EPM September 2018 by EPM Magazine

THE POTENTIAL OF MACHINE INTELLIGENCE

IMPORTANT CONSIDERATIONS IN SERIALISATION

A PREVIEW OF CPHI WORLDWIDE 2018

September 2018

PATH OF LEAST RESISTANCE Colorcon highlights how tablet coating can help with swallowability and inevitably patient compliance.

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Contents

September 2018 | Volume 18 Issue 6 REGULARS 5 EDITOR’S DESK

Some of the latest Brexit developments as we draw closer to the UK’s exit from the EU…

6 A SMALL DOSE

A brief round-up of some of the developments in the industry including a warning of a serious side effect and the landmark deal for NHS patients to access CAR-T therapy.

11 OPINION

Looking at patents and their role in the pharma industry, asking the question whether they are complicating business or enhancing opportunities?

14 COVER STORY

In this feature, Jason Teckoe, from Colorcon, examines tablet design aspects in more detail, paying particular attention to swallowability.

58 TECH TALK

This time in Tech Talk, Dr Neil Polwart, Novarum founder and BBI Group head of mobile, looks at blockchain technology in mHealth.

FEATURES 16 ARTIFICIAL INTELLIGENCE

Assessing the opportunities of artificial intelligence, how to get the best value out of big data and the uses of augmented reality in pharma.

23 SERIALISATION SUPPLEMENT

Within this special supplement, various aspects of serialisation are considered such as benefits of blockchain and how companies can drive a return on their serialisation investment.

34 FORMULATION

Insights into important considerations to ensure success in GLP toxicology studies and uses of modelling to minimise development risks.

38 ANALYTICAL LAB TECHNIQUES

Here, Thermo Fisher Scientific reveals how the latest tools are taking the complexity out of peptide mapping workflows.

41 APIS/HPAPIS

Examining the intricacies of risk assessment and the importance of a realistic approach.

44 CLEANROOMS

Discussing design strategies for more energy efficient cleanrooms and outsourcing of microbiological growth media.

50 CPHI PREVIEW

Previewing this year’s exciting CPhI Worldwide, taking place in Madrid, Spain.

53 DIGITAL HEALTH

Highlighting how technology is a major resource in various aspects of healthcare and how community is needed to make it all work.

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5 HEAD OFFICE

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SO LONG, FAREWELL…

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EDITORIAL

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

PRODUCTION

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A look over some of the latest Brexit developments as we draw closer to the UK’s exit from the EU…

t is fair to say that Brexit has oﬀered a substantial amount of ‘editorial fodder’ since I started my tenure here as editor of European Pharmaceutical Manufacturer. Even just over the past couple of months, we have seen some huge stories emerge around this topic.

In light of this, the UK government issued an initial series of technical notices, which set out to inform businesses and the public about what steps they should be taking to prepare for a ‘no deal’ scenario. These preliminary documents have been welcomed by the industry.

Most recently, there have been reports about the government discussing the issue of funding the extra costs of stockpiling vital medicines with drug companies just in case a ‘no-deal’ Brexit transpires, including the potential viability of ﬂying in medicines.

“By agreeing to recognise and use medicines and vaccines licensed and manufactured in the EU, the UK government has taken an important step to protect patients. We urge the EU Commission to do the same,” stated Mike Thompson, chief executive of the Association of the British Pharmaceutical Industry (ABPI).

Major pharmaceutical companies have already confirmed preparative works are underway for a hard Brexit outcome and the Medicines and Healthcare products Regulatory Agency (MHRA) has ratified that the issue of a medicines’ supply has its highest attention.

EDITOR’S DESK Sanofi UK’s MD, Hugo Fry, and the chief executive of AstraZeneca, Pascal Soirot, have both stressed that their respective companies are doing all they can to maintain a continuous supply of medicines, although an overwhelming sentiment coming from industry is that clarification from both sides of the Brexit negotiating table is urgently needed.

Additionally, we have witnessed the shock that the MHRA will no longer be allocated any centralised marketing authorisation applications as a result of the UK potentially becoming a ‘third country’ come March 2019. “The news that EMA has announced it will discontinue awarding contracts to the MHRA, is no surprise. It is, nonetheless, a shocking blow to MHRA,” stated Martin MacLean, life sciences partner at intellectual property firm, Mathys & Squire. So, as the UK and the EU prepare their ultimate farewells, I too must say my goodbyes as I close on my last edition as editor of EPM magazine. Thanks for your support and engagement with this esteemed publication, it has truly been an honour.

A small dose This rare and serious infection, necrotizing fasciitis of the perineum — also referred to as Fournier’s gangrene — is considered a urological emergency and has a mortality rate of more than 20%.

WARNING! Serious side eﬀect

The ﬂesh-eating disease is caused by bacteria that enter the body through a cut or break in the skin and then start to destroy tissue. It spreads quickly and requires antibiotic treatment as well as surgical removal of any dead tissue.

An important warning was communicated by the US Food and Drug Administration (FDA) recently regarding potential infections around the genitals and surrounding area occurring in patients taking sodium-glucose cotransporter-2 (SGLT2) inhibitors for type 2 diabetes.

Landmark deal — it’s CAR-Ty time! A landmark deal was revealed that will see the ﬁrst chimeric antigen receptor T-cell (CAR-T therapy) — Kymriah from Novartis — made available for children and young people via the NHS. WHY IS THIS BIG NEWS?

Personalised therapies are an exciting development that may potentially cure some patients, in particular those that are unresponsive to standard therapies. However, they are also extremely complex and expensive to produce. “CAR-T therapy is a true game changer, and NHS cancer patients are now going to be amongst the first in the world to

benefit,” asserted Simon Stevens during the first day of the Health and Care Innovation Expo in Manchester when oﬃcially announcing the deal. “CAR-T cell therapy is the most exciting advances in treatment for childhood leukaemia for decades,” commented Dr Alasdair Rankin, director of Research at the blood cancer charity Bloodwise. “Intensive chemotherapy can now cure the vast majority of children but a significant number still tragically die every year because they do not respond to treatment. CAR-T cell therapy oﬀers the genuine chance of a long-term cure for children who otherwise would have no other hope.”

‘FIRST OF ITS KIND’ DEAL

The cost-eﬀectiveness of personalised treatments has previously been highlighted as an issue by the National Institute for Health and Care Excellence (NICE), which recommended against the use of Yescarta (Kite Pharma) in England for the treatment of aggressive subtypes of non-Hodgkin lymphoma, earlier in the year. Kymriah costs around £282,000 per patient at its full list price. It has not been disclosed what reduction in price has been negotiated between Novartis and NHS England, however. This is the very first time within Europe that a commercial deal of this

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“We are requiring a new warning about this risk to be added to the prescribing information of all SGLT2 inhibitors and to the patient Medication Guide,” the FDA specified on its website. Approved medicines containing SGLT2 inhibitors include canagliflozin, dapagliflozin, empagliflozin and ertugliflozin. These drugs work by causing the kidneys to remove sugar from the body via urine.

kind has been made. “This constructive fasttrack negotiation also shows how responsible and ﬂexible life sciences companies can succeed — in partnership with the NHS — to make revolutionary treatments available to patients,” added Stevens. ‘FANTASTIC NEWS’ “It’s fantastic news for children and young people with this form of leukaemia that CAR-T cell therapy will be made available on the NHS, making them the first in Europe to have routine access to this exciting new type of immunotherapy,” added Professor Charles Swanton, Cancer Research UK’s chief clinician. “We applaud NHS England, NICE and the company for working together to make this immensely complex treatment available to patients quickly, through the Cancer Drugs Fund.”

ASTHMA BREAKTHROUGH IN US FOR AZ A breakthrough therapy designation has been granted by the US Food and Drug Administration (FDA) for AstraZeneca’s tezepelumab in patients with severe asthma, representing the ﬁrst for the company for a respiratory medicine. This designation, which is intended to accelerate the development and regulatory review of medicines intended to treat a serious condition, was based on clinical study data demonstrating that tezepelumab (which is being developed by AstraZeneca in collaboration with

Amgen) significantly reduced asthma exacerbations when compared with placebo. SEVERE ASTHMA Severe asthma, which is reported to account for around 10% of asthma sufferers, may be uncontrolled despite high doses of medicines and can require the use of chronic oral corticosteroids. The pathogenesis of the condition involves multiple inflammatory pathways, one of which is T2 inflammation driven asthma. This is found in more than two-thirds of patients with severe asthma, according to AstraZeneca’s website.

HOW DOES IT WORK? Tezepelumab is a potential first-in-class new medicine that works by blocking thymic stromal lymphopoietin (TSLP), which is involved in the initiation and persistence of airway inﬂammation. It is believed that by blocking the epithelial cytokine (TSLP) it may be possible to stop proinﬂammatory cytokines being released by immune cells and as such should prevent asthma exacerbations and improve control of the condition. As this blocking mechanism happens early on in the

inﬂammation cascade, it is hoped that tezepelumab may be suitable for a broad range of patients. EXCITING POTENTIAL “Tezepelumab is exciting because it has the potential to treat a broad population of severe asthma patients, including those ineligible for currently-approved biologic therapies,” explained Sean Bohen, executive vice president, Global Medicines Development and chief medical oﬃcer at AstraZeneca. “The Breakthrough Therapy Designation will help us bring tezepelumab to patients as quickly as possible.”

A small dose

Going viral… New research has shown that viruses may have potential in treating cancer as they retain their cancerkilling ability even after injection into the bloodstream. Oncolytic viruses are known to preferentially infect and kill cancer cells, however, when injected into the bloodstream it was believed that the human’s normal immune response neutralised them. In this latest study, which was published in the journal Cancer Immunology Research, the researchers found that cells in the blood can actually reactivate the virus as it travels to the tumour site, where it was then able to retain its ability to destroy the cancerous cells. “Viruses are a hugely exciting new type of treatment for cancer,” stressed co-lead author Alan Melcher, professor of Translational Immunotherapy at The Institute of Cancer Research, London. “Not

only do virus therapies kill cancer cells directly, they do so with only mild side eﬀects compared to traditional cancer treatments and they attract the immune system to the site of the tumour — which means they can work well when combined with other types of immunotherapy.” T-vec is a type of virus already approved for use on the NHS to treat advanced melanoma skin cancers. However, it is only suitable for the treatment of tumours that can be reached with a needle. In looking at a work around in which viruses injected into the bloodstream could be useful as a therapeutic option, the researchers determined that white blood cells could not only carry the virus to the tumour site, but were also capable of reactivating the deactivated viruses. “This discovery suggests that cancer treatments using virus therapy could be significantly

Pulling the plug Pfizer has terminated two clinical studies evaluating domagrozumab for the treatment of Duchenne muscular dystrophy (DMD).

expanded in future,” added one of the study’s lead authors Dr Elizabeth Ilett, from the Leeds Institute of Cancer and Pathology at the University. “We are only just beginning to understand how viruses can help us tackle cancer, but it is exciting to learn that our bodies are actually capable of helping them to destroy cancer tumours.” Three diﬀerent viruses — currently being used in clinical trials — were evaluated in the study. After they had been neutralised the researchers found that in two of the three viruses white blood cells were able to reactivate them and they were able to destroy melanoma cells in a lab setting. As a result of their findings the study authors believe that other viruses might also be eﬀective after being neutralised by the immune system via reactivation with white blood cells. Using antibodies from patients undergoing

virus therapy, the researchers neutralised viruses and added them to melanoma cells in the laboratory, which on its own had no eﬀect. But adding white blood cells, called monocytes, meant the virus became reactivated, allowing it to destroy the cancer cells. “Our study shows that, crucially, viruses retain their cancerkilling ability even in the bloodstream,” explained Melcher. “This research has profound implications for how we might use viruses to treat cancer in future, opening up virus therapy to many more patients with hard-to-reach tumours of diﬀerent cancer types.” A number of viruses are currently being looked at in a clinical trial setting, but only one has been approved for general use via injection directly to the tumour. It is hoped that with this latest work, it will be possible to gain a better understanding of how virus therapies work and will enable their future use in combination with other immunotherapies.

