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INNOVATION IN GENE THERAPY

OUR LATEST DRUG DELIVERY SUPPLEMENT

HOW SMART PACKAGING IS FIGHTING COUNTERFEIT DRUGS

June 2019

SMASHing it!

How Merck's new approach to packaging is improving sustainability in pharma


INTELLIGENT PROCESSES for more efficiency and advanced safety Coming September 2019


Contents June 2019 | Volume 19 Issue 4 REGULARS 5: EDITOR’S DESK Reece Armstrong examines both sides of the argument relating to the world’s most expensive drug.

6: A SMALL DOSE A brief round-up of some of the latest developments in the industry.

11: ANALYSIS Why pharmaceutical manufacturers need to adapt and become more flexible.

12: OPINION The digital tools being used to futureproof pharmacy in the UK.

14: COVER STORY How Merck’s new approach to packaging is improving sustainability in pharma.

FEATURES 17: DRUG DELIVERY SUPPLEMENT In this exclusive supplement we feature stories on the latest trends and challenges in drug delivery, plus a cover story from drug delivery specialist Nemera.

30: PACKAGING The latest advancements and trends in packaging.

34: BIOLOGICS Holistic approaches to gene therapies and how automation can assist development.

38: FROM THE FACTORY How advanced planning and scheduling systems can help pharma manufacturers.


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This was just one reaction to news that the world’s most expensive drug has been approved by US regulators.

EDITORIAL

Novartis’ Zolgensma treats spinal muscular atrophy (SMA), a rare neuromuscular disease that can lead to breathing difficulties, muscle paralysis and death in children. Zolgensma is a gene therapy which Novartis CEO Vas Narasimhan has said ‘could create a lifetime of possibilities’ for children and families impacted by SMA.

editor reece armstrong reece.armstrong@rapidnews.com group editor dave gray david.gray@rapidnews.com head of content, life sciences lu rahman, lu.rahman@rapidnews.com publisher duncan wood

PRODUCTION

The caveat? A cost of $2.12 million per patient.

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ADVERTISING robert anderton tel: +44 (0)1244 952359, robert.anderton@rapidnews.com head of media sales, plastics & life sciences lisa montgomery lisa.montgomery@rapidnews.com

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The fact that insurers have said they would pay for Zolgensma no matter the price should ring alarm bells for patients.

It’s no surprise that people are outraged by the cost of Zolgensma. After all, so called ‘big pharma’ doesn’t have the best reputation when it comes to drug pricing, with many patients being hit hard by cost increases for insulin, cancer drugs and EpiPens: all vital medicines that people desperately need. The approval of Zolgensma isn’t without merit. Clinical trials have shown promising signs and it being a one-off treatment is especially beneficial for parents, never mind the fact that it offers hope for their children. As it stands, many infants with severe

EDITOR’S DESK forms of SMA die within the first few years of their lives. Zolgensma’s price raises questions into the viability of such expensive drugs, especially for countries poorer than the US, and others like the UK which operate on a process designed to get the most out of the system’s limited budget, and which has resulted in some innovative treatments not being available in the past.

In all fairness, Novartis has launched a programme designed to give patients dedicated support, both medically and financially, and will offer (partial) rebates if the treatment doesn’t work. The company will also offer financial assistant programmes for eligible patients, but with such a high price, many patients could find themselves outside of the eligibility bracket. The fact that insurers have said they would pay for Zolgensma no matter the price should ring alarm bells for patients, especially given the rising trend towards gene therapies. Indeed, the need for such innovative treatments, coupled with the FDA’s willingness to expedite approvals for gene therapies, could see pharma companies being given free rein in regard to pricing. But pointing the finger at drugmakers – which have to undergo years of clinical research and face billions of pounds in costs to develop a new medicine – may not be the answer in this case. Many people forget that pharma companies are businesses first and foremost and shouldn’t be shocked when treatments – many of which are truly remarkable – are priced highly. Instead, governments and regulators should work towards models that promote transparency in drug development costs, in the hope that this helps reduce drug prices worldwide. Unfortunately, a recent resolution to do just this, discussed at the World Health Assembly (WHA), failed to attract the attention of the UK, Germany and the US. And while issues have been raised over the effectiveness of the resolution, its implementation marks a necessary step towards transparent models of drug pricing. Without them, drug companies will only act in their best interest and health systems will continue to pay the price.


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A small dose I HOLLAND

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MOLECULAR DIAGNOSTICS FIRM

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molecular diagnostics company has secured €25 million in funding to help address the spread of infectious diseases and antimicrobial resistance (AMR). The company, Mobidiag, secured the funding from the European Investment Bank (EIB) through the European Growth Finance Facility (EGFF) initiative.

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abletting company I Holland has launched an online training programme to help pharma professionals keep up to date with the latest industry technology. The company’s e-learning programme offers professionals comprehensive and flexible courses across a range of disciplines. I Holland launched the programme in response to the growing demand from pharma professionals to learn about how technology is being used within the industry. Training managers and supervisors will be able to track and report on how each employee is developing, with the programme issuing a certification once each course is complete. The programme includes a variety of

subjects which will offer pharma professionals everything from introductions to tooling, maintaining tooling equipment, and how to improve productivity. Alex Bunting, I Holland marketing manager said: “We believe in supporting those in manufacturing who are looking to improve their technical skills and understanding of tablet compression tooling. However, we recognise that in the busy modern manufacturing environment, people can’t always be available to attend training and seminars. With that in mind we have created I Holland’s Online Training courses. They are designed for everyone from director level to engineers and operators looking to improve their knowledge in areas of tablet compression tooling.”

Mobidiag will use the funding - which is being supplied as a fouryear loan - to advance

Cell therapy company relocates to Cambridge A

UK cell therapy company has relocated to Cambridge Science Park following the appointment of 15 new staff. Mogrify has moved to the Bio-Innovation Centre at the Cambridge Science Park after it hired a range of new staff to help the company

advance its cell therapy goals. The company hopes that the new hires and facilities will aid it building a scalable infrastructure to generate IP around novel cell conversion to power the development and manufacture of new cell therapies across multiple therapeutic areas. The Bio-Innovation

Centre is the first of its kind to be built at the Cambridge Science Park and features laboratories and facilities for biotech and healthtech research. Mogrify has developed a bioinformatic platform that can potentially accelerate the conversion of one


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SECURES €25 MILLION its research and development and help target commercialisation for its diagnostic tests and platforms. Tuomas Tenkanen, CEO of Mobidiag, said: "This EIB loan is a further validation of Mobidiag’s progress as we become a leading player in the molecular diagnostics market providing innovative and differentiated solutions that are adopted by key laboratories throughout Europe. Following extensive R&D and clinical validation, we are

proud that our stateof-the-art technology is now commercially available internationally. This loan will allow us to accelerate the development of the Mobidiag platform content to the next level, and build significant value over the coming years by building a comprehensive portfolio of diagnostics tests that can be used on our devices. We are delighted to have the EIB’s support and look forward to working with them again.”

Private equity firm acquires CDMO

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rivate equity firm Ampersand Capital Partners has announced it will acquire contract development and manufacturing organisation (CMDO) Vibalogics.

mature cell type into another. Dr Darrin M. Disley, CEO, Mogrify, said: “We are growing a world-class scientific and executive team that will enable Mogrify to become a global leader in the development of novel cell conversion IP that underpins the

development of lifesaving cell therapies. The new Bio-Innovation Centre at the Cambridge Science Park offers outstanding facilities, service and networks to its tenants and we’re thrilled to be joining them at this exciting time.”

Vibalogics focuses on complex live biological products and offers a range of services including process development, manufacturing and fill and finish of products for biopharmaceutical companies developing oncolytic viral therapies, gene therapies, and vaccines. Ampersand will invest in expanding Vibalogics’ capabilities to meet increasing industry demand for the development

and manufacturing of complex viral products. Stefan Beyer, CEO of Vibalogics said: “With the benefit of Ampersand as our partner, Vibalogics will now strengthen and expand its position in the US and European markets while further investing in additional process development and GMP manufacturing capabilities. The partnership solidifies Vibalogics’ existing presence in the biologics manufacturing space and will allow the company to continue to exceed our customers’ expectations by facilitating the development of innovative therapeutic approaches that significantly improve the treatment of patients suffering from cancer

and genetic disorders. We are very pleased to have Ampersand on board as we take Vibalogics through to its next phase of growth.” David Anderson, general partner at Ampersand said: “Vibalogics is a leading company in its field. Given the exciting developments within the complex virus market this is an excellent time for an investor with deep experience in the viral vector contract manufacturing sector to partner with the company. We are looking forward to working with the team at Vibalogics to accelerate and continue its success in delivering cutting edge therapies to patients in need.”


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A small dose

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CHARITY LAUNCHES PANCREATIC CANCER AWARENESS SCHEME

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ancreatic Cancer Action (PCA) has launched an awareness initiative to help improve the general public’s understanding of pancreatic cancer. Pancreatic cancer has one of the lowest survival rates in the UK as it can only be cured if it is diagnosed in time for surgery. Through its initiative, PCA will provide pharmacies with free resource packs to aid healthcare professionals in the diagnosis and management of patients with pancreatic cancer. The resource packs also include access to PCA's NPA accredited e-learning module which aim to educate and refresh professionals knowledge on the disease. The initiative is designed to utilise pharmacists’ knowledge of the disease and through customer interactions and medicines prescribed, they can potentially help diagnose pancreatic cancer early.

