Capitalizing on the Cannabis Moment

MAY 2019 #53

Upfront In My View Best Practice Sitting Down With The untapped potential of Kickstarting a Recognizing the role of WuXi STA’s renaissance aquatic bacteria (block)chain reaction pharma excipients woman, Jinling Chen

12 14 – 15 36 – 38 50– 51

Can big pharma construct a solid market for cannabinoid medicines?

20 – 30

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20 0 20 20 0 Now is your chance to shape next year’s Who will earn a place on this2 exclusive And for 2020... list: nominations are now open for 2020!20list? Nominate now at https://tmm.txp. But there is a twist. For the past four to/pl2020-noms. We accept nominations The Medicine Maker 2019 Power List is20 years the Power List has compromised from all areas of the industry (from the now online at https://themedicinemaker. 100 names. For20 2020, there will only bench, to manufacturing, to business com/power-list/2019, celebrating the be 60 names: leadership) and you can nominate most inspirational professionals working yourself if you wish. in the pharma industry including • 20 influencers in small molecule Business Captains, Industry Influencers, drug development Nominations will close in early Masters of the Bench and Champions • 20 influencers in biopharmaceutical January 2020 and the final list will be of Change. drug development published in April 2020. Email Do you agree with who was included • 20 influencers in cell and gene [email protected] (or not included) on the 2019 Power List? therapy drug development with any questions.

www.themedicinemaker.com ContentsContents

InI My View

141 Heather Zenk ponders if blockchain could help with the 36 US Drug Supply Chain Security Act.

151 Let’s rejuvenate existing antibiotics with synergistic combinations, says Anthony Coates. 03 OnlineOnline ThisThis Mont Monthh UpfrontUpfront

08 Solutions in Nanoparticles 07 Editorial Features Small – But Never Forgotten, 10 2023: Prices and Predictions by Stephanie Sutton 20 Under Construction: 12 Treasures of the Deep Pharma’s Cannabinoid Bid Medical cannabis and scientific 13 Business in Brief research around cannabinoids On The Cover Cover is booming, but what does this mean for the pharma industry? The pharma industry builds new business models to take advantage of opportunities in cannabinoid drug discovery. ISSUE 53 - MAY 2019 Editor - Stephanie Sutton [email protected] Deputy Editor - James Strachan [email protected] Deputy Editor - Roisin McGuigan [email protected] Assistant Editor - Maryam Mahdi [email protected] Content Director - Rich Whitworth [email protected] Publisher - Richard Hodson [email protected] Sales Manager - Helen Conyngham [email protected] Business Development Manager - Helen Johnson [email protected] Business Development Executive, Americas - Sarah Griffith [email protected] Head of Design - Marc Bird [email protected] Designer - Hannah Ennis [email protected] Junior Designer - Charlotte Brittain [email protected] Digital Team Lead - David Roberts [email protected] Digital Producer Web/Email - Peter Bartley [email protected] Digital Producer Web/App - Abygail Bradley [email protected] 50 Audience Insight Manager DPO - Tracey Nicholls [email protected] Traffic & Audience Database Coordinator - Hayley Atiz [email protected] Project Manager - Webinars - Lindsey Vickers [email protected] Traffic and Audience Manager Jody- Fryett [email protected] Traffic Assistant Dan- Marr [email protected] Events Manager - Alice Daniels-Wright [email protected] Best Practice Event Coordinator - Jessica Lines [email protected] Marketing Manager - Katy Pearson 36 The IPEC Story: Promoting [email protected] Ingredients for Global Success Marketing Executive - Sarah Botha [email protected] David Schoneker shares Social Media Manager - Joey Relton the story behind IPEC and [email protected] Financial Controller - Phil Dale explains why excipients deserve [email protected] more recognition. Accounts Assistant - Kerri Benson [email protected] Chief Executive Officer - Andy Davies 40 Perks and Pitfalls of Antibody [email protected] Chief Operating Officer - Tracey Peers Drug Conjugates Reports [email protected] Senior Vice President, Despite the challenges – and North America - Fedra Pavlou setbacks of the field – antibody 18 BASF x The Medicine Maker: [email protected] drug conjugates remain an Choosing the Right Excipients Change of address: [email protected] exciting avenue for development. for the Right Job Hayley Atiz, The Medicine Maker, Texere Publishing Limited, Booths Park 1, Chelford Road, Knutsford, Cheshire, WA16 8GS, UK 32 Built on Innovation General enquiries: www.texerepublishing.com [email protected] +44 (0) 1565 745200 NextGen [email protected] Distribution: The Medicine Maker (ISSN 2055-8201), 46 Bright SPARK Sitting Down With is published monthly by Texere Publishing How the SPARK program is Limited, Booths Park 1, Chelford Road, Knutsford, Cheshire, WA16 8GS, UK. helping academicians to get 50 Jinling Chen, Vice President, Single copy sales £15 (plus postage, cost available on request [email protected]) innovative new therapies to Pharmaceutical Development Non-qualified annual subscription cost is the market. Services, WuXi STA, China. £110 plus postage Reprints & Permissions – [email protected] The opinions presented within this publication are those of the authors and do not reflect the opinions of The Medicine Maker or its publishers, Texere Publishing. Authors are required to disclose any relevant financial arrangements, which are presented at the end of each article, where relevant. © 2018 Texere Publishing Limited. All rights reserved. Reproduction in whole or in parts is prohibited. www.themedicinemaker.com ARE YOU LOOKING FOR EXPERTS IN

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Contact us +49 40 55290-436 www.richter-helm.eu Small – But Never Forgotten A new publication will give the small molecule manufacturing Editorial community the attention and praise it deserves. Meet The Small Molecule Manufacturer.

he best-selling drugs in the world in terms of revenue are biopharmaceuticals. But when it comes to the amount of medicines most commonly used and Tprescribed, small molecules have large molecules completely beat. The over-the-counter medicine market is almost exclusively made up of small molecule products but, even when considering prescriptions, the most commonly used drugs are still small molecules. Lists vary depending on the sources used but, in the US, the most commonly prescribed medicines of 2018 were typically cited as levothyroxine, lisinopril, atorvastatin, metformin hydrochloride, amlodipine besylate, metroprolol, omeprazole, losartan potassium and albuterol. They are small molecules. The importance of small molecules to global health is further emphasized by the World Health Organization’s List of Essential Medicines, which includes general anesthetics, palliative care and pain medicines, antiallergics, antiinfectives, anticonvulsives, antimigraine medicines, immunosuppressants and cardiovascular medicines. What do most of the drugs on the list share in common? They are small molecules. Small molecules also account for the lion’s share of new drug approvals; over 60 percent of new drugs approved by the FDA in 2018 were small molecules. Innovation in small molecules is not dead. So it seems a little unfair that these workhorse medicines should be continually overshadowed by the latest biologics and “advanced” therapies. And so, to celebrate the continued leaps and bounds in the small molecule arena, we are launching a new magazine in July. The Small Molecule Manufacturer will focus on the people, processes and technologies driving advances in the development and manufacture of small molecule drugs – as the name suggests. You can register to receive this new publication for free at https://tmm.txp.to/tsmm-regform. “But does this mean that small molecules will be excluded from The Medicine Maker from now on?” – we hear you cry! Absolutely not. We will continue to report on the trends, technologies and personalities shaping all areas of the medicine making industry. Rather, The Small Molecule Manufacturer will serve as a special community for those working with an incredibly diverse and important selection of drug products that should never be forgotten.

Stephanie Sutton Editor

www.themedicinemaker.com 8 Upfront

With their capacity to Solutions in… shut off gene and cellular Upfront activity, we hope to see Nanoparticles more SNAs used as Reporting on research, personalized therapies Why are spherical nucleic for genetic disorders, personalities, policies and acids so exciting for drug as well as some types of partnerships that are development? cancer. Since developing these shaping pharmaceutical nanostructures in 1996, seeing development and Invented in 1996 by the Mirkin Lab them used to their full potential has at Northwestern University, spherical been a constant goal of mine! In 2011, manufacture. nucleic acids (SNAs) have the potential I founded Exicure, a biotech startup to treat an array of diseases. Now, which develops gene regulatory and We welcome information a group led by their inventor aims immuno-oncology therapeutics based on any developments in to optimize these nanoparticles for on SNA technology. We currently have immunotherapies using a new machine treatments for psoriasis, spinal muscular the industry that have learning technique (1). Chad A. Mirkin, atrophy, bowel and lung diseases, as well really caught your eye, Professor of Chemistry at Northwestern as ocular diseases in our pipeline. in a good or bad way. University, tells us more... Email: stephanie.sutton@ What are the current advantages and What are SNAs? limitations of SNAs? texerepublishing.com SNAs are nanoparticle structures made SNAs are customizable – their size, by chemically arranging nucleic acids core composition and DNA/RNA (biomolecules essential for life) on a sequences can all be fine-tuned to spherical nanoparticle core. Despite produce myriad variations. The ability having no known natural equivalent, to introduce variability to the design they are able to interact with living parameters of SNAs means that millions systems in various ways. Most notably, of combinations are possible, all with they enter cells rapidly, and in large differing compositions and structures. quantities, and resist degradation It is not currently understood how by enzymes. the different structural parameters We’ve observed SNA activity in collectively influence biological the brain, a commonly hard-to-access function, and using traditional methods, tissue, upon intravenous injection. In it would be impossible to study large addition, they enter the skin, eye, lung, swaths of the possible combinations. and lymphatic system when topically or This inspired us to devise a high- locally administered. These properties throughput method to synthesize have made SNAs attractive as gene large SNA libraries with thousands of regulation agents, and as structures for candidates and rapidly analyze them to modulating the immune system, making determine which parameters influence it possible for them to be used as nucleic immunostimulation. acid medicines for the last decade. How will your newly devised What can SNAs treat? machine learning technique SNAs represent an help optimize SNAs? exciting new class of Our machine learning nanomedicines and have models can analyze a wide scope in terms SNAs and identify of clinical applications. how their structural Upfront 9

variation contributes to SNAs provide a way to have been approved in recent years, their efficacy and biological exploit what is known about issues surrounding their delivery have activity. Our novel technique highlights nucleic acid recognition for medicine, prevented these therapeutics from important properties of SNAs, such without the limitations of linear nucleic reaching their full potential. We believe as their size-dependent ability to acids. Almost all aspects of life derive that SNAs hold the key to not only the stimulate the immune system, which from nucleic acids, so nucleic acid challenge of delivery, but also of potency would otherwise be overlooked using therapeutics have massive potential! in the way nucleic acids are recognized more conventional methods. The high- Furthermore, nucleic acids are signals and processed by the targeted cells throughput pipeline that we have that can be recognized and exploited and receptors. developed also reveals the “interaction” by the immune system to trigger an effects between multiple features immune response. By using nucleic Reference of SNAs. acids, we can target genes linked to 1. CA Mirkin et al., “Addressing Nanomedicine disease and immunological receptors in Complexity with Novel High-Throughput How do you envisage SNAs being ways to stimulate or suppress immunity. Screening and Machine Learning,” Nature used over the coming decade? While a few nucleic acid therapeutics Biomedical Engineering, 3, 318–327 (2019).

For more adventures featuring Gene and Eva check out our website themedicinemaker.com/additional-data/cartoons If you have any ideas you’d like to see in future comic strips about bioprocessing then get in touch with us at [email protected] or look up #TrialsOfAMedicineMaker on Twitter.

Brought to you by GE Healthcare 10 Upfront

2023: Prices and Predictions How will the industry shape up over the next ﬁve years?

GRINDING TO A HALT?

