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FIGHTING THE OPIOID CRISIS

THE FUTURE OF NANOTECHNOLOGY

WOMEN IN PHARMA

March/April 2020

MAKING

Waves

What key players in pharmaceutical logistics believe to be the major issues facing the sector.


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Contents Mar/Apr 2020 | Volume 20 Issue 2 REGULARS 5: EDITOR’S DESK

Why Covid-19 could represent a sea change in the way pharma and government work together.

6: A SMALL DOSE

A brief round-up of some of the latest developments in the industry.

13: OPINION

Bormioli Pharma writes how prototyping can help pharma manufacturers innovate.

16: COVER STORY

Lu Rahman asks key players in the logistics sector about the biggest challenges facing the industry.

18: IN THE NEWS

A short selection of stories from the world of science.

FEATURES 8: PERSPECTIVE ON PHARMA

How the use of a psychedelic plant could help treat opioid addiction.

24: SINGLE USE

How single use systems are aiding sterility during bioprocessing and helping manufacturers implement continuous supply.

32: WHAT’S TRENDING

Why pharma companies are shifting towards cell and gene therapies.

38: WOMEN IN PHARMA

The second part in a mini-series of articles examining the life sciences industry and its perceptions of women.

40: FROM THE FACTORY

Bora Pharmaceuticals explains how extrusion-spheronization techniques can improve API development and formulation.


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EDITORIAL editor reece armstrong reece.armstrong@rapidnews.com head of content, life sciences lu rahman, lu.rahman@rapidnews.com web content editor ian bolland publisher duncan wood

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"That time is of the essence is particularly important to the pharma industry."

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hilst the outbreak of the latest strain of Coronavirus – Covid-19 – is a scare for healthcare systems and citizens worldwide, it presents an opportunity to pharma and government to reassess the way they work together.

With Covid-19 surpassing 100,000 cases worldwide, including over 3,000 deaths, the pressure is on the pharma industry to accelerate a vaccine through clinical trials and into patients, as quickly as possible - easier said than done. That time is of the essence is particularly important to the pharma industry. In recent years, outbreaks of Ebola and SARS caused an influx of activity from pharma players. But when the time came for vaccines to be tested, patient cases had dwindled and companies were unable to recuperate the costs they’d put into research and development (R&D). At the time of writing there are 35 candidate vaccines for Covid-19 in pre-clinical development. Of these, only two could be classed as coming from major pharma players, with the bulk of activity into Covid-19 coming from biotechs, not-for-profit

EDITOR’S DESK

organisations and universities – essential institutes and companies, but those that often lack the capacity to scale-up and manufacture products on a large-scale. Big pharma could be criticised for its failure to act on Covid-19, but arguably, the situation is indicative of a wider issue with the industry’s market-based R&D model. The closest example pharma has to vaccine development is with its

conservative approach to antibiotic development programmes – another field in which pharma players are loathe to enter due to a lack of return on investment. With pharma companies cautiously avoiding public health crises and instead banking on profitable areas such as oncology and diabetes, there has never been a more pressing time for governments to develop public-private initiatives that encourage pharma players to invest in areas such as antimicrobial resistance (AMR) and neglected diseases. True, the Coalition for Epidemic Preparedness Innovations (CEPI) and Drugs for Neglected Diseases Initiative have been put in place to solve this problem, but like with Covid-19, the majority of interest comes from smaller-scale biotechs and academic institutes. The ongoing crisis of Covid-19 should hopefully highlight to political leaders the need for change in regard to public health crises. With the pharma industry preferring profits over risky R&D efforts, it’s up to government to develop incentive schemes that de-risk R&D efforts and encourage pharma players to enter areas such as AMR, vaccine development, and rare diseases. Comparatively, a ‘Review on Antimicrobial Resistance’ published in 2016 argued the need for incentive schemes in relation to AMR, - a crises which, at its worst, will likely kill far more than Covid-19. So, if the coronavirus doesn’t scare governments into action, the looming threat of AMR should.


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A small dose CDMO upgrades filling capacity with automated line

C PARTNERSHIP HOPES TO IMPROVE SUPPLY CHAIN FOR CELL AND GENE THERAPIES

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oftware developer TrakCel and cell and gene therapy (CGT) manufacturing company Ori Biotech have announced a partnership to improve supply chain operations for companies involved in the CGT sector. CGT developers using Ori’s platform are able to achieve automated manufacturing in a closed platform. Now, the collaboration will enable users of the Ori Biotech manufacturing platform to benefit from live supply chain visibility through TrakCel’s software. This will give customers greater insights into the manufacturing process through data services that will be available via a shared platform. “TrakCel has developed an extensive partnership network with contract manufacturers and companies across the cell and gene therapy sector. This enables therapeutic developers to be supported by

more standardised and integrated solutions,” said Fiona Withey, co-founder and CEO, TrakCel. “Closed system manufacturing is becoming progressively more important for the ongoing future of the cell and gene therapy sector, and we look forward to working with Ori to offer more integrated solutions to the wider industry.” “Ori Biotech is continuing to build a network of best-in-class partners across the cell and gene therapy ecosystem to help enable our provision of integrated, closed system manufacturing to the cell and gene therapy industry,” said Farlan Veraitch, cofounder and CSO, Ori Biotech. “The integration of TrakCel’s advanced therapy supply chain tracking software with the Ori full-stack platform is another step forward enabling our customers to have full visibility throughout the supply chain.”

ontract development and manufacturing organisation (CDMO) Pharmaceutics International (Pii) has expanded its aseptic filling capacity and capabilities with the addition of a new, fully robotic filling line. The company has installed a Genisys R filling machine from Automated Systems of Tacoma, which is able to process pre-sterilised, ready-to-fill vials, syringes, and cartridges on a single machine designed for small to medium scale aseptic manufacturing. Samuel Chia, director of Aseptic Manufacturing, said: “This automated solution enhances system productivity and controls contamination

risk by minimising operator intervention to the greatest extent possible while providing unrivalled flexibility for aseptic filling of medium-sized clinical and commercial batches.” Hank Nowak, Pharmaceutics International’s vice president of Business Development, said: “With our Pharmaceutics know-how and these expanded filling capabilities, Pii is positioned to deliver high quality and timely aseptic drug product for clinical and commercial needs. We look forward to working with existing and new partners on projects with batch sizes ranging from 1 L to 1,000 L.”

Dr Tom Ingallinera, Pii’s VP of Technical Support, advises that companies can benefit from the scalability of processes developed for the Genisys machine. “As customer’s products progress through the clinic, the aseptic filling process can be scaled to larger filling lines with minimal tech transfer,” he said. The new line is expected to be fully qualified to support vial and syringe operations by the end of Q1 2020, just one year after the initial purchase order was placed. The company has identified multiple programmes in early to late-stage development as potential candidates for transition to the new line.

most inno Switzerla


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AI COMPANY TO HELP IDENTIFY UNDIAGNOSED RARE DISEASES

AI

company Emedgene is to work with the world’s leading research institutes to help patients with undiagnosed rare diseases. The company will use its genomics analysis platform to re-run unsolved patient cases and see if it can identify any rare diseases affecting patients. As part of the project, Emedgene will utilise its machine-learning algorithm, Pathorolo, which is able to assess the likelihood of solving a genomic clinical case with currently available evidence. overtaken Germany as that Switzerland has across Europe – and delivery is accelerating innovation in drug highlights that Innovation Index from the Pharmapack Provisional findings shows. market, new research innovative drug delivery as Europe’s most overtaken Germany witzerland has

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executives – notably according to industry ‘innovation potential’ Spain) saw increases in UK, France, Italy and (Switzerland, Germany, European markets states. All six major market, the research solutions entering the devices and packaging being driven by new Innovation is largely drug delivery market. Europe’s most innovative

To solve cases, Emedgene will continuously run its algorithms on the data and alert patients once cases are recognised as solvable. Patients will then be recommended a follow-up through a certified medical geneticist, who will be provided with the new evidence for the case.

working with Emedgene is the Rare Genomics Institute. Debora Varon, a senior genetics analyst, attests to the benefits of automatically reanalysing patients’ cases with novel scientific approaches: “I’m extremely excited about the hope this new capability brings to our community of

undiagnosed patients,” she said. “Fewer than 50% of rare disease cases are solved on initial analysis,” Einat Metzer, CEO of Emedgene said. “But genomics knowledge is growing at a fast pace, and at re-run, an estimated 10% of cases can be solved with new

information. We’d like to close the gap between scientific knowledge and patient care. In this era of extremely rapid discovery, ironically, computational AI approaches can demonstrate human compassion.”

