EPM October 2018 by EPM Magazine

THE LATEST IN DRUG DELIVERY

WHATâ&#x20AC;&#x2122;S NEW IN LAB AUTOMATION

CLINICAL TRIALS FOCUS

October 2018

STEP IT UP

Natoli Engineering explains how to get the best from your tablet formulation strategy

the next medicine... We’ll develop it together.

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Contents October 2018 | Volume 18 Issue 7 REGULARS 5 EDITOR’S DESK European Pharmaceutical Manufacturer’s new editor, Reece Armstrong, examines personalised medicine and whether it’s time manufacturers change their approaches to the way drugs are developed.

6 A SMALL DOSE A brief round-up of some of the developments in the industry, including the UK’s EpiPen crisis, whether an old antibiotic can help treat melanoma and a preview of this year’s Lab Innovations.

11 ANALYSIS Arthur D. Little looks at how new supply chain capabilities can help drug manufacturers bring the most benefits to patients.

14 OPINION Decision making towards research & development is being hindered by organisational approaches, here Kinapse examines the solutions.

16 COVER STORY In this feature, Jonathan Gaik, director, Natoli Scientific, looks at how pharmaceutical manufacturers can optimise tablet formulation via a stepwise approach.

34 TECH TALK The latest Tech Talk looks at whether pharmaceutical manufacturers can go digital using only smartphones.

FEATURES 19 DRUG DELIVERY Why innovation in inhalers is key for global warming, the benefits and limitations of transdermal drug delivery systems, the connected health approach to chronic health and why microneedle technology is surging.

30 LAB AUTOMATION Take a look into the new automation advancements that are helping manufacturing improve efficiencies.

32 CLINICAL TRIALS The winning steps needed for drug formulation during first-in-human (FIH) trials.

Continuous innovation

Having recently sold a ConsiGma™ 1 oral solid dosage

GEA and its partners are leading the way toward smaller,

development unit to the US Food and Drug Administration

more flexible continuous processing technologies that have

(FDA), GEA has firmly established its tenure in the continuous

the potential to transform the future of drug development and

manufacturing (CM) market.

production — and deliver customized quantities of drugs to patients in need in a quick and efficient way.

We’ve successfully completed more than 70 projects involving a variety of filed and authorised products, including the first

Contact gea.com/contact for more information

ever FDA-approved breakthrough therapy developed and

and learn about how GEA is #MakingScienceWork.

manufactured using the ConsiGma™ platform. Meet GEA at: Pharmtech Moscow, 20–23 November 2018, Pavilion 2, B405. CPhI/P-MEC India, Delhi, 12–14 December 2018, Stand 10.A15.

5 HEAD OFFICE Carlton House, Sandpiper Way, Chester Business Park, Chester, CH4 9QE.

A PERSONAL TOUCH he pharmaceuticals industry is T going to be around for a while. But whilst the industry might be

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indomitable, the need for change - a symptom of worldwide health pressures such as ageing populations and chronic health conditions - is ever present.

EDITORIAL editor reece armstrong reece.armstrong@rapidnews.com

Take for example, the developments being made towards personalised medicine; medicines of which could change the very nature of how we treat disease. Scientists across the world have already shown that by analysing a person’s genome, we can better identify the types of diseases that can occur and be treated.

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

PRODUCTION haed of studio and production sam hamlyn design robert wood

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

SUBSCRIPTIONS subscriptions@rapidnews.com qualifying readers Europe - Free, ROW - £249 outside qualifying criteria UK - FREE, ROW - £249 please subscribe online at www.epmmagazine.com Address changes should be emailed to subscriptions@rapidnews.com European Pharmaceutical Manufacturer is published by Rapid Life Sciences Ltd. European Pharmaceutical Manufacturer is distributed in electronic and print formats to a combined readership of 14,000 pharmaceutical manufacturing professionals. Volume 18 Issue 7 © October 2018

While every attempt has been made to ensure that the information contained within European Pharmaceutical Manufacturer is accurate, the publisher accepts no liability for information published in error, or for views expressed. All rights for European Pharmaceutical Manufacturer are reserved and reproduction in part or whole without written permission is strictly prohibited.

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With healthcare needs changing around the world, is it time for manufacturers to change their approaches to the way drugs are developed?

Indeed, here in the UK, health secretary Matt Hancock recently announced plans to extend the NHS’ 100,000 Genome Project to sequence one million genomes over the next five years. Hancock’s plans show clear ambitions towards bringing personalised medicines to the NHS and hopefully it can achieve the target: as it stands, the project only recently hit the 85,000 mark. As the healthcare industry charges towards these new ways of treating disease, so too must manufacturers change aspects of their supply chain.

EDITOR’S DESK Historically, traditional batch processes have been used to manufacture large quantities of drugs but this “one-size-fits-all” approach cannot be applied to personalised medicines. Everything from harvesting and transporting patient cells to a manufacturing plant; ensuring an aseptic manufacturing process, freezing the batch, and of course transport, are critical steps to ensure the viability of the therapy.

That last factor might just be the most pertinent when we consider the variables that need to be put in place if personalised therapies are to reach patients. The shipping process, during which the stability of the product travels to a lab or a hospital is critical. This is where new concepts and approaches to manufacturing start to become vitally important if the industry is to change to the needs of health populations. One such approach decentralised manufacturing - is being used to manufacture products that are in demand at a specific region. For pharmaceuticals, this could mean that if a patient requires a form of personalised medication, a manufacturing site situated closer to that particular hospital could produce it, reducing both transport time and any possibilities of contamination. Now, researchers at the Massachusetts Industry Technology (MIT) have taken the idea of decentralised manufacturing and have applied it to biopharmaceuticals.1 The team has developed a compact manufacturing system, which as well being able to produce three different biopharmaceuticals, could also potentially produce personalised medicines. The system, which can easily switch between producing different drugs, could enable a point-of-care approach from manufacturers to develop therapies for rare diseases and precision medicine. As it stands, such therapies are only needed in limited quantities, meaning manufacturers cannot dedicate production sites to such small quantities of drugs. Throughout all this forward movement, one thing I hope doesn’t change is my position as European Pharmaceutical Manufacturer’s new editor. For the last couple of years, I’ve immersed myself in the life sciences industry and I’m pleased to take the lead on this exciting publication. REFERENCE: 1. http://news.mit.edu/2018/manufacture-smallbatches-biopharmaceuticals-demand-1001

A small dose

ICE TO SEE YOU:

Freeze drying at CPhI

ealthcare giant Bayer has announced the six startups to be included in its Grants4Apps accelerator programme this year.

urine to offer health insights, and a platform that can be used to compile data to bring about new health information.

Young companies from Canada, Germany, Israel, Spain, the UK and the US came out on top of more than 1,800 competitors from 100 countries. Now, with the expertise and investment from Bayer, the companies have 100 days to develop their products. The start-ups have been given offices in Berlin, along with access to pharmaceutical executives, industry executives and €50,000 in funding.

Winning start-up Cyclica has developed a cloudbased platform that uses artificial intelligence (AI) and biophysics to accelerate drug development.

The six start-ups are developing digital solutions that cover the entire value chain within healthcare. The winning companies have developed a range of solutions, including a combined VR and wearable platform for stroke rehabilitation; a personalised health programme; a smart device that analyses

The Grants4Apps programme was launched in 2013 as a way to help digital healthcare start-ups grow and bring their products to market. According to Bayer, the company is now seeking digital products that can be applied across the pharmaceutical value chain to help detect diseases at an earlier stage and develop medicines faster with more benefits to patients. “Digital solutions are essential to driving innovation in an evolving healthcare environment,” said Dieter Weinand, member of the board of management of

Bayer AG and head of the Pharmaceuticals Division. “In this endeavour, we benefit immensely from collaborations and the exchange of knowledge and skills with innovative start-ups.” The cooperation with start-ups comes from a company-wide transformation plan called “Advancing Digital” which sees Bayer fostering new solutions in healthcare. Eugene Borukhovich, head of the Grants4Apps programme said: “It’s incredible to see the tremendous impact that some of our startups have had in the industry. I’m impressed to see the maturity and significance of their innovative solutions. Through the Accelerator program, I’m convinced we will be able to make a significant contribution to truly change the experience of health as we know it. We will continue to put people at the centre of their health and care every single day.”

ne of the most exciting announcements at CPhI this year came from life sciences group Telstar, who has developed a method to effectively start nucleation during the freeze-drying process. The company introduced its vacuum-induced nucleation system Telstar Lyonuc - at the show to demonstrate the advances it has made. The new solution comes from the back of years of research, with Telstar’s innovation department developing the method to enable the pharmaceutical industry to run the freeze-drying process of product batches more efficiently. Telstar Lyonuc works by controlling the

temperature and pressure of a solution to induce the start of the freezing phase without modifying its main elements or adding gases or external substances. It does this by producing a change in the solid structure of the solution to standardise the moment when freezing starts. This causes all vials to nucleate at the same time and within a few seconds - a much shorter length compared to the 30-45 minutes the spontaneous nucleation process can last. Telstar’s newest system can be adapted to any type of freeze-dryer as it only requires measuring and controlling the temperature, vacuum and time parameters and it uses the actual tools of a freeze-drying prescription.