DESPITE BEING FORECASTED GROWTH BY REGION TO GROW BY

Emerging 5-8% markets 4-7% US $1.5 3-6% China

Region trillion by 1-4% Europe -3-0% Japan

-3 0 4 6 78 2023 2023 ...the annual growth rate of the pharmaceutical market is set to slow over the next ﬁve years from an average of... Sources: IQVIA, “The Global Use of Medicine in 2019 and Outlook to 2023: Forecasts and areas to watch,” (2019). Available at https://bit. ly/2HuZbxk. Last accessed March 19, 2019. ...TO A Kelly Scientific Publications, “Global Regenerative Medicine Market PREDICTED Analysis & Forecast to 2023; Stem Cells, Tissue Engineering, BioBanking 6.3% & CAR-T Industries,” (2019). Available at https://bit.ly/2U1sKgI. Last GROWTH RATE accessed March 28, 2019. Knowledge Sourcing Intelligence LLP, “CRISPR Market - Forecasts from BETWEEN 2018 to 2023,” (2018). Available at https://bit.ly/2HIPNXd. Last accessed March 28, 2019. Frost & Sullivan, “US Digital Therapeutics Market, Forecast to 2023,” (2018). Available at https://bit.ly/2HWne7K. Last accessed March 27, 2019. Markets and Markets, “Artificial Intelligence as a Service Market by Service Type (Software Tools and Services), Technology (Machine Learning and Deep Learning, and Natural Language Processing), Organization Size, Vertical, and Region - Global Forecast 2023,” (2018). Available at https://bit.ly/2WviPNb. Last accessed March 28, 2019. UpfrontUpf 11

CRISPR Regenerative medicine market -Cas9 was worth $28 billion in 2018

Will grow to over $81 billion by 2023 - a CAGR of 23.3%

Growth at a CAGR of 33.26% between 2018-2023

Total market size expected to reach $3.1 billion by 2023 Pluripotent stem cells

AREAS TO WATCH Neglected diseases

Artiﬁcial intelligence, machine learning and 5–10 new products to be deep learning launched in the next ten years programs Neglected tropical diseases (NTDs) affect more than a billion people across 149 countries and cost CAGR 48.2% between upwards of a billion dollars per year 2018 and 2023 Continued investment by international Total market size organizations and philanthropic expected to reach organizations could help to $10.88 billion by 2023 eradicate at least one neglected disease by 2020 12 Upfront

“The diversity of the natural world is and neuroblastoma cell lines. The team Treasures of unparalleled. The adversities presented also discovered two strains that produced by their environments forces living bioactive compounds not previously the Deep organisms to adapt mechanisms of featured in common databases of natural defense, which often results in the products, and are now investigating them Could aquatic bacteria hold production of compounds with useful with increased scrutiny to determine if the keys to bolstering our bioactivities,” explains Maria de Fátima they are indeed novel chemical entities. drug pipelines? Carvalho, Principal Investigator at the “Up to 90 percent of drugs are Interdisciplinary Centre of Marine rejected in preclinical drug screening,” On a rocky shore in northern Portugal, and Environmental Research of the says Carvalho. “Until now, no one had researchers from the University of University of Porto. characterized the Actinobacteria in L. Porto have been busy collecting heaps One of Carvalho’s interests lie ochroleuca. Our findings are an exciting of brown seaweed. Their purpose? in the isolation of Actinobacteria step in the right direction. The more drugs To explore the bioactivity of the from diverse sources so rather than candidates available and the more strains Actinobacteria found within it. focusing on the bench, she went to the of Actinobacteria we discover to feed drug Actinobacteria, a phylum of Gram- coastline in pursuit of new therapeutic development channels the better!” positive bacteria, are ubiquitous in soil, molecules (1). The team investigated Carvalho and her team intend to freshwater and marine environments, cultivable Actinobacteria associated explore Portugal’s waters further in the and are clinically used for many with Laminaria ochroleuca seaweed search of other species of seaweed and antibiotics, as well as anticancer and and were able to recover 90 isolates. 45 new communities of Actinobacteria. antiinflammatory agents. In fact, of the strains identified were capable more than half of the 20,000 microbe- of inhibiting the growth of Candida Reference derived drug candidates in development albicans (an opportunistic yeast which 1. MF Carvalho et al., “Actinobacteria Isolated stem from the terrestrial species of the causes candidiasis) and Staphylococcus From Laminaria ochroleuca: A Source of New bacteria. But aquatic Actinobacteria aureus, and a further 28 displayed Bioactive Compounds”. Frontiers in haven’t received as much attention. inhibitory effects on breast carcinoma Microbiology 10:683 (2019). Business in Brief pursuit of novel compounds Social responsibility at its using in silico ﬁnest, AI partnerships, and methods to identify a crack down on vaccine and design them. manufacturing malpractice... • BenevolentAI has What’s new for pharma in entered into a collaboration product over business? with AstraZeneca to produce novel concerns drugs for chronic kidney disease that they Corporate Responsibility and idiopathic pulmonary fibrosis. could lead The long-term partnership will to patient

• In an attempt to cut its CO2 see BenevolentAI combining their overdoses. The emissions, Novo Nordisk has invested target identification platform with patches were labeled as containing 12 in a 632-acre solar panel installation AstraZeneca’s genomic and clinical mcg/h, when in reality they contained in North Carolina. The installation trial data. The companies are confident more than four times that amount (50 covers the same area as 500 football that their alliance will lead to a greater mc/h). No adverse effects have been pitches and will help the company understanding of the mechanisms reported but Alvogen recommends reach its goal of achieving 100 percent underlying these diseases. that patients who are using carbon neutrality by 2030. The project mismarked patches immediately will provide the company’s entire Recalls discontinue their use. US operation with energy by 2020, severing the company’s ties with • Torrent Pharmaceuticals recalled Vaccines traditional energy sources. 104 lots of Iosartan (amounting to • Abbvie has pledged $40 million 1.07 million bottles of the drug) • Dengvaxia, Sanofi’s vaccine for to rebuild a school based near its in April over concerns that they dengue fever, has, again, faced headquarters in North Chicago. The contained cancer causing impurities. restrictions from the FDA. A donation to The Neal Math & Science The Indian pharmaceutical company regulatory committee ruled that Academy was the last in a series of recalled 36 lots of losartan potassium Dengvaxia can only be used in awards given from the company’s and 68 lots of losartan potassium/ patients who have contracted dengue $350 million tax rebate and will serve hydrochlorothiazide tablets, according before and in areas where the disease to transform the school into a “21st- to the FDA. In the weeks prior to is endemic, limiting its use to the US century learning space.” the mass recall, the FDA had called territories of Puerto Rico, the US for doses of Iosartan to be tested to Virgin Islands and Guam. Artiﬁcial Intelligence identify whether they contained any • Chinese drugmakers who are found of the impurities discovered in other guilty of making or distributing • With the intention of exploiting AI to blood pressure medications. Iosartan counterfeit vaccines will feel the full accelerate the drug discovery process, is now one of a dozen drugs to be force of the law after a second draft Janssen has partnered with Iktos to use recalled over safety concerns calling of legislation was released. China the company’s AI powered technology. into question inspection processes at wants to root out malpractice through The collaboration will allow the two international plants. tougher penalties for perpetrators. companies to share their expertise • Fentanyl, the frequently used (and The new legislation will allow victims in deep generative models and the addictive) pain relief medication has of vaccine counterfeiting to seek prediction of small molecule activity. been a popular topic of conversation compensation if they experience Iktos has also recently announced of late in US news media. Now, adverse events (including death, organ other newly formed partnerships mismarked packaging of the drug has injury or serious disability) due to with biopharmaceutical companies in led Alvogen to recall two lots of the immunization with such products.

www.themedicinemaker.com 14  In My View

With our existing systems, the new (Block)chain requirement would mean taking the In My serialized bottle from a pharmacy, Reaction scanning it to assess which manufacturer it belongs to, and then asking them View Blockchain could be one whether the serial number is valid – for solution to the saleable 15 million units. A mammoth task! returns veriﬁcation aspect What we need is a system that tells us In this opinion section, of the US Drug Supply Chain which manufacturer we need to contact. experts from across the Security Act. At the moment, that decision lies in the world share a single hands of the person trying to process the return. A larger system could scan the strongly held view or serial number, which has a global trade key idea. identification number called G10, and use a directory (akin to a phone book) Submissions are welcome. to understand which manufacturer the product belongs to. We started to Articles should be short, look into this, but issues arose when we focused, personal and considered how to manage the “phone passionate, and may By Heather Zenk, Global Secure Supply book.” Keeping it up-to-date would Chain Operations, AmerisourceBergen, USA. involve many manual interventions, deal with any aspect such as phone calls, emails and so on. of pharmaceutical In my view, one of the most exciting We also realized that we would run into development or aspects of blockchain is its potential problems if different manufacturers used to revolutionize the way the different technologies. And that led us manufacture. pharmaceutical industry exchanges to consider a new avenue: blockchain. They can be up to 600 data. Electronic medical records, clinical Blockchain would allow us to words in length and trial management, supply chain, and communicate with a community or scientific data sharing could all benefit pharmaceutical ecosystem in a non- written in the first person. from a distributed blockchain system, where data is managed by a cluster of Contact the editor at: computers, rather than any single entity. stephanie.sutton One example of blockchain’s applicability in the pharma industry is “There are a lot @texerepublishing.com the Drug Supply Chain Security Act (DSCSA) Saleable Returns Verification of opportunities with requirement in the US. By November 27, 2019, when a pharmacy returns the technology, but a product, the distributor will be required to verify that the serial number the industry won’t on the bottle is the same as the serial number the manufacturer applied to convert for the sake the package, before it can be restocked and resold. In today’s environment, of it. Blockchain the distributor would have to connect with a manufacturer on a one-to-one must be cleaner, basis. My own distribution company, AmerisourceBergen, works with 450- faster and safer.” plus pharmaceutical manufacturers. In My View  15

direct way. The request would go into data exchange then wholesalers can’t strength of its security systems given a pharmaceutical blockchain that could receive and process their information. that numerous pharma companies have use the lookup directory to request We’re beginning to see a significant been hit with ransomware attacks in information appropriately from the shift as companies understand that, if recent years. Merck, Sharp and Dohme right manufacturer. data doesn’t move when products move, had to halt production of new drugs To implement blockchain, we’ve we cannot deal with those products in in 2017 because of such an attack. As been working with a company called the supply chain. As the regulatory the industry looks for ways to shore up Chronicle through their pharmaceutical environment changes with DSCSA its IT systems, blockchain has risen working group: Medileger. But a and global serialization requirements, as a potentially useful option. And key question is: what if companies more companies are seeking to change with specific use-cases emerging, I don’t want to engage with blockchain their methodologies and enhance their believe companies will begin to see the technology? In the end, we’ve told our abilities in data exchange. Blockchain real opportunities. trading partners that if they don’t have is emerging as a tool that we can use to We used to say the pharma industry a means of interacting with the new move a significant amount of data – and adoption curve was eight to 10 years system, we won’t be able to process their it can be replicated across the trading for new technologies but, providing return, which would mean that two partner and blockchain environment, that regulators get on board, I think percent of their products would need without creating a multitude of different that blockchain could be mainstream to be taken out of the supply chain. databases or storing information in pharma in just three to five years. I would urge pharma companies separately. It allows a large company, There are a lot of opportunities with to seriously consider investing like ourselves, to keep all of our data the technology, but the industry won’t in blockchain. Traditionally, in one location that we can access convert for the sake of it. Blockchain manufacturing and R&D, not data efficiently and effectively. must be cleaner, faster and safer – and exchange, are key priorities for pharma Moreover, the industry has been I believe that, as use increases and we companies. But if they can’t do basic forced to seriously contemplate the iron out the kinks, it certainly will be.