Emedgene will collaborate with patient advocacy groups, research institutes, and non-profit organisations to make the programme available for its patients. One organisation

in terms of FDA a remarkable few years Markets, said: “It’s been director at Informa Silvia Forroova, brand overall gains. showing the biggest and Switzerland (10%) United Kingdom (5%) year-on-year, with the has increased by 4% innovation potential leader. On average, States as the world closing on the United

ovative drug delivery market and overtakes Germany as

Novartis generics division to pay $195m after court case ruling

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ovartis’ generics division Sandoz will pay $195 million in charges after admitting

it fixed the prices of certain drugs between 2013 and 2015. An investigation by

the Department of Justice (DOJ) Antitrust Division found that the company conspired with other pharmaceutical manufacturers to allocate customers and fix the price of generic products. Between 2013 and 2015, Sandoz was found to have provided patients with over 400 marketed generic medicines. Sandoz co-operated with the DOJ’s investigation and has stated how employees implicated in the case are no longer employed. As part of the

agreement, Sandoz will enhance its compliance programme, employee training and monitoring, and will also co-operate with the government’s ongoing investigation into the generic pharmaceutical industry. Carol Lynch, president of Sandoz, said: “We take seriously our compliance with antitrust laws, and in reaching today’s resolution, we are not only resolving historical issues but also underscoring our commitment to continually improving

our compliance and training programmes and evolving our controls. We are disappointed that this misconduct occurred in the face of our clear antitrust compliance policies and multiple trainings – and in full contravention of the company’s values.” Sandoz may also have to pay an additional $185 million into settlement negotiations with the DOJ Civil Division to resolve possible related claims.


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PERSPECTIVE ON PHARMA How psychedelic medicine is being used in the fight to end opioid addiction

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o one wakes up one day and decides to become opioid dependent. You might have been warned against the risks - aware that there’s a chance of developing a tolerance or dependence on the drugs. At the start they block the pain and release that feel-good rush of dopamine in your brain, helping you function and go about daily life. But, after a while, that impulse - for a rush, for relief, for a shift in consciousness - can become all-consuming. What starts as a way to relieve stress and pain can become a full-blown dependency, or opioid use disorder (OUD). Treatment options are limited. In 2018 alone, 2.1 million Americans met the diagnostic criteria for OUD. 47,600 people died from opioid overdoses. Some may argue that this crisis is a result of big pharma’s overzealous marketing, but, whatever your view, there is little doubt that the industry has faltered in finding a solution. Until now, therapeutic approaches have focused on substituting opioid use for treatments that replace the drugs with milder substances. CEO and co-founder of ATAI Life Sciences, FLORIAN BRAND explains why one psychedelic medicine might provide the key to fighting opioid addiction.


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There’s a significant risk for adverse health effects, including long-term dependency, cognitive issues and drug interactions. Results of treatments with currently available substitution therapies are variable, with relapse rates across substance use disorders estimated to be between 40% and 60%. ATAI Life Sciences was

formed to take a different approach. My fellow founders and I were inspired by our personal experiences of living with mental health disorders to create a company that leaves no stone unturned in our search for answers. We employ a decentralised, technology and data-driven platform model which includes eight companies working to responsibly accelerate the

development of impactful and evidence-based therapies. Many of these companies use innovative technologies like AI and computational biophysics to discover compounds that could hold therapeutic potential for people living with OUD, as well as other disorders like treatment resistant depression and anxiety. ATAI’s focus is on patients who have already tried – and failed – to find relief with other therapeutics. We aren’t alone in this thinking: Deborah Mash, CEO of one of ATAI’s close partners, DemeRx, has spent years investigating the therapeutic properties of the iboga plant in OUD. Together, we are now taking the next step for research by submitting Clinical Trial Applications for a Phase II study in opioiddependent patients. Ibogaine has been used in traditional ceremonies in West Africa as part of Bwiti religious practices since the late 1800s. It is known for its oneirophrenic and hallucinogenic properties and works by affecting a variety of neurotransmitter systems, including serotonin, opioid, and NMDA receptors. The exact mechanisms behind ibogaine’s dissociative psychedelic effects are unclear, but it has been speculated that the dream-like state induced in patients leads to a kind of “brain reset”. We want to see whether this reset might provide patients with a clean slate, empowering them to reframe their understanding of their behavioural patterns and play a more active role in reducing opioid use. Uncontrolled data from hundreds of patients supports this theory. The largest study of ibogaine to date, found that a single low, oral dose significantly reduced opioid withdrawal scores, the severity of cravings and concurrent depression. Importantly, these

9 effects persisted at a one-month follow up. Research into ibogaine is difficult to carry out. Ibogaine is a Schedule I drug. According to the US government, Schedule I substances have no currently accepted medical use and a high potential for abuse. Consequently, clinical investigation of ibogaine remains limited, outside of a few highly regulated centres around the world. Dr Mash found a way to continue her research at a patient-funded treatment centre called Healing Visions that operates on the West Indies island of St. Kitts. There she was able to treat over 300 people from 1996-2003 in a holistically person-centred setting while collecting and publishing data about ibogaine addiction treatment. Dr Mash stated: “If ibogaine stays in the underground, backdoors, and back alleys outside of mainstream medical use, it’s never going to get out of Schedule 1 or be approved as a therapeutic drug, and we’ll never be able to get it to the millions of people who are desperate.” We are working with Deborah to start a revolutionary shift in the way mental illness and addiction is studied, diagnosed and treated. Our partnership with Deborah and her team doesn’t mean that we are a “psychedelics” company; it just means that existing treatments just aren’t working and opioid users and their families are still suffering from this devastating disorder due to a shortfall in mental health innovation. And, perhaps, that a pharmaceutical industry - used to being at the cutting edge of science - might yet have a thing or two to learn from ancient medicines like ibogaine when it comes to taking on OUD.


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EVENTS

Ringing the bell at

CPhI North America SHOW SUMMARY:

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epresenting the world’s largest pharmaceutical market, over the past three years, CPhI North America has connected over 15,000 industry professionals to discuss the biggest trends and innovations occurring across the entire pharmaceutical supply chain. With the United States alone holding over 40% of the global pharmaceutical market, CPhI North America is well placed to connect industry professionals from across the entire industry. Whether you’re working in custom chemicals, ingredients and manufacturing, contract services, finished dosage, packaging or other sectors, CPhI North America is the place to be for professionals wanting to keep their finger on the pulse of the industry. AGENDA As one of the world’s largest pharmaceutical tradeshows, visitors this year to CPhI North America will be able to access a marketplace of over 570 exhibitors covering every aspect of the supply chain. And with Greater Philadelphia being home to big pharma names including Johnson & Johnson, GlaxoSmithKline, Bristol-Myers Squibb and AstraZeneca, this year’s show is sure to attract visitors wanting to see the biggest players in the industry. From drug development and delivery to bioprocessing and manufacturing, CPhI North America’s three-day conference

schedule will highlight the hottest topics trending within the pharmaceutical industry. Of particular note is the Women in Leadership Forum which will include a range of discussions that ask pharmaceutical leaders to examine their own biases and how they might affect dayto-day perspectives of others. Expect to hear from senior leaders across the pharma supply chain about their own personal experiences within the industry. NETWORKING A good tradeshow can live or die by its networking capabilities and with so many industry professionals set to attend CPhI North America, visitors need to know which companies they’re targeting. Thankfully, CPhI North America’s Live Pharma Connect Match & Meet Service helps

visitors discover the contacts they need. Be sure to check out the online portal which allows visitors and exhibitors to pre-arrange mutually beneficial meetings onsite during the event, with the aim of doing business. ETHICAL INNOVATION AWARDS With sustainability being such an important topic worldwide, the pharmaceutical industry is under enormous pressure to show social responsibility through innovative schemes designed to reduce emissions. That’s why Chemicals Knowledge is partnering with CPhI North America to launch the Ethical Innovation Awards – designed to highlight the projects pharmaceutical companies are undertaking to rise to the challenge of sustainable manufacturing.

At a glance: Representing the world’s largest pharma market Taking place: 5-7 May Where: USA Pennsylvania Convention Center, Philadelphia

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Opinion We are now at the beginning of a new decade, a decade that is destined to bring revolutionary changes in the pharma industry.

FACING PHARMA INNOVATION HEAD ON Author: Federico Piutti - innovation manager at Bormioli Pharma

The pharma industry is pushing forward on product innovation faster than ever before. The development of new, innovative drug formulations implies a new challenge for the supply chain, in particular pharma packaging manufacturers.

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o keep up the pace of innovation, packaging companies are required to accelerate their innovation processes, redesigning brand new approaches able to optimise internal and external capabilities. Open innovation models present several advantages in this situation: they allow us to rely not only on internal R&D know-how but also on start-ups, clients, suppliers and research centers, creating a porous environment able to generate new ideas and values.