The Phase II study, which was evaluating the safety and efficacy of the treatment, was stopped as it did not meet its primary efficacy endpoint. After further evaluation of all the evidence it was deemed that there was no significant treatment effect. The open-label extension study was aimed at evaluating the long-term safety and efficacy of domagrozumab was also concluded. “We are disappointed by these results and while we are not progressing with the studies, the data will contribute to a greater understanding of this disease and we will evaluate the total data set to see if there is a place for this medicine in muscular diseases,” said Seng Cheng, PhD, senior vice president and chief scientific officer, Pfizer Rare Disease Research Unit. “We are extremely grateful to all those involved with this trial, especially the boys who participated, and their families.”

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DRUG PRICE HIKES… NEE, DANK U WEL! A group of doctors and health advocates from the Netherlands (the Dutch Pharmaceutical Accountability Foundation) are taking an Italian pharmaceutical company to task after it raised the price of a life-saving drug 500-fold. The Financial Times,1 which reported the news in early September, spoke with the head of the foundation, Wilbert Bannenberg about the claim they were filing. “Some companies are misusing the system to get higher profits, and patients are being are being aﬀected when cheap, aﬀordable old products are no longer available. This may be legal but it’s not socially acceptable,” he said.

This specific case relates to the price hike of the orphan medicine Chenodeoxycholic acid Leadiant (CDCA), used in the treatment of cerebrotendinous xanthomatosis (CTX). Shortly after the European Medicines Agency approved the market authorisation for CDCA with an indication for CTX, the manufacturer — Leadiant Biosciences — increased the annual price from €30,000 to around €170,000 per patient. One can’t help but reminisce on the actions of the ‘bad boy’ of pharma, Martin Shkreli, who became infamous for hiking the price of Daraprim by 5,000%. Although, according to Stat, which reviewed financial documents, the drug’s manufacturer, formerly known as Turing Pharmaceuticals now as Vyera Pharmaceuticals, is now suﬀering from dwindling profits, in part believed to be due to the pricing scandal

1. https://www.ft.com content/e394d54e-ae16-11e8-8d14-6f049d06439c

Dangerous loophole With ongoing eﬀorts to tackle opioid addiction happening on a global scale, why is it still possible for patients to buy drugs online so easily?

orders are going to the same address, regulators are questioning whether opioid medications should be allowed to be supplied by online pharmacies at all.

The Guardian revealed that in a dangerous loophole for those with an addiction to the strong painkillers, opioids, it is possible to buy hundreds of drugs that are all delivered to the same address.1

“We have set out actions we’re proposing that online pharmacy owners would be expected to take to meet our standards and make sure that people obtain medicines safely online,” said Duncan Rudkin, the chief executive of the General Pharmaceutical Council (GPhC) when speaking to The

With no alert system in place ﬂagging up whether or not multiple

Guardian. “This includes identifying multiple orders to the same address or using the same payment details.” The ability to buy so many of these high strength pain killers is potentially very dangerous and with increasing numbers of deaths related to prescription drugs is in need of safeguarding imminently… 1. https://www.theguardian. com/society/2018/jul/25/ online-pharmacies-fail-spotmultiple-opiate-ordersaddiction?CMP=Share_iOSApp_ Other

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Opinion

Proper evaluation of the relevant IP landscape is crucial if you wish to be one step ahead of your competitors.

EXPERT ADVICE

Here, Dr Natasha Varvogli, intellectual property consultant, and Maria Andrielou, marketing & communication at VIO Chemicals, look at patents and their role in the pharma industry, asking the question whether they are complicating business or enhancing opportunities?

ith pharma’s portfolio shifting substantially toward new product types and personalised treatments, process technology needs to overcome multiple challenges across the supply chain. Competition is fierce and the need for new and revolutionary solutions for drug development starts as early as the selection of the optimal route of synthesis and starting material, often calling for ‘out-of-the-box’ thinking. Breakthrough solutions, as small as they may be, can drive your business forward. Nevertheless, if you have not considered the intellectual property (IP) landscape, then, you have only developed half a solution, which can drive your business right into the ground. STAY A STEP AHEAD Proper evaluation of the relevant IP landscape is crucial if you wish to be one step ahead of your competitors. In today’s era of abundant knowledge and technological advancements, where businesses grow across borders and continents, the intangible assets of human intellectuality cannot be underestimated.

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Analysing the IP landscape will give you a competitive advantage to avoid roadblocks and see hidden opportunities. It will also draw your attention to issues that require frequent monitoring and, why not, lead to an unforeseeable opportunity for the near future, upon change of facts.

be regarded as an invention, depends on a number of factors determined by patent oﬃces. Then the expert will guide you through all available options, analyse the cost, the markets you and your competitors are active in and the relevant timelines.

Just think of the multiple questions you are faced with when you are about to design, develop and manufacture a new product: • Are there any IP restrictions related to the specific product or activity you are planning to commercialise? • If there is room for innovation, can you create an IP asset and use it to become competitive? • How can you overcome any IP restrictions? • Are there any possible IP rights (IPRs) that a competitor might obtain? And how can you work around them? • And, last but not least, how can you ensure that you won’t stumble upon any legal bottlenecks if you plan to manufacture or commercialise your product in a country other than in Europe?

Why do you want an expert?

The breakdown before the breakthrough In a hypothetical scenario you and your R&D team have come up with a solution for a manufacturing process, which is easier, cheaper or faster in a novel manner. Do you need a patent to employ it in your business? Does a patent give you the right to manufacture and/or sell your product? What is a patent good for? The short answer is: to prevent competition. A patent does not give you the right to commercialise your invention, but it will stop others from doing so. This is an intangible asset that can provide your business with a unique opportunity to grow. What steps should you take to obtain a patent? Seeking expert support is your only option. At first, the expert will perform a novelty search to ensure that what you are seeking protection for is indeed something new. Whether or not this can

For many reasons. Firstly, a novelty search requires solid experience in process development to become effective. A single search is almost never enough and professional patent searchers perform indepth bibliographical research in multiple databases, driven by multiple strategies. Secondly, an expert can file a patent application in a proper manner. Preparing a patent application is a highly meticulous task. If it is not done properly from the beginning and the patent application goes public, there is no turning back, and filing another patent application for the same invention is not possible. Thirdly, an expert understands the implications caused by the differences in procedural law across borders and can save you from embarrassing and irreversible situations. Every patent office operates and examines patents under its own rules. SAILING IN SAFE WATERS Maybe your business is not driven by innovation and you are offering a well-established product. You still need to ensure that it is IP free in the place of manufacturing. And what about the manufacturing process itself or the starting materials? A successful product or manufacturing process may be patent-protected by the same token it would make sense for you to own IP rights for something useful and innovative. Taking into account that a patent may last for 20 years, your business might relate to something wellestablished, but you may not be ‘off the hook’ for a critical time span of two to three years. LAUNCHING A NEW PRODUCT The procedure by which your business activities are checked for possible

infringement of IP rights is called ‘freedomto-operate (FTO) search’. To perform an FTO search properly, one not only needs to know and understand patent language but must also be up-to-date with key patent issues across major markets. Through this search, you can identify and retrieve patents or patent applications that are or could potentially become roadblocks in your commercial activities. The evaluation of the search results requires specialised knowledge to assess: • the scope of the claims; • the legal status of the patent: that is, if the patent is still active and where, or if it is under some kind of invalidation procedure; • and the validity of the claims of a pending patent application: meaning, if it is likely to get granted and with what scope. All those issues need to be considered by taking into account the technical language of the claims and any special rules that a specific country or region may enforce. IN OR OUT OF EUROPE? Europe differs from other major markets in an important aspect: the European Patent Office. This common route chosen for commercial activities within the European territory has the task of issuing patents effective across the majority of the European countries, but it is not entitled to decide on the infringement of a patent. This is a matter resolved, for the moment, only within national jurisdictions. If you manufacture and/or plan to commercialise your product outside Europe, you need to be extra cautious when you analyse the IP landscape and file a patent. Take the case of China: European firms have long complained that patents in China are often misused and enforcing their IP rights in the country stumbles upon local judicial protectionism and ill-fitting law enforcement rules. Despite efforts for progress and reform, you still need an expert to cope with China’s IPR regime, avoid future violation of your IP rights and get a fair share in China’s market and courts.

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DIGITAL intelligence

The growing commitment towards digitalisation of production systems is leading us to Industry 4.0, the new industrial revolution that will change the way we work and live. Thanks to this evolution, we will be more and more connected: collaboration will become a new form of intelligence. At IMA, the work we do and the way that we think about the future have always combined to create one big collective brain. With digital systems, even more so. www.ima.it

COVER STORY

Path of least resistance Safety by design is fast becoming recognised as an integral part of tablet manufacture, where it can be used to improve medication adherence. In this feature, Jason Teckoe, Technical Director, EMEA at Colorcon, examines tablet design aspects in more detail, paying particular attention to swallowability…

n an environment where the senior population is on the rise and more people are taking multiple medications and dietary supplements (some of which are large tablets and capsules), swallowability is a growing concern. Regulatory agencies around the world provide guidance regarding the importance of tablet coating to not only address diﬀerentiation but to ease the swallowing of tablets and capsules to improve patient safety and compliance. SAFETY BY DESIGN TO TARGET PATIENT ADHERENCE Medication errors are reported to harm 1.5 million people every year, some of which result in sickness, injury and death. It is estimated that between two to 14% of patients are admitted to hospitals due to medication errors, and around one to two percent of those patients are harmed as a result.1

These numbers are alarming considering most, if not all medication errors could be prevented. Further, these statistics only include those medication errors that have actually been reported. The World Health Organisation (WHO) also reports that poor patient compliance can lead to additional medical costs and adverse health outcomes, which is why regulators around the world have decided to step in. Recent guidance from both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) highlights

the importance of ‘safety by design’, drawing attention to tablet dimension, coating and appearance.2,3 TABLETS AS PREFERRED ORAL DOSAGE FORMS Tablets remain the most common solid oral dosage form for many reasons, including ease of manufacture, convenience for the patient, accurate dose administration and good stability. Good tablet design can be used to provide product differentiation, avoid medication mix-ups and deter counterfeiting. The regulatory agencies consider ease of swallowing and patient compliance important issues for manufacturers to address, taking into consideration: • Tablet size and shape • Tablet coating and colour differentiation The number and variety of medicines available increases and patients are now taking multiple medications and living longer. Administration of medicines may be carried out by several healthcare professionals and communication failures can lead to mistakes. By creating your dosage form with the patient in mind, you can make a tablet easier to swallow, both literally and figuratively. From the patient’s perspective, coating makes the tablet appear easier to swallow and aids in visual differentiation, thus reducing the potential risk of medication errors. The coating also reduces tablet friability and overcomes any

damage or dusting issues often associated with uncoated tablets. The recent focus on medication errors has led regulatory bodies to consider tablet diﬀerentiation more prominently, encouraging manufacturers to think more about the patient’s perspective and whether they are likely to follow the recommended dosing regimen outlined in their prescription. The FDA, for example, has released two industry guidance documents on this topic4,5 intended to champion the patient’s perspective, improve patient compliance and medication outcomes. Adding a coating to a previously uncoated tablet would improve patient compliance and bring the tablet in line with the FDA’s recent recommendations. SIZE AND FINISH MATTER Now, more than ever, it’s increasingly important to create easily distinguishable tablets. Similar looking tablets — especially plain white ones — can be readily confused by patients, pharmacists, caregivers and even manufacturers. Smaller is also better. An FDA guidance on tablet design reports that complaints from patients about swallowing increase when tablets have diameters exceeding eight millimetres. And the agency states that the largest dimension of a tablet or capsule should never exceed 22 mm.5 In practice, formulators can address size by selecting ingredients and process to eﬀectively minimise overall tablet weight and size. Even so, we know that dose