Ade Williams, pharmacist and PCA ambassador said: “I am so pleased to see the significant increases in the uptake of the pharmacy e-learning module across the UK. Now with more community pharmacy teams engaging, we are set to play a vital role in the fight against pancreatic cancer. “There are 1.6 million visits to a community pharmacy every day. That adds up to 14 visits per person per year. I like to view that as 14 opportunities to make a contact that counts in improving their health and wellbeing, alleviating concerns or referring them on for more urgent treatment.” Ali Stunt, founder and CEO of Pancreatic Cancer Action added: “As someone who has had the fortune to be diagnosed early, we need to make sure other people can have the same outcome. “By ensuring that more people are aware of the disease, the symptoms and their risk, we can help change the story

for pancreatic cancer. It is not ‘the silent killer’, as it has been dubbed, and going to the GP with symptoms early can help more patients to be diagnosed in time for surgery and potentially save their lives.”

Life science groups join forces to become industry biometrics leader

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nalytical software provider Cytel and biostatistics company Axio Research have merged to create the largest global biometrics organisation for the life sciences industry. Operating under the Cytel brand, the merged company will focus on advancing clinical development and support its portfolio of pharmaceutical,

biotechnology and medical device customers. Axio will continue to provide its data monitoring committee services for clinical trials but will operate under the brand ‘Axio, a Cytel company.’ Joshua Schultz, chief executive officer of Cytel said: “We believe that better use of data will ultimately

revolutionise drug development. Our vision is to unite the combined expertise of our two companies to deliver powerful analytical solutions that address trial sponsors’ toughest drug development challenges and maximise the opportunities offered by emerging data sources.”


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A small dose

Whitepaper launched to address $40bn clinical trials challenge

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new whitepaper has been launched to help address clinical trial challenges around the globe. Released by Havas Lynx Group, the new whitepaper argues that a patient centric approach is needed if engagement is to approve within clinical trials. Havax Lynx Group has released its ‘Patient Centricity on Trial’ whitepaper in order to provoke conversation and offer potential solutions to a problem that is costing lives and the sector more than $40bn every year.

The whitepaper looks at new methods of recruitment for instance such as digital channels and step-by-step educational information in order to help patients navigate the application process of clinical trials. More so, Havas Lynx Group argue that more awareness is needed if patients are to recognise clinical trials as being potential treatment options. “Today, more than 40 million patients are needed in around 300,000 clinical trials worldwide every year,” explained Claire Knapp,

managing director of Havas Lynx, part of the Havas Lynx Group. “These are staggering numbers for the clinical trials arena to meet, especially when you consider that 85% of trials are failing to retain enough patients. “The challenges are mounting with exorbitant costs and a complex environment for clinical research, where the era of the blockbuster drug has made way for increasing niched drugs that cater to smaller, harder to find populations,” Knapp said.

CENTRAL PHARMA TO DIGITISE SUPPLY CHAIN THROUGH VERATRAK TEAM-UP U

K-based software provider Veratrak has announced it will work with Central Pharma (CPO) to help the company digitise its supply chain.

help them to connect with their network, digitise these manual processes and secure their supply chain operations moving forward.”

Jason Lacombe, CEO at Veratrak said: “We are really pleased to be welcoming Central Pharma and their extensive customer and partner network to our platform.

Veratrak’s platform leverages blockchain technology to store data as part of an immutable ledger, permitting secure data sharing across a company’s supply chain partners. It’s designed to provide companies with full transparency of their supply chains and to ensure secure and compliant critical document transfer. Alwyn Smit, managing director at Central Pharma added: “By

“At present, all document approval and onboarding processes at Central Pharma are running through email and internal working groups. By introducing our platform, we can

partnering with Veratrak we are taking the first step required to build a fully digital end-to-end supply chain network, that ensures data integrity and secure sharing of information between partners. “We chose Veratrak because its platform was designed with the industry in mind. Its solution not only gives us control over our supply chain but also has the potential to add value to our operations. By using a collaborative platform that facilitates efficient workflow, we will be able to reduce lead times by improving order management.”


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ANALYSIS

BRINGING FLEXIBILITY TO PHARMACEUTICAL MANUFACTURING

With the spectacular four-year bull run of pharmaceutical and biotech valuations from 2011-2015 over, manufacturers understand that their need to adapt is more urgent than ever before. Here, George Walker, managing director of Novotek UK and Ireland, explains how the pharmaceutical industry can increase asset use and improve lifecycles by becoming more flexible.

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study by McKinsey shows that the market leading pharmaceutical manufacturers are 53% faster at getting product to market than their average competitor. This allows them to produce more than double the quantity of product within the same time frame. This is due to re-investment in raising production process efficiency, with top producers not only out-producing competitors but also releasing 97% of their products to market without the need of rework.   An example of this reinvestment is the introduction of flexible production lines, which work by identifying cross-over steps in manufacture, when two or more processes share a similar step, allowing the same piece of equipment to be used in both processes.   For example, for some drugs, the active pharmaceutical ingredient must be mixed with a solvent, after which the solvent is removed by a separation column. As many drugs require this step, as long as the conditions required are similar, the separation column can be adapted

to work on multiple production lines – creating instant flexible production. Due to the high standards demanded of pharmaceutical production, thorough analysis is required to ascertain which equipment is suitable for use in flexible production. An IoT platform can be a good tool for performing this analysis. A  good  IoT platform will be able to gather and analyse operational data to provide detailed insight. This will include factors such as traceability within product flow, enabling more precise tracking of batches and will streamline validation, because detailed information will be automatically stored.   In addition to introducing flexible manufacturing to pharmaceuticals, an IoT platform provides the structure to implement other developing technologies. This was reinforced last year by track and trace business ACG inspection. “Technologies like blockchain, IIoT and machine learning will play a key role in securing the pharmaceutical supply chain from counterfeit goods. And we expect

that - in future - all countries will come together to standardise track and trace implementation,” explained Ettore Cucchetti, CEO of ACG Inspection. By adopting these measures, downtime can be prevented on two fronts. Increasing cross-over equipment that can be used for production, prevents downtime through lack of use. In addition, the IoT platform will give greater insight into the conditions of the equipment; facilitating maintenance and preventing downtime while enabling predictive maintenance.   A knock-on effect is the reduction of data-entry, reducing the time that operators and supervisors spend on time-consuming tasks. This means that technical employees are available for maintenance, problem-solving and decisionmaking, letting them concentrate on streamlining operations.   As the bull run becomes a trot, it is the ideal opportunity to reinvest and strengthen current production; it will be the most flexible manufacturers that come out on top.


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Opinion

The upcoming NHS digital transformation presents a huge opportunity for community pharmacies, opening up new patient services and opportunities to become part of a more connected healthcare system, which will improve patient care across the NHS as well creating efficiencies.

THE DIGITAL TOOLS NEEDED TO FUTUREPROOF PHARMACY To mark the launch of Bayer Consumer Health’s new Business Fit for the Future pharmacy training module, Oya Canbas, head of Consumer Health in the UK and Ireland talks about the future of pharmacy and the role technology plays. What do you think have been the key factors that have changed the landscape for community pharmacies? Pharmacists are currently operating under a huge amount of pressure – NHS cuts are squeezing smaller community pharmacists and revenues from prescriptions are also decreasing. This results in a great deal of economic strain and a need to adapt to a more commercial mindset. Pharmacists are the backbone of community healthcare, but they also need to put on their business hats and develop their commercial skills. The fact that consumers appear to have fallen out of love with the high street and the amount of spending online is also a key factor, with online pharmacies increasingly gaining a slice of the market.


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In addition, the public has become much more informed when it comes to healthcare. There’s a wealth of information available at people’s fingertips and an increasing willingness to self-care – a positive for pharmacies as they are best placed to help consumers make choices on the right products for them. As the high street comes under increasing pressure, how can pharmacies make sure they are offering a unique service to their customers? Pharmacists’ clinical knowledge is exceptional – they can offer recommendations within a few seconds of a customer coming into their pharmacy. The high levels of personal service and community support they provide cannot be replicated in an online-only model. The value of a face-to-face interaction with someone who is worried about their health cannot be underestimated – it gives reassurance and helps to build an ongoing relationship between pharmacist and customer, so that customer keeps returning. While it’s true that high streets are under pressure, there is a good level of footfall in pharmacies. When people walk through the door, they often have a specific need in mind. Pharmacists are problem solvers - providing good solutions builds trust and creates a high level of customer satisfaction.

by outdated processes. For example, one in five community pharmacies is still relying on a paperbased ordering system. The first serious challenge is removing this apparent sense of trepidation when it comes to adopting technology. In terms of opportunities, embracing technology will allow pharmacies to communicate with their patients and customers in ways that are more relevant to today’s world, such as social media platforms. Having a social media profile for their pharmacy can help drive people through the doors, as well as giving the pharmacy the opportunity to highlight the services it offers. What efficiencies can tech bring to community pharmacies? Efficiency is one of the most transformational opportunities that tech can bring. As part of the launch of our new training module Let’s Talk Tech, we spoke to a community pharmacist who had been spending up to two hours a day doing stock management on a manual system before switching to an electronic ordering system. When there are increasing pressures on community pharmacy, spending hours and hours on administration doesn’t make financial sense. It also takes pharmacists away from what they do best: providing patient care. While setting up a new system may involve an initial time investment, it will pay itself back as soon as it’s up and running.