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OPINION

Furthermore, pharma packaging manufacturers are also called to make a leap in order to become proactive innovators, reacting not only to customers’ requests but proposing new innovations based on the emerging needs of final users and consumers, using different techniques – such as ethnographic researchers - to find out latent opportunities. Nevertheless, a change of approach is not enough to deliver new concepts for the pharma industry. Indeed, prototyping and what we call “fast factory” are keys for success. The contribution of these new processes also applies to the industrial side, that means the massive production of new packages, with a consistent acceleration of go-to-market timings. As a company, we are applying our innovation efforts to four key topics of the pharma packaging industry: usability, traceability, connectivity and sustainability. In all of them, prototyping represents a drive in innovation and product development acceleration. Studies state that easy-to-use pharma packaging has a very positive impact on patient adherence, increasing the efficacy of the therapies. Moreover, other macrotrends – such as an ageing population and the rise of chronic diseases – together with new lifestyles characterised by ever faster pace, push the R&D departments to work on such solutions. These may consist both in add-ons or combined solutions allowing a more immediate or on the go drug consumption for different targets, like general consumers or professional operators such as nurses. Fast factory tools have accelerated the development of new, more usable concepts, through the massive use of additive manufacturing techniques, allowing quicker development of mockups, validation with clients and definition of the final product. Another point is that the increasing complexity of the pharma supply chain and upcoming serialisation regulations push product traceability to the next level. This is why the pharma supply chain is developing tracking systems able to provide complex information all throughout the drug’s journey, anytime and anywhere in the world. A key factor for the success of traceability solutions will be the implementation of a non-editable, technologically advanced tracking solution that can’t be counterfeited and can be recognised both by industrial systems and consumer appliances and

devices, offering different layers of information to specific target groups and ensuring consistency throughout the value chain. In this case, prototyping lets us evaluate – quickly and effectively – new concept features and assess potential manufacturing constraints. Technology and digitalisation also apply to packaging features. For example, the development of solutions able to connect to devices through the internet of things (IoT) network can enable people to effectively take control of their health, by tracking the process for drug administration or the optimal use of every single dose. Coming to this trend, prototyping allows us to explore the opportunities that come from connected objects - through the IoT network - related with our packaging, that could be able to provide added value to the final user. Last but not least, the environment – and growing waves of consumers - are asking for big changes, requiring immediate action to make businesses more sustainable. Plastic packaging is currently under international radars due to stricter regulation and strategy aiming at ensuring that more plastic is recycled, and that plastic waste is reduced. Even though pharmaceutical packaging has not yet been under attack, there is the possibility that consumer demand may soon press pharma companies for a wide range of more sustainable solutions. Given for granted the importance of plastic use in pharma, the most promising solutions could be seen in the first recycled polyethylene terephthalate (rPET) compliant solutions for pharma industries, as well as the development – still underway - of bio-based or biodegradable solutions suitable for drug contact. We are now at the beginning of a new decade, a decade that is destined to bring revolutionary changes in the pharma industry and in consumers’ lives. We strongly support the idea that old corporate models need to be reshaped, making innovation the central focus of companies’ management, governance and strategies, and promoting a companywide, innovationoriented culture.


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COVER STORY

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What key players in pharmaceutical logistics believe to be the major issues facing the sector.

he pharma supply chain faces many challenges. Counterfeiting, product damage, temperature control and continuity of supply, are just some of the issues that pose problems. Questions around Brexit in the UK have created further complexities. Pharmaceutical logistics companies face an evolving landscape that requires expertise and acute business acumen.

comply with national serialisation legislation. As the industry continues to experience mergers and acquisitions DHL helps companies integrate their supply chain approaches efficiently and with minimal disruption.

DHL manages the storage and distribution of products such as vaccines and biologics. It supports pharma manufacturers with seasonal supply forecasting, pandemic planning, temperature monitoring and keeping products safe. Counterfeiting is a growing problem. DHL helps by supplying direct-to-pharmacies or by providing additional labelling, to

“The industry increasingly has a requirement for temperaturecontrolled transport, storage and production, which adds an additional layer of complexity. It’s not uncommon for those managing supply chains to need to deal with the requirement for both strictly controlled and low temperatures, across a global network of facilities and transport methods,” he says.

David Pierpoint, managing director, UK life sciences & healthcare at DHL Supply Chain, outlines some of the issues facing the sector.

According to the European Union Intellectual Property Office, (EUIPO) fake drugs cost the EU €16.5bn. Pierpoint says: “Counterfeiting of products is a growing problem, intensified by the rise of online commerce. The need to ensure a safe and genuine product has led to a number of companies re-evaluating supply chain processes to prove e-pedigree.” Adam Johnson is director for Leeds-based Tudor International Freight. Tudor’s service is geared towards protecting the timesensitivity, confidentiality, integrity and security of vulnerable pharma products, such as medicines and vaccines - through fully traced, temperature-controlled compartments, within single vehicles. Johnson says: “There are various challenges. One of these is Africa. Six of the world’s fastest-growing economies in 2018 were on this continent. Africa’s population is forecast to have doubled by 2050 and done so again by the end of this century, by which time a third


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of the world’s people are expected to live there. Although life expectancy is generally increasing, public health remains an issue, so this already provides a significant focus for pharmaceutical manufacturers and their logistics partners. Challenges include transport links and infrastructure, as these are still inadequate and in need of improvement.” COST PRESSURE GEFCO has been providing integrated, end-to-end, logistics solutions across the life sciences and healthcare industry for almost 20 years. Karin Van Den Brekel, life science & healthcare global manager, sees cost pressure, globalisation and sustainability as the key pressures facing logistics in this space. “Although other requirements such as sustainability, social issues or risk-mitigation capabilities are increasingly discussed in the media, cost pressure seems to remain the ultimate criterion for customers. Logistics costs are playing an important role in reducing overall costs and represent a share of overall revenue that is as low as 5% on average. As global footprints expand, logistics performance as measured by delivery reliability has deteriorated. This is due to several factors including increasing customer requirements, market turbulence on the supply and demand side, as well as poor transportation infrastructure, which is a problem particularly in emerging markets.” REGULATIONS For Johnson, the growing scope of regulation is also impacting the sector. How much of a challenge does this put logistics firms under? “Companies find themselves subject to an ever-changing and growing set of regulations and compliance requirements that vary between countries and regions.

This places pressure on supply chains to comply with regulations without sacrificing efficiency and cost effectiveness, requiring agility to take advantage of regulatory changes,” says Pierpoint. BREXIT We can’t of course ignore the challenge of Brexit. Johnson is unsure of how much an impact it will have. “We’re preparing ourselves and advising our customers as best we can, but the government seems to be issuing pronouncements piecemeal and it’s impossible at this stage to distinguish firm intentions from pre-negotiation rhetoric. Worryingly, one thing the government has declared is that it wants no more from the forthcoming talks about the future relationship with the EU, which buys almost half our exports, than a free trade deal of the kind the bloc has with Canada. This is certain to mean the end of frictionless trade between the parties. “A free trade deal may avoid tariffs but is likely to mean significant new administrative and financial burdens for pharma manufacturers and their logistics providers. These will potentially include additional declarations - which HMRC has estimated will cost UK businesses overall £7.5bn a year - and regulatory costs.” Acknowledging that Brexit will impact the business, GEFCO has prepared and has created a solution that provides compliance and cost-efficiencies to support the 400 million yearly customs declarations from/to the UK including: additional resources and customs clearance sites, IT solutions, optimised processes and a full range of strategic and operational solutions. SUSTAINABILITY A sign of the times is that for any

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business sustainability is a key consideration. The Deutsche Post DHL Group (DPDHL) is working towards Mission 2050, an ambition to reduce logistics-related emissions to zero by the year 2050. Goals include increasing carbon efficiency by 50% by 2025, and certifying 80% of its employees as GoGreen specialists, getting them involved in environmental and climate protection activities.

Author: Lu Rahman head of content, life sciences

Tudor Freight is trialling electric vehicles in its UK collections and deliveries and is talking to Leeds council about switching some of its vehicles to electric this year, having already installed charging points. “We see sustainability as a solid foundation for increasing employee engagement, building closer relationships with suppliers and customers, respecting the environment and making a positive contribution to local communities. In short, accountability is a key driver of our business growth,” says Van Den Brekel. GEFCO has adopted external global standards, such as the United Nations Global Compact, which sets out 17 principles on human rights, labour, the environment and corruption prevention that correspond to 17 specific objectives on sustainable development. “At the same time, we are introducing our own policies. For example, our Global Framework Agreement on Corporate Social Responsibility (CSR) promotes best practices in human resources and environmental management, while our Code of Ethics supports human rights, employee health and safety, and environmental protection worldwide,” adds says Van Den Brekel.

A sign of the times is that for any business sustainability is a key consideration.


