of the main pharmaceutical factories in developing lakes. Other studies have reported API countries with weak environmental hot spots downstream of manufacturing drivers of the standards and regulatory systems. plants in the US, the EU, Taiwan, To be fair to the industry, even in the and Korea Given that the problem is problem is a lack of absence of manufacturing regulations for recognized, what factors are hindering APIs, it is taking significant voluntary efforts to reduce the industry’s overall regulation.” steps to make a difference. At the 2016 environmental impact? World Economic Forum, over 100 NextGenNexttGen 45

pharmaceutical and biotechnology the increased industry focus on reviewing or municipal wastewater treatment plants companies and associations signed the and tightening API manufacturing (WWTP) are either ineffective or unable Industry Declaration on Antimicrobial supply chains and outsourcing standards to treat them to the levels required to Resistance (AMR) as a collective to control the release of APIs into the minimize environmental impact. These commitment to combat the global threat environment. The Pharmaceutical Supply plants rely on primary (removal of solids of AMR to human health. The declaration Chain Initiative (PSCI) also supports via screens, grit chambers, and settling) was followed by the adoption of an Industry manufacturers by facilitating active and secondary (involves the use of Roadmap for Progress on Combating collaboration with the AMR Industry biological processes like activated sludge AMR and the creation of the AMR Alliance, providing information about and trickling filters) treatment processes Industry Alliance to research, develop, established PNEC values, and providing whose efficiency varies from facility to and implement solutions to address PiE. supply chain environmental audit facility. For example, though bacteria One of the outcomes of this work was guidance. Despite these systems being in secondary processes can break down the development of Predicted No-Effect in place to help address the challenge, some compounds or alter them enough Concentration (PNEC) values for APIs. we need to examine the technology to render them harmless, they don’t PNECs are industry-recommended requirements more closely. completely remove all APIs. Some fail targets for API concentrations in water to be completely degraded by biological that are deemed safe for wildlife and Current technology treatment while others will not degrade at receiving ecosystems. PNEC levels are APIs are chemically stable – often all. Furthermore, some APIs are toxic and very stringent, in many cases requiring recalcitrant and nonbiodegradable. In can kill the bacteria used, reducing the treatment at 1 part per billion or higher. many cases, this means that conventional overall efficiency of the plant. Therefore, Another outcome of the initiative was on-site systems installed at pharmaceutical manufacturers must employ other

www.themedicinemaker.com 46 NextGen

“Though the right technology will help in tackling the industry’s environmental footprint, work is required on

Figure 1. Graphical depiction of Axine anode and cathode processes during treatment multiple fronts to make a significant difference.”

the reactor, the positively charged anode electrode surfaces, directly and indirectly, oxidizes organic contaminants through multiple oxidation mechanisms (see Figure 2). Data analytics and automation software provide on-line, remote operation, performance monitoring, and verification. Contaminants are subsequently converted into intermediates, and ultimately to carbon dioxide, oxygen, hydrogen, and other trace by-product gases, which are vented. Figure 2. The redox processes at the anode and cathode of the electrolytic cell during treatment, and Evidently, there are many options for the transition of contaminants to intermediates and ultimately to by-product gases manufacturers to weigh up. However, companies need to keep in mind the fact disposal approaches as well as advanced verification of virtually any API to PNEC that they will continue to receive intense treatment technologies to ensure that all or non-detectable limits offer a newer scrutiny from all stakeholders including APIs are destroyed before treated water is approach to handling manufacturing the public, government, NGOs, investors, discharged into the environment. effluent. We, for example, use proprietary and industry. Though the right technology The most common approaches for electrochemical oxidation technology that will help in tackling the industry’s addressing API-contaminated wastewater lowers PiE levels without producing any environmental footprint, work is required are thermal oxidation, advanced oxidation residual liquid or solid waste. The core of on multiple fronts to make a significant processes (AOPs), evaporation, and our technology is the reactor (see Figure difference. We all need to consider activated carbon. Each of these approaches 1), which houses several electrochemical how we will continue to contribute to has advantages and disadvantages (see cells, each containing a pair of electrodes environmental research and commit sidebar). But technologies capable of selected based on the specific wastewater ourselves to monitor wastewater and water in-situ treatment, destruction, and application. When electricity is applied to quality; developing new drugs that pose NextGen 47