The UK’s EPI-demic

atients with severe allergies in the UK are being told to use EpiPens four months after their expiration date, due to a shortage of the devices.

and its contract manufacturer Meridian Medical Technologies, a Pfizer company, has caused global shortages of 0.3mg EpiPens.

A manufacturing delay in the US between device maker Mylan

Now, the Medicines and Healthcare Products Agency

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Evonik targets advanced manufacturing

lobal CMO Evonik has completed a €36 million expansion of advanced technologies to help boost its manufacturing capabilities across the US and Europe. Advanced technologies, such as high-potency API, fermentation and continuous processing have been introduced by

Evonik at a number of its sites over the past year. Dr Jean-Luc Herbeaux, SVP and head of the Evonik Health Care business line said: “Evonik will continue to be a leader in advanced technologies that make the industrialisation and commercialisation of these highly specialised products possible.”

(MHRA) has agreed to a request by Mylan to extend the use of specific batches of 0.3mg auto-injectors by four months.

four-month extension does not apply to the EpiPen Jr 0.15mg device intended for them.

Supplies of EpiPens are anticipated to stabilise towards the end of the year, according to Pfizer. Until then, Mylan is hoping that the extension will “temporarily address” the shortage situation. Children weighing between 7.5kg-25kg are at a particular risk, as the

“We appreciate how important it is for individuals with lifethreatening allergies to have access to adrenaline auto-injectors and understand the challenges this situation continues to pose for patients. We will continue to proactively and diligently update pharmacies, healthcare professionals

well as a pilot plant for the custom synthesis of highly pure PEGs (polyethylene glycol) and methoxypoly (ethylene glycol) for pharmaceutical applications. In Slovakia, Evonik has invested in a flexible pilot plant for downstream processing, making it the sixth plant in a worldwide network to support microbial fermentation projects from strain development through to commercial The technologies manufacturing. have been introduced in an effort to help Evonik has also Evonik customers bring increased its asset specialised molecules to footprint and has added market using advanced manufacturing processes. additional capabilities to support the production of highly potent For instance, Evonik has active pharmaceutical recently commissioned ingredients (HPAPI). a new modular cGMP The new additions, continuous processing which have been put plant at its facility in in place at its Hanau Hanau, Germany, as and patient advocacy groups across the country regarding any changes in stock availability,” Mylan said in a statement. The two alternative auto-injectors in the UK – Jext and Emerage – have also been rapidly depleted according to the Pharmaceutical Services Negotiating Committee. Guidance for allergy sufferers has been issued by charity group, Anaphylaxis Campaign,

which states sufferers should continue to follow their "usual risk management techniques" and avoid allergen to reduce the likelihood of a severe allergic reaction.

facility, alongside a plant in Tippecanoe US, enable Evonik to run several HPAPI projects in parallel. Dr Andreas Meudt, VP and head of exclusive synthesis at Evonik said: “Advanced technologies will continue to be deployed across our global network in response to emerging customer needs. In parallel, our commitment to quality and regulatory excellence will continue to drive all business activities.”

A small dose

What’s On Offer At This Year’s Lab Innovations L

NOVARTIS MANUFACTURING STRATEGY CAUSES JOB CUTS

ealthcare group Novartis will cut 2,000 jobs around the world in response to a changing product portfolio, the company has announced. In the UK, Novartis will cut 400 jobs at its Grimsby manufacturing plant with plans to fully exit the site by 2020. Changes to the company’s product portfolio, with fewer highvolume products and an increased focus on personalised medicines are the reasons the company has given for the job cuts. Haseeb Ahmad, Novartis UK country president, said: “Novartis has been a part of the Grimsby community for many years so this has been

a very difficult decision. The Grimsby site is an effective, well-running operation that is testament to the hardworking and dedicated employees. We will treat every employee with the utmost respect, sensitivity and fairness during this difficult time.” The plan, which Novartis has stated isn’t related to Brexit, will be a phased process lasting until 2020. During this period, the company will consider options such as divestment to enable the facility to potentially remain open. Novartis will work alongside its staff to support them through the cuts and will offer enhanced severance packages and outplacement services, if the facility is closed.

More so, in Switzerland where Novartis is based - more than 1,500 jobs will be cut across four sites by 2022. The majority of the cuts will be at its Basel campus, with a reduction of 700 employees planned during the four-year period. Commenting on the job cuts, Novartis CEO Vas Narasimhan said: “We are aware of the impact of today's announcement on potentially affected employees and their families. Although it is planned to spread the planned changes over four years, we wanted to communicate them as soon as possible and in a transparent way. We will do everything possible to help our employees who are likely to be affected to overcome this difficult transition.”

ab Innovations returns to the NEC, Birmingham, on 31 October & 1 November 2018, where alongside scientific innovation, sustainability will be at its heart. With 100s of new products to see, a new zone focusing on cleanroom solutions, and plenty of talks to learn from, there are many reasons to visit the UK’s only lab-dedicated exhibition. As the UK’s largest gathering of laboratory suppliers, Lab Innovations is supported by some of the nation’s top scientific institutions and has grown year on year, according to the show’s organiser. Besides from showcasing products and services Lab Innovations also offers CPD accredited learning and business opportunities, with 98% recommending lab Innovations as a ‘must attend’ event. Latest lab products and services Visitors to the show can see and source new products from a range of

industries including pharmaceutical, life sciences and healthcare. More so, Lab Innovations gives visitors access to the latest product advances and services from a line-up of over 135 leading suppliers. New for 2018 This year the new Cleanroom Pavilion and Hub will enable visitors to discover the latest cleanroom solutions and technologies and talk to the experts in the field. A new ‘Sustainable Laboratory’ area will highlight environmentally-friendly products and case study examples of sustainable initiatives in the lab. Attendees can find out how to make their labs greener and reduce running costs, whilst safeguarding the science. Other new features include the ‘Lab News Village’ - dedicated to new exhibitors not seen at previous shows - and a pavilion for Scientific Laboratory Supplies (SLS), the UK’s largest independent

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A supplier of laboratory equipment, chemicals and consumables. Thoughtprovoking lectures The laboratory industry is constantly evolving with new technologies, regulations and ways of working. The show is set to feature over 35 CPDaccredited sessions in the Royal Society of Chemistry Conference, the Laboratory News ‘Insight & Innovations’ Theatre sponsored by Perkin Elmer, and the Clean Room Hub. The combination of renowned speakers, dynamic sessions, panel discussions, and practical learning on a wide variety of topics and themes, makes both days essential to attend. Keynote speakers in the Royal Society of Chemistry Conference will be scientific, medical and technology broadcaster Maggie Philbin and science presenter Steve Mould. The Insights and Innovations theatre will focus

on science in practice, featuring technology developments and their application in the laboratory with topics such as ‘Sustainability in the modern lab’, ‘Accreditation changes in the lab’, and more. Ideal for new ideas! Commenting on last year’s Lab Innovations, Bethany McNamara, lab analyst at Sainsbury’s, said: “Being from a small lab, our needs are quite niche and specific, so it was great that there was such a vast array of things to see and so many new technologies. It's given us some great ideas.” Stephen Bustin, professor of Molecular Medicine, Anglia Ruskin University added: “I’ve found the content on offer and the range of exhibitors to be of great interest. There has been lots for me to see and take back!”

developer of transdermal drug delivery treatments for pain and central nervous systems diseases has been awarded a Medicines Manufacturing Grant by Innovate UK. Medherant was awarded the £52,000 grant to help it buy equipment and prepare for the manufacture of transdermal patches formulated with TEPI patch technology for clinical trials.

Medherant scoops industry grant

The company’s TEPI patch technology enables manufacturers to produce transdermal patches containing doses of active ingredients. The technology is designed to provide better adhesion and more efficient delivery of drugs through the skin over a longer period. Recently, Medherant put its Ibuprofen TEPI patch through Phase I clinical

development and is expecting the initial results sometime in 2018. The company has also recently installed its own pilot-scale patch manufacturing plant where it has successfully produced non-GMP versions of its Ibuprofen TEPI patch.