18 Merck team up targets 3D printed tablets

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erck has teamed up with AMCM to 3D print tablets for clinical trials and potential commercial manufacturing services. Through the partnership, the companies hope to offer flexible and sustainable local tablet production that can be adapted to patient needs. Merck is currently targeting nextgeneration tablet manufacturing using 3D printing at its Innovation Centre in Germany. It’s thought that using 3D printing to develop active pharmaceutical ingredients can avoid costly reformulations throughout pharmaceutical development. The companies will work together on a novel, simplified process in the clinical development of drugs, using powder bed fusion methods, whereby a laser melts and fuses powder together layer by layer. “Our partnership with AMCM / EOS has the potential to revolutionise the way tablets are produced. It will be a massive move towards digitalisation of the industry,” said Isabel de Paoli, CSO, Merck.

folioNEWS IN THE

China bans virus simulation game amid Coronavirus outbreak

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he Chinese government has banned a popular game in which players design and then spread an infectious disease around the world. The game - Plague Inc. – was launched eight years ago as both as a simulative and educational experience designed to inform players about how infectious diseases spread throughout the world. Plague Inc. has players selecting a pathogen and evolving it over a number of years to transmit the disease across the world. Players evolve their disease's symptoms and must avoid government actions to tackle the spread –

with the ultimate aim of wiping out humanity. Despite the game’s nihilistic goal, Plague Inc.’s educational importance has been recognised by organisations like the Centres for Disease Control and Prevention (CDC). Indeed, the UKbased studio behind the game, Ndemic Creations, has stated it is currently ‘working with major global health organisations to determine how we can best support their efforts to contain and control COVID-19.’

is apparently ‘illegal in China as determined by the Cyberspace Administration of China’. Speaking about China’s decision, Ndemic Creations said in a statement: “We have a huge amount of respect for our Chinese players and are devastated that they are no longer able to access and play Plague Inc. It’s not clear

to us if this removal is linked to the ongoing coronavirus outbreak that China is facing. “Our immediate priority is to try and make contact with the Cyberspace Administration of China to understand their concerns and work with them to find a resolution,” the studio added.

Now however, the game has been pulled from China’s App Store and the videogame distribution platform Steam due to including content that

Did you know?

Coronaviruses are a large family of viruses that have caused severe outbreaks of MERS & SARS in the past.

There are over 100,000 reported cases of Covid-19 worldwide.

Covid-19 is a zoonotic disease – meaning it is transmitted between animals and humans.

Government advice so far ranges from self-isolating to washing your hands!


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LOGISTICS & DISTRIBUTION

FOLLOW THE MONEY The practical considerations for your global supply chain when bringing an orphan, high value drug to market.

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dequate preparation is vital in mitigating issues that may arise in a supply chain, particularly for a high value product. Proactively considering financial and customs considerations - and your entire supply chain - are crucial to your commercial distribution strategy, in order to ensure the most efficient and cost effective process with minimum risk. FINANCIAL & CUSTOMS CONSIDERATIONS ARE YOU MANAGING YOUR IMPORTER OF RECORD (IOR) PROCESS? It is highly recommended that sponsors consider the IoR process as early as possible when planning a supply chain. Imports into another customs territory cannot take place without a nominated IoR, which is a legal entity that has responsibility for ensuring the imported goods comply with local laws, filing completed customs declarations and paying the associated duties and taxes. In some EU jurisdictions, including the UK, the IoR should be the entity which holds title to the goods. If the IoR does not hold title, they do not have the ability to recall any Value Added Tax (VAT) payment they make at import. With VAT at approximately 20% of the goods value, this could be a significant cost. BREAKING DOWN CUSTOMS DUTY Customs duty is a tax which is charged on the importation of goods procured from outside of the customs territory. The rate, which typically can range from 0% to 85%, is pre-determined depending on the classification of the goods using commodity codes.

REDUCING THE VAT & CUSTOMS BURDEN VAT and customs duty must be included within budget forecasting and has the potential to become a more prevalent cost to businesses post Brexit. However, there are a number of ways in which businesses can reduce this burden on their finances when importing goods into the EU. For example, first consider: • If your goods are being imported for testing purposes, or being re-exported — if so, schemes exist to reduce or suspend duty payments. • If your designated active pharmaceutical ingredients (APIs) and pharmaceutical products appear on the International Non-Proprietary Names (INN) list — if so, you may

be subject to reduced or zero duty payment. • If your non-EU country has a trading agreement in place with the EU — if so, a preferential rate of duty may come into play. • If your goods have met specified origin rules in the country of export — if so, they may be imported at a preferential or reduced rate of duty. In addition to the above considerations, there are a number of accreditations companies can consider to manage the duty and VAT liability when operating an international supply chain. These include: AUTHORISED ECONOMIC OPERATOR (AEO) AEO indicates that a company’s role in the international supply

Author: Bryan Edwards - distribution manager & responsible person, Almac Pharma Services


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LOGISTICS & DISTRIBUTION

The advantages of this model for high value or orphan drugs is that the full supply chain is managed by one central provider. chain is secure and it has processes in place to manage customs compliance and security. While not mandatory, this option provides quicker access to certain simplified customs procedures, and in some cases, the right to ‘fast-track’ shipments through some customs, safety and security procedures. CUSTOMS WAREHOUSE (CW) A customs warehouse allows traders to store goods with duty or import VAT payments suspended. The benefit of using a customs warehouse is that there is no time restriction on how long goods can be stored. However, it’s important to stay mindful that once goods leave the customs warehouse, duty must be paid unless they are re-exported or moved into another customs regime. INWARD PROCESSING RELIEF (IPR) IPR is another method of suspending import duty and VAT payments on imported goods. An IPR strategy allows for the processing of input goods into different output goods. However, goods can also only remain in the regime for a period of up to six months. In most cases, you will want to utilise CW and IPR in conjunction for more flexibility. In order to do this, businesses need to have a system in place to manage their duty and VAT liability. CONSIDERING YOUR SUPPLY CHAIN - WHAT MODEL IS RIGHT FOR YOU? Using wholesalers is a common supply chain model in the pharmaceutical industry. Drug

manufacturers or packers are at the beginning of this supply model, who then distribute the product to a large wholesaler. From the wholesaler, the product will be distributed to a number of different in-country wholesalers. And finally, the product is then distributed to hospitals or clinics. There are some disadvantages with this model, especially in

terms of high value or orphan drug supply: • A high volume of stock is required to be held at a number of different sites, which can mean implications on cash flow. • Complex planning is required for the operations and contract management of this approach, to ensure there is adequate stock available to service patient’s demand.

CASE STUDY- LEVERAGING A 3PL Today, a common alternative supply chain strategy being utilised is 3PL—third party logistics. The term 3PL indicates that an organisation outsources elements of its distribution and order fulfilment. Consider a scenario where the manufacturing site is at the beginning of the chain, like in a wholesaler strategy. But, instead of involving multiple wholesalers, the product is transferred to one 3PL provider, who centrally manages the supply of product into hospitals and clinics. Almac often serves as a 3PL provider in scenarios like these, as well as being the manufacturer. In this case, hospitals typically place their orders directly with Almac, who then pack the product to order and aim for dispatch of the product within 48 hours of receipt. The advantages of this model for high value or orphan drugs is that the full supply chain is managed by one central provider, so there is one storage facility for the stock. This not only helps with stock holding and cash flow, but also negates the need for complex planning and helps to minimise risk.

GOOD DISTRIBUTION PRACTICE (GDP) In the EU, GDP guidelines do not just cover the physical distribution of product, but all activities related to the procurement, holding, supplying or exporting medicinal products. The key GDP considerations that any participant in the supply chain should be mindful are: • Temperature during transit • Security of shipment • Qualification of freight companies— agreements and audits • Supply chain qualifications These factors and their potential impact should not be overlooked. IN SUMMARY In summary, the considerations businesses should keep in mind prior to launching their orphan, high value product are: • Understand the financial implications of your supply chain movements. • Consider the most appropriate supply chain model for your product. • Understand the regulatory requirement of your supply chain, how the guidelines impact you and what your responsibilities are. By taking these factors into serious account, you will be best positioned to avoid unnecessary risk as you move your product through your global supply chain.


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SINGLE USE

Single use systems for patient scale cell and gene therapy (CGT) manufacturing that allow for end-to-end scalable manufacturing in a closed system.

Continuous supply

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Author: Senthil Ramaswamy - head of R&D for Cell and Gene Technologies, Lonza Pharma & Biotech

utologous cell therapies present a unique paradigm shift in terms of biologics manufacturing from a “one batch for many patients” to “one batch for one patient” model. Over the past two years, FDA approvals of genetically modified cell therapies Kymriah (Novartis) and Yescarta (Kite/ Gilead) for haematological cancers have generated tremendous excitement around autologous chimeric antigen receptor T-cell (CAR-T) therapies. There are now close to 100 autologous CAR-T/ T-cell receptor (TCR) products in clinical trials in the US alone, with around 40 of these in Phase 2 and Phase 3. Commercialisation of these therapies implies a significant increase in the number of patients to be treated - from hundreds to potentially hundreds of thousands. A reliable manufacturing process that ensures continuity of supply for these last-line treatments, from the point of acquisition of patient tissue through the manufacturing process and final infusion back into the same patient, is critical. Current standard workflow for autologous CAR-T therapies is often comprised of multiple process steps that are reliant on a mix of open manipulations and limited unit operation level automation. This can present a high risk in terms of process consistency, hygiene and ultimately batch success, and product safety, especially when the number of batches

to be manufactured increases by orders of magnitude from clinical to commercial. Moreover, since the drug product cannot be sterile filtered, the entire process must be run aseptically. Most importantly, systems that facilitate manufacturing scaleout while meeting all process requirements, as well as controlling cost of goods sold (COGS) to allow reimbursement, are key to the development of this modality.