The two most important things pharmacists must do are to put themselves in the position of the person who has come in looking for something to help their health, whether it’s eczema, allergies or heartburn for example, and to have belief in their knowledge and ability to find the right solution for that specific customer.

Profitability is one of the top factors in causing workplace stress for pharmacists – can embracing tech really address these concerns?

What challenges and opportunities for community pharmacies do you see with the upcoming NHS digital transformation?

Embracing electronic systems such as electronic point of sale (EPOS) for example can give so much insight into customers and their needs – so you’re much more likely to anticipate when there will be a seasonal demand for certain categories (e.g. allergy season) and capitalise on this. Statistics like rate of sale will be clearly explained so there isn’t a reliance on walking the shop floor and checking what stock is remaining.

The upcoming NHS digital transformation presents a huge opportunity for community pharmacies, opening up new patient services and opportunities to become part of a more connected healthcare system, which will improve patient care across the NHS as well creating efficiencies. However, recent research we conducted for our Business Fit for the Future programme indicated that the current work culture is weighed down

Technology certainly has a key role to play in boosting profitability: it can help reduce costs, improve cash flow and help to maximise sales.

It will also help with ranging and merchandising decisions so you can optimise shelf layout and ensure you have the right mix of products for your customers – and your bottom line.

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14

COVER STORY

SMASHing it!

European Pharmaceutical Manufacturer Editor Reece Armstrong sits down with Jeffrey Whitford, head of global corporate responsibility and branding and Fabien Thibault, global manager of product and packaging sustainability at the life science business of Merck KGaA to discuss the company’s new approach to environmental sustainability in packaging.

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he pharmaceutical industry has faced its fair share of scandals over the years - unfair hikes in drug prices and dangerous medicines to name just some – yet its impact on the environment has never been one. Yet a recent study from McMaster University made headlines due to its findings that the pharma industry is a significant contributor to global warming and even eclipses the automotive industry in terms of carbon emissions. One company is now trying to offset its environmental impact through a corporate responsibility plan that targets a four-year approach at improving packaging sustainability in the life sciences sector. Merck - through its life sciences business – has launched its SMASH Packaging Plan to match previous efforts in improving product sustainability. With a deadline of 2022, Merck is targeting four aspects of packaging to reduce the amount of packaging it uses; achieve zero deforestation; improve plastic sustainability and maximise recycling. Considering the company ships 30,000 packages each day, not to mention the complexity of the pharma supply chain, it’s an almost unfathomable task, but one that is necessary in an era in

which environmental concerns are becoming more widespread. “It [SMASH] has been in the pipeline for a few years and I think it builds on a consistent approach for us in terms of how we’ve approached our corporate responsibility,” Whitford said. Recent years have seen Merck undertake a number of acquisitions in order to transform itself into a major science and technology player; undercutting its original focus solely on pharma and chemicals. More so, 2015 saw the company undergo a major rebrand which represented, in Whitford’s view, an opportunity to ‘strategically pair how we can look at materials, sustainability and partnering this with a branding change’. The plan’s holistic approach to tackle sustainability across its entire packaging line is evident when Whitford explains the challenges the company is facing to improve its environmentalism. “One of the things you see from customers is they’ve got a lot of unnecessary packaging and excess material that doesn’t need to be included,” Whitford said. “How do we do a better job of getting our teams to select the right package for the product that the customer’s ordered? Look at plastics sustainability. How do we

increase what we’re doing to try and find replacements for certain substances? How do we deal with or handle polystyrene? That’s a huge component, certainly in today’s discussion around plastic waste in the ocean. This is a really important one for us to be talking about. Looking at deforestation. When customers purchase from us, how do we ensure they know they’re not contributing to deforestation?” The company’s approach to sustainability can be seen across other areas of its business. For example, Whitford explained that Merck has just launched a novel greener alternative in the solvents space, Cyrene, to act as a replacement for NMP (N-Methyl-2-pyrrolidone) and DMF (Dimethylformamide). However, the company saw that without a proper strategy in place for packaging, then its plan doesn’t make sense, according to Whitford. “We want to be able to provide that full platform and options for the customer, but you’ve got to have all the pieces in place. If you try to have that conversation about green chemistry and novel materials but you have this gap in the packaging front, the story doesn’t fully make sense.” For a company that ships such large numbers of products every


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day, it makes sense for Merck to improve its packaging sustainability. Pharma might have emerged so far unscathed from any media scandals regarding environmentalism but this isn’t guaranteed to last, especially in an age where a company’s reputation can be brought down by a single tweet. That’s why Merck is looking to invest in new methods and technologies to reduce the amount of packaging excess it creates. “In our distribution centres we are investigating solutions like packaging on demand, the types of innovative solutions that can create the distribution box that can be used to ship your product, case-by-case,” Thibault said. According to Thibault, the idea is to create packaging that is the perfect fit for a customer’s product, and which optimises the use of corrugated and excess material. And while changes to the company’s operations might be invisible to the customer, Thibault states that this too ‘has an impact’. He cites examples such as notifying packaging teams to be more aware of the amount of packaging they’re using and also of the excess materials used during manufacturing. “This is something that is not visible to our customers but we are looking at optimising this internal packaging to reduce the amount of packaging we use, for instance when we ship a material from a distribution centre to another,” Thibault said. With a deadline of 2022 it will be interesting to see what conversations emerge around pharma’s role in protecting the environment. Industries like food and beverage have so far been at the forefront of environmental concerns and Whitford believes

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there is ample opportunity to learn from their mistakes. “I think one of the good opportunities here is how do you take what we’ve learned from the food and beverage debate and figure out how it’s worked in this space and is applicable to this use case,” he said. Whether the industry follows suit and improves its environmental standing is still up for debate but Whitford certainly hopes so. “We hope the industry follows suit but while it is a competitive advantage, at the end of the day, what we want is what’s better for the global ecosystem and landscape. And that is more people making changes and if we can help lead that, that’s probably one of the highest compliments we can be paid.” *The life science business of Merck operates as MilliporeSigma in the U.S. and Canada.

Pharma might have emerged so far unscathed from any media scandals regarding environmentalism but this isn’t guaranteed to last, especially in an age where a company’s reputation can be brought down by a single tweet.


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NEWS ANALYSIS

The Path to Potential Reece Armstrong examines the story behind a Cambridge-based biotech’s potential treatment for diabetes.

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Cambridge-based biotech company has developed a novel way of potentially treating a range of diseases. ET-traps has developed a therapy targeting the Endothelin – 1 (ET-1) molecule which has significantly elevated levels in a host of different diseases including diabetes and neurodegenerative disorders, where it is largely responsible for the pathological processes in these diseases.

The idea is that controlling the levels of ET-1 could potentially save the lives of millions of patients.

ET-1 is a vasoconstrictor, proinflammatory and proliferative endothelial cell-derived peptide that helps the vascular system function properly. First discovered in 1988, ET-1 was quickly identified as being an important molecule due to it being present in all humans, with its levels significantly elevated in different diseases. While there are endothelin antagonists in clinical use to block ET-1’s function, there are many side-effects such as an increased heart rate associated in doing this. More so, certain endothelin antagonists can interfere with anticoagulants, necessitating a move away from these types of therapies. That’s why ET-traps has developed a novel tool to bind and sequester these pathologically elevated ET-1 levels in different disease models. The idea is that controlling the levels of ET-1 could potentially save the lives of millions of patients. ET-traps was founded by Dr Arjun Jain who started developing the idea when he was a Marie Curie

post-doctoral researcher in Bern, Switzerland. Dr Jain took an innovative approach by sequestering ET-1 at a time when many experts thought that the idea was impossible.

ET-traps has now filed a patent for its therapy and is working with investors on extending the patent life and applying it in other therapeutic areas.

The company has now completed proof of concept studies in cellular and animal models in the diabetes disease space.

Commenting on the drug’s use for diabetes, ET-traps founder Dr Arjun Jain said: “Currently, other than insulin, which controls glucose levels, there is no real cure for this devastating disease which often starts in childhood. The endothelin receptor antagonists are currently not approved for use in children, as they are associated with toxicity. The ET-traps exhibited no toxicity in the proof-of-concept studies done. Therefore, we believe that this would offer a new cure that could help save millions of lives!