SCIENTISTS FIND NEW USE FOR OLD ANTIBIOTIC IN TREATMENT OF MELANOMA

n old antibiotic could be the key to killing off dangerous skin cancer cells, new research shows. Scientists from the University of Edinburgh conducted a study which found that the drug nifuroxazide could complement existing therapies for melanoma. The team, from the Medical Research Council (MRC) Institute for Genetics and Molecular Medicine, tested the drug on melanoma cells within mice which had been implanted with human samples of the disease. Current research on melanoma therapies focuses largely on blocking a type of

enzyme called aldehyde dehydrogenase 1 (ALDH1), which is secreted by many of the more dangerous cells in melanoma tumours. The team from Edinburgh attempted to use nifuroxazide to selectively kill cells producing a high level of ALDH1. Nifuroxazide is activated by the enzyme ALDH1, meaning that it only becomes toxic once it is inside cells producing the enzyme. By using the antibiotic, the researchers were able to effectively kill the tumour cells within the mice, without significant toxicity spreading to other parts of the body.

The team now hopes that the strategy can complement existing melanoma therapies, though they do warn that more research is needed to determine if it will be effective in humans. Dr Nathan Richardson, head of molecular and cellular medicine at the MRC, said: “This imaginative study exploits the sensitivity of some cancer cells to an existing antibiotic and could reveal an exciting new approach to both combination treatment and ‘personalised’ medicine by directly targeting drug resistance - a key priority for the MRC.”

NEWS ANALYSIS

How predictive analytics can boost pharmaceutical manufacturing New technologies are changing the way pharmaceutical supply chains operate. Here, Marc Herlant, Arthur D. Little, discusses how predictive analytics offers pharmaceutical manufacturers new supply chain capabilities.

he pharmaceutical industry has been changing rapidly, with changes to distribution and drug consumption models driven by new business avenues around individualised medicine, combination therapies, drug and device convergence, and other exciting developments. These, combined with advanced data analytics solutions, are making treatment more effective and affordable and less intrusive, while enhancing quality of life. However, with all these positive changes come challenges for the supply chain. So how can organisations manage the increased complexity in the supply chain to make improvements work for patients and caregivers?

ESTABLISHING NEW SUPPLY CHAIN METHODS Supply chain imperatives are evolving, from drug production and delivery that are limited in scope towards a versatile supply chain addressing the needs of multiple stakeholders. The traditional supply chain approach based on materials requirement planning has progressed to its limits. From the patient perspective, the current supply chain creates frustration and complications in individualised treatments, or even fails to offer satisfactory performance with new treatment types. As new treatments become available, new types of supply chains need to be established, with new actors, as well as new technological and logistical systems. Managing these new treatments with traditional supply chain methods is costly and complex, with high risk of non-compliance. Yet,

while creating new challenges in terms of regulatory compliance and scaling, the incorporation of these players also provides opportunities in terms of data collection for predictive analytics. The challenge for companies is to develop new capabilities by identifying useful and necessary initiatives, without putting the ongoing operations at risk by building service models on the basis of correlations that will not be sustainable in the future. The intelligent supply chain, based on predictive analytics and machine learning, is better at demand anticipation (SKU, quantity) and characterisation (localisation, service levels) by identifying and understanding the patterns influencing it, rather than projecting past demand. However, seeing patterns is not sufficient; understanding the “why” behind them is key. IDENTIFYING THE PREDICTIVE VALUE Moving beyond the world of descriptive statistics, which relies mainly on the extrapolation and (often poor) observation of recurring patterns, companies are entering the domain of predictive analytics, which requires deep data analysis to understand causal links. Leveraging those links, predictive analytics will be able to predict potential states. The complexity of such models is to identify and select the links with predictive value. At Arthur D. Little we’ve developed a maturity model to evaluate the current situation and development priorities in the supply chain. This

methodology allows thorough testing and leveraging of existing analytics pilots to outline key causal factors to integrate into the predictive supply chain: 1. Better understand methodologies applied to various pilots, confirm their underlying hypotheses, and identify other available options. 2. Pilot methodologies need to be tested on historical company data, and their results compared to actual history, in order to exclude most of the “false positive” methodologies and identify repeated correlations. Those methodologies should be tested in an exhaustive, systematic and automated manner. 3. At this step, the correlations have proved to be resilient over time; hence, causality can be assumed, but is not yet proven. A qualitative assessment of the repeated correlations is the best way to identify meaningful and useful causality links. 4. Ultimately, the stability of the methodology is pressure-tested, applying “derived laws” in Step 3 against all possible future scenarios to evaluate maximum variability and their implications. CONCLUSION In spite of being a nascent technology, predictive analytics is a top priority for healthcare supply chain executives. Companies need to reflect on how to minimise risks linked to predictive analytics initiatives. Combining the above model with analytical methodology provides a concrete starting point for leaders who want to develop new capabilities in the supply chain.

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ANALYSIS

Do you know the benefits of contract packaging services? Dale Pittock, Valley Northern, looks at the benefits of using contract packaging services across the pharmaceutical manufacturing sector.

istorically, all elements of a production cycle were managed by a single organisation, from prototype testing right through to order fulfilment. However, with production costs increasing and profit margins becoming tighter, many companies look to outsource some areas of the process. Manufacturing plants are constantly changing to meet the varying pressures within the industry. For the healthcare sector, these challenges are multiplied by the additional regulations and standards, such as the Falsified Medicines Directive (FMD), that a plant must meet to ensure safety and sterility. NEW TECHNOLOGIES Smart manufacturing - the increased connectivity between equipment within and across a plant - is a growing trend; enabling plant managers to harness the power of data and use analytics to better run a manufacturing line or whole facility. Smart plants can be more energy efficient and produce higher quality more consistent products. Despite these benefits, installing and configuring new systems can be costly and time intensive. Most manufacturers are choosing to undertake these improvements gradually to spread costs while reaping the benefits. Using a contract packager is one way to take advantage of smart factory benefits, including reliability and lower costs per unit, without incurring these increased, up front, charges.

Contract packagers rely on suppliers of not only pharmaceutical drugs and medical devices but also pharmacy packaging providers. These three parties must work closely together to avoid costly downtime and ensure crucial medication is available. COUNTERFEIT Similarly, the threat of counterfeit medication is a major challenge to the pharmaceutical industry. The European Commission is countering this threat with the updated Falsified Medicines Directive (FMD), the final phase of which will come into effect in February 2019. The FMD requires a system to track and record legitimate products throughout the supply chain. This data can be used to serialise each pack with an individual, random number that can be authenticated before shipping. While this tightened regulation is wonderful for patient safety, it does pose challenges to pharmaceutical manufacturers. Thereâ&#x20AC;&#x2122;s an additional phase to add to the packaging process, which will necessitate changes to production lines alongside the dramatically increased data management burden. Each of these changes will require an investment, from sensors that can also be used to collect data for analysis, to upgraded IT functionality to meet the data capture and sharing requirements of FMD. For an individual manufacturer, this could pose a massive capital investment. However, if they choose to outsource to a specialised

contractor who is already set up with a smart factory and local and cloud networks, they could be spared this particular financial hit. INNOVATIVE FORMATS Since the days of tinted glass bottles to signify medicine or poison, pharmaceutical packaging has been designed for safety and cleanliness. Technological developments over the years have led to a wealth of changes, both in terms of packaging and in the pharmaceuticals contained within. In recent years, medical technology has made some amazing advances. Weâ&#x20AC;&#x2122;ve seen the development of several new drug delivery methods that are of great benefit to patients, such as auto-administered biologicals and oral thin-film dissolvable medication. Each new type of drug developed has new packaging, labelling, storage and shipping demands. These demands are perhaps best met by contract packagers, who are able to invest in the technology required to safely manufacture and meet these demands. Pharmaceutical manufacturers face a range of challenges each day, from keeping up with manufacturing trends to ensuring they are operating in the most efficient way. Outsourcing to contract packers means manufacturers can benefit from a range of expertise and technology to meet customer demands, whilst also ensuring the best value end user experience without compromising safety or traceability.

Opinion

Robotic process automation, machine learning and AI technologies offer a means to complete many routine tasks more swiftly, accurately and intelligently.

W HY P HA R M A I S FA I L I N G W HEN IT C OM E S TO R& D For all the effort and investment drugs companies have put into improving business agility, the gap between vision and reality is glaring. This could be because companies have yet to transform R&D decision-making, says James Man, Kinapse. Attempts to improve R&D agility in life sciences have not had the desired results to date, a likely result of the convoluted way companies reach portfolio decisions. Real organisational agility and improved market responsiveness means being smarter about the programmes companies take on. This comes down to their ability to prioritise according to the criteria that matter most â&#x20AC;&#x201C; for example, what the market actually wants (and will continue to demand in future). Yet, too often, effective decision-making is thwarted by restrictive governance structures, functional silos and a lack of 360-degree insight at key investment points. STRATEGIC ALIGNMENT Fragmented decision-making, divided across different teams and governance processes, leads to protracted rounds of approvals and a loss of perspective. The first step should be to bring down such barriers and bring decision-makers across R&D into closer alignment. Having a clear framework and criteria for decision-making will help to keep everyone and everything moving in the same direction towards known goals.