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strength, compressibility and other factors make it a challenge to keep tablet size down. CHOOSING THE PATH OF LEAST RESISTANCE Coating makes tablets easier to swallow and improves tablet mobility; this is recognised as even more important for elderly people (recent EMA guidance).3 And as far as coating goes, the glossier the finish and more slip it can provide, the better. Through extensive research and development, Colorcon has created a unique coating system to address this recognised and growing patient problem. This new Opadry EZ, Easy Swallow Film Coating has been found to provide increased motility during the swallowing process, satisfying both the perception and reality of easier swallowing, in a recent study. The swallowability study, conducted by the University of Birmingham (2018, in preparation for submission), aimed to assess the potential for coatings to improve swallowability and to evaluate the mouthfeel of coated versus uncoated tablets. Participants evaluated the swallowability of tablets along with their mouthfeel, described as roughness, adhesiveness, slipperiness, and palatability. The study results confirmed that presence of coating improved the ease of swallowing and that uncoated tablets are clearly diﬀerent to the coated tablets, being more diﬃcult to swallow with poor mouthfeel. Tablets coated with Opadry EZ coatings were found to be most palatable from all the samples. Uncoated tablets rated as the least acceptable for the participants. So, remember, when designing a tablet to ease swallowing, make it small, oval or a shape with more rounded edges, and don’t forget the coating.

…coating makes the tablet easier to swallow and aids in visual diﬀerentiation, thus reducing the potential risk of medication errors.

REFERENCES: 1. United States Institute of Medicine, 2006. 2. FDA Guidance: Safety Considerations for Product Design to Minimize Medication Errors. https://www.fda.gov/downloads/drugs/ guidancecomplianceregulatoryinformation/guidances/ucm331810.pdf) 3. EMA Guidance; Good practice guide on risk minimisation and prevention of medication errors. http://www.ema.europa.eu/docs/en_GB/ document_library/Regulatory_and_procedural_guideline/2015/11/ WC500196981.pdf) 4. https://www.fda.gov/downloads/drugs/ guidancecomplianceregulatoryinformation/guidances/ucm331810.pdf 5. https://www.fda.gov/downloads/drugs/guidances/ucm377938.pdf

ARTIFICIAL INTELLIGENCE

Unify and conquer According to Frank Austin Nothaft, GTM lead for Genomics, Databricks, a uniﬁed approach to big data is the best way to get the most value. Here, he tells us more…

ith the cost of sequencing dropping dramatically over the last decade, genomic data volumes have grown exponentially. By 2020, genomic data is expected to be reaching upwards of 40 exabytes per year.1 Pharmaceutical companies are rushing to tap into this genomic data goldmine in hopes of accelerating the costly long-tail of drug development.

Early population sequencing eﬀorts, such as the Geisenger/ Regeneron DiscovEHR collaboration,2 have demonstrated the ability to identify novel links between genomic variants and phenotypes of interest. By using information gleaned by integrating genomic data along with phenotypic sources, pharmaceutical development organisations can more precisely target treatments to the underlying biology driving a disease.

REFERENCES: 1. http://journals.plos. org/plosbiology/ article?id=10.1371/journal. pbio.1002195 2. http://www. discovehrshare.com/ 3. https://databricks.com/ session/building-the-futureof-drug-discovery 4. https://databricks.com/ session/insights-frombuilding-the-future-of-drugdiscovery-with-apachespark 5. https://datascience.nih. gov/blog/cloud

This can result in more eﬀective drugs with reduced side eﬀects and accelerate time to market. However, a number of technology hurdles must be overcome for organisations to fully draw value from their genomics data with advanced analytics and machine learning. THE CHALLENGES OF LARGESCALE GENOMIC ANALYSIS The sheer scale of genomic data is daunting, as a whole genome study can have upwards of 100GB of data per individual. While the data from one individual’s genomic

profile provides insight into their biology, genomic data is most powerful when viewed at a population scale and with the added context of phenotypic datasets like EMR and imaging studies. While bioinformatics tools have traditionally been designed for on-premises High Performance Computing (HPC) architectures, it is diﬃcult to scale these storage systems to petabyte/exabyte volumes of data in a costeﬀective manner. For a pharmaceutical R&D team, the real value in advanced analytics is obtained once these techniques can be made easily accessible to domain scientists. Following the example of the Regeneron Genetics Center, advanced analytics can provide tremendous value when deployed through a web portal that allows bench scientists to rapidly drill down on the data that supports a link between a gene and a phenotype.3,4 ACHIEVING AGILITY AND SCALE IN THE CLOUD One approach that pharmaceutical manufacturers have traditionally leveraged for large-scale bioinformatics is on-premises HPC architectures. Unfortunately, the financial model for managing an HPC installation requires a significant up-front CapEx investment, which does not eliminate OpEx. An alternative approach is to use cloud computing.

Cloud computing allows elasticity around data infrastructure. Large public cloud companies have all made huge strides in readying their services for enterprises. These public cloud platforms now have more security and controls implemented around data that is being stored in them, essential when managing highly sensitive data. GENOMIC DATA NEEDS UNIFIED ANALYTICS As commoditised sequencing allows more organisations to gain access to massive -omic datasets, success will be determined by an organisation’s ability to rapidly turn raw genomic data into actionable biological insight. A disjointed approach to data forces bioinformaticians, computational biologists and bench scientists to work in silos, which hampers the discovery and analytics process. Building a homegrown patchwork solution of tools and technologies pulls valuable cycles from domain scientists whose expertise is in the biology rather than large-scale data. By leveraging cloud computing technologies to rapidly analyse genomic data along with bioinformatics platforms that bring together large-scale data processing and advanced analytics in one connected toolset, disparate teams across bioinformatics, computational biology, and bench science can be unified to accelerate R&D.

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06.09.18 14:24

ARTIFICIAL INTELLIGENCE

BRAVE NEW WORLD Machine learning oﬀers considerable potential for streamlining and transforming routine information processes in life sciences — but could more creative applications of artiﬁcial intelligence take things further still? AMPLEXOR’s Siniša Belina assesses the opportunities…

he scope for artificial intelligence in life sciences is potentially significant — enabling accelerated scientific breakthrough, thanks to new potential to identify the minutest anomalies in unwieldy global data masses, and facilitating greater drug personalisation. Far from hovering on some futuristic horizon, the technology is already available too — which means pharma companies need to build it into their agendas and plans now, if they don’t want to risk sacrificing competitive advantage. From intelligent internet and content searches that adapt to user preferences, to automated personal assistants like Alexa and Siri, and customer care channels such as web chat, AI is already in common use as part of people’s routine activities.

REFERENCE: 1. AI early diagnosis could save heart and cancer patients, BBC News, January 2nd 2018: http:// www.bbc.co.uk/news/ health-42357257

One of the great appeals of AI is the scope for process automation and acceleration, using clever algorithms that can complete complex tasks previously limited to human capacity. The technology is also highly adaptive — machine learning tools can be guided to respond to the conditions they are exposed to and the results they find, so that they get better and better at the job they’ve been tasked with. So over time they are able to absorb more and more human tasks, to the point that the only intervention needed is in the form of supervisory quality checks.

THE HUMAN-MACHINE CONTINUUM Although countless articles have been written about the threat to people’s jobs presented by AI, if machines can get to grips with routine knowledge work and do it more rapidly than humans ever could, why wouldn’t companies want to take advantage — especially if it allows them to free up experts for more advanced, value-added work? AI technology oﬀers to transform patient outcomes — as is already being seen in frontline patient diagnostics. UK researchers in Oxford recently announced the availability of AI technology that can diagnose heart disease and lung cancer at a much earlier stage from analysis of patient scans.1 Meanwhile, connected devices are being used increasingly to transmit patients’ data to those managing their care — to enable earlier interventions. In pharma, machine intelligence has substantial potential for enhancing R&D, through the ability to analyse large volumes of data leading to richer insights. To this end, applications, systems, and platforms have already been developed to transform clinical trial innovation. This isn’t just about distilling subtler patterns from once unmanageable volumes of disparate data either. It is also about modelling and extrapolating from such findings to arrive at

bolder hypotheses and deeper and more targeted work, to accelerate discoveries and the development of treatments. SCALING DATA MOUNTAINS Machine intelligence at scale also offers a viable means to track global patient trends, concerns, experiences, behaviour and needs, enabling the life sciences industry to understand what is happening in the real world — to a degree that hasn’t been possible previously. This offers potential not only for more proactive and thorough monitoring of adverse events and other safety signals as drugs move into markets, but also for identifying emerging requirements, triggering new innovation. Where the life sciences industry has traditionally been one step removed from patients, public internet forums and social networks offer an opportunity to understand evolving demands and engage with patients in new ways. AI is already proven for social media monitoring in other markets, whose best practices could be carried across to life sciences with a few adjustments. For all the excitement around AI, though, the life sciences industry is not exactly known as an early adopter of new technology. So, there are a number of things that need to happen if companies are to adapt to and exploit the potential ahead of them.

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TESTING AI’S POTENTIAL Once firms have accepted that change is coming, the next step is to prepare an IT and data environment which allows for new experimentation and insights — within the restrictions of regulatory control and privacy protection. This isn’t just about developing ‘big data’ strategies, but rather preparing that data so it can be analysed eﬃciently, accurately and holistically using AI platforms — to spot emerging trends, anomalies, concerns and opportunities in a very eﬃcient and granular way. For now, regulatory pressures are driving most data-related initiatives in life sciences. So, this is a good place to start with AI — even if just for taking over some of the more repetitive or preparatory stages of submission creation, or content checking, to accelerate

speed to market. (Using machine learning, systems could ‘learn’ how to produce better output, or the conditions most likely to result in a new marketing submission being accepted first time.) If data preparation work has to be done to fulfil regulatory demands, why not exploit this — laying the foundations for future innovation, and testing just how powerful AI can be in transforming everyday processes? The critical enabler for maximising the potential of data is the creation of a comprehensive master data model — one that also includes inter-dependencies between the data, in a way that can drive new eﬃciencies and increased impact through proactive process automation, boosted by AI/ machine learning. Today, just about every life sciences business is striving to be more agile,

responsive and patient centric. But this relies on a strong sense of purpose and a foundation of rich, ready-to-exploit data. So, if companies are going to start anywhere, this is as good a place as any.

One of the great appeals of AI is the scope for process automation and acceleration, using clever algorithms that can complete complex tasks previously limited to human capacity.

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ARTIFICIAL INTELLIGENCE

The next dimension As we go further down ‘the rabbit hole’ in terms of technological advancements, we discuss augmented reality and its uses for pharma manufacturers with Jean-Yves Balﬁn, product manager at Korsch, which has recently launched PharmaView* — a mixed reality environment.

ore and more we are witnessing increasing applications of technology across all areas of life. Augmented and virtual reality has found use in many sectors and, as can be viewed when walking the vast exhibition halls of any pharmaceutical event nowadays, is securing its position within healthcare too. But how can this advancement truly help pharmaceutical manufacturers? “The sort of mixed reality environment that we can now create can raise both efficiency and safety in machine operation to a totally new level,” explained Balfin. “We have based the PharmaView on the Microsoft HoloLens-technology, which beams holograms and additional information into the user’s actual visual axis, enabling hands-free, interactive capabilities.” These interactive capabilities include operational assistance through holograms to assist in setup, operation or maintenance, multimedia support that can be directly beamed into the smart glasses, machine control and operation as well as a virtual service via secure video call function.