As one of the most common diseases in the world diabetes now affects over 422 million people, according to the World Health Organisation. In fact, the NHS is estimated to spend around £14 billion every year on treating diabetes and its complications, making it one of the largest expenditures for the organisation. Indicated to treat both type-1 and type-2 diabetes, ET-traps will aim to bring back the pathologically elevated levels of ET-1 and repair any damage caused to a patient’s vital organs due to complications caused by their diabetes. In particular, what ET-traps has developed is an Fc-based fusion protein that has a very high binding affinity in the picomolar range, which the company states is higher than the endothelin receptor antagonists (ERAs) that are already in clinical use. Results from the company’s in vivo studies demonstrating ETtraps’ efficacy in treating diabetes showed that the drug significantly reduced collagen 4α1 expression in the heart and kidney, returning it back to non-diabetic levels.


| DRUG DELIVERY SUPPLEMENT

OPHTHALMIC DELIVERY:

A smarter approach

Nemera's e-Novelia: 0% preservatives + smart compliance = maximum compliance


DRUG DELIVERY SUPPLEMENT

Contents DRUG DELIVERY SUPPLEMENT REGULARS

Drug Delivery Supplement Picture the pharma industry; its contract and development manufacturing organisations (CDMOs); the major players invested in research and development; its supply chain specialists and experts in serialisation - with its many moving parts the industry, for the unaffiliated, can be almost impossible to imagine. Though difficult to imagine, these parts work in tandem with each other to run an industry which ultimately serves billions of patients; something of which many of us may not appreciate. Within life sciences pharma can often be viewed on the outside, as an industry wholly dependent on itself and one which medical devices, medtech and digital health have rarely played their part. Of course the increasing advancement of technology has now paved the way for greater collaboration from pharma and the rest of life sciences – and for my money, drug delivery may be the sector where this is most prevalent. Take our lead feature in this supplement in which Nemera outlines how a recent digital add-on for ophthalmology is helping patients to improve adherence to treatment. It’s an example of the innovative way technology can benefit both patients and pharma companies. Apply digital reminders to a clinical trial where patients must remember to take their medication at set times of the day and you get results which are more accurate and which better serve the company. But this is just one example of the many innovations that are occurring in one of the industry’s fastest growing sectors. And within this supplement you’ll find just a brief snapshot of those advancements.

20: COVER STORY Nemera explains why its e-Novelia add-on is benefitting patient adherence to ophthalmologic treatments. 22: PAEDIATRICS Cambrex examines the challenges in developing and administering oral doses for the paediatrics market. 26: Q&A Reece Armstrong chats to Lonza to find out about its new portfolio for dry-powder inhalation (DPI) capsules. 28: CASE STUDY Technoflex outlines its new technology for reconstituting drugs in a simpler way.

Enjoy reading.

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DRUG DELIVERY SUPPLEMENT

OPHTHALMIC DELIVERY:

A smarter approach Nemera's e-Novelia: 0% preservatives + smart compliance = maximum compliance

I

t’s well known that the quality and success of a treatment can depend on patients’ adherence.

In 2016, the estimation of the revenues lost globally by pharma due to non-adherence was $637bn.1 In the case of ophthalmic therapy, the quality and safety of eye drop use for patients treated in a healthcare setting play a vital role in the delivery of healthcare. Underdosing, because of either poor adherence or poor performance, means that patients are not receiving their prescribed medication. Overdosing, as seen in a 2009 American Medical Association’s study, has the

potential for several problems, including systemic adverse events, ocular adverse events and a more rapid use of the bottle. 2 Today there is still a very poor compliance in administering drops into the eyes and a big room for improvement. A study in 2012 showed that nearly 9 of 10 glaucoma patients were unable to instil eye drops correctly, and this may be an important cause of unintentional noncompliance in glaucoma medical therapy.3 In order to improve their compliance to treatment, patients really need an innovative system to deliver their drops easily into

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their eyes and limit negative side effects. That’s why at Nemera we’ve developed a multidose closing tip system which avoids the need for preservatives in the drug and prevents bacterial contamination over the duration of treatment. The system, called Novelia, limits the distribution of liquid to one drop at a time, with a precise and consistent drop size in order to improve patients’ adherence. The need for preservativefree medicines in the field of ophthalmology has been outlined by the European Medicines Agency (EMA). For instance,


COVER STORY

also conducting a user test evaluation is key because, even if it is successful according to the in vitro tests, an eyedropper may not necessarily be appreciated by patients due to poor usability.

the EMA has stated that preservatives should be avoided in patients who are on long-term treatments, or do not tolerate eye drops. It’s believed that by switching from preserved to preservativefree topical ocular medications can diminish the harmful effects caused by preservatives.4 Novelia has been tested by patients in user evaluations studies which showed that it was their preferred eyedropper. Eyedropper performance is mainly evaluated by in vitro tests, such as the dose variability against shelf life, the sterility of the content and the delivered drop. Despite these important in vitro tests, the usability aspects of the drug delivery system are not fully considered. Therefore,

During four user studies conducted between 2009 and 2018 Novelia was shown to be the preferred ophthalmic system. The studies contained a total of 230 people including senior users with chronic eye diseases and showed that 43% of patients thought that Novelia would enhance compliance over their current treatment, and that 76% of patients preferred using Novelia. A DIGITAL WORLD In response to the digitisation of day to day life and considering the low patient adherence in ophthalmic treatments, we’ve developed an electronic addon in order to assist patients in administrating their treatments. The e-Novelia add-on has been designed to add new functions to Novelia due to limitations of standard mechanical devices. The add-on includes a range of features to assist patients in administering and tracking their medication. By using the add-on, patients are reminded to take their dose and refill their device, are given digital and interactive

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instructions and are supplied with information about their drug’s expiry date, dosage and batch number. Importantly, the add-on also offers feedback and guide to patients on how to use their device the right way, and will produce tilts, shakes, and buzzes if it detects it is being used wrong. This new technology will be useful not only for patients, but for the entire industry: healthcare professionals will benefit from the dose tracking analysis and will be able to adjust the treatment; researchers will perform more efficient clinical studies; pharma companies will also use the data collection to launch better performing drugs while payers will be able to check if the patients comply with their prescriptions.

REFERENCES 1 https://healthprize. com/blog/medicationadherence-pharmas-637billion-opportunity/ 2 (Jennifer L. Stone, Alan L. Robin, Gary D. Novack, David W. Covert, Gerald D. Cagle. An Objective Evaluation of Eyedrop Instillation in Patients With Glaucoma. Arch Ophthalmol. 2009;127(6):732– 736. doi:10.1001/ archophthalmol.2009.96) 3 http://journals.lww. com/glaucomajournal/ Abstract/2012/03000/ Evaluating_Eye_Drop_ Instillation_Technique_in.11. aspx 4 Steven, DW et al. Preservative in glaucoma medication. British Journal of Ophthalmology 2018;102:1497-1503

Nemera’s smart eyedropper showcases several electronic features, which could be transferred across multiple device platforms: • Compliance rate

• User instructions

• Treatment history

• Smartphone application and notifications

• Remaining volume indication • Optimal  position for drop into eye (via traffic lights) • Actuation ease of use

• Shaking formulation indication • RFID tag on eyedropper bottle to collect data


DRUG DELIVERY SUPPLEMENT

Child’s play Dr Anthony Qu, vice president of scientific affairs at Cambrex and Dr Yanjun Zhao, market intelligence manager examine the complexities of developing oral doses for the paediatric market.

I

nfants, children and adolescents require different oral dosage forms depending on their swallowing abilities, taste preferences and dosage requirements. The development of tailored solutions that are practical to manufacture increases medication adherence and provides a competitive advantage.

children, but traditional capsules and tablets work as well, as do liquid dosage forms. Adolescents prefer capsules, chewable tablets and mini tabs. For all children, the palatability of medication can have a direct impact on treatment success. For many younger children, easy-to-swallow formulations are equally necessary.

GROWING PAEDIATRIC MARKET Currently there are nearly 1,300 paediatric clinical trials underway investigating the safety and efficacy of over 600 drug substances for the treatment of various cancers, central nervous system disorders, infectious diseases and other ailments.

CHOOSING THE RIGHT DOSAGE FORM Once the age-appropriate dosage form options are identified, the next step is to determine the most appropriate dosage form for the specific API in question. The first consideration is whether a measurable dosage form is required, such as dosing based on milligram (mg) of drug per kilogram (kg) of body weight. If yes, then liquid formulation will be suitable. Tablets and capsules would not be suitable in this case. Next, it is important to consider whether taste masking is needed and effective in the drug products. If it is not effective, then sprinkle powders or granules, tablets or capsules are the best choice because taste masking can be effective and achieved via coating technology in solid dosage forms. For liquid formulations, drug products must be chemically stable over a two-year period.