wastewater into smaller organic molecules. However, evaporators do not treat or Traditional Conventional AOPs include ozone destroy the APIs; they concentrate the combined with hydrogen peroxide (O / APIs in a liquid or solid waste stream Approaches for 3 H2O2) and ultraviolet light combined with that must be collected and transferred hydrogen peroxide (UV/H O ). AOPs off-site for disposal and incineration. Contaminant 2 2 can be effective at treating some APIs Evaporators are also capital intensive Removal at low concentration but are expensive and generally suited to small-volume to implement and have performance segmented streams. The presence of Thermal oxidation/incineration: Trucking limitations. One of the main drawbacks of organics solvents can also be a limiting and incineration of API-contaminated AOPs is they are often unable to achieve factor for the application of evaporators. wastewater is a well-established complete destruction of APIs to meet practice in the pharmaceutical industry. stringent PNEC values and can produce Activated carbon: Activated carbon is a Wastewater is collected in drums, totes, toxic oxidation by-products. media commonly used to adsorb natural or tanks, transferred to trucks, and then In the case of O3/H2O2, ozone is typically and synthetic organic compounds from transported, often hundreds of miles, to generated on-site and is toxic, requiring wastewater. In certain applications, it can be incinerated at special waste facilities. rigorous monitoring and destruction. be an effective treatment technology due

Wastewater is conveyed to oil- or natural- H2O2 is also a hazardous chemical with to the highly porous nature and large gas-fired furnaces and incinerated at regulatory requirements for storage surface area to which contaminants may temperatures between 800 and 1,200°C and handling. UV/H2O2 also requires adsorb onto the media. However, activated to ensure complete destruction of APIs. significant upfront capital investment and carbon is only effective on certain APIs This approach is expensive, energy- has high operating costs including energy, and in most cases cannot reduce API intensive, and introduces risks associated UV lamp replacement, ballast replacement, levels in wastewater to PNEC levels. Like with verifying the destruction of API and H2O2. In addition to the safety and evaporation, activated carbon does not contaminants. It is also frequently regulatory considerations of H2O2, there treat or destroy the APIs. The exhausted at odds with corporate sustainability is an additional requirement for disposing media must either be shipped off-site for goals aimed at reducing waste, lowering of UV lamps, which in most cases disposal or regenerated on-site, which greenhouse gas emissions, and improving contain mercury. results in another API-contaminated environmental performance. waste stream that requires management Evaporation: Various types of evaporation and disposal. Activated carbon systems Advanced oxidation processes (AOP): systems use heat to reduce the overall are also expensive to operate and maintain AOPs use chemicals to generate hydroxyl volume of wastewater. The evaporated because the carbon media requires radicals (OH*), which oxidize APIs in water can be collected as a clean distillate. frequent replacement or regeneration.

less risk to the environment; creating as reputational damage, access to markets, as Available at https://bit.ly/36FNVJC. an environmental certification standard well as legal and financial liabilities. If we can 2. J Fick et al., “Contamination of surface, ground, and for APIs in manufacturing effluent, and take bold steps in the right direction today, drinking water from pharmaceutical production,” improving supply chain reporting. we will have fewer repercussions to deal with Environ. Toxicol. Chem., 28, 2522 (2009). Unlike other sources of pharmaceuticals in the years to come. 3. TM Scott et al., “Pharmaceutical manufacturing in the environment, wastewater discharged facility discharges can substantially increase the from manufacturing plants is under the Jonathan Rhone is President and Chief pharmaceutical load to U.S. wastewaters,” Science of direct control of the industry. Proactive Executive Officer of Axine Water Technologies the Total Environment, Vol. 636 (2018). management of these emissions will not only 4. DG Joakim Larssen, “Pollution from drug reduce environmental and health risks but References manufacturing: review and perspectives, “ Philos will also mitigate potential future risks, such 1. WHO, “Antimicrobial Resistance” (2020). Trans R Soc Lond B Biol Sci., 369 1656 (2014).

www.themedicinemaker.com 48 NextGen

Hello World! Subscribe for free at: www. texerenewsletters. Welcome to our Cell + Gene Curator roundup based on our com/cellandgene ever-popular newsletter! Hot topics in the field this month include using CRISPR to engineer cell therapies and recent advances in bioengineering – key to unlocking the potential of regenerative medicine and tissue fabrication.