Lastly, the impact of leachables, extractables and particulates from the plastics in SUTs on cell growth, performance and drug product quality needs to receive more attention. In light of these challenges, it is critical to optimise the number and volume of single-use consumables that are included in the manufacturing process, and at the same time ensure good control over the source and quality of these parts.

THE CHALLENGES OF SINGLEUSE TECHNOLOGIES Single use technologies (SUTs) are the only practical option to meet the requirements of autologous cell therapy manufacturing and are already exclusively used for this purpose. However, there are a number of challenges with SUTs that need to be overcome as processes move into commercialisation. Firstly, critical consumables (eg. specialised cell culture vessels) are often single-sourced and may pose a high risk to the supply chain. Secondly, due to the need for aseptic open or partially open operations, manufacturing normally occurs in a Grade B cleanroom with open processing steps occurring in a Grade A biosafety cabinet (BSC). Consequently, a large number of consumables must be passed through areas of increasing classification while maintaining material sterility. This leads to a high reliance on manual sanitisation, increasing the burden on technicians and also the risk of contamination.

Another area of significant risk to commercialisation is from labour-intensive manual aseptic processing. As the number of batches required multiplies, so does the need to recruit, train, qualify and retain a highly motivated manufacturing labour force. The time and effort needed to conduct adequate training and retain proficiency are significant and pose a major bottleneck to scale out. Overall, the large number of single use consumables that must be transferred into cleanrooms, open processing activities, and the laborious nature of the processes, lead to a high risk profile, as well as high costs which will severely limit access to these curative therapies. FROM AUTOMATED UNIT OPERATIONS TO CONTINUOUS WORKFLOWS These challenges can only appropriately be addressed through closed, controlled, automated operations with a limited number of integrated SUTs that are appropriately qualified and with good control


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over the source of supply. Currently, such available automation technologies for autologous cell therapies can be split into two groups: unit operation automation, where each connected step is automated in an independent proprietary machine, and fully integrated systems where most or all of the process is performed in an automated closed system. Examples include automated units that represent a significant step towards reduced labour and improved process and hygiene control, but still require routine manual intervention introducing variability and contamination risk. Operations must remain within a Grade B cleanroom to enable product transport between equipment as well as multiple sterile welding and disconnect operations. The number of consumables from a variety of sources remains high and this continues to pose a challenge in terms of control. The next generation of automated systems for autologous cell therapies comprise fully integrated processing capabilities from selection to culture to formulation. Systems such as the Lonza Cocoon and the CliniMACS Prodigy system from Miltenyi are designed to enable automation of most sequential unit operations for a CAR-T process within a single system. An integrated sterile SUT assembly is used for the processing and sampling with built-in process monitoring and control capability. Scale out is achieved through multiple units for parallel operation with each unit dedicated to a single patient process through the duration of manufacturing. The modular nature, high level of traceability, integrated process controls and highly compact form, particularly of the Cocoon, are factors that

facilitate effective scale-out and a range of manufacturing options from centralised to point-of-care operations. Such integrated automation systems significantly reduce the number of SUT components required for processing and effectively addressing a number of the challenges described previously. Most importantly, having a validated closed, automated system opens up the possibility of eliminating the need for Grade A and B clean room operations, thus significantly improving therapy COGS. As the current pipeline matures and more therapies need to scale to meet demand, it is imperative that the industry migrate rapidly to end-to-end automation and other similar single-use manufacturing technologies. Only by fully combining unit operations into an integrated automated system would it become possible to serve the full population of patients needing these therapies and ensure continuity of supply at a reasonable cost.

Single-use technologies (SUTs) are the only practical option to meet the requirements of autologous cell therapy manufacturing.

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27

SINGLE USE

Hybrid theory How to ensure sterility during bioprocessing through the use of single use technologies.

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he global single use bioprocessing market was valued at $9.71bn in 2017 and is projected to expand at a CAGR of 13.6% by 2027. A rise in demand for small batch, novel therapies, is in turn, leading to an increased need for vigorous and flexible containment strategies to ensure product sterility during bioprocessing. Consequently, the technologies used in aseptic processing have seen much innovation in recent years but it’s important for such solutions to also achieve cost reductions, process efficiencies and improved quality in line with industry regulations. The growth of the bioprocessing market is also fuelling the booming contract services space. Much of the development, manufacturing and packaging of products is completely outsourced. While supporting the development of novel biologics, this can bring added complexity to the manufacturing journey, as drug products often need to be transferred between different facilities and geographies. Current solutions for transporting pharmaceutical powders include fibre or plastic drums with flexible liners, which can pose challenges around the filling, sealing, handling

and emptying of packages while maintaining sterility. Because of this, manufacturers are now investigating hybrid, single use technologies that can ensure the integrity of products while in transit, as well as within the manufacturing facilities. Split butterfly valve (SBV) technology is an established solution for the transferring of powders (including drug substance and drug product) during bioprocessing. Consisting of an active and passive half, the active half is connected to the biomanufacturing process, while the passive half is connected to a filling container. A disposable version of the passive half of the valve now exists, which can be connected to a single use flexible bag to enable the contained and sterile transfer of pharmaceutical powders between manufacturing process steps and facilities. Such hybrid solutions provide a flexible means of powder transfer, while also removing the time and cost associated with cleaning, maintenance and validation. Ensuring single use solutions are manufactured with high levels of quality control within an ISO6 cleanroom environment as well as being gamma sterilised, makes the

new hybrid solutions ready for use in aseptic processing. FINAL THOUGHT Whilst traditional single use technologies claim to deliver the same level of performance as some of the more traditional multiple use solutions, the reality is that this is not the case. The hybrid solution of the SUP and the active part of the SBV delivers repeatable performance as well as other advantages to pharmaceutical manufacturers. The convenience and control benefits associated with prevalidated, ready to use solutions, that are easily integrated and perform to the highest level of containment and sterility assurance, are invaluable. As the bioprocessing market continues to thrive, it is expected that new innovations will continue to focus on the challenge of product sterility without compromising manufacturing efficiency.

Author: Ben Wylie senior product manager at ChargePoint Technology

REFERENCES

1) https://www. grandviewresearch. com/industryanalysis/single-usebioprocessing-market

Hybrid solutions provide a flexible means of powder transfer, while also removing the time and cost associated with cleaning, maintenance and validation.


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AN INSIDE LOOK

AN INSIDE

L

K

at Thornton & Ross Web content editor Ian Bolland sits down with Roger Scarlett-Smith, executive vice president at Thornton & Ross in Huddersfield.

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y its own admission Thornton & Ross has been flying under the radar. The Huddersfieldbased company was acquired by pharma company STADA and merged with Genus Pharmaceuticals in 2013. The company is responsible for the manufacture of some household brands, with its portfolio including recognisable names such as Covonia, Eurax and Savlon. Though it is starting to stick its head above the parapet, it is trying to maintain the feel of a family business about it, with previous owners still operating in the background and attending major events for the company, such as its launch of the Future of Health report back in November. Explaining the company’s strategy, Scarlett-Smith said: “We do think that building really strong stakeholder relationships and being more transparent about what we’re trying to achieve can help us build the business. “We’re working quite closely with local authorities to see how we can collaborate on future investment opportunities.