In the US, paediatric drugs based on new molecular entities (NMEs) must be evaluated in paediatric clinical trials. Existing drugs marketed for adults only can, if proven safe and effective for children, receive approval from the FDA as paediatric medications with six months of marketing exclusivity. Similarly, existing drugs proven safe and effective as paediatric medications for different indications can also benefit from marketing exclusivity. NEED FOR AGE-APPROPRIATE DOSAGE FORMS Consequently, developing paediatric dosage forms for both new and existing drug substances provides an effective means for expanding market reach and improving the lifecycle management of many different products. The paediatric population includes children ranging from infants to teenagers, and each age subgroup has different pharmacokinetic responses, dosage requirements, swallowing abilities and taste preferences. Therefore ageappropriate formulations are essential. Liquids are ideal for newborns, infants and toddlers. They are also effective for pre-school children, along with mini-tablets. Chewable tablets may be the best solution for school

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FORMULATION DESIGN REQUIREMENTS Overall design requirements for paediatric oral dosage forms are primarily based on the age, body size and swallowing ability of the target population. In addition to liquid and solid forms such as tablets and capsules, multiparticulate formulations like granules and mini-tabs, and alternative oral delivery pathways such as dose-sipping technology are available. Liquid dosage forms are ideal for patients with trouble swallowing, allow for flexible dosing and are more rapidly absorbed than solid dosage forms, but they often have shorter expiration periods; require special storage conditions (i.e., refrigeration); require careful dosage measurement; have unpleasant tastes and can be difficult to administer.


PAEDIATRICS

Traditional oral solid dosage forms leverage the most established manufacturing technologies with control costs, have long-term stability, do not require dosage measurement and are relatively easy and effective to taste mask via coating. They can, however, be difficult or young children to swallow and do not afford and dose flexibility. Fast-dissolving tablets allow absorption of the tablets in 60 seconds or less. They are appropriate for smaller molecule weight of APIs with no bitter taste that are delivered at doses of less than 20 mg and can diffuse into the epithelium of the upper GI tract and permeate oral mucosal tissues. However, they do not work for APIs that have a bitter taste, short half-lives and for formulations requiring sustained or controlled release. Chewable tablets provide fast absorption and better bioavailability through bypass disintegration and tend to have high paediatric patient acceptance. They also offer convenience to caregivers because no water is required for swallowing. On the other hand, these formulations contain sorbitol, which can cause diarrhea and flatulence. Due to their hygroscopicity, they must be kept dry and may require specialised packaging and storage conditions. The formulation must also have the right flow, lubrication, disintegration organoleptic and compressibility properties. Multiparticulate formulations are popular for paediatric populations because as a solid dosage form they have long-term stability; several options are available; they provide maximum dose flexibility; modified release formulations are possible; and taste masking is generally effective. Mini-tablets are small tablets averaging 1.5-3mm in diameter that can be filled into capsules, compressed into bigger tablets or loaded into sachets or stick packs. They not only provide

flexible dosing (by simply increasing the number of mini-tabs) and sustained/timed release options with coating but are easy to swallow, can be effectively taste-masked and allow different incompatible APIs to be formulated into a single dosage form. If APIs are unstable in liquid forms, mini-tablets can also be reconstituted and dosed as a suspension. Modified feeding bottles allow delivery of medication while the baby drinks its formula. Dose-sipping technology, which consists of a specially designed straw, enables the delivery of a single dose of small-sized pellets. SPECIALISED EXPERTISE IS OFTEN REQUIRED The choice of formulation type for paediatric patients is often dictated by the physiochemical properties and the taste of the active drug substance, along with the intended dose for different age groups. Each formulation must be appropriate for the child in terms of dose, convenience and acceptability to ensure compliance. Expertise in the wide range of possible oral dosage forms is essential for ensuring the most age-appropriate, efficacious and costeffective option is selected for any given API. Collaboration with contract development and manufacturing organisations with longterm experience and demonstrated success developing and producing right-sized dosage forms tailored for children from infants to teens at clinical to commercial scale can provide competitive advantage, reduce time to launch and ensure market success.

The choice of formulation type for paediatric patients is often dictated by the physiochemical properties and the taste of the active drug substance.

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ADVERTORIAL

STEPWISE

TO FUTURE RESPIRATORY CARE More than 500 million people worldwide suffer from Asthma and COPD. These major chronic decisions lead to more than 3 million deaths per year. Also, the associated cost burden is significant and exceeds €150 billion in the USA and Europe taken together. A major driver for this disastrous status is insufficient adherence to controller medication, which even after the first prescription has been filled ranges between 30% and 66%. Connected, external “add-on” devices for Asthma and COPD inhalers track patient adherence and connect patients to their physicians and other healthcare providers. In clinical studies, these devices have demonstrated to improve adherence to Asthma and COPD medication and therewith clinical outcomes . Despite the fact, that they also offer advantages for other key stakeholders, like physicians, payers and pharmaceutical

companies, their market adoption has been poor so far. The reasons, we at H&T Presspart believe, are that a stepwise approach to connected respiratory care is needed and that the short-term requirements for mass adoption have not been fully met yet. Long-term connected devices might be “purpose-designed” like a Tesla electric car is around its electric drivetrain, track technique via advanced sensors and might even actively regulate device characteristics, such as the flowrate. For a short-term market success, devices also need to have embedded electronics, but should be simple, intuitive, costefficient and represent limited changes to the status quo. In an effort to realize a broad market adoption in a stepwise manner, H&T Presspart and Cohero Health formed a strategic device development and marketing partnership. As

H&T PRESSPART'S EMDI CONNECTED INHALER

a result, the companies created the first market-ready, fullyembedded, connected metered dose inhaler solution: H&T Presspart’s eMDITM powered by CoheroTM. The eMDI device design is inline with the requirements stated above: It is an evolution of existing metered dose inhaler technology and its connective hardware and software are fully-embedded. The changes to existing MDIs form and function are minimal. As a fully disposable, non-reusable unit, the eMDI secures that users do not need to do anything other than press and breathe, as with their standard MDI. Also, the electronic componentry is separated from the medication delivery pathway and the device incorporates an FDA-approved mechanical dose counter. With our partners, we hope that we can pave the way for a broad market adoption of connected technology in respiratory care. A change is needed, as “drugs don’t work in patients who don’t take them”.

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1 Akdis CA et al., “Global Atlas of Asthma”, EAACI, 2013. 2 GARD, “Chronic respiratory diseases”, http://www.who.int/gard/ publications/chronic_ respiratory_diseases.pdf 3 Akdis CA et al., “Global Atlas of Asthma”, EAACI, 2013. 4 WHO, “Burden of COPD”, http://www.who.int/ respiratory/copd/burden/ en/ 5 Ford ES et al., “Total and state-specific medical and absenteeism costs of COPD among adults aged ≥ 18 years in the United States for 2010 and projections through 2020”, Chest, 2015, 147, 1, 31-45. 6 CDC, “Asthma in the US”, https://www.cdc.gov/ vitalsigns/asthma/ 7 Gibson GJ et al., “The European Lung White Book: Respiratory Health and Disease in Europe”, European Respiratory Society, 2013. 8 NICE, “Smartinhaler for asthma – Medtech innovation briefing”, NICE, 2017. 9 NICE, “Smartinhaler for asthma - Medtech innovation briefing”, NICE, 2017. 10 Jung B, Shears D, “Embedded connected metered dose inhalers meeting requirements for mass adoption”, ONdrugDelivery, 2017, 76, 6, 44-48. 11 Jung B, Shears D, “Embedded connected metered dose inhalers meeting requirements for mass adoption”, ONdrugDelivery, 2017, 76, 6, 44-48. 12 C. Everett Koop.


Smartphone app connectivity to allow real-time tracking and care management

Mechanical Dose Counter

Introducing the next generation MDI For more information contact H&T Presspart: www.presspart.com eMDI@presspart.com

H&T Presspart are pleased to introduce the first market-ready, fully-embedded, intuitive and connected metered dose inhaler (eMDITM) established to optimize care of patients ensuring from asthma and COPD. The eMDITM integrates seamlessly with BreatheSmart from Cohero Health, the only respiratory disease management platform that enables tracking of both controller and rescue medications, along with clinically accurate lung function measurement, in real-time.


DRUG DELIVERY SUPPLEMENT

Take a deep breath Capsugel Zephyr is a new portfolio for dry-powder inhalation (DPI) capsules of different polymers and compositions. European Pharmaceutical Manufacturer Editor Reece Armstrong caught up with Frederique Bordes-Picard, business development manager for innovative products, capsule delivery solutions at Lonza to learn more. WHY DID LONZA CHOOSE TO DEVELOP A NEW DPI CAPSULE PORTFOLIO? The Capsugel Zephyr portfolio responds to the marketplace needs for comprehensive inhalation solutions that seek end-product efficacy with consistent and optimal release performance regardless of formulation characteristics or DPI device principles. With the launch of the Capsugel Zephyr portfolio, Lonza now offers full end-to-end solutions for capsule-based DPI products. Our specialised capsule technology provides to our customers with the right solution to deliver optimal product performance for the pulmonary route to patients; a testament to how patient-centricity and customer focus are at the heart of Lonza’s healthcare continuum. CAN THE PORTFOLIO HELP INCREASE COMPLIANCE RATES FOR RESPIRATORY PATIENTS? Addressing patient compliance issues in the inhalation field is indeed essential as clearly stated during the recent RDD conferences in Lisboa. This should be done through patient-centric drug product development combined with deep patient education. For capsule-based DPI products, it is essential to ensure optimal performance of the DPI capsule with the selected device and the specific formulation. Thus, the importance of a complete portfolio of solutions as there is no “standard DPI” capsule: the critical parameters impacting the end performance should be customised to maximise emitted dose and fine particle fraction as well as finished product stability. Moreover, DPI capsule visual appearance including colour combination, transparency and printing can also be used to increase patient compliance. WHAT BARRIERS DO INHALATION DRUG PRODUCT MANUFACTURERS CURRENTLY FACE AND HOW DOES LONZA’S NEW PORTFOLIO ADDRESS THEM? Drug product manufacturers working in the inhalation field have to develop efficient and safe treatments with increasingly complex formulations while ensuring cost effectiveness and access to essential treatments for highly prevalent respiratory diseases. In addition, there are now calls to develop connected solutions to improve patient compliance as well as a more “green” device selection with lower environmental impact.