The control that can be gained from this sort of assistance has massive potential from a manufacturing perspective. Any potential faults or maintenance that may be required to the machinery can be caught much earlier and help to streamline processes. Another important function that can be gained through augmented reality is training. “Realistic three-dimensional training at scale in the presence of the machine provides the opportunity to instil the best practices for machine operation and service,” added Balfin. As augmented reality can delve deeper into the subassemblies of the machine through holograms it is possible to train operators with virtual tutorials in a way that is not really possible in the real-world. “We have also looked at training prior to delivery of machines and will aim to do this with PharmaView,” he continued. “In this way, downtime can be reduced and it also gives the companies more ﬂexible options for training.” But what of safety, are there any potential safety issues when using augmented reality that

operators and companies should consider? “When using a mixed/ augmented reality environment, the operator is not immersed in a completely virtual reality,” said Balfin. “This means that the operator doesn’t lose contact with the real environment but simply has holograms and additional information beamed in around them to combine with the real surroundings. However, it was noted that care should be taken in some areas, such as defining the safety distance for machine remote control as well as the duration of time the operator wears the smart glasses, which obviously should comply with health regulations. “Augmented reality, such as the PharmaView, is the first step towards enhanced communication between operator and machine,” concluded Balfin. “Artificial intelligence will lead to further steps in this exciting technological journey.” *PharmaView is a registered trademark of Korsch.

FROM THE EDI TOR

The final countdown As we close in on the date for companies to be serialisation compliant vast gaps in industry preparedness have become apparent. The ﬁnal countdown is on and it’s time to get serious about serialisation…

arly on in August we passed the six-month marker before pharmaceutical companies will be required to comply with the European Falsified Medicines Directive (FMD). For some, who have gotten their preparations underway, this milestone will go without much notice but for others it may be a wholly diﬀerent story. The Falsified Medicines Directive (FMD) 2011/62/EU, which is due for adoption in February 2019, will require pharmaceutical companies to apply serialisation codes to every applicable pack. The impending legislation will aﬀect all prescription medicines for the European market and as underlined by Gill Wright from Cirrus, it is here to stay irrespective of Brexit!1

In a recent survey performed by TraceLink a large gap in industry readiness for drug serialisation was highlighted.2 Only a third of respondents of this survey stated they are ‘very prepared’ for the upcoming deadlines in both Europe and the US and none reported completion of all of the fundamental steps for serialisation compliance. “These survey results are startling,” commented Shabbir Dahod, president and CEO of TraceLink. “Despite goodwill eﬀorts by industry and regulators to meet compliance on time, the industry is extremely behind in being ready for serialisation. In 2018, as we reach

the final hours of serialisation in both the US and EU, the industrywide lag in full serialisation implementations remains a concern and emphasizes the criticality of trade partner connectivity within the supply chain.” In this special section of our September issue, we are focusing on serialisation, looking at the potential challenges and benefits that being compliant with the upcoming legislation may bring in more detail. Also, we discuss the potential of blockchain and how to drive value beyond compliance. But, it is important to remember that the final countdown is now on and overwhelmingly key opinion leaders in the industry are all advocating the same thing, there is no one-sizefits-all solution and if you haven’t already done so, take action now!

CONTENTS 24 THE MISSING LINK?

Looking at the significance of blockchain in closing the supply chain trust gap.

26 THINKING LONG-TERM

Here, David Carpentier, Adents, reveals how tech solutions may add serialisation return on investment.

28 GO THE EXTRA MILE…

Evaluating the value of serialisation beyond compliance and outsourcing with six leading solutions’ providers.

30 MEETING SERIALISATION HEAD ON

REFERENCES: 1. https://www.epmmagazine.com/opinion/the-clock-isticking-for-fmd-compliance/ 2. https://www.epmmagazine.com/analysis/serialisationsurvey-highlights-large-gap-in-readiness/

Discussing how best to meet the serialisation interoperability challenges head on and drive return on investment.

32 THE KEY TO SUCCESS

In this interview, Simon Cole, Atlantic Zeiser UK, points out why blockchain is gaining importance and what effects can be expected from Brexit.

SERIALISATION SUPPLEMENT | SYSTECH

The missing link? In this article, Joseph L Lipari, director, Cloud Implementation Services, Systech International, reveals the importance of blockchain in closing the supply chain trust gap.

xperts agree that there exists a fundamental gap in the supply chain today. That gap is trust. Manufacturers, distributors, importers, exporters, logistics providers, health systems and many other trade partners have had their sights set on compliance as deadlines rapidly approach. I would argue that as regulations come online, the need for a secure, interoperable system becomes all the more critical. Enter blockchain, a technology which touts values such as immutability, security and trust. A technology that has captured the attention of global companies across all verticals and which promises to change the way business is done. THE TRUST GAP Let’s get in our time machine and rewind to the mid-1990s when a little-known company called Amazon was just starting to sell books online. This time period signified the pendulum swing from brick and mortar to the genesis of online retail. Fast forward to today... We see more and more companies close their physical doors and expand their online presence. That fundamental shift changed the face of global business and pointed consumers to websites and portals and apps where digital information reigns supreme. The life sciences supply chain is no diﬀerent. With the advent of serialisation regulations, detailed digital information must accompany physical product as it transverses the global landscape.

This ecosystem is missing a layer of trust, a layer which will protect that critical data and will provide an attestation of ownership and integrity. BUT HOW? Blockchain relies on cryptography, distributed ledgers and consensus to provide trust. The cryptographically hashed transactions are distributed to all trusted participants creating a decentralised ledger. There is no dispute regarding transactions because all participants agree to the same version of the ledger, thereby achieving consensus. What emerges is a secure infrastructure for trusted companies to safely exchange data backed by an immutable platform. Will we look back at this period as the time when blockchain revolutionised the way not only businesses, but consumers transacted with each other? Let's face it, as human beings the main reason we transact with another person is based on the trust we have that the other party will respond as expected. That type of gut instinct trust does not exist in the same manner in the digital world. Blockchain technologies have the potential to fill that trust gap, with one caveat.

CONNECT THE PHYSICAL TO THE DIGITAL FOR COMPLETE TRUST If your supply chain challenge demands comprehensive visibility and trust, consider this: connecting the physical product itself with a trusted digital identity, ensuring authenticity when an event is recorded and managing all the transactions by a blockchain network is the closed loop required for complete, absolute trust. This blockchain would likely be private, with known, subscribed entities. When an entity joins the permissioned blockchain network they will be granted a private key, representing them on the network for posting and unlocking transactions. This provides an additional barrier for grey market infiltration or diversion, as all the players and assets are known in the blockchain. However, that link is only as strong as the established trust. Serial numbers can be copied and the blockchain would be unaware. Truly linking the physical to the digital and creating that immutable trust requires a diﬀerent approach, an approach that can uniquely identify two identical items. An approach that absolutely creates that trusted link.

Will we look back at this period as the time when blockchain revolutionised the way not only businesses, but consumers transacted with each other?

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SERIALISATION SUPPLEMENT

Thinking long-term As the EU Falsiﬁed Medicines Directive deadline nears, CMOs & CPOs should embrace tech solutions that add serialisation return on investment. David Carpentier, founding partner & CTO for Adents, tell us more…

nsuring the safety of the pharmaceutical supply chain has become a worldwide priority, and two important deadlines are about to close in on the global market. With Europe’s Falsified Medicines Directive (FMD) set to come into full force in less than six months (February 2019), and the US Drug Supply Chain Security Act’s deadline to be imposed November 2018, it behoves all players in the pharma manufacturing sector to make intelligent decisions about the systems they employ to ensure serialisation compliance.

technologies will give CMOs and CPOs a critical competitive edge as the industry moves toward Industry 4.0 connectivity.

At this critical juncture, it’s important for manufacturers to think long-term and to seek ways to maximise opportunities for growth. Forward-thinking pharma companies need to look beyond the need to print unique product identification codes on all Rx units of sale. That’s easy enough to achieve… but what comes afterward? And how can manufacturers benefit from the changes they’ll need to implement to comply with the more complex serialisation requirements?

The key is to find hardwareagnostic serialisation solutions that can adapt or scale up to meet future track & trace mandates, as well as help improve business practices. The objective is to integrate tools that can better utilise the reams of data generated by the serialisation process. This data can be mined and analysed to produce worth that goes well beyond its initial purpose of tracking and storing for brand owner regulatory reporting. Cyber-security poses another threat. As we move toward enterprise-level serialisation, solutions will need to be interconnected in a way that, in the age of ‘Internet of Things’, can expose vulnerabilities.

With an overabundance of supply chain data at their fingertips, it’s vital for manufacturers to figure out a way to harness and use this information. Those companies that embrace regulatory changes and use them as an opportunity to optimise their supply chains are likely to be the ones left standing amid continued consolidation. And the same is true for their hired contract manufacturers and packagers. Embracing new

GOING BEYOND BASIC REQUIREMENTS Smart pharma companies are seeking out partnerships with CMOs and CPOs whose solutions go beyond basic requirements. Success lies in the implementation of systems that oﬀer elevated capability, scalability and ﬂexibility — and, in turn, a high level of integration in terms of data exchange and process alignment.

For those pharma companies considering forgoing a previously planned transactional-only (Level 2) serialisation system in favour of a more ﬂexible enterpriselevel solution (Level 4), the importance of proper encryption and virus protection cannot be

overstated. Similarly, the necessity of protecting cloud storage and securing data transmission between trading partners must be emphasized. Communication standardisation is another important issue. Part of the EU FMD is the formation of the European Medicines Verification System (EMVS), a pan-European system designed so that medicines can be verified at the point of dispensation. Upon the FMD enactment, Marketing Authorisation Holders (MAHs) that commercialise drug products distributed in the FMD’s jurisdiction will be required to upload their product serialisation data to the European Hub. Reporting to the European Hub will entail generating and managing serialisation data compliant with each target market. This involves certification as an oﬃcial OBP (On-Boarding Partner) Gateway Provider — a designation European pharma manufacturers would be wise to seek in serialisation partners and vendors. THE POTENTIAL OF INTEGRATING TECH According to the Organisation for Economic Co-operation and Development (OECD), an estimated 10% of pharmaceutical products sold worldwide and 2.5% of global imports are counterfeit. With trust and transparency of significant concern for businesses, government agencies and consumers around the globe, tighter control of supply chains is crucial.

ADENTS

While blockchain presents unprecedented opportunities to secure entire supply chains, comprehensive end-to-end security means more than just documenting transactions on a shared ledger. In collaboration with Microsoft, my company recently developed Adents NovaTrack, a platform that lends itself to the building of traceability applications using such technologies as blockchain, Artificial Intelligence (AI), etc. This marriage of technologies brings comprehensive visibility throughout product distribution chains and life cycles and addresses not only performance and security, but also governance and scalability. CONCLUSION The need to find creative solutions to address both current and emerging serialisation and track & trace regulations is clear. Hardware-agnostic solutions are part of the answer, as they are much less likely to become

obsolete, and lend themselves to making adjustments as production needs change or evolve. A process as intricate as serialisation requires an outsized number of components to ‘play nicely’ with each other, and these ongoing transactional relationships are best mediated by software.