Bacteria are constantly evolving to be The Killer Combo antibiotic resistant and are a real and present danger to our ability to treat “Innovation in both A longer-lasting strategy to common infections and carry out rejuvenate existing antibiotics standard medical procedures, including the short and long with synergistic combinations organ transplantation, major surgery is likely to be an integral and cancer chemotherapy, among term is essential if part in the development of others. According to the O’Neill UK treatments against antibiotic government AMR report (2016), global mankind is to resistant pathogens. deaths from AMR may reach 10 million per year by 2050, which is more than keep pace with cancer and diabetes combined (1). Innovation in both the short and ever smarter long term is essential if mankind is to keep pace with ever smarter and and deadlier deadlier microbes. The fight to outsmart infection falls broadly into rapid microbes.” diagnostics technology and targeted By Anthony Coates, Professor of Medical treatment strategies involving new and Microbiology, St George’s, University updated antibiotics. (NCEs) hasn’t been so promising London; Founder and Chief Scientific But the pace of discovery and and has failed to keep pace with Officer, Helperby Therapeutics. production of new chemical entities the unpredictable rate of bacterial 16  In My View

evolution. In fact, big pharma has old antibiotic also on the market. The antibiotic biopharma called Helperby mostly ruled itself out of the antibiotics ideal combination of drugs boost each Therapeutics has been developing game. The high cost of creating a new other, which is known as synergism. This combinations for 15 years and has shown chemical entity and the low market route re-uses old antibiotics by boosting that some combinations have unique price of new antibiotics deters large them to overcome mutations developed synergistic mechanisms of action that pharmaceutical companies, leaving by bacteria-conferring resistance. ARBs differ from other antibiotics in clinical the fight for antibiotic survival with work in many different ways, including use. Helperby Therapeutics has already the small biopharma companies, in by facilitating the penetration of bacterial completed a Phase I clinical trial and is what is the most urgent field of drug cell walls to allow existing antibiotics to Phase II ready with the first combination development. But small biopharma work more effectively. of azidothymidine (AZT) and the so- companies, even those which reach the called last resort old antibiotic colistin market, struggle to sell NCEs. This is against highly resistant carbapenem- because, under present conditions, the resistant pathogens. market will not accept a price per course The World Health Organization has which will reimburse the high cost of “The pharma identified three multi-drug resistant developing an NCE. For example, if species of bacteria which they classify the cost of developing an NCE is say industry is as critical priority (2). These are all $200-500 million and the maximum carbapenem resistant and require unit price of a course of the NCE is $1- responsible for the immediate development of new 2000, it is difficult to make a reasonable treatments. The bacteria are called profit. This conundrum is illustrated countless Acinetobacter baumannii, Pseudomonas by Achaogen’s filing for bankruptcy, aeruginosa, and Enterobacteriaceae. in spite of reaching the market with groundbreaking Multi-drug resistant bacteria pose a an FDA approved NCE. Other small particular threat in hospitals, nursing companies have and will survive in the therapeutic homes, and among patients whose care market with NCEs, but achieving the requires devices such as ventilators equivalent profitability to successful innovations, but and blood catheters. But we also need blockbusters in other medical fields longer-lasting strategies. In my view, looks to be remote at the moment. it will all be rejuvenating existing antibiotics with An alternative to the traditional synergistic combinations should be an pharma model is to use combinations wasted if we integral part of the fight against drug of antibiotics. This is a route used to resistance. These strategies, combined reduce the emergence of resistance in ignore the with progress in the areas of prevention diseases such as tuberculosis, malaria and diagnostics, are crucial to preserve and AIDS. Curiously, combinations growing issue a world where simple infections do (excluding those with beta-lactamase not routinely kill healthy people. The inhibitors which do not prevent of antibiotic pharma industry is responsible for resistance unless the inhibitor also has countless groundbreaking therapeutic potent antibacterial action) are not resistance.” innovations, but it will all be wasted often approved by the regulators for if we ignore the growing issue of common bacterial infections. However, antibiotic resistance. combinations hold the potential for a longer lasting, lower development The ARB rejuvenation process can References cost, and lower price per course market be performed repeatedly with different 1. J. O’Neill,”Tackling drug-resistant infections solution. This strategy is based upon combinations of existing antibiotics. globally: Final report and recommendations. employing synergistic combinations. These new combinations can restore Review on Antimicrobial Resistance” (2016). Simply, an old drug already in the the original potency of existing Available at: https://bit.ly/2sGcZOz. market (called an antibiotic resistance antibiotics, against both Gram positive 2. WHO, “Antimicrobial resistance” (2018). breaker (ARB)) is combined with an and Gram-negative bacteria. A small Available at: https://bit.ly/2EdaHLq. It’s About Increasing Throughput Enduring quality and reliability to help increase your efficiency Efficiency is critical in manufacturing. Breaks, interventions and rejection rates put product volumes and supply chain at risk. Valor® Glass can enable greater than 80% glass speed efficiency on both old and new filling lines and reduces rejects up to 60%. With so much riding on your capacity, isn’t it time to consider a more efficient option? Visit www.corning.com/valor to learn more about Valor Glass technology.

property for processes such as tableting and Choosing the hot melt extrusion, so excipients that can improve powder flow for “difficult” powder “The number of Right Excipients blends are of interest to formulators. These can be excipient grades with particular poorly water- for the Right Job particle size and shape to provide good flow properties or co-processed materials soluble compounds When it comes to formulation, (for example, silicified microcrystalline many choices should be cellulose), which offer similar advantages. emerging from carefully considered – and Indeed, co-processed materials – which regulators expect excipient combine the properties of two or more drug development selection to be justiﬁed. separate excipients into one – have become more widely available. These pipelines is The average timelines and costs of bringing provide formulators with a single, a new drug to market vary depending on multi-functional excipient option (for increasing year- who you speak with, but are generally in example, LudiFlash) that can help reduce the range of 10 years and over $2 billion, development time and cost, certainly on-year.” respectively. The broad hurdles of drug during early drug development. development are considered, but a topic that Easy-to-prepare products, such as coating receives far less attention is formulation, preparations for tablets (for example, Acryl- particles and, hence, improve the solubility including the choice of excipients. EZE) are now also available and can cut of the drug in aqueous media. The right excipients can reduce down on processing time. Regulators are now encouraging and manufacturing costs, improve shelf life demanding the development of more and stability, and enhance the patient What trends are driving innovation pediatric versions of medicines, so it experience. The competitive contract in excipients? has become a key area of focus for the development and manufacturing landscape The number of poorly water-soluble industry – with a subsequent influence on has given rise to CDMOs who hold compounds emerging from drug the excipient space. Ease of swallowing impressive knowledge and know-how in development pipelines is increasing and palatability are essential requirements terms of applying good scientific common year-on-year. Thus, there is a constant for patient acceptability and, therefore, sense in selecting the most appropriate battle to develop suitable formulations excipients that can offer benefits in these excipients for the job at hand. Here, we for these poorly soluble drugs to allow areas are useful aids for formulation speak with Rob Harris, Chief Technical administration and good bioavailability. scientists. A number of excipients with Officer, Oral Drug Delivery, Catalent, Excipients that can enhance the solubility attributes well matched to pediatric UK, to find out more about the latest of otherwise challenging compounds are formulations are now available; for trends and drivers in the excipient field. of great interest to formulation scientists. example, fillers and disintegrants that Non-ionic surfactants (for example, provide good “mouth feel” for orally How have excipients improved over the Vitamin E TPGS and Kolliphor RH40) dispersible tablets and coating materials last decade? are becoming common ingredients in that prevent premature release of the drug For some of the solvent excipients, such as oils pharmaceutical formulations. So too in saliva (for taste-masking). and PEGs, greater purity has been a major are polymer excipients that can be used improvement. Even low levels of impurities to produce amorphous solid dispersions How can formulators ensure they choose (for example, peroxides and aldehydes) can through spray drying and hot melt the “right” excipients? have a significant detrimental effect on drug extrusion, such as PVP, HPMC and It’s extremely important to consider your stability. Also, reactive impurities can cause HPMC-AS and block co-polymers. choice of excipients – and have clear reason cross-linking of gelatin shells, affecting Mesoporous materials with particles that for their use. All formulation scientists disintegration properties. have extensive internal surface area are also should have a thorough understanding of Better functionality for excipients has gaining popularity. It is possible to trap the attributes of excipients used for a given been another improvement. For instance, poorly soluble drugs in the amorphous type of formulation, and when certain powder flow is an extremely important state within the narrow passages in these materials should be used in preference The Medicine Maker × BASF  19

impurities. Due care should be taken to use suitable types/low-impurity grades of excipients for such drugs. Low-peroxide-containing excipients are being made available, such as BASF’s Kollidon 30 LP, to help address this issue. • Particle size of fillers (for example, lactose, microcrystalline cellulose) is important depending on the formulation and manufacturing process.

What about a specific example – cellulose or PVP – how do you choose which is most suitable? Most formulators favor specific excipients for particular types of formulation. For dry-granulation formulations, Kollidon VA64 has become the go to dry binder of choice for many because its properties are well suited to roller compaction processes (good compressibility and plasticity). However, in general the selection of functional excipients (binders and disintegrants) for a particular formulation should be based on the experimental evaluation of a range of candidates. amounts used. Different grades of the In the selection of excipients, it is also “All formulation same excipient can have marked effects important to consider potential interactions on the desired behavior of a formulation. with charged drug substances. Such scientists should Formulators should also consider: interactions can result in incomplete recovery of the drug from the formulation, which can have a thorough • Compatibility with the drug lead to assay irregularities or, worse, reduce substance to ensure that there is the bioavailability of the drug. Non-ionic understanding of no undesired interaction between binders and disintegrants (for example, the drug and the excipient that L-HPC, crospovidone) are less likely to the attributes of could impact the stability and interact with these types of drugs. shelf life of the product. A drug- excipients used for excipient compatibility study is Where is there further room for normally one of the first activities improvement in the excipient field? a given type of undertaken for any formulation Solubility enhancement is one of the development program. main issues facing formulators right now, formulation.” • Moisture content of the excipient – but the tool kit of available, acceptable if the drug substance is moisture- excipients has grown substantially in sensitive (for example, use of an recent years; however, there continues to others. In all regulatory submissions, anhydrous grade versus hydrated). to be a need for new excipients that can the reviewers expect a rationale for the • The drug substance may be sensitive help overcome the challenges presented selection of excipients, including the to trace amounts of reactive by difficult compounds.

www.themedicinemaker.com 20 Feature

The cannabis business is booming as century-old legal conventions restricting use begin to unravel. Can pharma ride the wave with cannabis-based medicines? And how will drugmakers entering the fray deal with the dosage, delivery and bioavailability challenges? By James Strachan