“We think that we can, by reaching out to more stakeholders, we can find ways of collaborating and accelerating our growth trajectory. It’s in our business benefit to engage more openly with external stakeholders.” Following the acquisition of five brands from GSK, the business had a strong 2018 having recorded turnover in excess of £100 million, and is expecting to report strong growth again for 2019. This has allowed them to open a new 6,500 sq ft bottling and filling line this January which is incorporated into the company’s Huddersfield warehouse. Despite claiming that Thornton & Ross is a recession-proof business, Scarlett-Smith says there are various challenges for the company, primarily because of the slow growth of some of the markets it operates in. “We’re doing well within it by finding the right kind of scenes of opportunity and acting with a bit more agility. The challenge is to be different because if you’re the same as everybody else there’s a strong price comparison, and you can end up fighting a very generic battle for price. For us as a business, we’re looking to add value and offer things which promise a bit more and work a bit better than the competition. “The most recent example of that would be when we introduced

a product for multiple myeloma in our generics pharmaceutical business. It was formulated by STADA in Germany and it was a view to completely changing the market for treating multiple myeloma. It’s a ready-made injectable format whereas the standard product needs to be compounded and made up from powder.” Despite having a global business with expertise to tap in like STADA, Scarlett-Smith was keen to emphasise the local element is still a big part of the company’s strategy. Its support for local sport even includes once being the sponsors of Huddersfield Town Football Club’s away kit in 2009/10. “Most of the effort and staff goes into the local affiliates and that’s still very much our strategy. There are certain things that are worth doing – like managing HR resources across the world. Systems manufacturing, in many cases, is nowadays a global decision. “From our point of view, based in Huddersfield, we are keen to demonstrate we can be investable as a business within that context. Growing our business, driving efficiency, creating the skills locally is very important so that in the future, STADA will continue to see this site as investable and continue to support our growth – which they’re doing at the moment, I’ve no complaints.”


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30

FORMULATION

It’s a small world How nanotechnology is poised to change the landscape for medicines development.

T Author: Andrea Cusack - CEO of Leon

here’s a lot to be happy about with modern medicine. Through the application of cutting-edge science and technology, huge progress is being made in finding treatments for diseases previously thought incurable. There is, however, a problem. Often, the very nature of the therapeutic agent presents a major barrier to translation into a medicine capable of treating patients in an effective and convenient manner; a simple mix of drug and ingredients incorporated into, for example, a tablet, capsule or injection, is frequently not viable. There is an increasing realisation of the power of nanotechnology and its potential to enable solutions to many of the technical obstacles facing the development of modern medicines. Which is precisely where Leon comes in, taking on the challenge of progressing nanomedicine. “Nano really excites people,” Cusack says. “Even just as a word, it has a very modern, technological sound to it - there was even an iPod nano! So, it captures the imagination. But actually that’s

As we look into the 2020s and consider the technological advancements around us, there’s something appropriate and perhaps inevitable about nanomedicine.

very fitting, because this really is a high-tech advancement.” As we look into the 2020s and consider the technological advancements around us, there’s something appropriate and perhaps inevitable about nanomedicine. “It’s simply the next stage of progress,” Cusack affirms. “Nanomedicine has been around for two decades and is enjoying a resurgence after its initial rise. It’s developing rapidly and, between active ingredient and nano formulation, offers multiple benefits for both acute and chronic diseases, as well as industry trends towards continuous manufacturing processes.” Today, small molecule drugs account for a major share of pharmaceutical revenues and the current pharmaceutical pipeline. Despite the large entry of new biological entities, industry remains dependent on small molecules, which continue to dominate FDA approvals with almost 70% of new molecular entity approvals over the last five years being small molecules. The question on many people’s minds of course is Why nano? What is the problem being solved? “The big one is that circa 80% of pharmaceutical pipeline drugs and 40% of on-market drugs suffer with water solubility or stability limitations. That’s the challenge that the industry is wrestling with.” Indeed, those are well recognised problems. For oral administration, poor drug solubility in the gastrointestinal tract too often

means low and unreliable absorption. Overcoming such a shortfall in absorption may mean administering a larger dose of drug, which is wasteful and costly for the manufacturer, and may have undesirable consequences for the patient. If you need to formulate the drug as a fast-acting injection, inadequate solubility may simply mean it cannot be done. “Nano steps in as the ultimate solution,” Cusack explains. “For manufacturers, the aim may be improved onset of action or better absorption or increased stability for less investment. For the healthcare professional, it will be ease of administration and efficacy. We mustn’t forget that healthcare professionals are the ones communicating with


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patients, explaining the benefits and potential drawbacks of a medication and they’re also on the receiving end of any criticism from the patient if they aren’t happy with what they’re given. If effectiveness and convenience of administration can be improved, that’s a significant change, especially where a condition is being treated long-term.” As nanomedicine has been around in some form for 20 years, and at points in that time has been touted as the next big thing, some cynicism is bound to appear. But 20 years is the blink of an eye, and a first attempt is neither the barometer for whether something will ultimately succeed nor will necessarily resemble the finished product.

There’s been a lot of progress in those 20 years. Many nanomedicines are made using what’s called a top-down approach, which takes an existing drug in solid form and then reduces it in size. In simple terms, it’s the industrial equivalent of grinding drug powder using a pestle and mortar. The pharmaceutical version is a little more advanced, but not without its limitations, notably the generation of heat, which destabilises many drugs, and the difficulty in controlling particle size, which is critical to performance of the final medicine. It’s also a complex production, requiring multiple cycles and different hardware for different batch sizes. This makes development and scale-up difficult and certainly does not lend itself to a continuous manufacturing approach. Leon takes a different approach: “We have bottom-up technology,” Cusack says. “The top-down approach is essentially trying to retrofit new technology onto existing production, whereas we are building from the ground up. This removes the heat and shear problems, the capacity limitations are removed as well, because the same hardware is used regardless of the batch size. It’s also quicker and less complex, and highly controllable; whereas the top-down approach needs many cycles, the bottom-up approach needs only one. When you add all of these advances together, it’s an entirely different proposition. “To summarise the Leon process, we select suitable solvent and antisolvent systems for the active ingredient. The drug solution and the antisolvent are then mixed very

All of this suggests that nano is no longer just a tiny concept with big ideas. rapidly under highly controlled conditions within our proprietary ‘MicroJet Reactor’; when the drug solution and antisolvent come into contact, the drug is precipitated as nanoparticles. We have huge flexibility to engineer bespoke particles by modifying process conditions and adding other ingredients. Everything from simple drug nanocrystals through to complex, multi-component nanoparticulate drug delivery systems can be produced. Our nanoparticles can be incorporated into all types of dosage form for all routes of administration and with world class integrated network partners we are now in a position to run a ‘one-stop-shop model’ from bench through preclinical to clinical trial supply and beyond.” All of this suggests that nano is no longer just a tiny concept with big ideas. “It’s a lot closer than people might think,” Cusack says. “The concept was always there for why nano was worth pursuing, and we’ve now reached the stage of being able to produce nanoparticles in the right way, with no capacity limitations or thermic - or mechanical-induced stress. It’s exciting to be at the forefront of the development, but not as exciting as considering the impact nano will have when it goes mainstream.”

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32

WHAT'S

TRENDING

A SHIFT IN PERSPECTIVE How pharma companies are shifting deal strategies for cell and gene therapies.

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Authors: Lev Gerlovin - vice president in the Life Sciences Practice at Charles River Associates Pascale Diesel former vice president in the Life Sciences Practice at Charles River Associates

n recent years, drug development has been transitioning from a “one pill fits all” approach to a focus on more targeted and personalised therapies, including many cell and gene therapies. These innovative treatments often bring the promise of high efficacy and even curative benefit and, in many cases, are options for patients with diseases that previously had limited or no treatments available. With several cell and gene therapies now approved and many more advancing toward late-stage clinical development, patient communities and healthcare systems are rapidly recognising their potential benefits, whilst pharmaceutical companies are considering opportunities including mergers, acquisitions, licensing agreements, and partnerships. The deal-making landscape for cell and gene therapies is already very active and positioned to grow exponentially in the years ahead. While the pace of deal-making is accelerating, the unique qualities of cell and gene therapies are also requiring dealmakers on both sides to consider some innovative and previously untried strategies designed to optimise returns and reduce risk. They are structuring deals to address many factors, including the lack of commercial benchmarks for these products and limited long-term safety and efficacy data often associated with cell and gene therapies. We conducted an analysis of more

than 30 deals executed in the cell and gene therapy sector recently and compared them to deals executed for monoclonal antibodies (mAbs) between 19992013. Emerging cell and gene therapies are often considered “magic bullets” in the treatment of many serious diseases – a claim that was applied to many mAbs when they were first introduced to the market about 20 to 25 years ago – and the level of interest in deal-making for these therapies is a reflection of the level of optimism companies have regarding their clinical and commercial potential. Findings from our analysis show that the pace of deal-making in cell and gene therapy is faster and occurring much earlier in the drug development process compared to deals seen in the past for breakthrough therapies including mAbs. ROLE OF BIG PHARMA When the first mAb was approved in the mid-1980s, deal-making interactions were mostly limited to collaborations and licensing agreements between smaller biotechnology firms. It took more than 20 years for big pharma to become significantly interested in mAbs and start proactively pursuing deals for these drugs. Conversely, deals within the cell and gene therapy sector have shown a much faster uptake, quickly growing in momentum since approval of the first cell and gene therapies in the early