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Q&A

In this regards, capsule-based DPI products can accommodate different formulations (from standard carried base to innovative engineered particles), from small to larger doses for combination products or new systemic indications, using standard high speed capsule filling machine equipment widely available. There is a large offer of re-usable, off the shelf capsulebased devices, now including connectivity options as well. In this respect, Capsugel’s Zephyr DPI capsule portfolio addresses the need of tailored high quality DPI capsules that can offer optimal performance of the final inhalation product. WHAT DOES THE CURRENT MARKET LOOK LIKE FOR INHALATION SOLUTIONS AND WHY DOES IT NEED CUSTOMISABLE SERVICES LIKE LONZA’S DPI PORTFOLIO. There is an increasing interest in the inhalation route looking at respiratory diseases primarily with COPD, now the third leading cause of death worldwide (65 million people with moderate to severe COPD according to WHO) but also looking at new systemic indications (antibiotherapies, CNS and cardiovascular diseases). The pulmonary route not only represents a non-invasive needle-free alternative to the oral route but the lungs also offer an enormous absorption surface area, highly permeable with slow clearance that can be utilised for delivery of small molecules to peptides and larger proteins as well as long lasting formulations. IS THE NEW PORTFOLIO IN ANY WAY A RESPONSE TO THE WAY DRUG DELIVERY DEVICES ARE BECOMING MORE INTUITIVE AND ADVANCED? Absolutely yes, again, the ability to customise critical parameters of the DPI capsule allows Lonza to achieve optimal performance of DPI capsule in combination with capsule-based devices currently on the market as well as the new connected device solutions like the RS01x developed by Plastiape –RPC. COULD YOU OUTLINE THE PARTICLE ENGINEERING APPROACH USED THROUGHOUT ENCAPSULATION AND THE BENEFITS THIS BRINGS? The primary consideration in pulmonary drug delivery is the ability for DPI to create stable fine particles of APIs in the range of one to five microns that can be deposited into the lungs. A number of particle size reduction and particle engineering technologies can be used to generate particles in aerodynamic sizes within this specific range. Conventional particle size reduction techniques, such as jet milling works for most of the asthma/COPD drug substances on the market but other particle engineering approaches such as spray drying allow for drug substance that cannot be treated by micronising to be converted into respirable particles. The latest approach can be utilised to develop the higher doses products (beyond 5mg API) or biotech type product where drugalone formulations are the preferred path forward. Spray drying approach can also help address bioavailability challenges in case of low soluble compounds. As such these techniques may impact material characteristics, morphology, surface properties, stability of the API, the quality of the final formulation in terms of aerolisation performance, physical and chemical stability, delivery and absorption in the lungs will be impacted by all these contributing factors including process, DPI capsule and selected device.

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DRUG DELIVERY SUPPLEMENT – CASE STUDY

Who: Technoflex What: A new technology for reconstituting unstable drugs in a simpler way

Case study

How: An innovative approach to packaging

MIXING THINGS UP Getting drugs with unstable characteristics to the patient is a complicated process. One company believes it may have the solution, as Sylvie Ponlot from Technoflex explains. Drugs which are unstable in solution have, until today, been packaged in powder or lyophilisate form in glass bottles. They then need to be reconstituted at the patient's bedside, or in the hospital pharmacy, in aseptic conditions. There are many errors and accidents linked to reconstitutions which pose a real risk for patients and healthcare personnel: errors with diluents, dosage errors, needle stick injuries1, contamination, etc. To reduce these risks, Technoflex has developed Dual-Mix, an innovative primary packaging which meets three challenges: storing the drug to be reconstituted, making its reconstitution secure and ensuring the safety of healthcare staff and the patient. Dual-Mix is a patented bag which contains a medicine in powder/ lyophilisate form and the associated diluent in the same dual-chamber primary packaging. It facilitates and makes safe the packaging of very unstable molecules which need to be reconstituted just before administration to the patient. Designed in Inerta polypropylene, the material in contact with the main active ingredient and the diluent is fully compliant with European and American pharmacopoeias. The bag is delivered sterile and consists of a lower chamber for the diluent and an upper chamber for the main active ingredient. The latter is the component which requires the highest protection. So, a peelable aluminium label, which can be placed on both sides of the bag, protects the powder or the lyophilisate from light and humidity. It is easy to remove at the time of use, and the nurse can very simply check the integrity of the product before its reconstitution. The two chambers are separated by a peelable seal. It is sufficiently hard wearing not to break spontaneously during transport or storage, but is however easy to break by using simple appropriate pressure on the lower chamber to ensure that the main active ingredient and its diluent are mixed just before infusion. Reconstitution is achieved in under 10 seconds and in a totally safe way. The bag’s closed system ensures that the product is sterile and avoids risks of contamination during handling. Finally, Dual-Mix has a twist-off compatible with the majority of spikes and infusion sets used in Europe and the United States.

REFERENCE: 1. In the United States, 1000 people, 58% of whom are nurses, are affected every day by needle stick injuries, generating $1 billion in extra costs. (Source: Becker Hospital Review)

Dual-Mix is available in three different volumes of 50, 100 and 250ml and opens the way for standardised ready-to-use doses of drugs. By avoiding the need in some cases for preparation in the hospital pharmacy, Dual-Mix optimises preparation and administration by medical staff. A not inconsiderable advantage and a great advance, making reconstitution and administration simple, fast and totally safe in a hospital environment, but also during hospitalisation at home or in emergency or conflict zones.

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PACKAGING

Business as... However much improved life sciences firms are in their approach to regulatory information management, labelling continues to buck the trend. Siloed systems and an over-reliance on manual checks continue to incur risk, delay and cost, especially across international operations. In this article, Amplexor senior life sciences consultant Agnes Cwienczek advises on an alternative way forward.

L

abelling management is increasingly becoming a point of pain that life sciences companies cannot ease with existing approaches. Failure to respond quickly to changing product information or market requirements can result in delays to market, or rejected product registrations, with an impact on sales, revenues and market profile. A major sticking point is the way content interdependencies are managed– i.e. how a change anywhere along the safetyregulatory-

manufacturing-supply chain continuum will affect all label content, from the global ‘core data sheet’, to patient-facing product information in each country. More often than not, label status tracking still happens in Excel spreadsheets or home-grown systems, with content updated on a country-by-country basis using dedicated labelling tools. These are rarely connected to companies’ registration and submission planning and management tools, preventing a clear line of sight, and management capability, across all labelling activities. BRINGING ORDER TO INCONSISTENCY The main challenge is companies’ inability to efficiently map country/ label interdependencies, so that changes can be rolled out promptly and reliably wherever new requirements apply. This is often far from straightforward Latin American countries, for example, may be dependent on Europe for labelling convention for tablets, but on US product information for medicinal solutions.

Where submissions are bundled and/or split at country level in order to comply with local regulations or company internal needs and strategies, there are further considerations as companies try to maintain traceability – especially as changes trickle down to dependent countries. And of course, labelling changes can be triggered at different points in the drug ecosystem. While a change to the benefit/risk profile of a drug will drive revised labelling requirements from the global core of the organisation, regulatory changes local to a reference country can drive a need for amendments both up and down the chain – up to the core, and down to dependent markets. So any solution cannot be one-directional in its treatment of cascading changes. BEYOND THE PORTAL APPROACH One approach life sciences companies have taken to manage labelling changes, is to create data-exchange portals between global and local functions – so that the different points in the international labelling management


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usual? chain can collaborate and report back on requirements and related progress. But even this relies too heavily on manual updates and process repetition. And none of this takes into account the fuller safetyregulatory-manufacturing-supply chain continuum. Complete labelling traceability, for compliance, reporting, and safety/ risk management, depends on content and processes being open to easy scrutiny right from one end of the chain to the other - from a safety signal, to the regulatory submission and approval, through to product receipt by pharmacies or hospitals. True end-to-end label and product tracking and change management ideally needs to encompass artwork updates, and followthrough into and beyond warehouses. While up to now, this broader perspective and ambition remains largely aspirational, achieving complete end-to-end traceability and control is something life sciences organisations are increasingly attuned to in their vision for process improvements.

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Certainly, the bolder and more innovative firms become in their quest to expand their markets and portfolios, and the more they become subject to intensifying regulatory/ public safety criteria, the more meticulous and efficient they must be in their monitoring and process controls.