n 2017, The Medicine Maker took stock of the surging interest in medicinal cannabis and cannabis-based medicines. Two years on, the trend continues... Since the beginning of 2017, Germany, Cyprus, Greece, Mexico, Peru, ILuxembourg, Lesotho, Malta, Portugal and Zimbabwe have legalized cannabis for medical use, as well as five more US states. Denmark, Belize, plus the US states of New Mexico and New Hampshire have also decriminalized the drug, while Canada, South Africa and the US states of Vermont and Michigan have legalized cannabis for recreational use. With recreational cannabis legal in 10 US states and medical cannabis legal in 32 states, cannabis has become big business. One at GW Pharmaceuticals. “We believe this study found that, in the US, manufacturers and distributors, on tried and tested approach, honed over 20 both the recreational and medicinal sides, created 64,389 new years, allows us to develop a safe, consistent, jobs in 2018 – making it the fastest-growing labor market in and standardized product that patients and the US (1). Sales of recreational cannabis are expected to grow clinicians require/demand.” 18.4 percent yearly, from $3.2 billion in 2018 to $12.5 billion in Tovey believes that plant-based cultivation is not 2025, while sales of medical cannabis are expected to grow 11.8 more costly nor less efficient than synthetic production. “There percent per year from $5.1 billion in 2017 to an estimated $12.5 are a number of different aspects to synthetic manufacturing billion in 2025 (2). that can make it a very costly process; for example, extensive But what about cannabis-based medicines? With medicinal equipment and chemical processes where maintenance and clean- cannabis becoming more widely accepted, will an increasing up to remove toxic by-products can be difficult and expensive,” number of pharma companies seek to explore the therapeutic says Tovey. “It is not uncommon for a medicine to be derived from potential of the plant? Or does the “medical” or “medicinal” plant-based material due to the inherent biological advantage in label only create confusion (and competition) for companies the synthesis of specific chemical isomers.” whose products are held to much higher standards of evidence Johnson Matthey, which has over 15 years of developing by pharmaceutical regulators? and commercializing cannabinoids, focuses on the synthetic The FDA approval of GW Pharmaceuticals’ Epidiolex route for its cannabinoids, such as THC and cannabidiol. was seen as a watershed moment for the industry, potentially “Synthetic routes reduce problems with yield and impurity ushering in a new era of cannabinoid medicines. Indeed, a that arise through botanical extraction,” says Kevin Hennessy, number of companies are now addressing the manufacturing Global Director, New Business Development at Johnson challenges of working with the cannabis plant to create safe and Matthey. “Methods that rely on botanical extraction could effective cannabis-based pharmaceutical drugs: is extraction or have a high-degree of variability because of crop-to-crop chemical synthesis the way to go? What about bioavailability? differences.” Synthetic routes may also provide for more reliable What about regulatory hurdles? regulatory compliance, especially where GMP manufacturing is required. “There are no issues with raw material traceability IS SYNTHETIC THE REAL DEAL? and compliance, whereas farms could be resistant to GMP audits and issues with regulatory bodies,” he adds. A handful of cannabis-based medicines have already received Alyn McNaughton, Technical Director for Lonza Pharma, regulatory approval, namely Sativex, Epidiolex (both from GW Biotech & Nutrition at its Edinburgh site points out that Pharma) and Dronabinol (marketed as Marinol and Syndros). synthetic cannabinoids do have an advantage over plant-derived The active ingredient in Epidiolex is cannabidiol (CBD), which is products because most plant-derived cannabinoids are classified extracted and purified via crystallization from the cannabis plant, as controlled substances unless they can be purified to a point whereas Dronabinol is synthetic delta-9-tetrahydrocannabinol where the psychoactive components are below the threshold at (THC). There is some debate as to which route holds most which they would be considered controlled (which can create promise for the cannabis-based medicines industry. some additional legal hurdles). “GW has developed extensive expertise in the growing, But Andrew Badrot, CEO of C² Pharma, which manufactures extraction, and manufacture of cannabinoids for use within and distributes APIs extracted from plants, including cannabis, these medicines,” says Chris Tovey, Chief Operating Officer objects to the idea that synthetic APIs and naturally extracted Feature 23

THE CANNABIS TRAILBLAZERS

A short introduction to GW within. They were originally based in The first 10 years or so of research Pharma, the company behind Kent Science Park, where the company was really the groundwork for our the world’s ﬁrst approved still maintains a strong presence. For exploration of new therapeutic areas. cannabis-based medicine. the first 5-10 years, the focus was on We see promise in other areas of research and development, but that neurology, oncology and psychiatry, By Chris Tovey, Chief Operating Officer, work eventually led to the world’s including autism spectrum disorder. GW Pharmaceuticals first cannabis-based pharmaceutical Today, we have nearly 6000 patients medicine: Sativex, a cannabis extract involved in our clinical trials around GW Pharmaceuticals is a UK-based administered as a mouth spray, for the the world, we’ve published 80 articles company born in the late nineties – treatment of multiple sclerosis – thus in peer-reviewed journals and we a time when similar conversations directly responding to the original have generated 80,000 years’ worth to those we have today – about the challenge set by the Lords committee. of safety data. potential medical benefits of the Sativex, originally approved in GW obviously generates a lot of cannabis plants – were taking place. the UK in 2010, is now approved interest because of the plant we’re Indeed, just as in 2017, patients in over 25 countries. It is 50/50 working on. But I’d like to point marched on parliament to demand CBD and THC, and is a natural out that first and foremost, we are access to cannabis for medical purposes. plant-based material. Subsequent a pharmaceutical company trying In 1998, the House of Lords work focused on a cannabidiol oral to develop medicines that will Science and Technology Committee solution, Epidiolex; and, in 2015, we make a difference to patient lives. delivered a report on cannabis and initiated Phase III clinical trials for It just so happens that we work cannabinoids. They concluded that, treatment of two orphan conditions with the cannabis plant. We believe although cannabis and its derivatives in children – Dravet and Lennox- passionately in the potential of the should “continue to be controlled Gastaut syndromes. GW also received cannabis plant and that the best way drugs” due to their potential harms, fast track designation from the FDA to unlock that potential is to subject “clinical trials of cannabis for the to treat children with epilepsy, which it to traditional pharmaceutical treatment of MS and chronic pain was given FDA approval in June scrutiny so that we can ensure that should be mounted as a matter of 2018. This was a key milestone for the highest standards of safety, quality urgency” (1). The message was clear: the cannabis medicines industry – and efficacy are met. go forth and seriously study the the first cannabis-based medicine potential therapeutic benefits of the approved in the US. Sativex isn’t yet Reference plant through the usual scientific approved in the US, but we’re hopeful 1. Select Committee on Science and channels and create a bonafide that will change in the next couple Technology Ninth Report, medicine. And that was the challenge of years. And we’re also hopeful of “Chapter 8 opinion of the that Geoffrey Guy – who remains an EU approval of Epidiolex in the committee” (1998). Accessed 25 chairman – embraced, working coming months, which would be April, 2019. Available at: alongside Brian Whittle, to found the first centrally approved cannabis https://bit.ly/2PwgTC0. GW Pharmaceuticals that year. medicine in Europe. We’re also Together, they set out to properly looking at additional indications, such investigate the cannabis plant and the as tubular sclerosis (TSC), where we 100-plus cannabinoids contained have a pivotal study coming out soon. 24 Feature

APIs are “different.” He says, “So long as we are talking about extracted APIs,” he explains. the pure compounds and not an ‘extract,’ which may contain a Badrot argues that for pharmaceutical companies, the difference combination of hundreds of different compounds, from a chemical will be with the impurity profiles of the API obtained naturally standpoint, there is no difference. The molecule is the molecule.” versus synthetically, given the different processes through which Badrot believes the only difference for API manufacturers is they are obtained. “The synthetic API will typically be ‘cleaner’ the starting material and the work up methods and purification and only contain the target cannabinoid; therefore, especially of the compound versus having to produce it synthetically. for pharmaceutical indications, the plant extract will need to be “There are different costs and considerations associated with the purified in such a way that the level of ‘immaterial’ cannabinoids manufacturing methods employed for synthetic versus naturally left in the extract are below the limit of 0.2 percent,” he says.

MAKING THE MEDICINE “WHETHER Whether extracting and purifying or chemically synthesizing EXTRACTING cannabis compounds, there are a number of manufacturing challenges facing companies. For C² Pharma, the challenges AND PURIFYING aren’t at the API level, but rather those around regulations and OR CHEMICALLY how to grow and manage cannabis crops. “Hemp can be grown as a crop in certain locations, but with limitations regarding SYNTHESIZING concentrations of THC in the plant,” says Badrot. “We are still CANNABIS COMPOUNDS, facing a very fluid landscape, and governmental organizations THERE ARE A NUMBER OF MANUFACTURING CHALLENGES FACING COMPANIES.”

Analthe ytical Scientist CANNABIS COMPRESSED Feature 25

Natoli Engineering has over 45 years in wasted API, loss of time, and missed as this dictates the processability and of experience in tablet compression production deadlines. release nature of the product. Once the tooling and has been actively working oil is loaded into the carrier, additional in the cannabis space for over five years. WHAT ARE THE BIGGEST blending with other excipients, such as Here, we speak with Jon Gaik, Stephen DIFFERENCES COMPARED binders and taste masking excipients, Natoli, and Randy Jung about the WITH CONVENTIONAL APIS may be needed to fulfill the target unique tableting challenges presented by AND FORMULATIONS? product profile. cannabis-based products. In typical OSD (oral solid dosage) pharmaceutical or nutraceutical HOW CAN COMPANIES WHAT ARE THE MAIN products, the API is a solid powder at ENSURE THAT THEIR CHALLENGES OF room temperature. A primary difference CANNABIS FORMULATIONS MANUFACTURING for both THC and CBD is that the WILL “PLAY NICELY” DURING FORMULATIONS THAT USE product often comes in a semi-solid oil MANUFACTURE? CANNABIS OR CANNABINOID- and this semi-solid must be loaded into The most important step is to BASED APIS? a carrier before being compressed into characterize the formulation and The largest challenge when working a tablet. understand the manufacturing scale-up with cannabis/cannabinoid-based The target product profile for a process. Characterizing a formulation APIs is the viscosity of the product. typical cannabis tablet can be separated is accomplished by using a single- We are often approached by our into three categories: efficacy/ station press or an R&D rotary tablet cannabis customers to evaluate their release, processability, and consumer press in single tablet mode to examine processes and to provide assistance in preferences. Efficacy/release refers to the compressibility of each ingredient troubleshooting their formulation as a how much API is needed and when is separately. Evaluating the compressibility result of inconsistent tablets or difficulty it delivered, such as a 5 mg immediate of the ingredients and determining how during tablet compression. We are able release tablet. Processability is largely they compress when they combine is to use our experience in working with determined by the excipients that are known as characterization processing. many “difficult” product formulations used to help overcome deficiencies in Once the characterization process to offer assistance to solve cannabis the tableting of the API – this could is complete, the next step is to make a tableting challenges that occur as a include binders that are used to enhance small batch of test tablets on a rotary result of the formulation. Although the compaction or lubricants to assist with tablet press. Understanding various API is the most significant challenge, tablet release from the compression troubleshooting techniques will play we have also helped customers solve tooling. Other excipients may be added a pivotal role during batch testing. other “common” tableting issues. Other to the formulation based on consumer For example, product sticking to the challenges with cannabis tableting preferences; flavors and flavor enhancers tooling or within the identifier (letters, include: punch binding, tooling damage, are used for taste-masking and numbers, logos, etc.) on the tooling may high tablet ejection forces, inconsistent coloring can be used for branding or be the result of poor tablet design. Other products, poor product quality, or customer attraction. issues that may occur are likely a result of failed third-party testing. We also have powder flow in the hopper, die fill that customers who encounter difficulties CAN YOU EXPLAIN HOW controls tablet weight constancy, or heat during tableting because of how they THE “OIL-TO-POWDER” build-up. Having a tablet press that is are processing or blending the different PROCESS WORKS? designed to reduce product flow issues ingredients and API before tableting. The oil-to-powder process is required and is equipped with turret and punch Improper methods of processing the to make a viable tablet. One process lubrication as well as an automatic cam formulation can result in manufacturing occurs by heating the THC distillate greaser is going to be best-suited press issues during production on the tablet (oil) to a specific temperature then for cannabis tablet production. press. These difficulties include poor adding the distillate to an API carrier powder flow that results in inconsistent excipient powder. This is then mixed Jon Gaik is Director of Natoli Scientific, tablet weights, tablets not achieving the using a standard induction mixer or, in Stephen Natoli is International Technical desired hardness, and material adhering some instances, a high-shear mixer. As Training Manager, and Randy Jung is to punch tips or collecting in the die mentioned above, a critical parameter is Global Tablet Press Sales Manager, all at walls. These circumstances often result the ratio of the oil to the carrier excipient, Natoli Engineering Company. are not in-sync with the chemistry. He sees three main challenges facing cannabis- each other. As the based medicine manufacturing. The first is in handling and the industry matures, and regulatory aspects. “The non-psychoactive cannabinoids do not organizations see the always fall under controlled substances regulation, but for those broad range of potential, products that still retain their controlled drugs status, the strict we believe all those things controls around handling and transport means that development will be ironed out.” activities are extra challenging,” he says. Another key problem that Tovey agrees. GW’s growing facilities and protocols, manufacturers face is removing therefore, require highly stringent logistical and regulatory unwanted cannabinoids during the controls. “We are inspected by health regulators like the UK extraction of APIs. “THC presents a real challenge for MHRA and the US FDA, and require further inspection and purification because it is naturally a non-crystalline oil. Impurities a special license from the UK Home Office to operate,” says are chemically closely related, and prone to thermal and oxidative Tovey. Much like all medicines, cannabis-based medicines are degradation,” says Hennessy. “Purity is critically important as in accordance with “Good x Practices” (GxPs) during their even trace amounts of THC are discouraged by our customers development, which continue beyond regulatory approval and and regulatory bodies.” Johnson Matthey invested early in large throughout the lifecycle of a medicine. “For us, these include scale super-critical fluid chromatography (SFC), which Hennessy Good Manufacturing Practice (GMP) and Good Agricultural says works well for water insoluble lipophilic compounds, such Collection Practices (GACP),” says Tovey. “These GxPs are as THC. policed and enforced by statutory bodies with the legal powers McNaughton agrees with Badrot that the major challenge to revoke licenses when not followed or adhered to.” in manufacturing synthetic cannabinoids is not necessarily in Tovey notes that achieving batch-to-batch consistency for plant- “MANY CANNABINOIDS ARE LIPOPHILIC AND EVEN IN THEIR PUREST FORMS ARE EITHER OILS OR OILY SOLIDS, RATHER THAN THE WHITE POWDERS SO derived drugs shouldn’t be underestimated. “Due to the differences in cannabis starting materials and methods of manufacture used COMMONLY SEEN to prepare cannabinoid/cannabis-based medicines, the chemical WITH MORE TYPICAL profile of the extracts and finished products have the potential to vary enormously – both in terms of the presence of desired PHARMACEUTICAL components (cannabinoid profile) and undesired components APIS.” (impurities, degradants and potential adulterants [fungal or bacterial contaminants, pesticides, heavy metals, and so on]),” says Tovey. Cannabinoids are present in the cannabis plant as acids and are inherently unstable in this form at room temperature. According more typical pharmaceutical APIs. And that poses challenges to Tovey, the instability means that it is important to control the for dosage, delivery and bioavailability. “Most cannabinoids extraction and other processes within the manufacturing method suffer from first-pass metabolism and are broken down in the (for example, decarboxylation) carefully, as these can affect the liver before they reach general circulation,” says McNaughton. content and stability of the resulting extract or product. “It can be “Consequently, the oral bioavailability of cannabinoids is generally challenging to control all of these parameters to maintain batch- in the region of four to 20 percent, resulting in most of the material to-batch consistency and stability. Achieving a highly bioavailable, swallowed having no effect on the body. Lipidic formulation convenient, stable dosage form of an appropriate size to allow enables the transformation of oily material into an emulsion that appropriate titration is therefore a significant challenge when it is miscible with water and, therefore, better absorbed by the body. comes to cannabis-based medicines or cannabinoid/cannabis- In addition, because these materials are so greasy and have such a based products,” Tovey explains. high affinity for oils, lipids can also be used to promote lymphatic McNaughton echoes the same problems – especially absorption, which bypasses liver degradation but still delivers the bioavailability – as a second challenge. Many cannabinoids are drug substance to the bloodstream.” lipophilic and even in their purest forms are either oils or oily Tovey adds, “For complex plant-based extracts (such as solids, rather than the white powders so commonly seen with cannabis extracts), the presence of other non-cannabinoid, typical