By James Strachan

Walter Isaacson writes about people going to do with CRISPR may be the Hutch researchers developed “T who change the world. His biography of defining issue of this century. But, let's cell optimized for packaging” (TOP) Franklin shows how he brought together not get wrapped up in sci-fi dystopias and vectors for delivery of CRISPR-Cas9 to the passionate Adams brothers, the focus instead on the significant positives: primary T cells that showed ~5–9-fold rectitudinous Washington, and Jefferson the end of debilitating diseases. higher transduction efficiency than the and Hamilton's intellects to create the commonly-used epHIV7 vector (4). Constitution and Declaration. Similarly, Engineering the future of oncology Meanwhile, Rice University his book on Steve Jobs shows his A current trend is using CRISPR to researchers have developed a CRISPR/ lasting impact on cell phones, personal engineer cell therapies. For example, Cas9-based tool for editing the human computers, music, publishing, retail – AbbVie has entered into a collaboration epigenome – specifically histone the list goes on. with Caribou Biosciences – which will phosphorylation. Their programmable So it's telling that his next subject is use its CRISPR gene editing platform to chromatin kinase, called dCas9- none other than Jennifer Doudna – who, engineer off-the-shelf CAR T cells with dMSK1, allows for site-specific control along with Emmanuelle Charpentier, the ability to withstand host immune over histone phosphorylation for the first won the Nobel Prize in Chemistry for attack (1). AbbVie will then continue time, and potentially opens the door to her role in developing CRISPR. the programs into clinical development cracking the “histone code” – in other From what I've heard, The Code and commercialization. Let’s see if the words, understanding how histones Breaker details Doudna's deal – worth $40 million upfront and up control gene expression. The researchers remarkable personal story, to $300 million in milestone payments were also able to use dCas9-dMSK1 as well as discussing the – will bear fruit as quickly as AbbVie's to identify seven new genes linked to future implications for 2018 deal with CALIBR, which has melanoma resistance (5). gene editing. already led to clinical trials (2). Continuing with the epigenome, a "Suddenly after Another example in the research comes proof-of-concept study from the University a billion years of from Guangxi Medical University: a of California San Diego suggests that evolution one species team there recently used CRISPR to CRISPR could be used to treat pain had the talent and design nanobody-based anti-CD105 instead of opioids. The researchers used also the temerity to CAR T cells for solid tumors. The CAR catalytically inactivated “dead” Cas9 edit its own genes T cells prolonged the survival time of (dCas9), which does not cut DNA, – to hack its own tumor-bearing mice and human tumor but maintains its ability to bind evolution," said xenograft models (3). to the genome, and fused Isaacson. We’re also seeing a lot of improvements it to a repressor domain Deciding, as a to the CRISPR system and new (KRAB). KRAB then species, what we're applications for the technology. Fred temporarily repressed NextGenNeN xt 49