QUESTIONS TO PONDER As companies move toward implementing more comprehensive, beyond-compliance serialisation systems, they should ask themselves several questions.

Beyond-compliance ROI and the creation of true business value requires utilising the massive amounts of data generated by serialisation eﬀorts to improve business practices. Solutions now exist that open new horizons beyond regulatory compliance in terms of data analysis and machine learning tools.

The most common ﬂaw with many current serialisation solutions is that they are inherently short-sighted and likely to be obsolete sooner rather than later. It’s important to keep in mind that more stringent serialisation regulations will be phased in eventually, as the ultimate goal is full supply chain traceability.

The bottom line: Smart pharma companies, CMOs and CPOs require comprehensive solutions to help meet the challenges of current and future serialisation deadlines. To meet this need, new tools to strengthen and futureproof supply chains continue to be developed — of which Adents NovaTrack is one example.

Will my long-term needs be met by my overall strategy?

Why invest in a technology that will need to be replaced in the near future? Serialisation solutions should not be approached as one-time, singleuse drop-ins; rather, they should be scalable systems that can address rolling deadlines with phased-in requirements. What knowledge have we gained since starting the serialisation implementation process? Having come to a greater understanding of the serialisation process, we need to look back and consider what we have learned. What have we done correctly? What might we have done diﬀerently? What improvements can be made going forward?

it’s important for manufacturers to think longterm, rather than short-term, and to seek ways to maximise opportunities for growth.

SERIALISATION SUPPLEMENT | ROUNDTABLE

GO THE EXTRA MILE… As we draw ever nearer to the time that compliance with the European Falsiﬁed Medicines Directive (FMD) is required, we discuss the value of serialisation beyond compliance and outsourcing with six leading solutions’ providers…

VALUE BEYOND COMPLIANCE

OUTSOURCING: BEFORE IT’S TOO LATE

While investment in serialisation is being driven by compliance — businesses should look to add value to their operations by implementing hardware and software solutions that oﬀer multiple processes.

The FMD is likely to push many CDMOs away from packaging altogether, as some don’t have adequate resources to continue this while also delivering serialisation. The outcome of this will likely be CDMOs partnering with CPOs, which should be better prepared for the new regulations. This will allow them to deliver the services that their clients require while meeting FMD compliance.

Aggregation may not be a condition of FMD but most global regulations require it, and many pharmaceutical businesses desire it of their partners. Adding aggregation capabilities to a packing line after, instead of in conjunction with a serialisation solution will be costly.

For CDMOs large enough to operate from multiple sites, centres of excellence for the implementation of serialisation may become necessary.

Paolo Landriani, technical department director — SEA Vision

Staffan Widengran, director corporate projects, Recipharm

As the legal landscape for drug serialisation continues to evolve, companies must look beyond short-term compliance requirements and the next major deadline to consider how this will adapt to future legislation, both in the markets they currently cater for, markets they intend to enter in the future and relevant markets that are not yet regulated.

Time is simply too tight to be able to tackle the challenge of serialisation independently. Many companies are now considering external serialisation solutions simply because they have underestimated the scale of the challenge. Many are either still struggling to understand what is required, do not have the in-house expertise or have misjudged the time and resource requirements, not to mention the upfront investment involved.

Future-proofing solutions can be more easily achieved when outsourcing as a partner contract packaging organisation (CPO) can look beyond the day-to-day and will be more versed in the potential future requirements. Colin Newbould, director of regulatory affairs and QP services at The Wasdell Group At FutureLink 2018, industry leaders from across the sector discussed the ways they plan to drive increased business value from their serialisation solution in a series of polls. When asked in which areas they would use predictive analytics to inform their decision making: 63% of respondents said supply and demand forecasting, 16% said inventory management, and 13% said it will inﬂuence decision around operating costs. Attendees were also asked what areas of the supply chain would most benefit from serialisation data, 35% said supply chain services including recall management. Dan Walles, VP Solution Marketing, TraceLink

Engaging the support of a CPO can help to minimise these hurdles, with tried and tested lines, as well as access to expert knowledge making the process more straightforward, eﬃcient and stress-free. Dexter Tjoa, director corporate strategy, Tjoapack Serialisation is far more complex than just placing a barcode on a package. To ensure that all the dynamics of the equipment, the data, and the processes work as they should, implementation cannot be treated as a project for just one or a few functional areas. It requires changes and adoption of new technology and processes in almost all areas of an organisation and the supply chain. Collaboration with each functional area can help to avoid challenges and missed opportunities. Organisations should partner and leverage product solutions that are proven in serialisation and can help aid in not only meeting the minimum requirements but can be scalable to provide additional functionality and services. Being innovative and ﬂexible by making smart investments early on can help set the stage for moving beyond compliance. Lauren Catalano, technical services manager at Sharp

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SERIALISATION SUPPLEMENT

Meeting serialisation As we get closer to the deadline for the European Falsiﬁed Medicines Directive and the need for companies to be fully ready for serialisation, Markus Rosenkranz, leader Serialisation Solutions, Rockwell Automation EMEA, discusses how best to meet the interoperability challenges head on and drive return on investment.

he need for pharmaceutical companies to introduce serialisation technologies into drugs manufacture and distribution to meet existing, incoming and future compliance requirements is well documented. It’s difficult to overstate the scale of damage caused by drugs counterfeiting; the human cost in lives lost and the suffering associated is incalculable. Widely reported cases blaming counterfeits include contaminated blood-thinner medication, home Botox kits, erectile dysfunction pills, and medicines used to battle malaria, tuberculosis and other lifethreatening diseases. Trusted pharmaceutical brands have suffered in public perception, and the combined financial effect on the industry is estimated at around $75 billion per year. A reliable method to prove the authenticity of drugs sold around the world has been a priority for governments and international regulatory bodies for several years, and although there is some way to go before a harmonised global standard is possible, many regions are well on the way to requiring pharmaceutical companies to provide track-and-trace coding on packaging in order to be licensed. A number of companies that operate internationally have advanced strategies and are compliant in regions already requiring various levels of trackand-trace labelling, such as the US (since November 2017) or

are on course for forthcoming EU (February 2019) legislation. Many more however, are faced with a steep learning curve or implementation challenges to remaining compliant; not least overcoming the significant interoperability challenges of an extensive supply chain. MEETING THE SERIALISATION CHALLENGE While the regulations make it clear that serialisation is the solution to protect the supply chain from rogue elements and counterfeit products, it is not prescriptive about how the requisite technology should be implemented. Moreover, there is no universally adopted data format for capturing the aggregated trackand-trace information produced by serialisation to make it available to partners along the supply chain. At the manufacturing level, the new regulations require that every stage of the end-of-line packaging process has tracking capability. This includes machines, printers, labellers and associated vision systems, including barcode scanners. Every stage in the finished goods packaging process must provide a unique serial number to the product barcode or RFID tag. For some products, this might include five levels of what is known as parent-child aggregation, with serial numbers applied from the unit or dose level all the way up to the pallet level. For example, the pallet serial number is a ‘parent’ and must be paired to the unique case serial

ROCKWELL AUTOMATION

head on

numbers it contains — the ‘children’. Similarly, the case serial number is a ‘parent’ of the cartons (‘children’) it contains and so on. INTEROPERABILITY One problem for many pharmaceutical producers at the manufacturing stage is that, historically, many have installed ‘black-box’ automation solutions for their packaging lines. Black-box solutions often contain unique or customised machines, customised software drivers, proprietary networks and unique application software. Applying such complex individual identifiers retrospectively is a huge undertaking that requires high speed data handling capability. Moreover, the re-engineering (and potentially reverse-engineering) required to re-programme and update such a system to the new requirements, where it is even possible to do so, often involves a prohibitive amount of downtime. The resulting system, if it reached the required compliances of today would still be very difficult to adapt again for new regulations in the future, and may struggle to manage any regional variations to requirements to produce drugs for different markets. In addition to all of this, such systems are unlikely to be able to take advantage of some of the benefits and potential return on investment (ROI) of moving to a serialisation solution, such as the kind of the Industrial Internet of Things (IIoT) gains in productivity and efficiency possible in a modern, connected enterprise.

Serialisation legislation requires investment from up and down the supply chain, and a signiﬁcant investment from manufacturers. Importantly though, as with any such investment, manufacturers should also seek a return on investment (ROI)

RETURN ON INVESTMENT Serialisation legislation requires investment from up and down the supply chain, and a significant investment from manufacturers. Importantly though, as with any such investment, manufacturers should also seek a return on investment (ROI) — beyond the indirect contribution to a beneficial reduction in counterfeiting. The latest serialisation methods can help achieve a rapid ROI by making the interoperability between device-level machines and enterprise level information and business systems. This in turn oﬀers manufacturers the opportunity to harvest data that can help increase throughput, aid long-term profitability and further adapt their solutions to future regulation changes. A serialisation solution that includes an integration gateway with preconfigured channels for order creation and the export of EPCIS data that is simple to integrate into the existing system can greatly reduce the up-front engineering cost and reduce the time to achieving ROI. Sustainability for pharmaceutical manufacturers in the face of changing regulations now hinges upon not just meeting the serialisation challenge but leveraging the required improvement in data handling capabilities to safeguard their business in the digital era. The good news is that through serialisation adoption, and particularly when coupled with the best MES technology now available to manufacturers, this is entirely possible. Moreover, by partnering with the right vendor to implement the right solution and lean on the recent and relevant experience they can bring to the factory, drugs producers can benefit from the advantages already being enjoyed by early adopters.

SERIALISATION SUPPLEMENT | ATLANTIC ZEISER

The key to success More and more markets require certain drugs to be serialised. Pharmaceutical manufacturers should not lose sight of the opportunities arising from this obligation. In this interview, Simon Cole, sales executive at Atlantic Zeiser UK, also points out why blockchain is gaining importance in track & trace systems, and what effects can be expected from Brexit. Q. What are the benefits of Track & Trace systems to pharma companies and their customers? A. First of all, they fulfil legal requirements which aim to protect the consumers against counterfeiting. Yet, these systems can also do much more. For example, they can monitor packaging systems as well as internal and external logistics processes. Based on this, processes can be optimised, and components with best versus worst performance and/or quality can be identified throughout the entire supply chain. The overall picture can also provide valuable market information for different regions. Last but not least, serialisation and track & trace codes can be used to establish direct communication to the consumer, which opens the door for generating customer loyalty and gaining valuable customer insight. Q. In the next 10 years, what technological developments can we expect in the field? A. Track & trace systems are becoming ever more powerful and secure.

In particular, the introduction of additional counterfeit-proof coding will increase security and facilitate checks for product authenticity. Also, these systems will increasingly oﬀer further analysis options, with a specific focus on process optimisation and market analysis. But customer loyalty and advertising are also becoming more important with track & trace systems, not least because of the convenient communication options via smart Internet-based portal systems. Q. Can we expect to see a rise in the use of blockchain? A. Blockchain will be the appropriate means to ensure data integrity and validity. This is already being implemented within some track & trace systems, e.g., to secure audit trail messages in databases. Increasingly, however, this technology will also be used in external communications. It typically manages a peer-to-peer network, collectively adhering to a protocol for validating new blocks. Once recorded, the data in any given block cannot be altered retroactively without the alteration of all subsequent blocks, which requires collusion of the network majority. In this respect blockchain is secure by design.