www.themedicinemaker.com “EVEN IN COUNTRIES, SUCH AS CANADA, companies in this space is whether debates around legalization WHICH HAVE ALREADY and scheduling would make it easier to develop and manufacture DECRIMINALIZED cannabis-based medicines. C² Pharma sees its business as being totally separate from debates around legalization. “We are talking CANNABIS, THERE IS about two different things,” says Badrot. “If you take caffeine as an example, it is applied in both social and pharmaceutical STILL VARIATION IN THE markets, and each one can create their own value stream. Like INDIVIDUAL PROVINCE caffeine, the cannabis market has plenty of space to thrive, but our interest remains on the pharmaceutical side.” OR TERRITORY Lonza, on the other hand, has found that differences in legislation LEGISLATION.” can create some logistical problems. “The controlled drugs laws are a large complication in the development of cannabinoids; firstly, as there is a lot of variation in these laws from country to country or even state to state, such as in the US,” says McNaughton. “Even plant-based components, such as waxes, flavonoids, terpenes, in countries, such as Canada, which have already decriminalized sesquiterpenes and so on, all add to the complexity and solubility cannabis, there is still variation in the individual province or issues when trying to find an appropriate formulation.” territory legislation. Transporting products to legal zones without Finally, according to McNaughton, the dosage form also needs impacting areas where it remains illegal is a logistical challenge.” to be adapted to the oily liquid nature of these formulations. GW Pharma has been asked a lot over the last couple of years “Liquid filled hard capsules and soft gel capsules are ideally suited whether the legalization of cannabis would make their lives easier. for this family of medicines,” he says. The answer, according to Tovey, is that it wouldn’t make a big difference. “Ultimately, because we have chosen to go down the MEDICINAL, MEDICAL AND RECREATIONAL traditional pharmaceutical path, we’re almost entirely removed from the debate around legalization and even scheduling, to Following the legalization of cannabis in Canada, South a certain extent,” he says. “We’ve never had a notable issue in Africa and several US-states, a big question for pharmaceutical getting the licenses to grow and research cannabis, to do all of Feature 29

the clinical trials and to turn in cannabinoid research, partly through GW’s work, it into a medicine and get but also through the extensive network of academics we regulatory approval.” Although work with.” Tovey does admit that there were some challenges. “It required a lot of COMBATING CONFUSION AND CONFLATION expertise, time and attention to detail. And you have to constantly ensure that you’ve got your licenses up to Despite GW’s success in the field, there are some misconceptions date. But we have shown that it is possible to do all of this work that pharma companies face. within a system in which cannabis isn’t legalized, and even where “We are looking at products derived from a plant that has cannabis was schedule one.” substantial social implications. Some people believe that Tovey has many good things to say about the environment in the anything related to the plant is to be avoided, while others may UK for manufacturing and developing cannabis-based medicines believe that cannabis-derived compounds will heal everything – despite the legal status of the plant. “The UK government from your head to your toes,” says Badrot. “What we are and regulators have always been supportive in the way they looking to do is to create a realistic balance between realizing approach things, and we’ve found the UK to be a conducive and the potential of cannabis and its constituents, and delivering attractive environment for growing and manufacturing cannabis patient solutions that work. Over the next decade, we expect and cannabis-based medicines.” He believes that his experience to see a lot of progress in the space and are excited to be one is similar to that of other companies in the UK that hold licenses of the trailblazers in the market.” for growing cannabis and undertaking cannabinoid research. For McNaughton, a major misconception is that all “The UK should be proud that the country is a world leader cannabinoids are psychoactive, which isn’t the case. In fact,

www.themedicinemaker.com most are not psychoactive at all (cannabidiol, for example). “In some cases, the psychoactive effects may have therapeutic advantages in disorders such as depression, but there is also an increasing body of evidence for the potential for the non- psychoactive cannabinoids as therapies,” he says. Another major misconception noted by Hennessy arises out of conflating cannabis-based medicines with “medical marijuana” and even recreational pot smoking. “Unlike some of the cannabis- based products that are more readily available in states where they are offered, cannabis-based pharmaceutical medicines have gone through rigorous clinical testing to prove that they are safe and effective,” says Hennessy. trials cannot be conducted with cannabis “Unfortunately, the science around the active compounds of derived medicines, according to Tovey. “With cannabis – CBD and THC mainly – is still nascent, and even more Epidiolex and Sativex, we have shown that this so when you consider interactions between the two,” Badrot adds. is not the case.” The current lack of randomized “Legally, the term ‘medical cannabis’ is open to interpretation.” controlled trials performed with cannabinoid/ Within the cannabis space, there is a broad array of different cannabis-based products, says Tovey, is due to the products that are commonly referred to as medicinal cannabis or lack of quality investigational products. “This is as a result of the medical cannabis. Tovey says, “That might include some of the challenges around the ability to manufacture and supply a consistent, finished products you see being sold in the US or Canada, but it could stable product which can be reproduced throughout a medicine’s include some of the CBD products on the shelves, or even people development and life cycle after market authorization.” smoking a joint for purported medical reasons. This whole category of Despite this, Badrot believes that the medical cannabis industry is products vary greatly in their safety, quality and efficacy, but none have breaking down stigmas, which can only encourage more companies been subjected to double-blind placebo controlled trials – what the to enter the cannabis-based medicines industry. “The stigma that pharmaceutical industry would consider hard evidence.” He also adds has been created since the 1920s and the initial ban of ‘Indian that the term “medical cannabis” is sometimes deliberately conflated hemp’ during the International Opium Convention is starting to with cannabis-based medicines. “There isn’t a strong evidence base loosen, particularly in a time where we see a critical gap in the pain for those products and we cannot extrapolate from data generated medication market and the crippling effects of the opioid epidemic. by cannabis-based medicines to a whole group of products,” he says. Cannabis offers great potential for safe, effective solutions,” he says. In a Q&A note, the FDA has stated it “continues to be “Cannabis is effective, but it is also misunderstood.” concerned at the proliferation of products asserting to contain As public interest grows in the space, Badrot believes CBD that are marketed for therapeutic or medical uses although more pharmaceutical companies are willing to explore the they have not been approved by FDA [...] Unlike drugs approved opportunities that cannabis presents. “We are just starting to by FDA, products that have not been subject to FDA review as explore what the full potential could be.” part of the drug approval process have not been evaluated as to whether they work, what the proper dosage may be if they do References work, how they could interact with other drugs, or whether they 1. CNBC, “The marijuana industry looks like the have dangerous side effects or other safety concerns” (3). fastest-growing job market in the country” (2019). Tovey points out that the evidence for GW’s cannabidiol Accessed 25 April, 2019. Available at: https://cnb. oral solution should not be extrapolated to other cannabidiol cx/2Tb4P9a. containing product formulations. “Each product needs to be 2. Medical Marijuana inc., “Industry overview: legal assessed on its own merit through thorough pre-clinical and cannabis is the fastest-growing industry in the clinical evaluation. The safety and efficacy demonstrated in pre- United States” (2019). Accessed April 25, 2019. clinical and clinical trials of approved or late-stage investigational Available at: https://bit.ly/2UUYPr8. medicines does not equate to the same efficacy or safety profile 3. FDA, “FDA Regulation of Cannabis and in different products of similar or the same cannabinoid Cannabis-Derived Products: Questions and composition – doing so assumes different products have been Answers” (2019). Accessed 25 April, 2019. grown and manufactured to exactly the same standards.” Available at: There is also a common misconception that randomized clinical https://bit.ly/2Vr2Se7. Biocompatibility Redefined.

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Built on Innovation

Innovation in glass continues to be a key enabler for allowing pharma manufacturers to make better, safer products for patients. This has been SCHOTT’s mantra for more than 130 years – why stop now?