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Simplicity is key, for example having a single approvals and review processes per therapeutic area, then an overarching governing body. This will create a clearer line of sight, so leaders will be better able to see the competing priorities of the R&D programmes and agree on trade-offs. In time, it may be possible to perform project portfolio reviews as a continuous, in-stream activity. BROADER DATA ACCESS Increased observational research and capturing real-world evidence from the growing range of external sources, including online patient communities and scientific literature, are among the possible strategies for making the patient perspective central to all decision-making. There may be some challenges in keeping the right data flowing into the decision process – such as access to external data for certain populations. Even harnessing internal data can throw up hurdles, needing to be drawn and collated from different sources, and combined and compared in reliable and meaningful ways to support confident decision-making. But appropriate technology and process automation can help with this. Agility in decision-making should continue right across the product lifecycle, too, to ensure that medicines continue to be of value and remain differentiated in the market long after launch, and that R&D is able to react with speed to changes in market conditions and requirements. BRINGING PROCESS EFFICIENCIES & QUALITY PRIORITIES IN LINE Agility in strategic decision-making must be matched by operational agility if companies are to get products to market quickly, efficiently and reliably.

Robotic process automation, machine learning and AI technologies offer a means to complete many routine tasks more swiftly, accurately and intelligently, accelerating routine processes – as long as plans for using these tools and techniques are wellcoordinated. It follows that supply/ service partnerships should be aligned with any plans too. It’s all very well having a strong agenda for change internally, but if this isn’t supported by agile partner processes and innovative solutions, the potential for transformation will be compromised.

15 Last but not least it will be important to review approaches to risk management to ensure these aren’t an unnecessary barrier to agility. One option is to adapt processes and systems so they provide more of a positive support to the business – geared more toward what could be done, rather than what shouldn’t. This may involve giving quality teams more direct input into strategic decision-making, rather than restricting their role to compliance and fine avoidance. Certainly, a willingness to think differently is an important precursor to sustainable agility.

Increased observational research and capturing realworld evidence from the growing range of external sources are among the possible strategies for making the patient perspective central to all decision-making.

COVER STORY

Step it up Jonathan Gaik, director, Natoli Scientific, offers a stepwise approach to pharmaceutical manufacturers looking to optimise their tablet formulation strategy.

ablet formulation development is a stylised process. Each formulator uses their own methodology. Some use the systematic Design of Experiments (DOE) approach, some test one variable at a time, and many use a combination of the two. However, all formulators need a methodology that gives them reliable and useful information to identify problems before tablet manufacturing begins. New formulators can find it difficult to know where to start in the development process. A rigorous and creative stepwise approach will help a formulator identify issues in an active pharmaceutical ingredient (API) that would hinder its processability. Following an approach like the one outlined below can help your formulation become a great product. TESTING THE API The first and most crucial step of developing a formulation is to determine how the API behaves. Some formulators do minimal studies on the API alone or skip this step entirely. However, it’s important to characterise the API so the correct excipients can be identified based on the API’s behavior. The four main API features to examine are: • Compatibility • Physical characteristics • Compactibility • Flowability The best place to start when characterising an API is with

compatibility and physical characteristics. These studies are the most time-consuming and can be run concurrently. Compatibility studies usually run from one to four weeks. In this step, a formulator is evaluating the API and how it interacts with standard excipients or excipients that are necessary to adhere to the target product profile (TPP). For example, if the TPP calls for an extendedrelease profile, the API needs to be tested for compatibility with controlled-release polymers. Compatibility studies are usually conducted as a binary mixture of the API with each excipient to determine whether any of the materials are incompatible with the API. Compatibility studies also should include the neat API powder as a control. This will give the formulator information on the mechanism of degradation and which storage conditions are appropriate. For example, a neat API that is stored at elevated stress conditions (40°C/75% relative humidity) can be a complex endeavor because accelerated conditions usually don’t reflect what happens in real time. Are accelerated conditions yielding acceptable data? Conducting morphology, crystallinity, and particle size studies in addition to compactibility and flowability is strongly recommended to determine physical characteristics. Understanding the effects of irregularly shaped particles and highly ordered crystalline structures will help determine

whether a granulation step is needed to improve flow or the solubility of the API. Compactibility studies are best conducted on an instrumented single-station press. Using a singlestation press, or a rotary press that can operate in single-station mode allows the formulator to conduct strain rate and dwell time studies to understand consolidation of the API. For example, if an API is highly compactible, the formulator knows they can use significantly less binder. Flowability studies can be as simple as putting the API into a glass vial and watching how it flows. Establishing the angle of repose, Carr index, and Hausner ratio are other easy tests. Another simple test is evaluation on a Flodex or another flow-throughorifice apparatus. Other flowability studies are more analytical and involve instrumentation such as a powder flow rheometer. These instruments help the formulator understand the angle of internal friction and wall friction based on material of construction. In assessing flowability, the formulator is looking for how well the powder flows as well as other problematic characteristics such as tendency to bridge, rathole, or agglomerate. There’s rigorous debate among formulators about whether determining the characteristics of an API is necessary. However, understanding the material properties of the API alone will determine which excipients

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and processes are needed to overcome significant deficiencies of the API or to achieve the TPP. Testing the API provides a starting point before evaluating its interactions with other materials.

process. Many formulators spend a lot of time troubleshooting later in the development process. Troubleshooting is reactive, with the formulator responding to an issue he hadn’t anticipated.

ADDING THE EXCIPIENTS AND PROCESS SELECTION After the API has been evaluated the formulator can add excipients to develop the formulation. Any excipient added should be in service to the API or the TPP. In other words, the data gathered while testing the API should inform the decision on which excipients and at what concentration to start the formulation development. Each excipient should be chosen to overcome the issues identified when testing the API or to achieve the TPP.

A stepwise approach, on the other hand, allows you to be proactive. For example, if compatibility studies are not completed, you might find a prototype formulation is not stable over a three to six-month stability study. Troubleshooting the issue will lead to many questions: What is causing the instability? Which excipient or combination of excipients is the culprit? Could the issue be the API in a specific storage condition? A proactive approach earlier in R&D will give you the best chance to succeed.

Using a less organised approach can lead to wasted time and money as a formulator tries to determine where in the process the formulation began to experience problems. The data generated by a stepwise approach is crucial to pinpointing where problems began, saving valuable resources and accelerating product development.

In this phase of development, it’s important for the formulator to have more than one formulation to evaluate. There’s a good chance a formulation will fail at some stage, so having more than one available for testing means not having to go back to the beginning of the process. Tests during this phase should include evaluating a blending process, blending order of addition, granulation method if needed, and the tableting process. Once the formulator has prototype formulations and processes, they should start short-term stability studies that last no longer than three to six months. This is the stage in which to gauge process development and identify tablet defects like sticking and picking or coating issues like tablet chipping. All the tests help set parameters for scalability and increase the odds of the formulation succeeding in clinical batch manufacturing, validation, and commercial-scale production. TROUBLESHOOTING IS REACTIVE – BE PROACTIVE Formulation development is an iterative and often frustrating

A rigorous and creative stepwise approach will help a formulator identify issues in an active pharmaceutical ingredient (API) that would hinder its processability.

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DATA INTEGRITY IN GXP ENVIRONMENTAL MONITORING BEYOND BYTES AND SIGNATURES

This online tutorial will focus on how to maintain data integrity in environmental monitoring software used in GxP-regulated operations. Along with best practices for managing your data, it will provide an upto-date overview of the current regulatory expectations for practices that ensure data integrity.

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PAUL DANIEL | Senior Regulatory Expert Vaisala Paul Daniel has worked in the GMP-regulated industries for over 20 years helping manufacturers apply good manufacturing practices in a wide range of qualification projects. Daniel’s specialties include mapping, monitoring, and computerised systems.

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JANICE BENNETT-LIVINGSTON | Marketing Manager Vaisala Janice Bennett-Livingston is the global life science marketing manager for Vaisala’s industrial measurements business area.

• Review recent guidance and documents • Learn how to evaluate data integrity risks • Discuss common pitfalls of data management in GxP applications • Review best practices for ensuring and preserving data integrity

Observations for a better world. At Vaisala, we enhance safety, efficiency and decision making through environmental and industrial measurement, and related services. Our products and services provide our customers with the means to influence and better understand their environment.