Q. Is Brexit having an impact on pharma serialisation? A. Brexit is making very little difference to pharmaceutical trading in the UK at present although there is a noticeable reluctance by companies to make certain Capex purchases. It is, however, unlikely that any significant changes will be made to UK law, once the EU divorce deal becomes final. As the UK remains a significant player in the pharmaceutical sector, it is extremely likely that pack serialisation will have to be adopted, in order to maintain global reputation and access to worldwide markets. Q. How will the pharma industry regard track & trace technology in the future? A. The pharmaceutical industry will recognise that the big investment in track & trace technology will make our lives safer as counterfeiting will become progressively more difficult. This will also be beneficial for pharmaceutical manufacturers, as counterfeited products will no longer detrimentally affect their image, reputation and turnover. In 10 years from now the pharmaceutical industry will also recognise additional benefits of this technology, which will result in optimised processes, deeper market insight and better access to their customers. Finally, track & trace will become one of the key technologies which is essential for being successful in the pharmaceutical sector.

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FORMULATION

RUN TO FORM? GLP toxicology studies are designed to provide an insight into a drug’s safety proﬁle, however, formulations need to be carefully developed before these studies can be eﬀectively performed. In this article, Stephie Lee, scientist, Oral Drug Delivery at Catalent Pharma Solutions, goes through the important considerations for a successful study outcome.

LP toxicology studies are designed to give an insight into a drug’s safety profile. As the aim is to predict at what level a drug becomes toxic, the doses administered are likely to be substantially greater than those that will ultimately be given to patients. If exposure increases with dose in a linear fashion, development is likely to be simpler and responses become more predictable. However, this is frequently not the case, particularly if the drug is poorly soluble or permeable, where its exposure may plateau before toxicity is achieved, or may not even reach the minimum eﬀective level. Because the exposure is neither linear nor proportional for these drugs, the lack of predictability may lead to unforeseen safety concerns as increasing numbers of subjects are dosed. It is therefore important to design studies very carefully, with the first step to identify a formulation that can provide the exposure needs. Several factors are to be considered: the toxicology dose needed to achieve exposure goals; which animal species are being used, and what the expected translatable results to humans will be; whether

crystalline form of the drug will give sufficient exposure, based on the efficacy and toxicity observed in dose range-finding and escalation or exploratory toxicology studies; how exposure can be increased if the drug has low solubility; and what role permeability, metabolism, transporters and efflux have on exposure. FORMULATION CHOICE A successful study outcome is more probable if the approach to formulation is based on a sound knowledge of a molecule’s properties. Therefore, a good starting point is to determine where in the developability classification system (DCS) it falls. (Figure 1) Class 1 molecules, with good solubility and permeability, are the easiest to work with, as it is normally appropriate to dose them to animals as a solution or suspension. For molecules in Class 2, poor solubility must be overcome, and some form of enhanced formulation should be used to increase solubility and, therefore, exposure. Those in Class 3 and Class 4 have low permeability, which can make them tricky to use as drugs.

FORMULATION DEVELOPMENT When the native form of a molecule exhibits dose proportionality in early pharmacokinetic studies (often DSC Class 1 molecules) and is anticipated to give sufficient exposure, a solution or suspension should suffice. It allows for great dose flexibility and is suitable for both non-rodent species and rodents. Solubility can often be maximised and maintained by optimising the pH, or adding surfactants, co-solvents, or complexing agents to the mix. If a solution is not possible, then a suspension may be developed instead. Typical suspension media include surfactants like sodium lauryl sulphate and suspending agents such as methylcellulose. Appropriate suspensions should be easy to administer at the desired concentration, homogeneous upon preparation, and easy to re-homogenise after storage. If a solution or suspension is not practical, potential alternatives include tablets, or capsules filled with the neat drug substance or a simple blend. While these can be given to non-rodent species, the dosage size may be too large for rodents. The final clinical formulation is often a capsule

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or tablet for a DCS Class 1 molecule, whether the GLP toxicology studies are done with a solution, a suspension, or a solid dosage form. IMPROVING SOLUBILITY DCS 2 molecules have good permeability but poor solubility, and therefore a simple solution or suspension is unlikely to provide dose proportionality or sufficient exposure to achieve toxicity. Bioavailability enhancement will be required to improve the molecule’s kinetic solubility, and possibly also retard or prevent precipitation. However, development strategy is not usually as straightforward as for molecules in DCS 3 and 4, where permeability is poor. For those DCS 2 molecules where absorption is limited by dissolution rate, micronisation, or co-micronisation with a surfactant, may suffice. For those that are solubility-limited but lipophilic, the answer may lie in using a lipid-based delivery system. These formulations are usually straightforward to develop, cost-efficient to make and can be adapted to give a clinical formulation. For those where solubility is a result of its stable crystalline structure, an amorphous dispersion may be necessary, using spray drying or hot melt

extrusion technologies. However, physical and chemical stability challenges are common, and they are more expensive and diﬃcult to develop than the traditional dosage forms. Therefore, an amorphous dispersion should only be considered as a last resort.

dosage form, but if the toxicology formulation is, say, crystalline or amorphous, then the clinical formulation should be too. The exception would be, if the predicted human dose is much lower, then it could be that an amorphous form will not be necessary.

ADDRESSING PERMEABILITY Any molecule that falls into DCS Class 3 or 4 has permeability challenges, which makes formulation for a GLP toxicology study more complicated. It may be possible to promote alternative uptake pathways, such as via the lymphatic system or inhibit active eﬄux pumps, by using certain excipients.

It takes time to develop a formulation for GLP toxicology studies, and to carry out the necessary analytical work to support development and testing of the formulation. Typically, this will require two to four months. It can, however, save both time and money in the long run, as some of the critical questions around solubility, permeability and exposure for the drug will already have been answered.

EXCIPIENT CONSIDERATIONS Careful consideration of excipients is also important: they can aﬀect costs, regulatory pathway and timeline. If a novel excipient is employed to increase exposure, it must always be remembered that extensive supporting safety data will be required. Others, while safe for humans, may have adverse eﬀects in the animal species used to conduct the study. The formulation used in the GLP toxicology study should, ideally, be related to the formulation that will be used in the clinic, albeit at a higher dose than will be given to human subjects. It does not have to be exactly the same formulation or

It takes time to develop a formulation for GLP toxicology studies, and to carry out the necessary analytical work to support development and testing of the formulation. It can, however, save both time and money in the long run…

FORMULATION

A model future Here, Rob Harris, chief technical oﬃcer, and Matt Ling, technical director, Juniper Pharma Services (now a part of Catalent Pharma Solutions), explains why modelling can help to minimise the risks associated with the development of poorly soluble drugs.

hether it’s quickly checking the weather forecast or using a travel app to choose the fastest route home, the use of predictive technology is fast becoming a prominent feature of our lives. In the pharmaceutical industry the use of predictive applications is also starting to change the way we develop medicines. For instance, predictive technologies are now helping to improve the speed and accuracy of decision-making in formulation strategy.

A promising orally administered drug candidate must be suﬃciently soluble within the aqueous environment of the gastro-intestinal (GI) tract to be absorbed into the body. However, it is estimated that as many as 90% of new drug compounds have poor water solubility,1 presenting a significant challenge for producing an eﬀective medicine.

REFERENCES: 1. Am. Pharm. Rev., April 2013, 16(3). 2. AAPS Pharm. Sci. Tech., 2011:12(3):932–937. 3. Mol. Pharmaceutics., 2018:15(5):1826–1841. 4. Mol. Pharmaceutics., 2016:13:3206–3215. 5. Acta Pharm. Sin B. 2016:6(5):430–440. 6. Drug Metab. Dispos., 2015:43:1823–1837.

Fortunately, this problem can be addressed through the use of solubility-enhancing techniques, which can improve the solubility of even the most challenging drugs. Dosage forms such as amorphous solid dispersions, lipid-based self-emulsifying systems and nanoparticle systems can all provide a much-needed boost to solubility. But which solubility-enhancing technique is best suited for your drug? Rigorous in vivo testing of

various formulation types is both time consuming and costly. An approach that is being adopted by pharmaceutical scientists is the use of modelling software to simulate the behaviour of drugs. These can predict the stability of drugs in formulations,2,3 in addition to predicting drug absorption and clearance from the body.4,5,6 By inputting the known or calculated pharmacokinetic characteristics and physicochemical properties of a compound into a computer model that simulates the human body, the virtual system can predict the uptake and clearance of the drug. This predictive software can enable drug developers to assess the merits of diﬀerent formulation types, narrowing the scope of required experimental assessment. The information obtained can then feed into the formulation development strategy and help assess the overall risk of development. Moreover, modelling helps identify information gaps in preclinical studies, informing the drug developer about what further experimental work needs to be undertaken. Another important area of drug development where modelling software can assist is in designing and developing formulations for specific patient populations, which may have diﬀerent physiological characteristics. For example, a formulation specifically for the treatment of young children

must account for the physiological differences compared with adults (such as rate of absorption and metabolism), which can impact on the pharmacokinetics of the drug, influencing its oral bioavailability and overall efficacy. While software modelling is proving to be a valuable tool for assisting drug developers in streamlining drug development programmes, the accuracy of the simulations generated will always depend on the quality of the data applied to the model. Insufficient or inaccurate data will result in a model that does not reflect the actual in vivo activity of the drug. It is therefore imperative that drug developers are armed with sufficient and accurate information to input into the model. The high proportion of practically insoluble drugs emerging from drug discovery pipelines is showing no signs of slowing anytime soon. The developmental hurdles created by these poorly soluble drugs will place a burden on those involved in the process and increases risk of extended timelines and extra costs. Modelling systems are useful tools that generate meaningful data to alleviate the time-consuming in vivo R&D required for understanding and improving drug efficacy, mitigating the risks associated with drug development.

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ANALYTICAL LAB TECHNIQUES

Putting biotech on the map Large molecule drugs are valuable for both the clinic and biotech companies, however, they present a number of additional manufacturing challenges over small molecule therapeutics. Here, Amy Farrell and Jonathan Bones of The National Institute for Bioprocessing Research and Training, and Ken Cook, Suraj Patel, Alexander Schwahn and Jon Bardsley from Thermo Fisher Scientiﬁc, reveal how the latest tools are taking the complexity out of peptide mapping workﬂows.

he biopharmaceutical industry continues to develop proteinbased therapeutics on an ever greater scale. From cytokines to growth factors, hormones to monoclonal antibodies, the growth in protein biotherapeutics has been driven by their value in the clinic and to biotech companies.

Figure 1: Overlaid peptide maps obtained for manual digestion of the monoclonal antibody rituximab performed by five people. Measurements were obtained using a Thermo Scientific Vanquish Horizon UHPLC system, with UV detection.