SCHOTT’s history dates back to 1879 when the company’s founder, Otto Schott, invented a special lithium- based glass with novel optical properties and shared his discovery with Ernst Abbe. This laid the foundation for a close collaboration, which soon Tell us about the company’s $1 billion resulted in Otto Schott, Ernst Abbe, investment… Carl and Roderich Zeiss founding the As the overall pharma market grows – Schott & Associates Glass Technology and particularly with new drugs such as Laboratory in Jena, Germany, in 1884 biologics growing at an above average (today’s SCHOTT AG). The company rate – there is a risk of shortages in quality also invented chemically resistant pharmaceutical glass. We are investing borosilicate glass, which has since $1 billion globally in our pharmaceutical become the main primary packaging packaging business through 2025 to shore material for use in pharma packaging. up our capacity. The investment will be SCHOTT’s history is built on enabling used for a number of different projects, customers to develop high-performance including a glass tubing production products and the company continues facility in China and additional tanks and to innovate today. SCHOTT produces infrastructure in India, where we are 11 billion pharmaceutical containers seeing increasing demand. Particularly every year and is also one of the few in India, there is huge growth as drug companies that is in control of its entire production is transferred from Europe value chain – something that is becoming and the US. more and more important to pharma Other projects for the investment customers. Companies no longer just include a new glass syringe operation new EVERIC pure vials and investment want a container; they expect services in Switzerland, and a new factory in in our iQ platform of ready-to-use vials. to come with it too, such as leachables the south of Germany (Müllheim) Several investments will be completed profiles, extractables profiles and for SCHOTT TOPPAC ready-to- by the end of 2019. regulatory support. use polymer syringes and customized We speak with Dr Frank Heinricht, container solutions. Overall, our capacity Why is innovation in glass so important? Chairman of the Management Board for polymer packaging will be expanded My background lies in physics and I’m of SCHOTT AG, to talk about the by 50 percent by 2020, and an additional passionate about innovation – and for a company’s recent $1 billion investment in 50 percent over the coming years. We’ll materials-based company like SCHOTT, its pharma glass business, industry trends also be expanding our high-value vial it is imperative that innovation is the and the importance of glass innovation. production line, including a boost for our driving force of what we do. Our designs Sponsored Feature  33

must be led by science and the science of also looking to follow FDA standards when Cost is always an issue for pharmaceutical glass is more fascinating than most people overhauling their own pharma regulations. companies so with a modular approach realize. Glass is not all the same – a lot of In addition, drugs are becoming more they can select the performance they effort goes into making the right glass for sensitive and specialized. There are over really need, balanced with their budget. use in pharmaceuticals. For example, the 3000 drugs in the pipeline and roughly There are three main modular elements: bottom-near heel region of standard vials two thirds of these are biopharmaceuticals. Pure, Strong, and Smooth. EVERIC Pure, often acquires an inhomogeneous chemical 8LIWI WIRWMXMZI HVYKW LEZI WTIGM½G which is available now, is all about the structure during the forming process and requirements in terms of packaging – and interaction with the drug and container, is prone to ion exchange, which may this is why we have launched products and is suitable for sensitive drugs with low potentially harm the drug. Physics and VIGIRXP]XLEXWTIGM½GEPP]GEXIVXSWIRWMXMZI ½PPMRKZSPYQIW-XIRWYVIWHVYKWXEFMPMX]F] chemistry dictate that there will always be drugs. There is also a lot of focus on cell and using an improved Borosilicate glass tubing. some kind of interference between the drug gene therapy and personalized medicines. The other modules are currently in testing. and the glass, and there is an art to designing Many new drugs will target smaller patient EVERIC strong emphasizes strength the right container made out of borosilicate TSTYPEXMSRW WS PS[½PP STIVEXMSRW ERH and preventing breakage by optimizing glass that really minimizes this interference ¾I\MFPIQERYJEGXYVMRK[MPPFIWMKRM½GERX the geometry through mathematical – getting it as close to zero as possible. trends for the foreseeable future. simulation. EVERIC smooth is designed We have developed different coatings and XSKMZIMQTVSZIHGSRXEMRIV¾S[XLVSYKL different glass treatments to ensure that we What are some of the latest innovations GSRZIRXMSREPFYPO½PPMRKPMRIWXLEROWXSE GERSJJIVEZIV]WTIGM½GWSPYXMSRJSVIZIV] from SCHOTT? coating on the outer surface. To ensure that API, ensuring that products have a long shelf SyriQ BioPure was launched in 2018 unimpeded visual inspection can still take life with no risk to the patient. and has had a positive reaction from place, the surface treatment is abrasion- We want to give our customers options. customers. With the newest innovation of free, fully transparent and limited to the Not everyone follows the same path forward SYVW]VM5&MS4YVIVERKI[I[IVIXLI½VWX most relevant areas of the vial, such as the so it’s impor tant for suppliers like us to have company to introduce a syringe that uses sidewall. We can therefore improve the a huge toolbox that allows customers to RSPYFVMGERX-X[EWWTIGM½GEPP]HIWMKRIH GSIJ½GMIRXSJJVMGXMSR '3* F]TIVGIRX select the right product to suit their needs with the sensitive needs of biologics in – perhaps a ready-to-use container that mind. The interaction between silicone How do you ensure your new has been made in the right way with the and biologic drugs has been a concern in innovations are easy for pharma right raw materials, or a container with a industry, but being silicone free eliminates companies to adopt? WTIGM½GWXVIRKXLJSVI\EQTPI6MKLXRS[ that problem. EVERIC is based on the gold standard in requirements are becoming tighter and In 2019, we launched EVERIC, which the pharmaceutical packaging industry, tighter when it comes to particles and there is something I am very excited about. namely borosilicate glass. Depending is also a growing demand for traceability in EVERIC has been designed as a modular on your chosen options you can better the supply chain – customers want to know concept. It provides customers with control delamination, or have an improved the history of a container, including how it a unique combination of attributes to ) 0TVS½PIFYXYPXMQEXIP]MXMWXLIWEQI was made, when it was made and so on. package biologic drugs – they can pick glass. With any of our innovations, we Traceability has always been very important what they need; for example, they may collect a lot of data and use this to steer to SCHOTT. choose to prioritize strength, machinability our design process, and we also work with or an order of magnitude improved the FDA on pre-registration to make it What other trends are you seeing in the I\XVEGXEFPIWERHPIEGLEFPIWTVS½PI%W easier for our customers to go through pharma market? I mentioned earlier, it is important to the regulatory processes. Although quality expectations are already give customers options so that there is SCHOTT’s role is to always support high in the pharma industry, the bar is being always something that suits their products the pharmaceutical industry as much as raised even further. The FDA is constantly and processes. With EVERIC, customers possible. Our $1 billion investment is all pushing manufacturers to provide better can use the material they already know about enhancing our capability to support medicines. With particulates, for example, and have registered, namely FIOLAX® the industry. Our slogan is, “Innovators at the standard limit a few years ago was CHR borosilicate glass, and then select the heart and enablers at work.” Our role is around 300 microns. Today, it’s closer to 100 additional features they would like to add to to innovate to help our customers come microns. Regulators in other countries are improve the performance of the product. up with better products for patients. 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36-38 The IPEC Story: Promoting Ingredients for Global Success Dave Schoneker has been involved in IPEC since the very beginning. Here, he remembers the humble beginnings and celebrates the federation’s successes to date.

40-43 Perks and Pitfalls of Antibody Drug Conjugates: Lessons Learned with Charlie Johnson. Antibody drug conjugates have had their ups and downs, but interest in the field remains high because of their therapeutic potential. 36 Best Practice

many years, excipients were the second- been involved in IPEC since its inception in The IPEC Story: class components of drug development. 1991 and, over the course of three decades, It’s understandable why the API steals I’ve seen the benefit of the policies and Promoting all the glory. The API is what gives a guidelines that we have created for the medicine its therapeutic properties, but industry. Many companies have grown to Ingredients for without excipients we wouldn’t be able to become top-quality industry suppliers that deliver medicines effectively to patients. meet globally vetted standards thanks to Global Success The right choice of excipients can enable the work of IPEC. companies to more readily manufacture One of the biggest challenges with High quality excipients make their drug product, produce a stable regulating pharmaceutical excipients is that all the difference to the drug dosage form, improve shelf life, help with most are made by chemical companies, who development process. And swallowability, enhance patient safety in make materials for wider industrial use. As yet, for years, excipients terms of compliance, and more. Excipients well as producing excipients for medicines, were often overlooked by make up a huge percentage of an actual they will also be marketing these products the industry. Today, IPEC is tablet – in some cases up to 99.9 percent! to food companies, paint companies, plastics helping to give excipients the Today, more and more people in the companies, and more. In fact, excipients for recognition they deserve. industry understand and respect the role pharmaceutical use make up only a fraction that excipients play. And I think a lot of of customers for the chemicals industry – and With David Schoneker this comes down to the work that the yet the pharma industry has specific GMP International Pharmaceutical Excipient regulations for excipients because of the way My mentor – and now departed friend Council (IPEC) has done. The IPEC in which they will be used. – Lou Blecher used to say, “Excipients Federation is a global organization that When IPEC was first finding its feet, don’t get any respect.” He was right. For promotes quality in pharma excipients. I’ve the unique challenges of the industry were Best Practice 37

not being addressed with the same level of their thoughts at a conference in Orlando, were GAF (which later became ISP, then scrutiny that was given to the production of Florida, which I attended. Ashland), Hercules, (now Ashland), Merck, finished pharmaceutical products or APIs. Though these early intentions of the Sharpe and Dohme, Dow Chemical (now There was simply no clear GMP regulation pharmacopoeias were noble, at that time Dupont), Hoffman La-Roche (now Roche) in place for excipient operations and the they didn’t have the scope and experience and Servier to name a few specifically. lack of harmonization left many in a state that we, whose careers revolved around During one of IPEC’s early meetings, I of confusion about what specifications and excipients and formulation, had to truly suggested that, as well as working with the controls the sector should be using. For understand what was needed. After the international pharmacopoeias to harmonize example, it was quite normal for an excipient first day of the conference, Lou Blecher, their standards, an effort should be made to supplier to be told by one customer that its invited me and others to his hotel room to help unify GMP standards for excipients. In processes were exemplary, and completely discuss what we had heard and what those my role as Director of Quality at Colorcon, I unacceptable by another… a frustrating of us in the industry could do to assist the was having to deal with the issue of differing experience! Standards were being interpreted pharmacopeias’ efforts. opinions from one customer to the next, and in different ways and arguments were Around 18 chemists and formulators I wondered if others were also experiencing hindering the industry. Some pharma descended on Lou’s room, and were invited the same problems. From the perspectives companies wanted the standards at excipient to enjoy a spread of cheese and wine. As of both the end-users and producers of plants to mirror their own but there are limits thoughts were thrown around (and wine excipients, the idea made sense for the to what chemical companies are able, or poured), Lou proposed that we form a trade industry and was welcomed by both sides. indeed willing, to do when pharmaceuticals association. Unlike others, this association IPEC’s GMP committee was set up soon are such a small part of their business. would be about science, not business, and after and was involved in the development the association would be for both the makers and publication of the first excipient GMP Wine, cheese, and humble beginnings and the users of excipients. We decided that guideline in 1995. Internationally recognized Many businesses have stories of humble if we were meeting the needs of patients and and used as the basis for most of the standards beginnings. Apple, for example, began in working to ensure that the guidelines we on excipients (to date), the publication was a garage in California and when Starbucks produced helped harmonize the industry, one of our first major accomplishments – first opened its doors in 1971, neither a coffee then an increased market presence would and a powerful statement as to what the was brewed nor a pastry sold (the company naturally occur. The idea certainly sounded association could achieve. sold coffee beans and roasting equipment). good at the time, but we all realized that the IPEC has been going for almost 30 years But when I tell people the story of the early wine might be influencing our reasoning... now, and we’ve had some great successes and days of IPEC, people chuckle in disbelief. By the next morning, we still thought the a huge impact on the international mindset Today, IPEC is an internationally recognized idea was worth pursuing and could make toward excipients! Not bad for a group of organization, with regional groups in the a huge difference if we formed such an scientists who crammed themselves into a Americas, Europe, Japan, China and India. organization. We also acknowledged that, tiny room late one evening for cheese, wine IPEC also has partnerships with other as scientists, we knew little about the legal and a discussion about excipients! associations in Canada, Mexico, Brazil processes required to bring this concept into and Argentina. It has tremendous respect reality. Fortunately, Lou was able to contact Out with the old worldwide. But the organization’s story a friend (Bob Pinco), who was a lawyer that IPEC has helped solve a number of issues began with a good wine and cheese party… previously worked for the FDA, to help us for excipient and pharmaceutical companies In the early 90s, as part of International formulate a legal framework for our new and published a joint IPEC-PQG Good Council for Harmonisation of Technical project. And within weeks we had our first Manufacturing Practices Guide, a Good Requirements for Pharmaceuticals for organizational meeting. Distribution Practices Guide, an Excipient Human Use (ICH) initiatives, the US, Several companies were great supporters Qualification Guide, a Certificate of European and Japanese pharmacopoeias from the start, including my own employer, Analysis Guide, the Significant Change were eager to harmonize their standards. In Colorcon; with a number of employees Guide for Pharmaceutical Excipients, a particular, they identified that specifications around the world involved in IPEC from Technically Unavoidable Particle Profile and test methods for excipients were, the start! The company was certainly Guide, and many more (all available at frankly, a bit all over the place! They felt supportive of our cause to help harmonize www.ipec.org). But there are still other it was a good area for them to start to standards for excipients. Other companies challenges. One frustration is that although work on harmonization and they outlined that also got involved in those early days excipient companies are developing some