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REECE ARMSTRONG | Editor EPM Magazine Graduating with an MA in Journalism from Newcastle University in 2016, Reece has immersed himself in the life sciences world, tackling a range of topics from digital health and robotics to medical device scandals. Now as editor for EPM Magazine, Reece is looking forward to serving the sector to provide thought-provoking content for the community.

European Pharmaceutical Manufacturer is a highly regarded brand covering the pharmaceutical manufacturing supply chain from conception to production, keeping readers informed of the latest news, opinions, developments and breakthroughs in this innovative and technologically advanced sector.

DRUG DELIVERY

Breathe it in Pressurised metered dose inhalers (pMDIs) are essential medical devices for patients with asthma and COPD, but there is growing concern about the carbon footprint these treatments place on the environment. Dr David Lewis, director of Aerosol Research, Chiesi, assesses the situation.

ressurised metered dose inhalers (pMDIs) have long been the major treatment of choice for treating asthma and chronic obstructive pulmonary disease (COPD), but the effect of pMDI propellants on the environment is the subject of ongoing governmental and industrial debate. The ban of chlorofluorocarbons (CFCs) in 1996 due to the substance’s role in the depletion of the ozone layer led to the redesign of pMDIs and the development of hydrofluoroalkane (HFA) as a new propellant. Now, however, there is building evidence that HFAs, namely the widely-used HFA134a, have high global warming potential, and are being targeted for regulatory reform. There is an argument that dry powder inhalers (DPIs) may be a suitable replacement for pMDIs, due to their clinical equivalency, but the fact that not all patients are able to use DPIs and the cost implications make this a complex issue and one that needs careful review of the facts and evidence. Patient preference is another key factor in choosing the appropriate technology for treatment. Compliance with medication is an ongoing issue and if patient choice is removed, there is a risk that adherence to prescriptions could drop.

PMDIS AND DPIS – WHAT’S THE DIFFERENCE? The inhalation technology behind pMDIs and DPIs differ in a number of ways, including how the drug dose is delivered, the inhalation procedure, and the way the active pharmaceutical ingredient (API) is contained within the formulation. In a DPI, the API is formulated in a dry powder blend and, in contrast to pMDIs, requires energy from the patient’s inhalation maneuverer to draw a pre-metered dose into the lung. pMDI formulations contain a propellant, the most common being HFA-134a and HFA-227ea, which provides the energy needed to atomise the formulation and deliver the API. The advantage of using a DPI is that drug delivery is automatically coordinated with the patient breathing in, whereas the actuation of a pMDI (not fitted with a breath actuation mechanism) must be coordinated with inhalation – an action which some patient groups find challenging. Breath actuated mechanisms are available for pMDIs, but they are not required by regulation. However, a major disadvantage of DPIs is that they require the patient to breathe deeply and forcefully to effectively deliver the dose. Different patient groups, such as geriatrics and paediatrics and those with significantly compromised lung

function (for example COPD, lung cancer and emphysema patients) have variable breathing profiles, potentially resulting in limited aerosolisation of the formulation and therefore compromising effective drug delivery. COST IMPLICATIONS OF DIFFERENT DEVICES It is important for the government to consider the cost implications when assessing the regulations behind HFA use. Determining the relative costs of pMDIs and DPIs depends on a number of factors, such as device complexity, formulation, and number of doses per device. For example, pMDIs are cheaper devices, and provide between 100-200 doses per device, whereas DPIs have approximately 30-60 doses. Therefore, the approximate price per dose of DPIs is 40% higher than pMDIs1. If, due to their effect on the environment, the removal of pMDIs was mandated in regulation, the cost implications for the NHS could be significant.

DRUG DELIVERY

INNOVATE AROUND REGULATION pMDIs and DPIs are both associated with relative environmental impacts, and the emissions are attributed to different stages of each device’s life cycle. For example, a Product Carbon Footprint Certification Summary Report conducted by the Carbon Trust on behalf of GlaxoSmithKline (GSK)2, showed that the majority of CO2 emissions from DPIs are derived from the production of the plastic device and the APIs Fluticasone Propionate (FP) and Salmeterol Xinafoate (SX). The primary contributing factors of pMDI emissions are from actual use, and end of life when the product is disposed of.

REFERENCES: 1 Minister questioned on UK progress on reducing F-Gas emissions, Environmental Audit Committee, 12th December 2017 https:// www.parliament.uk/ business/committees/ committees-a-z/commonsselect/environmental-auditcommittee/news-parliament2017/f-gas-evidence3-17-19/ 2 GlaxoSmithKline Product Carbon Footprint Certification Summary Report, Carbon Trust, 2014. 3 Jeswani, H. and Azapagic, A. (2017) Environmental Assessment of Metered Dose Inhaler Propellant: Potential for a Reduced Carbon Footprint Alternative, Respiratory Drug Delivery Europe Abstract. 4 Corr, S. and Noakes, T. (2017) Pressurised Metered Dose Inhaler Propellants: Going Forward, Respiratory Drug Delivery Europe Abstract.

The position of companies such as GSK, as well as the government, is to try to reduce the UK’s dependency on pMDIs. However, some companies are looking for ways to reduce the global warming potential of pMDIs, whilst still ensuring this treatment is available to the patient groups that rely upon it. For example, Mexichem is a company that develops propellants for pMDIs, and is at the forefront of innovation. In order to meet the requirements of pharmaceutical and environmental regulation, Mexichem is investigating the medical potential of 1,1-difluoroethane (HFA-152a), a propellant already used in consumer aerosols. The company claims that by making the switch, the carbon footprint of pMDIs could be reduced to similar to that of DPIs, which is 12 times lower than the emissions from HFA-134a3 (figure 1). Initial studies have shown that HFA-152a has promising emitted dose efficiency and suspension stability, and the propellant could even enhance the stability of certain APIs4.

Carbon Footprint (kg CO2 eq./100 doses) 25 20 15 10 5 0

HFA-134a inhaler

HFA-152a inhaler

DPI

FIGURE 1 The carbon footprint of MDI devices with HFC-134a and HFC-152a, and a DPI.

Moving forward with MDIs The need to reconsider the propellants used in pMDIs is evident. As with the phasing out of CFCs, the regulatory pressure for the phase-down of HFAs has already begun with some force. However, it has been recognised that it is not yet economically or technically reasonable to entirely replace HFA-propelled pMDIs. The design of both pMDIs and DPIs should be the subject of ongoing innovation and, although a new takeover technology can take a number of years to refine, the industry should be investing in the development of the latest, most sustainable solution at pace.

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Taking the right route Transdermal drug delivery systems have brought about a change in the way medication is delivered to patients, and are now becoming one of the most popular forms of delivery. Here, Medherantâ&#x20AC;&#x2122;s Sukhy Nandra, Vasiliki Nikolaou and David Haddleton discuss the benefits and limitations of this technology. THE TRANSDERMAL ROUTE The efficacy of a medicine is highly dependent on drug delivery, the capacity of the drug to reach its target in the patient. Most active pharmaceutical ingredients (APIs) are delivered via the oral or parenteral routes, oral being the most popular. However, many drugs fail to progress as effective delivery is limited or not possible. To overcome this problem, transdermal drug delivery is a rapidly developing area and is becoming increasingly popular. Delivery of the drug through the skin can be used to alleviate local pain, treat a disease via systemic delivery or even detect an illness as wearable diagnostics become more common. These systems can improve therapeutic efficacy and safety as the drug is delivered through the skin at a predetermined and controlled rate. The drug is absorbed via the skin and enters the circulatory system. Among the various types of transdermal delivery, transdermal patches dominate the market and have now become a proven technology to deliver a specific dose of medication directly into the bloodstream.

All patches are made up of the following key components; a backing liner, a release liner, the adhesive and, most importantly, the drug itself. Depending on the nature of the drug, different types of patches can be used. The two main types are reservoir patches which utilise a membrane to hold the drug in a reservoir and allow gradual release, and drug-inadhesive patches which contain the drug dissolved in the adhesive. Polymer selection and design are the most important factors in determining the success of a transdermal patch. The overall performance of the system depends on efficient skin adhesion as a detached patch surface will reduce the amount of drug permeating the skin, compromising the efficacy of the therapy. Nevertheless, some of the currently available transdermal patches utilise adhesive matrices that do not provide sufficient adhesion to all body parts or under specific circumstances (e.g. while bathing), are painful to remove and can leave a residue of adhesive on the skin. The development of novel adhesive matrices therefore requires further scientific research.