However, these large molecule drugs present a number of additional manufacturing challenges over conventional small molecule therapeutics. Their greater structural complexity and the requirement for more extensive manufacturing processes mean that robust quality control and assurance are essential to ensure products are safe and eﬀective. As a result, regulatory bodies such as the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have established rigorous guidelines around the control of biotherapeutic production protocols. Comprehensive product characterisation is essential to ensure these complex products function as intended and are safe for patients to use. Peptide

mapping is commonly used to confirm the molecular structure of peptide therapeutics and determine post-translational modifications and sequence variants. This technique is also used to understand how these products interact within biological systems and identify signature peptides for quantitation. Liquid chromatography coupled with mass spectrometry (LC–MS) has established itself as a powerful tool for these purpose, and ongoing advances in technology mean that the technique is capable of delivering powerful insights into protein structure. Despite this uptake in peptide mapping, the numerous, manual steps required as part of workflows have proven time-consuming and vulnerable to human error. In response, the latest advances in sample preparation, automation, separation and detection are simplifying peptide mapping workflows and accelerating the collection of reliable and robust characterisation data. Here, we look at how the latest approaches are cutting complexity and redefining what’s possible from peptide mapping workflows. ENHANCED MANUAL PROTEOLYSIS PROTOCOLS USING DIGESTION KITS Proteolytic digestion plays a key role in peptide mapping. It is used to break up the complex architecture of protein therapeutics into bitesize fragments that can be

used to piece together the overall structure. Trypsin is most commonly used for proteolytic digestion due to its high enzymatic specificity. However, despite being wellestablished in peptide mapping workflows, the in-solution trypsin digestion protocols commonly used for sample preparation are often labour intensive and prone to errors that can compromise reliability. With accurate characterisation fundamental to patient safety, especially in workflows that only employ ultraviolet (UV) detection without confirmation by MS, robust sample preparation and separation methods are essential. Digestion protocols must therefore be reproducible and separation steps must be stable to allow unambiguous peptide identification based on chromatographic retention time. Given the importance of peptide digestion for many biotech workflows, equipment and reagent suppliers have responded by developing kits containing all the relevant solutions required for the robust and reliable digestion of biotherapeutics. These proteolysis kits are capable of providing rapid protein digestion with exceptional reproducibility and sensitivity to deliver high-quality characterisation data. While traditional in-solution digests could often take days to perform proteolysis, some of the latest protein digestion reagents, such as Thermo Fisher Scientific’s SMART Digest kit,

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typically take around 60 minutes to reach completion. When used in combination with the high measurement consistency offered by ultra-high performance liquid chromatography instruments, these workflows provide exceptional levels of measurement reproducibility. In fact, the resilience of the latest systems even allows individuals with no prior experience of protein digestion techniques to achieve accurate and reliable results. Figure 1 highlights the peptide map obtained through the manual digestion of rituximab, a large monoclonal antibody. The digestions were performed by five individuals, several of whom had not conducted a protein digestion previously. In each case, 5 µL of digest solution was injected for LC–MS without further purification, and the peptides were separated using the gradient method. The average relative standard deviation (RSD), across all 20 peaks was 2.74. These impressive findings highlight the measurement robustness that can be achieved using the latest workflow solutions. AUTOMATED DIGESTION PROTOCOLS USING MAGNETIC BEADS Novel digestion technologies are helping to further reduce the complexity of peptide mapping workflows by minimising the level of human involvement required. Magnetic beads are a proven support medium for many sample preparation and purification processes in life science research, and many of the latest automated systems use this technology to boost the productivity of highthroughput workflows.

Automated systems based on magnetic bead technology minimise the manual handling required for protein digestion and ensure that the reactions involved in these workﬂows are timed to perfection to reduce the possibility of post-translational modifications. As a result, these automated systems can reach levels of reproducibility that extend even beyond the high levels achieved using manual digestion kit protocols. Automated systems such as the Thermo Scientific KingFisher Duo Prime platform, for example, can achieve 1.5 times less variance in results compared to those obtained by manual digestion. This high level of performance can make a considerable diﬀerence when more complex proteins are involved.

TOWARDS RELIABLE PEPTIDE MAPPING, EVERY TIME To ensure innovative protein therapeutics are effective and safe to use, and reach patients in the shortest possible timeframe, the quality assurance protocols involved in their manufacture must be robust, reliable and efficient. The latest tools for peptide mapping are helping biotech companies optimise their manufacturing workflows by taking the complexity out of protein characterisation. Thanks to powerful proteolysis digestion kits and automated LC–MS systems, these modern techniques are accelerating output and delivering more accurate results. And because these resilient protocols can be operated by individuals of any experience level, human error is minimised and more consistent results can be achieved.

The latest tools for peptide mapping are helping biotech companies optimise their manufacturing workﬂows by taking the complexity out of protein characterisation.

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APIs/HPAPIs

Curb your enthusiasm… …not all highly potent compounds require extreme containment! In this article, Jeﬀ Pavlovich, senior process safety engineer at Cambrex Charles City, examines the intricacies of risk assessment and the importance of a realistic approach.

here is a growing demand for capacity for the manufacture of highly potent active pharmaceutical ingredients (HPAPIs). This is partly due to the growing number of molecules in drug development pipelines that are thought of as highly potent, but it also reﬂects the fact that some of these drugs are now reaching patent expiry, and are now subject to generic competition. HPAPIs need to be carefully handled in a contained environment and before a synthesis is begun, a full assessment of the potential hazards of manufacturing and handling of the products must be carried out. As well as the HPAPI itself, every reagent and intermediate requires assessment, and for a contract development and manufacturing company (CDMO) or plant manager, there is a careful interplay of ensuring the appropriate potency strategy for the safety of operators and the local environment, and the avoidance of overlaying excessive operating costs to customers by over-specifying the containment required.

DEFINING POTENCY If a compound has an eight-hour time-weighted average occupational exposure limit (OEL) of 10 µg/m3 or less, it is deemed ‘potent’. In the absence of a formal definition of ‘highly potent’, however, diﬀerent risk assessors may define the hazards posed by an individual compound diﬀerently. Some take a very conservative view, and may decide that most potent molecules are in fact highly potent; whereas others will deem very few to be highly potent.

including the OEL. A large amount of safety data will already have been compiled for any molecule that is heading into large scale manufacture. As well as pre-clinical toxicology and animal studies, this may also include insights gleaned from Phase I clinical trials. This is used to inform the OELs and Occupational Exposure Bands (OEBs) determined by risk assessors, and then to select the appropriate containment and personal protective equipment, as well as the engineering strategies that will be applied.

It is important to remember that potency is not the same as toxicity. A drug may be both highly potent and toxic, but this is not necessarily the case. A highly potent drug is one for which only a very small dose is required to give a therapeutic eﬀect, but by no means is it a given that it will also be highly toxic. Both have an impact on the way it will need to be handled in the manufacturing facility.

However, toxicity data from preclinical and clinical work do not directly translate into the process of determining an OEL: they are designed to discover at what level the drug should be dosed to humans, bearing in mind its therapeutic effect and the side-effects it may cause. There is a huge difference between orally imbibed or intravenous exposure, and the route by which operators might be exposed in the facility, which is far more likely to be inhalation or topical contamination.

The first step for any risk assessment is to gather known information about the safety properties of the molecule,

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It does, however, give insight to what effects might occur with both acute and chronic exposure. Acute problems might include respiratory or lachrymatory problems, whereas chronic effects could be that the compound is carcinogenic, mutagenic or a sensitizer on prolonged exposure. THE SPECTRUM OF EFFECTS The dose–response curve gives an insight into effects. At the no observed effect level (NOEL), a compound has no biological effect. Next is the no adverse event level (NOAEL), which is often mentioned in risk assessments. Continuing up the curve, there is the low effect level (LOEL), and the low adverse effect level (LOAEL), then well-tolerated doses. After the maximum tolerated dose has been reached, any higher doses are likely to prove hazardous. In animal models, ED50 represents the dose at which half the test subjects will experience an effect, whereas at TD50 half will experience toxicity, and LD50, half of test subjects will experience a lethal dose.

When calculating a molecule’s OEL, various uncertainty factors will be included to compensate for the fact that not everything is known about the compound. Components that can affect it include the duration of the study, inter-subject variation, the severity of the effect, and factors such as bioavailability, bioaccumulation and pharmacokinetics. Some risk assessors will also include modifying factors. These might be the slope of the dose–response curve, the clinical significance of a critical effect and whether it is reversible, and whether this is relevant to operators within the plant. With so many uncertainty and modifying factors that might be included, there is little wonder that there is so much variability from one risk assessor to the next — it is not unheard of for the OEL from one assessor being 100 million times greater than the OEL established by another. LOOKING AT THE REAL WORLD Getting around this variability in risk assessments involves the application of real world context, notably a consideration of what level of exposure risk is acceptable for an operator. A starting point of one-in-a-thousand, is probably more true than one-in-a-million. Taking a more realistic view can have a huge impact on cost, and this is why the use of categorisation of molecules into OEBs is more

useful to inform containment requirements. A compound in OEB1, the lowest level, is non-toxic, and an OEL of 500 µg/m3 is appropriate. Moving up, an OEB2 compound will be more hazardous, and so the OEL has to be lower; and similarly, OEB3 chemicals have greater hazards. The highest banding, OEB4, represents those molecules where the hazards are extreme, and containment must be at the forefront of engineering design. It is at the OEB3 level where significant savings can be made by taking a real-world view. A theoretical OEL is based on an eight-hour exposure, but if the operator could only ever be exposed for a few minutes, then containment and protection requirements are not so great. It may be that containment within a normal plant will already be acceptable; otherwise relatively low-cost options such as HEPA filters or additional soft-sided isolators could be suﬃcient. Surrogate testing should be used to prove that this approach will be successful. By taking a realistic approach, it is clear that some compounds that might be considered highly potent do not, in reality, require extreme containment. Isolators should be reserved for those projects for which they are truly necessary. HPAPI capacity can easily be maximised and costs minimised by not using an isolator where it is not needed.

By taking a realistic approach, it is clear that some compounds that might be considered highly potent do not, in reality, require extreme containment.

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CLEANROOMS

TIME FOR A CLEAN OUT Here, Andrew Ramage, microbiology product specialist, Cherwell Laboratories, puts outsourcing of microbiological growth media under the microscope revealing the beneďŹ ts and what makes an ideal media manufacturer.

nyone who manages or works in a microbiology laboratory will know how time consuming and resource hungry making microbiological growth media is. Speaking from experience, during the early days of my career as a microbiologist working in a small food testing lab, the making of media and the subsequent growth promotion testing took up a significant portion of the day. Valuable time when there were hundreds of samples to test and report. The autoclaves had to be cleaned regularly, as well as maintained and calibrated. Any problems with the autoclave would bring testing to a grinding halt, especially if you did not have an adequate stock of media. The same could be said if the media failed growth promotion and pH testing. If all the above seems familiar, maybe it is time to consider outsourcing your microbiological growth media? SHORT-TERM VERSUS LONGTERM SAVINGS You may think that making media in-house is a lot cheaper than purchasing media externally. However, that depends on how you do your calculations. At the most basic level, you may only be looking at the cost of the media dehydrate, supplements, water and containers (petri dishes and bottles). Compared to pre-prepared media, that is true. To get a more accurate reďŹ&#x201A;ection of the cost have you

factored in the cost of employing and training staďŹ&#x20AC; to make the media? The cost of running the autoclaves daily? Equipment calibration and maintenance; balances and pH meters as well as autoclaves? The cost of validating autoclave cycles? Maintaining a clean environment to manufacture media to avoid cross contamination with other media? Investigating media quality issues? Not as cheap now, is it? Outsourcing of microbiological growth media removes all the above from your workload. A highquality media manufacturer will do all that for you, freeing up your valuable time and resources. The media manufacturer is also able to buy raw materials in bulk, which reduces the unit cost compared to the relatively small usage of an individual laboratory. ENSURING QUALITY As a customer, you will expect the highest quality product. To do so internally is a drain on resources. What makes a good media manufacturer and what does a media manufacturer do to ensure quality? Starting at the top level, the manufacturer should have a defined, robust quality system in place, in all areas of the company. This will encompass sales, accounts, quality, production, maintenance and warehouse. You should expect a minimum of ISO 9001 accreditation. The manufacturer will make media in dedicated facilities of cleanroom grade to reduce the chances

of contamination and crosscontamination. All the equipment will be calibrated regularly with a planned preventative maintenance regime to ensure reliable operation. The water used, whether WFI (water for injection) or demineralised, will be of the highest quality, so should have a low microbial count and conductivity. The raw materials will be sourced from trusted suppliers who have been vetted by the manufacturer, both for quality and reliability of delivery. Such materials will include media dehydrates, supplementary additives, petri dishes, glass containers, even the labels and packaging. Combined, the media will be manufactured via a validated, consistent, fully documented process. After manufacture comes the quality control checks and inspection. The media manufacturing process is not perfect, so it is vital you can have confidence that the media performs to your expectations. There should be no particulates or air bubbles in agar plates that may give false results, and no excess moisture on the agar surfaces before packing. A good manufacturer will have a thorough inspection process of the media before packing, employing a well-trained team able to spot the smallest imperfections. The quality control testing in the laboratory should conform to the prescribed methods depending on the regulatory requirements that medium will be used in. These will