the group reported the phenomenon of References molecular reshuffling, where molecules 1. Caribou, “AbbVie and Caribou Biosciences migrate over long distances and self- Announce Collaboration and License organize to form larger, "superstructured" Agreement for CAR-T Cell Products” (2021). bundles of nanofibers. Now, they've shown Available at: https://bit.ly/3bjs5y7 that these superstructures can enhance 2. Scripps Research, “Calibr’s ‘switchable’ CAR-T neuron growth (8). The ultimate aim is platform for cancer moves forward with FDA to grow healthy neurons from a patient’s clearance of Investigational New Drug own cells using these superstructure- application” (2020). Available at: https://bit. enhanced biomaterials, and transplant ly/3uV1wal them into the brains of patients with 3. F Mo et al., “Nanobody-based chimeric neurodegenerative conditions. antigen receptor T cells designed by CRISPR/ the Nav1.7 gene In a related story, researchers at Cas9 technology for solid tumor – epigenetic the University of Illinois at Chicago immunotherapy” (2021). Available at: https:// repression, in other describe their new bioengineering go.nature.com/3ebSwrB words – which has been material as “4D”, which means it changes 4. Fred Hutch, “TOP delivery of CRISPR-Cas9 linked to insensitivity to pain. shape over time in response to stimuli machinery to primary T cells” (2021). The result? Lowered pain sensitivity in – it can morph multiple times in a Available at: https://bit.ly/3sMPHRy mice lasting several months (6). preprogrammed fashion or in response 5. J Li et al., “Programmable human histone And in a brief departure from cell to external trigger signals. And that could phosphorylation and gene activation using a and gene therapy news, researchers allow the researchers to engineer tissue CRISPR/Cas9-based chromatin kinase” from Columbia University in New York architectures that more closely resemble (2021). Available at: https://go.nature. are using CRISPR to encode binary native tissues (9). com/30ecEBd data into bacterial cells. By assigning Researchers at Lund University in 6. AN Moreno et al., “Long-lasting analgesia via different arrangements of DNA Sweden also designed a new bioink, targeted in situ repression of NaV1.7 in mice” sequences to different letters of the which allows for 3D printing of small (2021). Available at: https://bit.ly/3rxiPLF alphabet, the team were able to encode human-sized airways that support growth 7. SS Yim at al., “Robust direct digital-to- the 12-byte text message “hello world!” of blood vessels into the transplanted biological data storage in living cells” (2021). into DNA inside E. coli cells. “This work material (10). Available at: https://go.nature.com/3edOgb8 establishes a direct digital-to-biological Finally, Carnegie Mellon University 8. AN Edelbrock et al., “Superstructured data storage framework, and advances researchers have developed a new Biomaterials Formed by Exchange Dynamics our capacity for information exchange 3D-bioprinting method that could enable and Host–Guest Interactions in between silicon- and carbon-based the fabrication of adult-sized tissues and Supramolecular Polymers” (2021). Available entities,” said the study authors (7). organs (11). The Freeform Reversible at: https://bit.ly/3uUSUjX Embedding of Suspended Hydrogels 9. A Ding et al., “Cell‐Laden Multiple‐Step and Mighty morphin' biomaterials (FRESH) approach involves a yield- Reversible 4D Hydrogel Actuators to MimMimicmicc Elsewhere, a number of advances have stress support bath that holds bioinks in Dynamic Tissue Morphogenesis”siis (2021).(2020021)211 . been made in biomaterials and 3D place until they are cured. This prevents Available at: https://bit.ly/2PCt4kJt.l.lly/2y/y PCtPCC 4kJ printing for regenerative medicine. distortion of bioinks, which results in 10. MM De Santis et alal.,l.,, “Extracellular‐Matrix‐“Ex“EExE trarar celllullul ar‐arr‐r‐MatMMa rixix‐ A Northwestern University team has a loss of fidelity – a major barrier to Reinforced Bioinksoinkskss forfof r 3D3D BioprintingBiopoprinrii tinti ggH HumanHumaumumam n discovered a new printable biomaterial advanced tissue fabrication. Tissue” (2021).021).1) AvAAvailableailillablaba le at:at:t htthhttps://bit.ps:ppss://b///bit.t. that mimics the properties of ly/31wL8PGL8PL8L PG brain tissue. In 2018, This article is based on a selection of the 11. DJ ShiwarskiShihiwara skisk et alal.,., “Emergence“EmEmE ergencncce ofoffF FRESHFRESR H breakthroughs that have recently been 3DD printingpriintitingng as a pplatformlatl tforf m ffororr advancedadvancncceedd tisttissuessuesu featured in The Cell + Gene Curator - a biofabrication”biofabfabriciccatia on”on (2((2021).021020 ). AvailableAvaAvaailaablele ataat:t: hhttps://ttptpps:/:// weekly newsletter covering the latest news bit.ly/30ibfcAbit.lyly/3030ibfibbffcAA and research in the cell and gene therapy space. Subscribe for free at: https://www. texerenewsletters.com/cellandgene

www.themedicinemaker.comwwww w.ththt emeemm dicineemakker.r.comc m The Only Science Is Good Science

Sitting Down With… Johannes Khinast, CEO and Scientific Director of the Research Center for Pharmaceutical Engineering (RCPE), Graz, Austria Sitting Down With  51