The skin has been exploited as a drug delivery route for many years, whether this involved using homemade ointments or more recently, transdermal patches. The first product to reach the market was a Scopolamine patch in 1979, used to treat motion sickness.

COMPARING TRANSDERMAL PATCHES TO ALTERNATIVE MEDICATIONS With transdermal medicated patches, drug release can be controlled by the use of excipients and a rate limiting membrane. This introduces a control over

release rate that is not possible with oral drugs. These systems also remove the need to constantly readminister the drug, which is very useful for people suffering from conditions that inhibit memory or those with busy schedules. In case of an emergency such as a change in condition or an allergic reaction, a drug may need to be removed immediately, something that is easy to do with a transdermal patch. With oral drugs, digestion can break down the drug before it is released into the system and can exert its effect. There are several drawbacks to this. Firstly, the digestive tract is susceptible to damage over extended periods of use with drugs such as ibuprofen. This can induce stomach ulcers and intestinal lining damage. It is also an issue for people who already take several oral drugs, as gastric reflux issues are a common issue. Secondly, a substantial amount of the drug can be digested, meaning that only a small amount is actually available to carry out its function (bioavailability). Transdermal patches allow the drug to be kept localised at the site of administration or become systemic, depending on the nature of the drug. Patches are also less invasive than intravenous injections, allowing better patient compliance and comfort. RECENT ADVANCES The advent of transdermal drug delivery systems has unlocked a new area of research with large potential and which is progressing

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quickly. Despite the remarkable advances made so far, there are still hurdles to overcome including biological barriers, elimination of initial burst release and formulation of poorly water-soluble drugs to include more drug classes. One area of innovation has therefore been to improve the adhesive formulations used in patches. Many polymers are routinely employed as the adhesive matrix including polyacrylates, polyurethanes and silicone-based polymers. Among the different adhesive formulations, hot-melt pressure sensitive adhesives (HMPSAs) are of interest due to their low irritation and good adhesion. Moreover, they are solvent-free systems and they can be formulated to contain little or no chemical functionality, reducing the possibility of interactions with the active ingredients. Medherant

has developed a user-friendly transdermal technology platform based on a novel pressure sensitive adhesive. This platform enables a high payload of various active ingredients while maintaining good adhesion. Weâ&#x20AC;&#x2122;re currently performing clinical trials of the company's first ibuprofen patch (TEPI) which is estimated to be on the market by 2020. The invention of transdermal drug delivery systems initiated a revolution in the world of drug delivery, offering several advantages over traditional routes. However, the potential of these systems is not yet fully realised, and more research needs to be done in order to achieve the technological advancements that will lead to enhanced disease prevention, diagnosis, control and improvement in health for patients worldwide.

The advent of transdermal drug delivery systems has unlocked a new area of research with large potential and which is progressing quickly.

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DRUG DELIVERY

CONNECTING THE DOTS With the cost of chronic diseases continuing to spiral and patients commonly failing to comply with medication, Chris Evans, West Pharmaceutical Services, explains why connected health could be the answer.

REFERENCES 1. http://www.who.int/chp/ knowledge/publications/ adherence_Section1.pdf

Chronic diseases and conditions continue to be among the most common, and costly, of all health problems. Research indicates that a patient’s medication adherence is directly linked to favorable treatment outcomes for those managing chronic conditions. Yet patient compliance with chronic medication therapies is remarkably low – the World Health Organization estimates it at 50% internationally.1 Non-compliance can lead to poor clinical outcomes, increased costs for many healthcare financial stakeholders, including patients themselves, and lost revenue for pharmaceutical companies worldwide.

One way to achieve this is by integrating the self-administration process with technologies patients use in their everyday lives: smart devices. Applying connected health in chronic disease management can certainly help. This could include incorporating apps and other systems that add positivity and leverage game dynamics, into treatment regimens with integrated drug delivery. When combined appropriately in a holistic platform, these elements can give patients new motivation to help care for themselves, while offering providers and payers data to better monitor patient compliance and outcomes.

To help address the ongoing issue of compliance, the industry is undergoing a rapid shift toward greater patient centricity, spurring significant advances in injectable drug administration and new thinking around how and where medications are delivered. For example, new dosing intervals, along with the growing trend of self-administration at home, are giving patients and healthcare a newfound freedom in self-care.

West’s collaboration with HealthPrize Technologies is designed to help improve and reward medication adherence with technologies in a gamified environment. It’s an example of how connected health can help address potential barriers to adherence for patients tasked with self-administration. Gamification has made inroads in online marketing by applying elements of game playing, but it is showing promise in other sectors as well, including fitness and healthcare, helping patients find new ways to meet the daily challenges of managing diabetes and other chronic conditions.

With this rise of self-administration though, it’s increasingly important for patients to be fully engaged and invested in their treatment regimens. As patients take administration into their own hands, there is greater potential for adherence levels to drop, particularly when they are asymptomatic. Connected health is showing great promise for improving the patient experience, helping to drive greater adherence in these cases.

The West and HealthPrize offering integrates HealthPrize’s Software-as-a-Service (SaaS) medication adherence and patient engagement platform into injectable drug delivery systems with an app and online interface that tracks and rewards patients for taking their medication.

This type of rewards-based patient motivation and engagement can be tied into delivery system training regimens as well, better preparing new patients for that first self-injection. In the first offering from West and HealthPrize, patients will manually scan barcodes or otherwise enter data about their medication compliance into a smartphone/ tablet app, or on an internet browse. In the future, we intend to expand this notion by incorporating universal technology into drug delivery systems to allow customised data collection to address the needs of a therapy and its corresponding patient population and stakeholders. For example, sensor-equipped drug delivery systems or packaging will be able to signal a smartphone to confirm, in real-time, that a particular dose was at the appropriate temperature, the syringe safety system was deployed, all the medication was injected, and other details of use. The shift toward patient centricity is an important step toward improving health outcomes for those managing chronic and other conditions—one that is forcing our industry to go beyond just developing innovative therapies to truly incorporating a patient’s lifestyle into how the drug is delivered. Pharmaceutical companies are addressing this by tapping into the ubiquitous nature of smart devices to provide patients with a more connected and personalised self-administration experience that supports ongoing adherence, rather than hindering it.

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HOW TO SIMULTANEOUSLY IMPROVE MANUFACTURING, INNOVATION AND QUALITY LEVERAGING SYNERGIES WITH AN INTEGRATED SYSTEM

Taking an advanced and comprehensive approach to quality can help improve manufacturing and innovation. Integration and platform technology can help organisations move away from compliancedriven isolated initiatives to a holistic datadriven quality approach. This helps increase operational performance and reduce time-tomarket while reducing compliance efforts and ensuring data integrity. The presentation will discuss the value of this strategy, detail the elements to be included and identify the initiatives that are benefiting most from the synergies of quality, manufacturing and innovation using customer examples.

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DR DANIELA JANSEN | Director Solution Marketing Dassault Systèmes BIOVIA Holding various positions in marketing, sales and business development Jansen has long term expertise in life sciences, laboratory processes and informatics as well as in regulatory compliance, quality and operational excellence. Today Jansen is responsible for the development and communication of the strategic positioning and customer value of BIOVIA’s products and solutions.

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If this is something you would like to know more about, please join us in our webinar to: • Understand the synergies of quality, manufacturing and innovation for sustainable business success • See how using a platform with integrated capabilities can automate processes of operational intersections • Learn how customers have been able to realise tangible benefits through integrated implementations

Dassault Systèmes, the 3DEXPERIENCE company, provides businesses and people with virtual universes to imagine sustainable innovations. Its brand BIOVIA, powered by the 3DEXPERIENCE platform, provides global, collaborative product lifecycle experiences to transform scientific innovation. BIOVIA solutions create an unmatched scientific management environment that can help science-driven companies create and connect biological, chemical, and material innovations to improve the way we live.

DRUG DELIVERY

On point EPM speaks to Kirsty Gapp, 3M Drug Delivery Systems about the challenges and trends within the industry and why interest in microneedle technology is surging.

EPM: With many years’ experience in drug delivery, could you give an overview of available solutions and important factors that must be considered when designing an appropriate delivery system? KG: When designing an appropriate delivery system, it is essential for each system to meet the needs of the patient. Solutions can include inhalation, transdermal and microneedle technologies, all of which have the same goal of delivering efficient, cost-effective and patient-centered solutions. As scientists and engineers begin drafting new designs for drug delivery methods, they are now starting with the patient at the ground level and working their way up. Previously, the patient’s input came later in the research and development process, but that is changing fast.

REFERENCE: 1. Lavorini et al., 2008. Respir. Med. 102(4):593604.