2010s. More than 50 cell and gene therapy-related partnerships and investments were established between 2010-2016, with big pharma involved in many deals from the beginning. In one example, Novartis initiated a collaboration with GenVec in 2010 for clinical development of adeno-based gene therapies – a deal worth potentially $213 million (excluding royalties). That same year Novartis also formed a strategic alliance with GlaxoSmithKline and the Telethon Institute of Gene Therapy to pursue additional gene therapy research and development. ESTABLISHING AN EARLY PRESENCE Larger pharmaceutical companies such as Novartis seem more eager to embrace cell and gene therapies compared to prior innovative therapies including mAbs, but the types and values of related deals are evolving compared to what has historically been seen. While the largest mAb deals were often characterised by the acquisitions of late-stage and marketed products, which present more robust data and potentially lower risk to acquisition or licensing partners, most major cell and gene therapy acquisitions involve product pipelines, platform technologies, and manufacturing capabilities rather than one single product. Larger pharmaceutical companies are also targeting earlier stage opportunities,


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More than 50 cell and gene therapy-related partnerships and investments were established between 2010-2016.

with a higher proportion of partnerships involving Phase 1 or even preclinical stage assets. For example, Pfizer established a collaboration deal with Spark Therapeutics for the development and potential commercialisation of a Phase 1/2 gene therapy for the treatment of haemophilia B. Pfizer also acquired Bamboo Therapeutics based on a promising gene therapy portfolio, including one Phase 1 and several preclinical assets for the treatment of rare diseases impacting the nervous system. TAKING STEPS TO MITIGATE RISK As more companies work to establish a presence in this sector, both larger and smaller companies now often prefer innovative licensing and collaborative agreements, whereas the majority of deals executed for mAbs were straightforward mergers or acquisitions. Given that cell

and gene therapy development is still in its nascent stages and many stakeholders, including payers, have questions related to their long-term clinical benefit and budget impact, the fact that mergers or acquisitions are deemed less attractive is unsurprising. Innovative partnerships can be a lower risk option for licensors or investors who want to expand their cell and gene therapy portfolios without assuming full financial responsibility. Partnership and licensing deals can also help reduce the risk of possible disruptions in business operations and productivity, which often occur following M&A deals and the subsequent restructuring of company resources and teams. The opportunity to access complementary business capabilities is another factor that is driving interest in innovative licensing and collaborative agreements. With licensing

arrangements, a licensor might be seeking a partner who can offer specialised expertise in a specifi c indication whereas a licensee might see the benefit of collaborating with a company with technical abilities or assets that align with their own product pipeline. The partnership between Neurocrine Bioscience and Voyager Therapeutics reflects this type of synergistic collaboration, where Neurocrine provides expertise in central nervous system (CNS) drug development as well as fi nancial support for the clinical development of gene therapies for Parkinson’s disease and Friedreich’s ataxia. In return, Neurocrine gains the opportunity to co-commercialise and potentially obtain global rights to portfolio-compatible therapies. STRATEGIES MOVING FORWARD As new cell and gene therapies emerge and others progress to late-stage clinical development and regulatory approval, most industry stakeholders anticipate that both the structure and value of deals in the sector will mature. Companies will exercise the option to follow up on previous collaborative deals, punctuating the space with potentially massive exclusive licensing agreements and acquisitions. *The views expressed herein are the authors’ and not those of Charles River Associates (CRA) or any of the organisations with which the authors are affiliated.

The authors wish to acknowledge the contributions of Súil Collins and Alex David to this article.

33


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COVID-19

EPM speaks to a range of pharma players to find out how Covid-19 is affecting the various aspects of the pharmaceutical supply chain.

T

he latest strain of coronavirus – Covid-19 – has shook the world, giving countries, their health systems and indeed patients something to seriously consider. Alongside its human impact and the economic downfall caused by its spread, Covid-19 is affecting a large majority of the pharmaceutical supply chain. CLINICAL TRIALS With 35 candidate vaccines currently in pre-clinical development for Covid-19, the race is officially on to find a solution and prevent the virus from spreading even further. Of course, development timelines for vaccines are rarely short, and the pharma industry is facing an almost insurmountable task of developing a vaccine before Covid-19 burns itself out. Finding a candidate isn’t necessarily the most timeconsuming part of the process though. Rather, companies face the long but vitally important task of progressing a vaccine through clinical trials, so to ensure it’s safe for human use, and effective against Covid-19. One method of data collection which could help is real world evidence (RWE) – clinical data which are produced through studies that assess how therapies perform in everyday settings.

According to Karen Ooms, executive vice president and head of statistics at clinical research organisation (CRO) Quanticate, “real world evidence is now being utilised more in clinical trials and its use in a situation like [Covid-19] could potentially increase the speed of approval as drug developers may not have to perform analysis on all data from a clinical trial setting.” Data taken from patient health records for example, could help

biostatisticians analyse candidate vaccines and prove their efficacy. More so, cases of self-isolation and quarantine centres “provide further environments for data collection”, according to Ooms, due to their similarities to clinical trial data collection environments. “An area of focus would be the method for collecting data of any patients in self-isolations/ quarantine and with emerging technologies could support a faster drug approval process,” Ooms says.

Author: Reece Armstrong – editor of European Pharmaceutical Manufacturer


36

COVID-19

Given that Covid-19 has spread to almost every corner of the globe, if and when a vaccine is produced, the challenges don’t stop there. Of course, though time is of the essence to find a solution to stop Covid-19, rushing a vaccine through development has its own dangers, according to Ooms. “The danger of rushing any vaccination is that the virus itself can become stronger in the meantime, which would render a vaccine ineffective or a vaccine may have safety and efficacy issues that could put patients in further danger or potentially support the virus mutating and becoming stronger,” she added. LOGISTICS Given that Covid-19 has spread to almost every corner of the globe, if and when a vaccine is produced, the challenges don’t stop there. Logistics providers will face the particularly daunting task of transporting potentially timesensitive Covid-19 vaccines across the world to be delivered into patients. More so, vaccine developers could face a situation

where the peak of the virus has passed, meaning that research and development (R&D) efforts may have been squandered and financial reimbursement opportunities limited. However, if a vaccine is developed in time - a situation becoming more likely with expectations that Covid-19 could last into next year – then it may not just be the private sector who handles transportation. Adam Johnson, director of Leedsbased logistics company, Tudor International Freight, explains how in the UK, the army could become involved. “The government has already said soldiers may be needed to help the police maintain law and order if an epidemic ensues,” Johnson says. Johnson goes on to explain how in these circumstances, the private sector will face challenges such as how to handle their fleet capacity when they have existing customers needing products shipped, and the risk of their own staff being absent. With the UK government estimating that up to 20% of UK employees could be away from work due to Covid-19, it’s very likely that companies involved in the pharma sector will be affected. “If we at Tudor are being relied on to transport supplies of a vaccine speedily, to prevent suffering and even deaths, however, we’ll of course make this overwhelmingly our top priority. We’re confident our other customers will understand if their non-urgent consignments are subject to very slight delays for a temporary period while this happens,” Johnson clarified. SUPPLIES AND MATERIALS The importance of China’s pharmaceutical supply chain has,

arguably, not been felt until the spread of Covid-19. With China being the world’s largest producer of pharmaceutical ingredients, the industry in large swathes has become dependent on the nation for its exports. One country which may be particularly affected by this development is India. John Warchus, partner and specialist in Commercial Law at Moore Blatch, explained how India’s government has already restricted the exports of 26 active pharmaceutical ingredients (APIs) – amounting to 10% of all drug exports from India. “The reason this is so problematic is because India is the biggest supplier of generic medicines worldwide and imports 70% of its APIs from China – meaning that it will inevitably face shortages as the virus spreads that will impact its export of generic medicines,” he said. On the supply and demand side, contract development and manufacturing organisation (CDMO) Recipharm, has noted an increase in one product that could be used to treat people with Covid-19 associated pneumonia. The CDMO noted an increase in demand for chloroquine phosphate, which is typically used to treat malaria prophylaxis and rheumatoid arthritis, but has antiviral effects and has been highlighted by the World Health Organisation as a research option to treat Covid-19. “Recipharm is presently focussing on securing supply of its chloroquine product in case the demand suddenly increases, and new recommendations are introduced. Because of the current situation with the new coronavirus we believe it is of utmost importance to take every measure to be prepared,” the company said in a statement.


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WOMEN IN PHARMA Mentorship and sponsorship ­ — you need both A scientist by training with a PhD in organic chemistry, Barbara Morgan is responsible for the Pharmaceutical and Nutraceutical businesses, including the CDMO division of the Lubrizol Life Science Health unit. She is passionate about women in leadership and science, and is the co-chair for Women in Lubrizol Leadership (WILL). In this series, she discusses key themes around women in the industry and offers advice for aspiring female leaders and their wider teams.

Author: Barbara Morgan - global business director, Pharmaceutical Solutions and general manager, CDMO services, Lubrizol Life Science Health.