What influenced you to launch RCPE The second project is about using sensors molecules with the same selectivity and in 2008? to understand coating quality, measure activity as large biomolecules. Biologics The idea was simple: I wanted to coating quality, and control it in real time. are very selective and can do amazing conduct research that could be applied to It’s a completely new sensing concept, things, but they are also very expensive pharmaceutical manufacturing. I gained which was not invented by us, but taken and sensitive, which makes them difficult feedback on interest in such a center at the from another field and applied as a real- to manufacture and transport. I think University of Graz and we had a tremendous time tool. Coating is a very old process, but there is room for new modalities based on response from pharmaceutical companies. a lot of things can go wrong, so it’s an area small molecules. Eventually, perhaps we They told us this type of center was “exactly” that deserves more attention. can replace biomolecules with these new what they needed! We started with just generations of small molecules… The three people and now we have over 160 – How did you get into the pharma pipeline for small molecules is still very and we’re still growing. At the beginning, industry initially? good and there is a lot of innovation. it was like baking cookies with friends, but In all honesty, it was partly because I was Almost certainly, we will be making we’ve professionalized the center over the a little lazy! When I was a young professor drugs in completely different ways in the years. We have created groups within the at Rutgers University in New Jersey, many future – faster, with fewer people, and a center and we have leaders of those groups of my colleagues were working with big oil lower environmental impact. – and our work is internationally visible; we and gas companies – and they had to travel a push out a lot of publications. But we don’t lot. I preferred to stay local, and New Jersey How receptive do you find pharma take money and bend the work towards is a hotspot of pharmaceutical development. companies to new technologies and that. We would rather do good science – It was quite new at the time for a chemical approaches? and then the money flows to us! We have engineer to work with pharma companies, In my experience, innovation is very four main areas of focus: modeling and but it created a new field. much appreciated. There is a stereotype prediction; advanced products and delivery; that pharmaceutical companies are very process and manufacturing science; and What else are you working on right now? conservative – and they are because they continuous flow synthesis and processing. Many things! I’m very excited about should be! But if you create something nano-based manufacturing. We’re also that is really helpful, companies are You recently received funding from working on spray drying of proteins and typically open to innovation. I’ve had the FDA… a big demonstration plan for continuous great experiences working with pharma That’s right. And I’ll note that it’s super manufacturing – for both the API and companies to bring new technology into unusual for an EU company to receive FDA downstream manufacturing. We also have a their manufacturing plants. funding (only around one percent of these focus on individualized manufacturing – such grants are given to non-US companies). We as how to make small batches or even a single How do you feel when you look back were fortunate in that we were working pill for a patient. We’ve designed a system that and think about how RCPE has grown with many US companies, such Pfizer and can make a single pill for a single person in over the years? MSD, who suggested we put a proposal around 40 seconds. I realize that’s actually I really didn’t expect it. And it still feels like together. We did a great job and got very slow – but there are huge amounts of I’m in a movie sometimes! Nevertheless, I do funding for two projects: digital simulation potential for accelerating the process. believe that RCPE is the premier research tools for drug product manufacturing and center in the world! There are other similar process development; and optical coherence What are your thoughts on the future of centers around the world that are university tomography for real-time monitoring and drug manufacturing? based, but their great PhD and postdoc control of the tablet coating process. There’s no doubt in my mind that we need students take all their knowledge when I’ve been pushing the concept of digital to have continuous processes in almost all they inevitably leave. We have permanent twins for a long time – so I consider the aspects, with quality assured in real time. jobs here rather than just relying on students. first project to be a personal success; it’s The old paradigm of batch manufacturing And we have good people from all over the fantastic for the center’s expertise in this leads to super-long supply chains, which world in many disciplines – good physicists, field to be recognized. The industry needs are risky and costly. We need to reduce good programmers, good pharmaceutical to move away from empirical trial and the size of technology and create processes scientists and engineers, and good biologists – error approaches. There are big benefits in that continuously make drugs. and that allows us to take a multidisciplinary powerful simulation coding combined with My personal prediction is that, maybe 20 approach to projects. I am extremely proud good understanding of material properties. or 30 years from now, we will have small of how far we have come.

www.themedicinemaker.com DRUG DEVELOPMENT & FORMULATION IS SCIENCE. DOSE DESIGN TO CREATE SUCCESSFUL TREATMENTS IS ART.

Successful treatments are built on drug development science, superior formulation technologies and the art of dose form design that meets the needs of patients, doctors and innovators.

Catalent’s NEW OptiDose‰ Design Solution helps deliver a comprehensive assessment of your Molecule, Patient, and Market. Our scientific advisors will combine expertise across dose forms, thousands of molecules and advanced delivery technologies to deliver optimal dose form, scale-up and manufacturing solutions. We aim to help differentiate your product, improve patient acceptance, and turn your science into commercially successful medicine.

expert optidose® design assessment | advanced technologies | superior dose forms | integrated solutions

WHERE SCIENCE MEETS ART.™

us + 1 888 SOLUTION (765-8846) EUR 00800 8855 6178 catalent.com/optidosedesign ˝2021 Catalent, Inc. All rights reserved.

TMM.indd 1 4/13/21 9:22 AM