Changes in the marketplace must also be kept in mind when designing a delivery system. For instance, the rapid growth of the global biologics market is greatly influencing the approach to microneedles. In the last 10 years, pharmaceutical and biotech companies have been increasingly focused on the discovery and development of large biologic molecules. This is because of their ability to target previously hard-toaddress diseases like cancer.

However, delivering larger molecules to a patient is much different than delivering smaller molecules. Most biologics cannot be given orally and are instead typically delivered via injection. Many patient groups aren’t used to injecting themselves using the standard needle and syringe, and microneedles offer great potential to bridge that gap. EPM: How do you approach the different patient groups when looking at which delivery system would be best used for each product? KG: Individual patient groups often face their own sets of unique challenges. We work hard to help them overcome those challenges by creating a delivery system that is as user-friendly as possible and that they can have confidence in, and ultimately trust. That is key to ensuring adherence and long-term success. Our approach is really focused on functionality. Within the elderly population, for example, swallowing tablets – often in large numbers - can be difficult, as these patients often take multiple drugs daily. Transdermal drug delivery can provide a solution as they work to deliver a drug over time, often over several days. Because they comfortably adhere to the patient’s

skin, they can improve compliance – and because they can allow the treatment to be continuously delivered over several days, they can eliminate the need to remember, and track, individual doses throughout the course of the day. Transdermal patches can also make it easier for the caregivers of patients battling elderly diseases such as Alzheimer’s disease to ensure compliance, because they can see if the patch is present. Additionally, with some patches, caregivers/family members can even write date and time information on the backing for increasingly accurate compliance monitoring. Another example would be designing delivery devices for patients with limited dexterity, where the design of an easy-touse application system for delivery of biologic therapies is important. Hollow microneedle devices can help make administration easier. EPM: Could you provide a rundown of some of the common pitfalls that may be encountered when companies try to decide on which delivery system to use for a drug? KG: One pitfall we often see is an attempt to alter a delivery method after a drug is already far along in

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the development process. It is impossible to overstate the importance of understanding the best route for the specific drug as early on as possible. At 3M, we work together with our partners to help identify the best delivery route in the early stages of development. Microneedle technology is experiencing a surge in interest of late, how exactly can this technology benefit the manufacturer and patient and are there any difficulties with implementing this technology? New technologies can take time to get off the ground and through the regulatory process for the first time. They also often require new manufacturing processes to be developed and scaled up for commercial supply, which can’t be underestimated. However, with the growth of drugs such as therapeutic vaccines, the benefits of intradermal delivery, which can be achieved using microneedle technology, are becoming clearer and garnering a greater willingness for drug developers to move to evaluate this type of technology. Intradermal delivery is challenging to achieve using a traditional needle and syringe. It requires specially trained practitioners and even then, the delivery can be inconsistent. In addition to this, many therapeutic vaccines require higher volumes to be delivered. Intradermal delivery using a needle

3M’s Hollow Microstructured Transdermal System is comprised of small needles designed to be less intimidating to patients

and syringe is generally restricted to 0.1 ml of volumes. For other biologic therapies, coated microneedles offer a distinct difference for patients unaccustomed to frequent injections or patients who are needle phobic. As for manufacturers, coated microneedles have the potential to reduce challenges posed by cold chain logistics. If you consider systems in which the drug is coated on the microneedle patch, these systems can be potentially stable at room temperature. EPM: How important are delivery systems in terms of patient adherence? KG: To help ensure patient adherence, it is extremely important to have a delivery system that addresses the needs of the patient. A 2008 research report showed that up to 94% of patients make mistakes when using their inhalers, and these were the dry powder inhalers that were intended to be easier to use.1 Additionally, up to 60% of patients don’t adhere to their medication. When patients forget to dose themselves or inadvertently use their inhalation devices incorrectly, it doesn’t matter how great the drug is – it will be less effective. For patients faced with regular injections, both needle fatigue and mobility issues can impact

29 compliance. For instance, if a patient must go to a clinic for an injection, but can’t drive, patient adherence will be greatly impacted. Microneedles have the potential to improve adherence because they can be self-administered in the comfort of a patient’s home. EPM: In your opinion, how do you see drug delivery systems evolving over the next decade? (Are there any important industry trends to keep an eye on etc.) KG: I think the patient-centered approach will continue to grow and be adopted by the industry as a whole. Today, patient empowerment is at the center of the conversation surrounding healthcare and drug delivery technology. I am encouraged by the fact that this mindset is becoming mainstream, because I believe it will result in vastly improved patient care. Empowering patients to take control of their own health, through the use of data and other insights, is a critical piece of the healthcare puzzle that has been missing for way too long. When we can help patients have the information they need to use their medication correctly and use it according to their protocol, it will improve the picture overall for stakeholders – patients, providers and payers.

For patients faced with regular injections, both needle fatigue and mobility issues can impact compliance. For instance, if a patient must go to a clinic for an injection, but can’t drive, patient adherence will be greatly impacted.

LAB AUTOMATION

The future of lab automation Lab automation has come a long way since the days of industrial robots, with new advancements increasing efficiency between systems and workers. Peter Harris, HighRes Biosolution, discusses how far the sector has moved and what the future holds.

he use of automation and robotics in scientific research has been around for quite some time, starting in earnest in the 1950s and progressing from decade to decade since. For many years, it was driven by an increasing focus on highthroughput screening for new small molecule therapies â&#x20AC;&#x201C; an application area that was wellsuited for the robotic technology available during the period from the late 1970s to the early 2000s. During that period, the robots available for use in laboratory integrations were industrial robots, principally produced for manufacturing environments, with high payloads, forces, and requirements for guarding and safety. As such, they were best suited for repetitive, high-volume activities where a large monolithic installation would work. From this historic base and thanks to some important technological advancements, much has evolved in a reasonably short period. Today, the core architecture used in the most advanced lab automation systems looks little like the large monolithic systems of the past. Rather, lab automation has become flexible, modular and mobile, enabling its use in a much broader range of environments and applications. Now, rather than being suited for only the

highest volume and repetitive tasks, automation and robotics are making their way into numerous new scientific research areas, frequently working in conjunction with humans on workflows rather than being separated by substantial safety barriers. Perhaps the most important technological advancement influencing this change is the development of collaborative robots. Unlike industrial robots, collaborative robots are equipped with a combination of sophisticated sensors and internal electromechanical design elements that make them safe to work alongside. Scientists can interact with them in close quarters without any guarding or separation requirements. This elimination of the need to separate people from robots has had sweeping implications on how laboratory automation is configured, and the range of workflows and places it can be deployed. For example, the guarding requirements of an industrial robot almost always require it to exist in a fixed location, surrounded by barriers to protect humans from its motion. With collaborative robots, all guarding can be removed, making it possible to both shrink the overall size of the system, and allow the entire system to be easily reconfigured as needed.

The ability to reconfigure without guarding has created a variety of key changes to the fundamental architecture used in laboratory automation. Today, automation can be done modularly. Using docks and carts (wheeled and mobile elements), systems can be assembled and reconfigured as needed without any additional fixed tooling or reconfiguration costs. For example, systems designed to perform a screening operation can be easily reconfigured with different imagers by simply undocking and docking a mobile cart. Today, the best automation systems can be easily adjusted to operate around user requirements. Extending beyond the use of carts, docks and modular elements, the next major wave of innovation that will likely come in core architectural design will be autonomous mobility. Robots that are safe to work alongside scientists can also be put on mobile bases capable of moving themselves to various locations around a facility to perform different functions. In many ways, the developments that have taken place in the warehouse robotics space by companies such as Locus Robotics, Fetch and 6 River Systems have paved the way for autonomous mobile robotics in a wide range of other industries, including biopharmaceutical

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research. Collaborative robots can be placed onto mobile bases and moved around lab environments without safety issues, opening up a wide new range of potential application areas. In fact, autonomous mobility technology is no longer the barrier to having effective mobile robotic solutions in labs. Rather, the challenge lies in developing the applications for such robots and optimising the central software that controls them. Autonomous mobile robots in labs are not going to be on the scene in the immediate future, but they are closer than you might think. As they start to become available, expect the range of applications and scientific disciplines robots address to grow significantly. It is also important to note some key trends in software, as anyone familiar with deploying laboratory automation solutions will tell you that software is just as, or even more important than hardware in delivering effective solutions. Perhaps the most important current trend in the lab space is cross platform connectivity. Where historically a sophisticated lab would have a variety of isolated software systems such as sample management, automation scheduling and management and data analysis systems, today these platforms are increasingly connected to one another, creating a more holistic environment for the scientist. With the right automation package, it is currently possible to order an experiment from a sample management system, which then communicates directly to the automation system and captures data downstream in a data analysis package, tying the whole process together. This trend of convergence and connectivity is sure to continue, producing powerful efficiency gains and enabling the possibility of closed-loop experiment control and iteration.