FOCUS FROM THE FIRST RUNG OF THE LADDER When discussing the progress of female talent in any industry, it is tempting to focus solely on women who have already made their way to the top. These leaders offer insights into their own journeys and the strategies that helped them get there. But what about the women just starting out and looking to lay the groundwork for a successful career? A recent survey for McKinsey and Lean found that obstacles facing women can start long before the leadership level and in fact, at the very first promotion, in what they call ‘the broken rung’. In their survey of 600 companies, they found that for every 100 men getting their first promotion, just 72 women are promoted1. Ensuring that women aren’t overlooked for opportunities early on in their careers requires a concerted effort and support from a variety of sources: inclusive organisational processes, supportive managers, mentors and sponsors. And while much of the corporate focus is on organisational infrastructure and training managers, it is important to also pay

attention to the vital role that mentors and sponsors can have in advancing careers. The mentor and sponsor terms often get conflated, but they serve different purposes. In short, mentors advise you and sponsors advocate for you, and while mentoring programmes are industry standard, it is just as important if not more important to have sponsors as well. This is especially critical for women, since the vast majority (85%) need navigational support to advance their careers, but studies have shown that they receive it much less often than men. In looking at mentor selection, keep in mind that they are there to provide support, advice and a trusted sounding board for ideas. They are not there to help you get a promotion or to provide you with new opportunities. Having been a mentor and mentee for several years, my key advice for effective mentorship is to have mentors, or be a mentor that offers a different perspective. Understanding what your challenges are and receiving feedback from someone with an alternative insight, style, and experience level to your own, can provide invaluable

learnings. This also builds on the continued theme from my previous article that diverse perspectives lead to improved outcomes. Keep in mind that mentors don’t necessarily have to be in top senior positions or even people within your own organisation - it’s important to think externally not just internally. It’s an obvious choice to ask those who work closest to you or who have followed a similar path to yours, but someone from another department, or in your broader professional network, may also offer invaluable advice that gets you thinking outside the box. If we apply this perspective principle to women’s careers, then there is a strong case for gender balanced mentorship, as opposed to all-female mentor groups. As mentioned earlier, the perspectives gained from mentorship are just one piece of the puzzle. Ideas alone will not get you very far if you don’t have people to speak up for you in senior meetings. For women especially, an important and often overlooked element of career progression is sponsorship. Many decisions about talent and opportunities


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are made when you’re not in the room, so it’s important to have an advocate who can put you forward for the right opportunities to fuel your progression. This figure may be the individual acting as your mentor but not necessarily. Sponsorship can come from someone who is outside of your day-to-day working circle - you may have impressed them on a one-off project, for example. Research has shown that men are particularly adept at sponsorship strategies and ensuring they have someone to keep them informed of upcoming opportunities. In contrast, women often lag behind on this with figures estimating that less than a third have a sponsor. To address the sponsorship imbalance and ensure that fewer females fall off at the first rung, it’s vital to have programmes in place that can guide and inspire. REFERENCES

1) https://www.mckinsey.com/featuredinsights/gender-equality/women-inthe-workplace-2019 2) https://inclusion. slac.stanford.edu/sites/inclusion.slac. stanford.edu/files/The_Key_Role_of_a_ Sponsorship_for_Diverse_Talent.pdf

My top tips for making the most out of mentorship and sponsorship include: • Don’t ask people to sponsor you if they have never worked with you. Make sure there is an existing relationship and that you both agree on your career direction. • Setting up mentorship and sponsorship partnerships is not just the responsibility of those seeking guidance and opportunities. Business leaders have a responsibility to mentor and sponsor the next generation and should ensure they have measures in place to set these up. • Make sure that a mentor and/or sponsor has adequate time for you and genuinely cares about your career progression. If it becomes a box-ticking exercise, then it will not be worthwhile.

39

For every 100 men getting their first promotion, just 72 women are promoted.


40

FROM THE FACTORY

A solid strategy Synchronising and controlling API delivery, extrusion-spheronization offers pharmaceutical companies a robust technique to manufacture today’s most complex therapeutics. Author: Bora Pharmaceuticals

M

and more reliably. The shape and density of spheres also promotes uniform coating with less material, offering flexibility in manufacturing controlled release characteristics.

anufacturing spherical oral solid dose (OSD) pellets via extrusion-spheronization is not new. What is new is that in the right hands, with the right capabilities, this well-understood process stands ready to help lead the development and manufacturing of both today and tomorrow’s complex oral solid dose drug products.

Spheronized particles offer an ideal shape for transport throughout most OSD manufacturing steps. Because extruded spheres offer improved hardness and reduced friability, they don’t generate dust—helping eliminate the possibility of contamination in processing— another of the sphere’s desirable attributes.

Extrusion-spheronization is an efficient, flexible and fast process for forming uniform pharmaceutical particles. The shape offers great utility to both drug developers and manufacturers. Offering a low surface area to volume ratio, spheronized active pharmaceutical ingredients (APIs) offer a number of distinct advantages that improve the overall manufacturability of complex dose forms.

Spheres offer an optimal shape for manufacturing finished drug products. The shape, for example, offers better packing and reproducibility in beds and columns and easier modelling because calculations are based on flow around symmetrical bodies. Spheres are more mixable as well, especially for incompatible APIs,

SPHERE OF THERAPEUTIC INFLUENCE Widely acknowledged as a predictable vehicle for the control, distribution and transportation of therapeutic agents around the body, spheronized pellets make a variety of common and emerging controlled release dose forms possible. This includes fixed-dose combinations (FDCs), combined modified release single-capsule forms and emerging multi-unit particulate system (MUPS) tablet designs. Ultimately sphereshaped pellets offer a variety of physical attributes that drug developers can leverage to control drug delivery, enhance therapeutic performance and aid the patient-centricity of oral solid dose drug products.

Suitable for many OSD forms, spheres help optimise finishing steps in manufacture. Spheres can be loaded and packed uniformly into capsules faster

AN EXTREMELY VIABLE TECHNIQUE FOR PRODUCT LIFECYCLE MANAGEMENT Extrusion-spheronization is proving to be an extremely

Spheres offer superior flow and handling characteristics.

versatile and economic manufacturing technique, viable for most of today’s oral solid dose products development paths, including new molecular entities (NMEs), life-cycle management (LCM) extensions and similar over the counter (OTC) marketing strategies. It can also support emerging (505(b)(2) development pathways including tailoring compounds for paediatric/ geriatric applications or developing FDCs to create a new best-in-class patient-centric product. FORM IS FUNCTION AND MUCH MORE Patient-centricity is manifesting itself across the life sciences industry in many ways. Tailoring medications to better suit a particular patient population’s special needs or enhance healthcare’s ability to prescribe and administer treatments more efficiently, are all, in principle, patient centric. But where the movement is being realised most profoundly is in drug engineering, with much of pharma pursuing fundamental improvements to


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42 the therapeutic formulation, functionality and form of oral solid dose pharmaceutical products. Single dose, daily regimen improves patient compliance. Modified release formulations can be effective for drug substances that have a narrow therapeutic index or need better dosage compliance. Most patient groups respond well to taking medications that are swallowed, but if a patient has to take their medications multiple times a day, dose compliance can be challenging. Modifying release means better control of API dosing in-vivo. By managing uptake and bioavailability precisely, modified release formulations offer pharma a way to deliver their actives with fewer, doses – and better control over time to deliver desired therapeutic effect and reduce negative side effects associated with dose spiking. A SOLID WAY TO MAKE COMPLEX ORAL DOSE PRODUCTS Development of extrusionspheronization over the past decade has been accelerated by science’s more comprehensive understanding of the raw materials, active ingredients, processes and controls behind the methodology. In addition, how to manage and manipulate those inputs to increase therapeutic performance or modify API release—without compromising the integrity of the compound or molecule has been vital. ADVANCED TECHNOLOGIES UNLOCKING EXTRUSIONSPHERONIZATION’S TRUE POTENTIAL Extrusion-spheronization is a mature method but the process

FROM THE FACTORY

and the equipment integral to it have advanced over time. The technology itself has seen steady improvement (along with a host of incumbent tertiary systems) and consequently some manufacturers may be better prepared to manufacture complex oral solid dose drug products with this technique than others. In the context of pharma manufacturing quality, current GMP thinking in extrusionspheronization means incorporating quality-by-design (QBD) chemistry, state-ofthe-art mixing, extruding and spheronizing equipment and entraining it in continuous flow. Pharma is relying more and more on its contract

manufacturing partners to make increasingly complex drugs. For those seeking more strategic outsourcing relationships, it is now more important than ever to match drug strategy as closely as possible to the expertise and technical capabilities of your manufacturing partners. It’s well known that more experienced project teams can help accelerate go-to-market schedules and technical/ operational mastery is a prerequisite. However, to unlock spheronization’s commercial potential the process requires both experience and the investment operationally to do it well and meet all commercial, financial and regulatory expectations.

Patient-centricity is manifesting itself across the life sciences industry in many ways.”


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