www.themedicinemaker.com than ever, pharmaceutical companies need new ideas to help develop drug formulations for their pipelines. There are more insoluble APIs than ever, thanks to new technologies and techniques, and new excipients may be needed to optimize formulations for emerging technologies, such as 3D printing and continuous manufacturing. Countless numbers of drugs sent to the FDA for approval have been scrapped because the right dosage forms required for the effective delivery of these products were not available – a terrible situation when we have so many innovative options in an industry that could help! IPEC and the IQ Consortium (https:// iqconsortium.org) have teamed up to hold discussions with the FDA to establish a novel excipient qualification process, which I really hope could result in the formation of an FDA committee to review data on new excipients. If the FDA David Schoneker recently received the Louis Blecher Memorial Outstanding Lifetime Achievement agrees to this, it would go a long way in award from IPEC. mitigating the industry’s concerns and allow companies to jump in and use newer truly innovative technologies, they are processed formulations of commonly used materials, which could resolve many issues not being used by the industry due to a excipients, such as spray dried versions of they face in terms of drug development, reluctance to be first. If new excipient corn starch and pregelatinized corn starch, stability and quality. The pharma industry products continue to be unused, then it that give better performance – pharma is one of the most innovative industries could affect innovation in excipients going companies have even raved about the in the world – and we can do better if forward; after all, a lot of work and cost goes benefits! But still they dismiss them in companies are given the help they need to into creating a new excipient, including preference of more established options that be confident in adopting new ingredients market research and regulatory work. have precedence of use. and technologies. Ever since the formation of IPEC, the The reluctance of pharmaceutical IPEC has, throughout its history, concern about bringing novel excipients companies to adopt new excipients may be helped put a spotlight on excipients and to market has lingered – perhaps hardly tied to the fact that the FDA lacks robust worked with regulators to affect change. surprising given the notoriously conservative regulation on the introduction of new We haven’t lost the enthusiasm or verve we and safety conscious attitude of the pharma excipients to market. Currently, there is no had when we first created the association! I industry. Historically, the industry has independent process for the FDA to review hope we will continue to make progress in continued to formulate with 100-year- the safety of an excipient; excipients cannot this area. The risks of ignoring the problem old excipients – and although these may be approved on their own and must be a are great. If companies continue to avoid work, they do not always work as well as part of a drug product and reviewed during novel excipients then it could lead to a they should. Pharmaceutical companies do the drug registration and approval. The only stagnation in innovation – a problem for acknowledge the benefits of new excipients, process available to pharma is to take the pharma and patients alike. but they rarely want to be the first to use plunge and see what happens when a novel them. Companies can also be hesitant to use excipient is added to their formulation – a Dave Schoneker is Global Regulatory modified versions of well-known excipients choice which many companies are simply Director, Strategic Relationships at Colorcon, in their drug products. I’ve seen excipients unwilling to make. and Vice Chair for Science and Regulatory companies develop some advanced co- The crux of the issue is that now, more Policy for IPEC.

40 Best Practice

Perks and Pitfalls of Antibody Drug Conjugates: Lessons Learned with Charlie Johnson

ADCs have suffered a few setbacks over the years, but interest in their therapeutic potential – particularly against cancer – remains high.

By Stephanie Sutton

Charlie Johnson has kept his eye on the antibody drug conjugate (ADC) field since its early days and was involved in developing the process for one of the first ADCs to hit the market, as well as helping to establish Avecia’s ADC manufacturing operations. Today, he is CEO of ADC Bio. Here, he talks about the ups and downs of the ADC market, and shares the lessons he has learned as ADC Bio gears up to jump into GMP manufacturing.

New classes of therapeutics take time to find their feet I’ve always been fascinated by ADCs. In many ways, ADCs combine the best of both worlds: the potency of cytotoxic agents with the specificity of antibodies. The targeting on the tumor may also be present in healthy but there is now a renaissance in the ADC ability has been of particular interest to drug tissue. The translational science of ADCs area, thanks to growing understanding developers working on cancer therapeutics. has been very challenging, but a lot of it and experience with ADCs. Two new But although the industry has been talking comes down to choosing the right targets. products were approved in 2017 and there about ADCs for years, approvals have been Right now, there is a great deal of attention are over 80 ADCs in clinical development, thin on the ground. ADCs have shown being paid to more exquisite targeting; for as well as thousands of patents filed. And promising data in terms of having an effect example, using bispecific ADCs. new research is being published constantly on tumor cells, but there have also been It is normal for new areas of science and as the community strives to improve safety unintended side effects as the target antigen drug development to suffer some setbacks, and efficacy (for just some example papers Best Practice 41

published in 2019, see the Recommended optimize it with the University of Sheffield. Reading sidebar). Oncology remains the ADC Bio was formed in 2010. Our initial top area for ADC drug development, aim was to license the technology out to Recommended but other areas are also being explored, pharma companies. Though there was a such as inflammatory diseases and even lot of interest, there was also a common Reading bacterial infections. theme: companies wanted us to actually do the work for them. M Abdollahpour-Alitappeh et al., Aggregation is a major So that’s the direction we went in. We only “Antibody–drug conjugates (ADCs) manufacturing challenge focus on ADCs. Our proprietary technology for cancer therapy: Strategies, As well as innovation in terms of is called Lock-Release, and we’ve done the challenges, and successes,” Journal ADC development, improvements in work to ensure it’s scalable and meets GMP of Cellular Physiology, 5 (2019). manufacturing have focused on speeding requirements. But we also do mainstream up, simplifying and significantly lowering ADC development too, including small- L Bourillon et al., “An auristatin‐ the production costs. My work with ADCs scale work that has gone into trials in non- based antibody‐drug conjugate began back in 2005. I was working in human primates. We were a small company targeting HER3 enhances the Scotland at a clinical manufacturing facility at first – we had nine people in 2014 but radiation response in pancreatic for small molecules (mainly cytotoxics) and things changed quickly. We’ve expanded a cancer,” International Journal of we received a visit from a small company lot and by 2015, we were turning over £1.5 Cancer (2019). that I had never heard of before: Seattle million. We signed many agreements and Genetics. They were developing what even won an award with the British Private C Duerr, W Friess, “Antibody- would later become Adcetris and we were Equity and Venture Capital Association! drug conjugates- stability involved in developing the process for them. But still customers wanted more. Many and formulation,” European After I left the company, I kept my finger clients were encouraging us to get further Journal of Pharmaceutics and on the pulse with ADCs. The field certainly involved in their development programs; they Biopharmaceutics,” 139, 168-176 had its challenges, but I was not only wanted us to move into GMP manufacture (2019). fascinated by the way they worked and their and clinical trials. It was a big move. ADCs therapeutic potential but also by the interest are still relatively new compared with JB White et al., “Design and shown by companies. Around 2009, I had a established monoclonal antibodies, but characterization of homogenous conversation with an ex-colleague who had after we discussed the expansion we were antibody-drug conjugates with come across a piece of intriguing chemistry confident it would work. Between us we a drug-to-antibody ratio of one that he thought could help us towards a solid had a lot of experience in ADCs, so the prepared using an engineered phase approach to ADC manufacture. question became: why not take the plunge?! antibody and a dual-maleimide Currently available ADCs get around The hardest part of making an ADC is the pyrrolobenzodiazepine dimer,” the aggregation issue with finely tuned design and development, but GMP is where mAbs, 3 (2019). processing, but many ADCs in development pharma customers see the most value as it’s now use pyrrolobenzodiazepines or directly connected to the patient. In fact, M Lin Yap, “Activated platelets duocarmycin-based payloads, which are GMP is relatively simple compared with in the tumor microenvironment very potent but also dramatically increase other aspects of ADC development. Once for targeting of antibody- the drug’s propensity to aggregate during a recipe has been defined, it’s simply a case drug conjugates to tumors and conjugation, which is expensive and time of following the recipe at scale – providing metastases,” Theranostics, 4, 1154- consuming to deal with. By using proprietary your process development is solid. 1169 (2019). beads to immobilize the antibodies, payloads The decision was made – and we went can be conjugated in situ, which physically to our investors and told them we wanted M Jose Costa et al., “Optimal prevents aggregation at the source. It also to build a clinical manufacturing facility. design, anti-tumour efficacy means you get a very high-purity ADC. It took time, but we got the funding. We and tolerability of anti-CXCR4 acquired a 6500 m2 facility in Deeside, antibody drug conjugates,” Pharma companies want you to do as UK, in 2017. Construction has finished Scientific Reports, 9 (2019). much work for them as possible and we’re awaiting inspections as we speak; Inspired by the technology, we worked to we have been liaising with the MHRA

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Best Practice 43

throughout the design and construction process. We are now part way through the accreditation to obtaining the necessary license to produce ADCs for human trials.

Build flexibility into your facility design Experts will tell you that the design and build of a new facility takes time – and they are absolutely correct! Flexibility is extremely important. While we were in the process of building our Deeside facility, there was a big shift in the ADC marketplace. There are four elements of manufacturing an ADC: you need an antibody, a payload, the conjugation, and then fill and finish. Not all pharma companies want to do this in house so outsourcing is a common option and, in some cases, each element will be manufactured at a different site. Today, however, companies tend to want their And they do go nowhere – for now! But underestimate the challenges of finding a partner to tackle multiple aspects – perhaps in the future, they will lead to new areas site and getting it up and running! make the antibody and do the conjugation of capability. I would say that flexibility is with the payload, or do the conjugation especially important for ADCs because A blank sheet of paper can be a joy and the fill and finish. The reason? Time. product demand his so variable. Some We’ve been hiring a lot of staff recently It saves the pharma company a lot of time ADCs have a global demand of only 5 kg – and we’ve been successful in attracting in development. They can also save costs while others may be in the region of 300 kg very experienced people. Some of them because they need fewer people and aren’t or more. It’s important to have a facility that have chosen to leave big pharma and dealing with complex work. can cope with those extremes, but be able come work for us because we offer a Having more than one part of your supply to scale if demand changes in the future. blank piece of paper – the ability to do chain with one vendor also contractually something from scratch and run your makes things a lot simpler and gives you Location matters own process. Big pharma has been (and more flexibility to overlap the next stage of One of the conditions of receiving can be) very successful but there are manufacture with completion of testing in investment was our presence in Wales, some downsides; big companies tend the preceding stage. If you are transferring to UK. But this also gave me a whole new to be systemized and procedural, so another site then you must ensure the product appreciation for how difficult it can be change does not come easy. At a new, is always to specification. But if you have to find an appropriate site for a facility smaller company you can employ what formulation under the same roof, the client – especially, as we didn’t want to invest you have learned in the past; you can can ask you to try different approaches with money on infrastructure unnecessarily. It cherry pick ideas and build your own the idea of compressing time or investigating was easy to find great sites, but they all process – it’s all been very exciting. It’s ways to make processes more efficient. required millions of pounds to install the also been stressful, of course! Often in As well as performing ADC electrical supply we needed. At almost the the contract manufacturing market, manufacturing and conjugation, we are also eleventh hour, the Deeside site became everything comes down to price, which moving into fill and finish. Fortunately for available. It had previously been used by is unfortunate. However, we decided us, we prioritized flexibility when looking Catalent for warehousing and distribution. to focus on building up our technical for a site so we have the ability to build in It had space. It had power. And it had capability before committing to a facility, this new expertise. You always need to think more space to expand into in the future. which allowed us to showcase the skills ahead when building a facility. If anyone Shortly after Catalent exited, it was and knowledge we have to offer. And we were to visit our facility now, they’d notice raided by thieves for copper wiring. But are delighted that clients have chosen to some corridors that seem to go nowhere. that’s another story… In short, never support us.