Thanks to some key technological innovations, lab automation has come a long way in a reasonably short time. Todayâ&#x20AC;&#x2122;s solutions are a great deal more sophisticated and powerful than those available even five years ago. Perhaps even more exciting is how much seems right around the corner. The next 10 years will almost certainly see another large wave of substantial advancements, rooted in scientists and robots working together, doing what each does best.

Now, rather than being suited for only the highest volume and repetitive tasks, automation and robotics are making their way into numerous new scientific research areas, frequently working in conjunction with humans on workflows rather than being separated by substantial safety barriers.

CLINICAL TRIALS

A WINNING FORMULA Torkel Gren, Recipharm and Anders Millerhovf, CTC Clinical Trial Consultants discuss the steps needed for drug formulation during first-in-human (FIH) trials, if regulatory approval is to be achieved.

ow a candidate drug is formulated for and assessed in first-in-human (FIH) trials are significant factors in determining whether it goes on to win regulatory approval. No drug is approved unless it shows efficacy and a favourable safety profile in a Phase III trial. However, the path to late phase assessment begins when a promising compound is selected for development. Decisions taken during early phase development, when the compound is being prepared for the clinic, have a significant impact on its progression through late phase research. To that end, it is vital that all steps along the early development pathway – from formulation through manufacturing and FIH studies – are carried out in an integrated manner, while the ultimate goal –approval – is kept in mind. THE FORMULA FOR SUCCESS IS … The first step on the pathway to clinic is formulation development. The aim is to choose a dosage form that can be produced to the correct quality specifications, quickly and cost-effectively. In general, simpler forms like oral liquids, powders or capsules are favoured. In formulating a product for FIH a number of factors need to be considered. Of these, bioavailability and stability are of particular interest as they often present challenges.

In terms of stability, FIH formulations do not need a long shelf-life, they only need to be stable for the duration of the study. In contrast, formulations used in late-stage trials do need to demonstrate long term stability. In addition, bioavailability is vital in order to achieve an adequate exposure to the drug. This is just as important irrespective of phase. However, many advanced systems such as nanoparticles may have disadvantages in later stages as they will call for more complex formulations and consequently increase manufacturing cost. In order to achieve satisfactory performance, the formulator may vary composition and processing: Composition – it is critical the best combination of active pharmaceutical ingredient (API) and excipient is used to minimise waste and dosage form size. Usually, excipients used for FIH formulations are selected because they minimise API degradation and ensure the required release profile and stability characteristics. Processing – producing FIH formulations is about balancing rapid, low-cost manufacturing with the need to establish a process that can be scaled-up. For example, when developing a process for an FIH formulation, it is important to ensure that it can be performed in a robust fashion on small batches. The process does not need to be identical in larger scale but it is advantageous if a similar process can be performed in large scale on standard pharmaceutical equipment.

… KEEPING LATE STAGE TRIALS IN MIND When creating an FIH formulation it is important that late stage development is kept in mind. The reality is that most drugs in clinical development fail, including those that show promise in FIH studies. Part of the reason for the high attrition rate is that key performance characteristics - such as solubility and bioavailability that are easily achieved in simple FIH formulations are hard to replicate in the more complex dosage forms suitable for large, late stage trials and launch. It may be that these problems are eventually overcome but with significant delays. To minimise the risk of such problems it is vital that teams involved in the development of FIH formulations work closely and share key data with those involved in creating formulations for later trials. The rationale for this approach is that useful stability and bioavailability data can shape development and production of formulations for later phase trials and - potentially commercialisation. One of the most effective ways of doing this is to work with a contractor experienced in both early and late stage development. Starting with the end goal in mind will allow challenges to be addressed early. Understanding of the parameters that impact drug quality and designing

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strong processes and control strategies will ensure manufacturing is optimised for late stage development. A lot of this can be achieved without delaying the FIH study. CLINICAL TRIAL PLANNING A number of factors need to be considered when planning and executing an FIH study, of which volunteer safety is always the primary concern. There are well established safety protocols for Phase I studies, such as the use of single ascending dose (SAD) cohorts and multiple ascending dose (MAD) cohorts as well as the employment of adaptive protocols. Also, as stated above, use of a formulation that is appropriate to the study is important. For example, if the candidate drug is considered a high-risk, it is preferable for it to be formulated for intravenous administration. A slow intravenous infusion can easily be stopped if serious/severe adverse drug reactions occur. Likewise dose escalation also needs to be considered during manufacturing to fit the planned dose levels in the FIH study and possible adjustments from the initial dose plan between cohorts.

Therefore it is very important that clinical trial teams work closely with those involved in formulation and manufacturing process development. In addition collaboration can help reduce any delays. For example, product development should be started when a quality API is ready, the clinical study should begin as soon as the regulatory approvals are in place and the product is released. GOAL IN MIND It is also crucial to keep in mind that FIH studies are part of an overall clinical development programme. Phase I studies are used to determine a candidate compoundâ&#x20AC;&#x2122;s safety and side effect profile as well as how it is absorbed, metabolised, and excreted. Clearly this information shapes the design of later Phase trials.

The reality is that most drugs in clinical development fail, including those that show promise in FIH studies.

FINAL THOUGHT The pathway from laboratory to FIH studies is important because it is part of a longer journey. Phase I studies are the foundation which support the entire clinical development and regulatory programme and how they are conducted is key.

TECH TALK

PHONING IT IN In this feature of Tech Talk, Dr Neil Polwart, Novarum founder and BBI Group head of mobile discusses how pharmaceutical manufacturers can go digital using only their smartphones.

ne of the simplest mHealth offerings that pharmaceutical manufacturers can implement is an automated drug dose calculator. These feed in simple metrics like height, weight, age and gender to perform relatively straightforward calculations that deliver a dose recommendation. Such tools are very useful to clinicians but could play a valuable role in increasing understanding of patient demographics. They could also enable a more direct communication channel to clinicians –alerting them to a potential product risk or to new data supporting the use of a particular drug in a wider range of applications. True innovation is likely to go beyond simple calculators or trackers to incorporate sensors or hardware devices. This moves the typical pharma company out of its comfort zone and into the domain of “medtech”. Partnership may well be the order of the day – as trying to manage that level of change through a large organisation can often be too difficult. However, before deciding to try and develop partnerships with

hardware providers, it's worth considering if the phone in your pocket already has some or even all the capabilities you might need.

It’s clear to see why a new generation of “digital” stethoscope is emerging and it will be interesting to see how and if they’re adopted.

Take the stethoscope, probably one of the most fundamental tools of clinical diagnosis which has evolved little since the 1940s. There are several stethoscope apps available for download, most for “entertainment purposes only” but some do have clear clinical potential. We may never see the traditional stethoscope being replaced by a smartphone but imagine the advantages of a patient in a remote area being able to send their chest sounds ‘over the phone’ to their doctor.

It can be tempting to follow the route of building a hardware product as you can specify and control every component and have a physical product to sell at the end. Certainly, there will be medtech applications where it’s simply not possible to devise a suitable solution that achieves the desired performance using the phone itself.

Doctors could even share the ‘sound wave’ to the junior doctors following the registrar on their ward rounds from an educational perspective. More so, machine learning algorithms could be implemented to alert doctors to a potentially missed heart murmur. What if it could be compared to the sound from the same patient recorded last week, or last year, to measure if a condition has improved or progressed?

However, consider measuring Bilirubin levels in new-borns – that is a procedure which classically is performed with a laboratory blood test, but can also be measured using a non-invasive optical instrument. Researchers at University of Washington have demonstrated that you can achieve similar results just using the camera on a smartphone, with a coloured reference frame in the image.1 That brings us closer to my day-to-day work, helping diagnostics companies read point of care devices using smartphone cameras. There is a huge temptation to over-specify the performance requirements,

forgetting that the clinician is often only really interested in normal or abnormal results or general measurement trends. If something is wrong, they may be referred for more precise testing, but just as important is to quickly screen out healthy patients so time is best spent on those who need support the most. Why then create the complication, cost and storage headache of smartphone addons, or laptop-sized instruments if the phone can achieve adequate performance on its own? Especially in a world where phone sizes and standards are constantly changing. As smartwatches gradually become more prevalent, the array of sensors will only continue to grow and they are likely, either directly or in combination, to make monitoring patient outcomes easier without having to build whole new dedicated devices.

REFERENCES 1. De Greef, Lilian, et al. "Bilicam: using mobile phones to monitor newborn jaundice." Proceedings of the 2014 ACM International Joint Conference on Pervasive and Ubiquitous Computing. ACM, 2014.

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