Certainly, the bolder and more innovative firms become in their quest to expand their markets and portfolios, and the more they become subject to intensifying regulatory/public safety criteria, the more meticulous and efficient they must be in their monitoring and process controls. AVOIDING NEW DEAD-END PATHS To keep pace with regulators’ growing safety controls, companies must upgrade their approach to labelling management with some urgency now. Many already have three-to-five-year change programmes underway, with the aim of establishing holistic, transparent and collaborative global label management environments. These comprehensive plans are encouraging, paving the way for a definitive source of labelling truth, in the form of central master data - from which everything else flows. They allow for intelligent workflow - as an efficient and reliable means to assess the impact of label changes/calculate interdependencies; to drive through changes with

reduced manual intervention; and to facilitate greater collaboration across departmental, country and supply-chain boundaries. Finally, plans should be cross-functional – that is, they should allow for connection with global ERP/manufacturing systems, and the potential for re-use of approved content assets. They should also leave room for future automation – for instance, structured authoring of labels and patient information built from approved master content assets. Being thorough and thinking laterally now will pay dividends later.


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PACKAGING

IN THE AIR

Gillian Ewers, vice president of marketing at PragmatIC examines how smart packaging is benefitting the pharmaceutical industry and helping to combat counterfeit drugs.

T

he worldwide pharmaceutical market is huge – it was estimated at over $1 trillion in 20161. A growing portion of this market is over the counter (OTC) medicines that are projected to be worth $178 billion in 20242, driven in part by governments encouraging people to check with the pharmacist before going to A&E (accident and emergency) to reduce the non-urgent load on hospitals. An increasing number of people are purchasing OTC medication online and the speed of growth in this segment of the market has focused the attention of the pharmaceutical industry, especially after Amazon’s quiet launch of its own branded products.

REFERENCES 1 https://www. businesswire.com/news/ home/20180614005484/ en/1.5-Trillion-Mid-SizePharmaceutical-MarketMarket-Assessment 2 https://www. businesswire.com/news/ home/20180614005484/ en/1.5-Trillion-Mid-SizePharmaceutical-MarketMarket-Assessment 3 https:// healthresearchfunding. org/20-shockingcounterfeit-drugs-statistics/

High revenue markets are very attractive to counterfeiters, who can reap high profits by either copying the formulation or making up a far more dangerous product that looks just like the original. The value of the total counterfeit pharmaceutical market is estimated at $200 billion3 of which online sales are estimated at around $75 billion. The World Health Organisation (WHO) claims that

16% of counterfeits contain the wrong ingredients and another 17% contain the wrong levels of necessary ingredients. Which means these illegal items can be harmful, or even fatal. There is also the issue of grey market diversion, which is when products are not counterfeit but are sold outside approved supply agreements. In general, the goods are bought in a low-priced region/ country, and then sold in another for a much higher price. Or in the case of pharmaceuticals, this can be medicines that are OTC in one country, but under prescription, or prohibited in another territory. Therefore, grey market diversion is not only a problem for suppliers, but also for consumers. Whilst it is not illegal to buy from grey market sources, there could be significant consequences if, for example, pharmaceutical products come without local language instructions or information. There are efforts to address concerns about authentication, such as the European initiative to serialise all drugs. The US is well along its path to package

level traceability by 2023, but less developed countries lag behind, with the consequence that they have high levels of drug related criminal activity. Across the board, one of the challenges for small and medium sized companies to meet new regulations is that their packaging lines are often very traditional, with a focus on high volume production as margins are so slim. The equipment is not set up to meet individual serialisation package requirements, and the investment in new digital printing lines that are capable of per unit identification are often beyond the reach of many converters. A possible approach to this is to rethink the whole problem and use technology such as RFID (Radio Frequency Identification) and NFC (Near Field Communication) solutions which can simplify serialisation but also bring other benefits. Adding a small integrated circuit (IC) into a package gives it a unique identification (UID), which can be tracked globally through the distribution supply chain and into the retail environment and can be


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used to assure every member of the supply chain of its provenance. This can also be used to deliver the same information to the consumer, as well as other details that can be relevant to where they are when they interact with the product. For example, complementary products and counter-indications whilst instore, then links to online forums and support groups when at home, even re-ordering facilities, all in their chosen language – and with a readable font! The technology has been available for some time, so why haven’t companies been implementing this into everyday pharmaceutical products? So far, it has not been economically viable for high volume OTC products, that are generally lower priced. What is required are truly low-cost ICs that are also imperceptible to the consumer and fit with existing high throughput packaging lines. Fortunately following the launch of a new generation of ICs, there is now a real prospect of bringing the benefits of item-level digital traceability and interactivity to pharmaceutical products across the globe.

Across the board, one of the challenges for small and medium sized companies to meet new regulations is that their packaging lines are often very traditional, with a focus on high volume production as margins are so slim.

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BIOLOGICS

Inte-greatness! Clive Glover, strategy director and cell and gene therapy lead at Pall Corporation, explains why we need to take a more holistic approach to gene therapy manufacturing processes.

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n just a few short years we have seen a huge surge in the development of new gene therapies. There are currently over 1,000 cell and gene therapy clinical trials underway worldwide1. While the majority of these are still in phase I or phase II, there are over 90 trials in phase III. Scott Gottlieb, former commissioner of the US Food and Drug Administration (FDA) stated at last year’s BIO International Convention that he expects the FDA to approve 40 gene therapies by 20222.

1 ARM 2018 State of the Industry: https://alliancerm. org/sites/default/files/ ARM_SOTI_2018_FINAL. pdf

The gene therapy revolution is happening. But despite all this promise and the rapid growth of an emerging industry, we’re still a long way from seeing gene therapies being manufactured in quantities even close to the level of current demand. This is arguably one of the biggest challenges in modern medicine manufacturing and an area in which we at Pall are investing heavily, namely how to scale up the manufacture of gene therapies and gene-modified cell therapies to industrial levels and do so in a way that remains efficient and cost-effective for those companies producing the treatments. If this revolution in healthcare is going to achieve its potential, we need to solve this manufacturing challenge first.

2 Terry, Mark. “Gottlieb at BIO 2018: 40 Gene Therapy Approvals by 2022” BioSpace, June 7, 2018. https://www.biospace.com/ article/gottlieb-at-bio-201840-genetherapy-approvalsby-2022/

OVERCOMING THE ROADBLOCK Viral vector manufacture is a case in point that reflects some of the wider challenges faced in cell and gene therapy production. Demand

REFERENCES

is soaring for the pre-clinical and clinical-grade viral vectors that allow for the delivery of genes of interest, but the industry has not yet adapted to meet the demand. Many think of the process as being very similar to the one used for monoclonal antibodies (mAbs) and assume it to be relatively simple to upscale. But there is far more risk and intricacy involved with each individual step. The viral vectors themselves, for example, are toxic to the cells that produce them, so the use of stable cell lines, similar to those used for mAbs, is challenging. Production systems depend on transient expression of the components essential to produce a virus, severely limiting titers. This is a serious issue in prevalent diseases such as haemophilia or Duchenne muscular dystrophy, where the number of patients appropriate for treatment is large and the doses required per patient is high, meaning that there is a need for larger viral vector batch sizes. There are countless reasons why scale-up has proved challenging, and as a company whose expertise is in industrialised biopharmaceutical manufacture, Pall is heavily invested in tackling the gene therapy manufacturing challenge. One main focus of our investment in this area has been to develop an automated, end-to-end integrated, platform solution that is scalable and can address issues that arise when gene therapy products are

manufactured using individual manual manufacturing steps. Single-use technologies, for example, can save not just days but weeks by reducing cleaning and cleaning validation requirements, set-up time, in-process hold steps and the time needed for an operator to oversee equipment. Automation can also play a vital role. When assays for viral vectors, both off-line and online, are of poor precision and accuracy, automation can help bring a degree of process control, improve process reproducibility and reduce the risk of batch failure. A fully integrated system ensures all unit operations are coordinated and that the consumables are appropriately specified and qualified for their intended function, allowing a process to run in exactly the same way each time. As long as the incoming raw materials are well controlled, it is likely that the process will routinely run at optimal productivity. Essentially, good integration and automation can be central to getting systems to work to certain performance measures every time. THINKING CONTINUOUSLY Changing the way in which to approach the manufacturing process for viral vectors is just the first step to the industrialisation of gene therapy production. If we’re going to tackle the industry’s productivity challenges, we need to think smart and commit to finding innovative manufacturing solutions.