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46-48 Bright SPARK SPARK, a translational research program, is proving that alternative models to drug development can work. Daria Mochly-Rosen explains how collaboration between industry and academia is allowing this to happen. 46 NextGen

Bright SPARK

Academics have a role to play in the acceleration of biomedical innovation. And SPARK, a translational research program at Stanford University, is proving how important academicians are in slashing the time taken to bring novel therapeutics to market.

By Maryam Mahdi

Many academicians will, no doubt, be able to attest to the fact that years of research can seem to fall by the wayside as pharmaceutical companies refuse to take their novel discoveries for further development into therapeutics, creating barriers to the progression of translational research. It’s well known that out of 10,000 new drugs developed biomedical research and help translate was estimated that over one billion at the bench, only one will often make them into new therapeutic options for people worldwide were affected by a it to the bedside, but are fixed ideas patients. The campus-based program is neglected disease – one-sixth of the about what the drug development based on collaboration between industry world’s population! process should look like preventing experts and academic investigators in the By focusing on filling in the white this from changing? Aware that the pursuit of novel drugs and diagnostics spaces around these therapeutic areas, starkly obvious cultural divide between for all diseases, with a special emphasis SPARK gained the attention of the academia and industry can create on pediatric, maternal and neglected Lucile Packard Children’s Hospital roadblocks to biomedical innovation, diseases areas. While being of significant at Stanford University’s School of Daria Mochly-Rosen, George D Smith clinical relevance, these disease areas are Medicine. They recognized the Professor in Translational Medicine, often left untouched in terms of drug importance of what we were trying and Professor in Chemical and Systems development. The regulatory challenges to achieve through the program and Biology at Stanford University, set out to and ethical issues associated with offered us funding. While the program create a new initiative to help academics maternal and pediatric pharmaceuticals is primarily funded by the university’s take their inspiring work further. have perhaps left many in the industry medical school, the fund it receives Daria is the founder and co-director of with the feeling that the stakes were too from other philanthropic organizations SPARK at Stanford and president of high when it came to the development of and the National Institutes of Health SPARK Global. new treatments for these areas of unmet have helped the program grow into clinical need. what it is today – a research center with What is the story behind SPARK? For us, it is a moral imperative to a success rate of over 50 percent when I believe we, in academia, have a part address these issues. The needs of these bringing potential therapies to the to play if we want to serve patients patient populations are just as severe as clinical trial or to a licensing stage. In worldwide. In 2006, I founded SPARK any other patient group and they cause comparison, the industry’s success rate as a not-for-profit program at Stanford a significant burden for healthcare is 10 percent for projects at the same University to take promising advances in organizations worldwide. In 2017, it stage of development. A major aspect 34th International Exhibition for Fine and Speciality Chemicals

of SPARK’s ethos is to operate effectively without commercial incentives, as funding derived from these types of channels would create a conflict of interest for the dozens of industry volunteers in the program.

How has your previous experience influenced the 26 – 27 June 2019 | Messe Basel, Switzerland development and evolution of SPARK? Four years before the commensal of SPARK, I set up KAI Pharmaceuticals with my student, Leon Chen. KAI was a biotech venture focused on the development of novel Europe’s most renowned industry hotspot therapeutics for cardiovascular diseases. The experience overhauled my perception of pharma and I gained a new Meet suppliers and experts from around the globe and appreciation for the complicated and intellectually stimulating find bespoke solutions, new approaches and innovative work carried out by an industry, which I must confess I had substances for your enterprise. previously viewed with a certain sense of scepticism! With SPARK, I wanted to provide other academic inventors the opportunity to learn from industry experts and push forward fine chemicals • pharmaceuticals • adhesives & sealants early ideas to benefit patients, in the same way I had at KAI. agrochemicals • paints & coatings • flavours & fragrances Our aim is to provide our SPARK scholar project teams household & industrial cleaning • colourants & dyestuffs (academicians whose projects we support) with enough exposure pulp & paper chemicals • leather & textile • surfactants and insight from experienced pharma experts to help enhance their chances of success. Open to professors, clinicians, postdoctoral polymers • plastics additives • petrochemicals scholars, and graduate students, SPARK also offers graduate level water treatment • cosmetics courses on drug development, helping academics with a blue-sky food & feed ingredients Fine and speciality approach to research to understand the highly regimented and electronic chemicals chemicals for regulated aspects of the commercial pharma industry. and much more various industries How can established pharma experts also contribute to SPARK? We have experts from the pharmaceutical industry who volunteer their time to the program, by sharing their stories of success and failure with our SPARK scholars. While they have no rights to the inventions developed through the program, their mentorship is crucial in helping move ideas from the bench to solutions at the bedside. SPARK hosts meetings, on Top conferences and workshops a weekly basis, where the process of drug development and offer valuable insights into commercialization is taught to our SPARK scholars, and every ongoing R&D projects! fortnight, our project teams receive feedback on their work from advisory panels whose expertise lie in pharmaceutical • Agrochemical Lecture Theatre • Chemspec Careers Clinic drug development. Fostering these types of healthy working • Pharma Lecture Theatre relationships, where ideas are shared between academics • Regulatory Services Lecture Theatre and many industry experts without the concerns or focus on • RSC Lecture Theatre financial return, defines SPARK and helps move translational • Innovative Start-ups research in a positive direction.

How does SPARK work with scholars? Championing talent whose work goes unnoticed is integral to SPARK’s DNA. Each year, SPARK selects between 10 and 15 scholars who are mentored under the program for two www.chemspeceurope.com

Organisers: years. The selection is carried out by a inhibitory drugs (and others from other How do you think the work from committee consisting of SPARK’s team, project teams) are currently under SPARK could shift the drug pharma industry experts, and Stanford clinical trial, but highlight the potential development landscape? faculty members. The proposed projects of SPARK Scholars for transforming the Our aim is to encourage unconventional are assessed on their ability to: clinical landscape and disrupting the solutions to drug development. As conventions that have seemingly been academicians, out of the box risk-taking • Address an unmet clinical need set in stone by industry players. is what drives our progress and underpins • Utilize a novel approach our successes. Here at SPARK, we are • Be moved to clinic or be What have been some of SPARK’s developing creative approaches that are commercialized within a two year biggest success stories? improving upon the current efficiency of time frame 2015 marked the official launch of the drug design process. Our academic and SPARK Global. As universities across non-for-profit status facilitate us to enter Scholars who join the program can the globe began to replicate the SPARK meaningful conversations with organizations only be described as powerhouses. model within their own institutions, like the FDA about transforming the drug So far, SPARK has launched over 30 the need to properly organize became development landscape. We also aim to work companies, licensed 48 technologies, and apparent. Currently, over 50 different with regulatory affairs bodies in Europe and led to 25 clinical studies – a great feat for institutions on all continents are involved Asia. We hope that these activities will allow both our scholars and the patients who in SPARK, forging partnerships to regulators to hear alternative modes as to will ultimately benefit from their work. improve upon the number of therapeutics how novel therapeutics can be brought to One of SPARK’s scholars, Teresa available for unmet clinical needs. patients faster. Purzner, conducted research on As just one example of how SPARK My colleagues and I want our impact medulloblastoma – the most common Global facilities help form connections to be far-reaching – beyond the scope form of pediatric brain tumor. She in different countries, consider the Zika of academic publications. I believe that has developed a potential therapy for crisis, which drew public attention in 2016, it is part of our social responsibility as the condition. Traditional treatment and remains a major threat for children scientists. We, as academicians, have the options for this form of tumor involve born to mothers bitten by the insect that capacity to make a difference to patient surgery, whole brain radiation and/ carries this virus. The profound effects lives and to complement other work that or chemotherapy. This can result in of this viral infection on the fetus results is strongly tied to the conventions of the intellectual and social impairment and in microcephaly (small heads) and many pharma industry. We are two sides of the deterioration of quality of life. Doing other severe developmental issues. In same coin and only by investing time in major basic research, Purzner identified an effort to help, researchers at SPARK having serious conversations about the that drugs which block CK2 – a protein Stanford are collaborating with SPARK future of drug development and working kinase – may benefit children with Brazil and Brazilian scientists to develop together can we fulfill our mutual goal this malignant cancer. One of these a novel vaccine to combat the disease. – to help patients. Meet… … the people shaping the world of cannabis science.

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Sitting Down With… Jinling Chen, Vice President, Pharmaceutical DevelopmentDevelopment Services, WuXiWu STA, China. Sitting Down With  51

What was your focus in the early days of across all aspects of CMC. My role is What are the specific considerations your career? very varied. I’ll often be in meetings with when making medicines for children? Following my PhD in physical chemistry, counterparts from API manufacturing or The first thing to remember is that I worked in the US for over 20 years. My other departments. I’ve found that some children aren’t just “little adults”; early career focused on drug delivery unique ideas and solutions can arise from there are many specific considerations technologies. I really enjoyed the bringing such a breadth of experience that formulators and developers must challenges in this field and I worked and knowledge together. There’s a lot of think about. The first is something that for a number of big players including things I love about my role – and being most parents are aware of: children are AstraZeneca and BMS for about 10 years. surrounded by motivated people who very sensitive to taste! This can make I ended up with over twenty patents in genuinely want to make a big difference administering medicines as a parent very drug delivery technology! But it’s good makes it even more enjoyable. difficult! Differences in the anatomy and to branch out to other areas. In 2002, I physiology of the infant and developing moved to Houston and worked for smaller How have you found the move to the child can affect metabolism and the pharmaceutical and biotech companies. outsourcing sector? pharmacodynamics of various drugs The switch gave me the opportunity The pharma industry has changed a lot and other xenobiotic compounds. to diversify – roles are usually quite over the years. When I was working for There’s also a large age range when specialized in big pharma companies, but the large pharmas, they had substantial we’re talking about children – young for the next 15 years I had the opportunity R&D departments in-house. Today, infants and teenagers have very different to work in drug development, research, strategic outsourcing is much more needs. A conventional tablet may work clinical supply, analytical, NDA fillings common, so it was a good time to make for a teenager but not for younger and taking products to launch. I really the switch. Luckily, skills from pharma children. When I’ve been involved enjoyed learning about different aspects manufacturers are perfectly transferable with developing a pediatric drug, I look of pharma development! to the contract services sector and it’s at the indication and the potential age interesting to see the industry from groups that could benefit. If it’s a wide What is your role today? different perspectives. Having had my range, it’s a good idea to design at least Early last year, I was presented with an whole career in the US, I didn’t quite two formulations – one liquid and one opportunity to return to China. Today know what to expect going back to China tablet or granular formulation. There are I’m with WuXi STA, a WuXi AppTec and working with the team in Shanghai, some good formulation options out there company – it’s my first time working at but I was taken aback by how dedicated for children, including mini tablets and a CDMO! My role here is heading the everyone at the company is. even formulations that can be sprinkled pharmaceutical development division of on ice-cream! Wuxi STA. We’re around 400 people How did you become interested in in the drug product division and we developing medicines for pediatric What would you like to see change in cover the full range of development – populations? this area? from the solid state characterization Today, regulators are asking for specific I would like to see the community of the API, salt and polymorph form- plans for pediatric development. For learning from each other to advance screening, preformulation, stability example, the Pediatric Research Equity pediatric formulation development evaluation, formulation development, as Act (PREA), passed by the FDA in 2003, in terms of the most effective dosage well as process development and scaling imposed a requirement that companies test forms. I also favor the approach taken up for GMP supply of clinical trial any new drug likely to be used in children by some regulators to extend patent- materials commercial manufacturing. in a pediatric population. Then in 2017, the life for drugs developed with pediatric The responsibilities span R&D and GMP FDA Reauthorization Act of 2017 gave the populations in mind. However, pediatric manufacture. So once again I’m branching FDA the authority to ensure appropriate medicines require special knowledge and out to new areas! pediatric labeling of drugs and biologics. technology – all of which costs money. Similar regulations were also introduced The importance of compliance should Sounds like you get involved with a bit in the EU in 2006. In my current role, never be underestimated, but ultimately of everything… we handle drug product development for we have a chance to make the lives of Indeed! WuXi STA is quite unique in our clients and considering the pediatric parents and children much easier when having a service that is truly integrated population is crucial. taking their medicines.

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