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Continuous bioprocessing, for example, could bring huge benefits to gene therapy manufacturing, if we can overcome some of the perceived – and often incorrect – assumptions about regulatory risks. Continuous bioprocessing offers potential for transforming how biopharmaceuticals are manufactured. Continuous processing offers multiple benefits including improved process economics, increased process design flexibility, reduced development times, scalability, and cost efficiencies in terms of improved productivity from unit operations. Generally speaking, compared to a batch process, continuous processing can significantly reduce the footprint of a manufacturing suite, while offering additional ‘soft’ cost savings through reduced build times for facilities, streamlined maintenance and management processes, and reduced workforce demands. As the industry moves towards full-scale manufacturing plants in gene therapy production, these significant cost savings will be key to improving speed to market for lifesaving treatments. A BRIGHT FUTURE There’s no denying that the rise of gene therapy has been due to the remarkable clinical results that have been achieved. The rise of single-use facilities, process intensification, integrated unit operations and continuous manufacturing is improving facility efficiency and flexibility, yet at the same time reducing footprint and processing times – but we’re only at the start of this journey and it’s a long road ahead. The industry collectively needs to think beyond the status quo of siloed systems and batch processes and think more holistically about the fundamental way we manufacture medicines.

As new breakthrough therapeutics continue to emerge and transform the healthcare industry, so do we as manufacturers need to think in groundbreaking ways about how we produce them. If we can get this right now, there is no limit to what’s possible and the benefits that these new treatments could bring to patients worldwide.

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A fully integrated system ensures all unit operations are coordinated and that the consumables are appropriately specified and qualified for their intended function, allowing a process to run in exactly the same way each time.


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BIOLOGICS

A PRECISE APPROACH As biologics steadily grow in pipeline development and commercialisation, inherently they require precise support to ensure effective delivery to the patient. In this article, Justin Schroeder, vice president for global programme management at PCI Pharma Services, looks at how to support the delivery of biologics through automated inspection systems.

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redominantly these medicines are delivered parenterally, and most commonly through injection. This may leverage traditional sterile vials, or increasingly methods such as prefilled syringes, or injectible systems leveraging a platform built out on prefilled syringe or cartridge as the sterile housing. Safety syringes, autoinjectors and pens, as well as more complex mechanisms for metered infusion, all leverage complex assemblies that work effectively and reliably due to extreme precision. These systems require this advanced precision in the moulding and fabrication of the various parts of the assembly, as well as utmost precision in both the subassemblies and final assemblies. In many instances this heightened level of sophistication is supporting a delivery mechanism that may be intended for only a single use. Conversely, multi-use pens inherently are designed to be used repeatedly or even refilled, and some applications such as diabetes may allow the user to customise their dosing in the delivery. There is an impressive amount of intricacy and engineering architecture to make complex dosing systems effective and intuitive for the average patient. Many biologics and sterile injectable non-biologics still rely on traditional vials for patient administration. While we naturally

infer that a complex autoinjector requires sophisticated automation and multilayered inspection, we do not necessarily infer that a traditional sterile vial in a kit may warrant the same. Take, for example, a kit containing the following: one sterile vial of lypholised drug product, one prefilled syringe of sterile water for injection (WFI), one alaris cap for vial extraction, one 20-gauge needle, one 22-gauge needle, one leaflet for regulatory information, and one set of instructions for use (IFU). While the vial and water for extraction may be a wellestablished delivery mechanism, it is abundantly apparent that without the needles, alaris cap, or other critical components, the entirety of the system fails. In short, this expensive drug is rendered ineffective if the kit is not complete in its entirety, and we have failed the patient. Often in the manufacturing environment, kitting is thought of as a manual process, achieved by workers hand-placing and loading individual components. Some companies may also rely on those same workers for the quality assurance responsibilities to verify and assure both the presence and correctness of these components. Unfortunately, the practical realities are that using human inspection as the primary means of verification leads to error.

Working in close collaboration with our client, PCI was tasked with the challenge of developing a system for a particular application. The complex kit required a foolproof system to provide automated machine inspection of the kit, while balancing the cost considerations since the overall product demand did not warrant a highly automated line with robotic placement. We were challenged therefore to blend the human elements with the automated inspections. The key to automated inspection systems is to provide inspection criteria that can be validated to assure robustness and reliability. These inspection systems are beholden to certain criteria and are built out with these. For the partnership, we needed to identify those critical elements that would allow us to successfully inspect a system that had many elements of variability. The components utilised in the kit were, for the most part, ‘off the shelf’ stock items providing little opportunity to add key identifiers such as barcodes, by which items could be scanned in the packaging assembly process. We were challenged to find other key characteristics of the existing packaging that would allow us to both verify the presence and correctness of the component’s location, as well as its correctness for use.


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One of the most challenging parts of the project was ‘creating a solution that identified the features of each individual component without slowing down the process,’ according to PCI’s Ray Hook, director, global serialisation. And while this did present variability challenges at the beginning of the project, Hook notes that PCI found an ‘optimal solution to address that real- world variability,’ settling on a solution ‘that is very robust’. Through considerable time spent in engineering analysis and proof-of-concept challenge testing, we were able to leverage combinations of critical text and colour to establish a basis of validated parameters by which the system could ensure the presence of each component. Variability, however, continued to provide an ever present challenge in establishing parameters. Green and yellow were two key distinguishing features for identifying the 20- and 22-gauge needles. Due to printing variability from the sourced components, the distinction between yellow and green was found to be particularly difficult. In the end, using colour with other key attributes allowed the system to deliver a robust solution. Once the key elements of the vision systems were fool-proofed, the remaining architecture of the line engineering elements needed to be established. With modest product volume requirements, full automation was not the optimal solution. The line ultimately blended human activities with automated elements, all governed by inline automated inspections at each critical milestone of the build. This included fully automated WFI syringe assembly, beginning with

sterile glass barrels and adding components such as finger flange, syringe labels, plunger rods and protective packaging. The WFI is paired with the labelled active drug product lyophilised vial, and the kit is then fitted out with the remaining components. At every step of this complex build, the vision system ensures the proper fit, placement, and correctness of each critical component. Once a kit is complete in its contents, anti-counterfeiting tamper stickers are added to provide additional security. Kits are then serialised with market specific requirements, vision inspected, and further aggregated to the case and pallet.

Marc Luebbing, PCI business unit manager, added: “Working closely with our customer ‘at the table’ meant we could develop a package design that was elegant and intuitive for the care-giver delivering the medicine, but also incorporated all the key elements for our packaging system to deliver with a high degree of confidence. The project called on resources across many functional groups and teams and yielded a great solution for everyone concerned.”

The key to automated inspection systems is to provide inspection criteria that can be validated to assure robustness and reliability.

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FROM THE FACTORY

AN ADVANCED APPROACH Rod Schregardus, supply chain technology specialist at Access Group, discusses the role of advanced planning and scheduling (APS) systems in pharmaceuticals manufacturing.  Digitalisation has transformed pharmaceuticals manufacturing in recent years, helping to get drugs to market quicker, demonstrate compliance and traceability and protect margins. Pressure to reduce drug prices, and competition from the Far East, has only underlined the importance of lean production, prompting many to review and, in some cases, overhaul their existing processes.   It is perhaps difficult to believe that, in a tech-driven industry like pharma, some manufacturers still rely on basic planning software and spreadsheets. Clearly limited in scope and functionality, these tools rarely provide the visibility required to avoid problems like bottlenecks

in a bioreactor, conflict due to shared equipment and the under-utilisation of resources. For others, however, the adoption of Advanced Planning and Scheduling (APS) systems has proved a gamechanger, particularly where production is complex.   We’ve worked, for example, with a biopharmaceutical vaccine manufacturer, which operates 24/7 and has a 200-strong team responsible for hundreds of processes, including making solutions and cleaning bioreactors and filtration systems. The fact that the facility is also hard-piped also means every process has to be accurately scheduled to make full use of resources.  

Relying on spreadsheets to manage multiple processes took up a great deal of the team’s time, with full-time planners manually preparing documents ahead of a weekly meeting, and updating them with anything that had happened in the past 24 hours.   Lack of cohesion and detail meant engineers sometimes arrived to carry out planned maintenance, then found out that production had started because the schedule had changed. Now, using an APS platform, the plan covers four weeks instead of one and takes an hour to complete, not a morning. Above all, it has a single plan that everyone can work to.   Greater efficiency is, of course, key to driving down production costs and helping manufacturers to future-proof their operations. More widely, an APS can align production processes to purchase orders, as well as reduce lead times, improve on-time-in-full (OTIF) and drive up customer service.

As well as tackling immediate challenges, like sub-optimal use of resources, a robust APS enables them to plan strategic initiatives and scale up in line with their ambitions. Importantly, they support ‘what-if’ capacity analysis, the results of which could determine whether a manufacturer is capable of delivering on a project, or whether investment in new equipment, or even a site, is likely to offer a strong return. Advances in drug development, coupled with commercial challenges, mean it has never been more important for pharmaceuticals manufacturers to keep a tight rein on every aspect of production. Taken together, inefficiencies in production will only drive up costs and put firms at a competitive disadvantage. But, as we have seen, those with the right strategy and tools in place to get the most value from every process can surely expect strong returns.


21 - 23 August 2019 | Seoul, Korea The Pharmaceutical Powerhouse of the Future

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Make the most of the booming pharma business in Korea CPhI Korea provides a dynamic meeting place for a wide range of industry suppliers to engage with purchasers and decision makers from the pharmaceutical industry in Korea and the surrounding region. The exhibition showcases the whole pharma supply chain as well as an extensive conference programme covering the latest trends and topics within the regional market.

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