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include numerous ISO standards, or GMP regulations as set out in the European Pharmacopoeia, or US Pharmacopeia. Testing of the product does not end at release, the manufacturer should be able to guarantee performance throughout, if not beyond, the stated shelf life of the product. BESPOKE SOLUTIONS Does your media supplier only sell catalogue items, or can they be flexible to meet your needs? To ensure minimal disruption and smooth validation of outsourced media you may want a product in a packaging format that is close to what you are making in-house. There is enormous variation in the types of products being tested, off-the-shelf products may not meet your exact requirements (which is why you are probably making media/buffers/diluents in-house). An exact or close match will make validation far easier. You should be able to talk to the supplier or manufacturer to have media that is manufactured to your specifications at a sensible price. DELIVERY AND RELIABILITY The one thing a media manufacturer cannot replicate is being able to make media immediately there and then. Even I admit that is one of the great attractions of making media inhouse. The manufacturer however should be able to guarantee a reasonable lead time on your order. The product that arrives should also have the maximum possible shelf life remaining. There is nothing more annoying than ordering an item with a six-month shelf life, only to find it has two to three months remaining when you receive it. Part of that reliability should be having a proven track record at processing orders efficiently. If you know of other customers of that manufacturer, it will be good to get their opinion on the service they supply.

OPEN AND HONEST The final point to make is that your manufacturer should be open and honest. It may be a regulatory expectation you audit your suppliers on a regular basis. Your supplier should be ready and willing to host customer audits with the appropriate personnel on hand to answer your questions. They should also take on board any issues you may find. A good manufacturer will always see an audit as an opportunity to make improvements, not as a box ticking exercise.

A good manufacturer will always see an audit as an opportunity to make improvements, not as a box ticking exercise.

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CLEANROOMS

Fresh thinking

John Rush subject matter expert — HVAC, from specialist cleanroom design and construction provider BES, discusses strategies for designing more energy eﬃcient cleanrooms.

he environmental footprint and operational cost of a cleanroom facility is usually secondary to considerations of functionality and performance. However, the aims of environmental efficiency and technical compliance are not mutually exclusive. In fact, a holistic approach to designing energy efficiency into the requirements of a cleanroom can result in a working environment that meets good manufacturing practice (GMP) requirements, while complementing the wider energy management strategy of the site or organisation. CAUSES OF CLEANROOM INEFFICIENCY Depending on the specific class or application of the cleanroom, up to 60% of the facility’s energy consumption is usually accounted for by its HVAC system. Ostensibly, this is unavoidable because of the need to maintain a controlled environment through heating, cooling, humidity control, air changes and pressure regimes. However, innovative design approaches and bespoke specification can reduce energy demand of HVAC systems by as much as 50% by avoiding common assumptions and overspecification. Generic commercial thinking often pervades specification of the HVAC system with a tendency to over-specify on a ‘just in case’ basis. This can have a significant and unnecessary impact on the facility’s energy consumption, far beyond the negligible additional energy loads involved in futureproofing a centrally air-conditioned office

of a similar size, where air flows are likely to be around five times less. Consequently, part of the cleanroom specialist’s remit is to fully interrogate the brief and understand the immediate needs of the organisation, which may result in a reduction of the proposed space or a modification of the layout aligned to the equipment, processes and designated staff numbers, when preparing the user requirement brief (URB). The impulse to over-specify is often underpinned by the lack of clarity offered by current guidance, which does not stipulate how air change requirements should be achieved. Moreover, common specification practice does not take sufficient note of advances in calculation methodology and filtration technology that could enable reduced flow rates — and enhanced energy efficiency — while achieving the required cleanroom standard. Energy consumption is also increased by the assumed need to ensure an operational environment within the cleanroom at all times, despite the disparity in particles entering the space when it is unoccupied. By altering the temperature, humidity and air change parameters for non-operational hours, energy consumption can be reduced by up to two thirds, without de-validating the cleanroom’s classification status. If a wider temperature and relative humidity band is set for non-operational hours during initial validation, and

pressure regimes are maintained during these periods, much less cooling (for humidity control) and re-heat energy (for temperature balancing) is required. DESIGNING ENERGY EFFICIENCY INTO THE SPEC It is commonly assumed that cleanrooms do not need to comply with Part L building regulations, but all cleanrooms can comply with Part L and it is often possible for them to meet the requirements for a RICS’ SKA rating for sustainable fit out too. To achieve this, the cleanroom specialist must evolve the specification in line with the developing brief from the end user, while using best practice data and modelling from previous installations to demonstrate how high standards can be achieved using less energy. The design team must also consider ancillary accommodation — such as change areas, stores and access routes — to ensure the pressure regime strategy supports an energy efficient approach. As the cleanroom requires more cooling energy than heating, cooling system efficiency should be prioritised. Where possible latent (moisture) and sensible (heat) cooling systems should be separated to enable the use of high efficiency chillers and free cooling. For higher ISO classes (with lower cleanliness standards), where the clean air requirement is similar to the cooling demand, a traditional air conditioning system may be sufficient, with

48 heat recovery contributing to the re-heat requirements of humidity control. For facilities with a lower ISO classification (higher cleanliness standards), where air change rates exceed those required for cooling, partial conditioning with separate latent and sensible cooling units will reduce the fan, cooling and re-heat energy load. Outdoor air conditioning is the most appropriate option for larger or multi-cleanroom high standard facilities, where air change rates exceed those required for cooling. Here, sensible cooling is provided by a separate, primary air handling unit (AHU), removing the need for re-heat and enabling the use of high temperature chilled water from very efficient chillers, combined with free cooling, to serve the primary AHU. In cleanrooms requiring very low space relative humidity, desiccant dehumidification may be specified for use in combination with the most appropriate HVAC. Selection of the most suitable HVAC approach is pivotal to an energy efficient specification, but it is the detail of the HVAC design that will provide the most substantial and sustainable energy reduction gains. Innovative design methodologies for reducing air moisture content before the air reaches the cooling system can significantly cut the cooling energy load, for example, and a more complex, multi-layered HVAC system will use substantially less energy over all. HOLISTIC THINKING An expertly-designed HVAC should be specified in combination with a thermallyefficient building envelope. The use of renewable energy sources can also enhance sustainability and drive down operational costs. For example,

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ground source heat pumps are ideal for the lower temperature outputs required by heating coils in air handling units and CHP is an energy efficient solution for larger sites. Low energy plant and equipment, such as efficient boilers, chillers and fans can all contribute to more energy efficient cleanrooms, along with LED lighting and presence-detection controls, which can enhance the lighting scheme while reducing energy waste.

ACHIEVABLE CHALLENGE The core principles of energy eﬃcient building services still apply to cleanroom facilities; they simply require a more sectorspecific, innovation-led design approach. As the pharmaceutical industry continues to be held to account on matters of environmental impact and sustainability, while addressing the challenges of operational cost management, designing energy eﬃciency into cleanrooms is an achievable challenge that should and can be met.

…a holistic approach to designing energy eﬃciency into the requirements of a cleanroom can result in a working environment that meets GMP requirements, while complementing the wider energy management strategy of the site or organisation

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CPHI PREVIEW

A CAPITAL IDEA!

As we look towards this year’s exciting CPhI Worldwide, taking place in Madrid, Spain, the organisers detail the multitude of opportunities event attendees can proﬁt from during their stay in the Spanish capital.

PhI Worldwide is back, and this time in one of the worlds burgeoning biotech and pharma hubs, Madrid. The city is perfectly placed in the centre of Europe to serve as the ideal location for following pharma trends, finding pharma products and meeting pharma people. CPhI Worldwide will be held 9–11 October at IFEMA, Feria de Madrid, Spain. A TIME FOR INNOVATION The event returns in what has been a particularly stellar year for new drugs, with an outstanding 46 FDA and 92 EU approvals made in 2017. Not only this but innovation is finally reaching the market with the approval of Luxturna heralding a new age of fast-tracked gene therapies. With over 1000 biologics under development and artificial intelligence (AI) and 3D printing technologies advancing, the pharmaceutical market is currently a hotbed of innovation. In this dynamic time for the global pharma industry, CPhI Worldwide provides an opportunity to come together and focus on the latest trends, technologies and insights. Above all else, it is a platform for the industry to drive forward new partnerships, do business and grow. WHAT TO EXPECT AT THE EVENT? Building on last year’s success, which saw a record 45,000 senior pharma professionals in attendance, CPhI Worldwide 2018 will host 2500+ exhibitors in 20 easy-to-find zones covering the end-to-end supply chain — from ingredients, APIs, excipients,

contract services, packaging, machinery and more. Away from the pharmaceutical ingredients hall, attendees will also have access to co-located events, allowing them to easily locate exhibitors ready to meet their business needs: • ICSE connects the pharmaceutical community with contract service providers — with representatives from clinical trials services, logistics providers, data management, CROs and CDMOs. • InnoPack allows buyers to investigate the newest innovations in pharma packaging solutions, including anti-tempering devices, drugstable barrier solutions and single dose applicator systems. • P-MEC Europe features international exhibitors and manufacturers from pharmaceutical equipment companies focused on instrumental analysis, measuring and testing technologies, materials testing, laboratory and quality control. • Finished Dose Formulation (FDF) brings together every aspect of the finished dosage supply chain, from big pharma and CMO to in/out licensing and dossier specialists. INTRODUCING… In a year that has seen rapid advancement in the biologics field, CPhI Worldwide will host pioneers from the bio-industry — including top industry execs, R&D’s innovative thinkers and bio-service providers — at new event, bioLIVE.

Focused on examining the intersections between business and biotech, bioLIVE will present special sessions on the emerging role of AI, tackling the workforce shortage, and the technical and scientific innovations that are shaping the industry today. Industry thought-leaders will exhibit their ground-breaking ideas and technologies, ready to grow partnerships in the most efficient way. BEYOND THE EXHIBITION A series of Pharma Insight Briefings provide the go-to space for pharmaceutical professionals looking to explore emerging therapeutic areas and new business opportunities. In these in-depth, high value seminars, unbiased information on trends, industry developments and the latest regulatory insights will be shared — encouraging attendees to develop strategies that will grow their business. Meanwhile a snapshot of the most interesting, innovative and game-changing products coming to the market can be found in the Innovation Gallery. For a more in-depth look, register for an Innovation Tour, where the CPhI exhibition floor will be explained with inside information on API selection and successful generic formulation development. CPhI’s Women in Leadership Forum (Wednesday, 10 October) will return for the fifth year, in what has been described by attendees as a ‘wonderful opportunity to think outside of the box, in an industry dominated by men’.

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Serving as an exceptional networking opportunity, the forum allows women to share their experiences, expertise and leadership techniques. For the first time this year, men will be welcomed to join their female colleagues at this event to facilitate conversation around how men and women can work together to diversify pharma. Additionally, CPhI will this year play host to the Big Data & Machine Learning Summit — Europe (Wednesday, 10 October) in collaboration with The Innovation Enterprise. Covering key topics such as the role of big data in the supply chain and analytics in drug development and discovery, this conference will bring together forwardthinking researchers and data scientists to discuss their latest findings. STAY CONNECTED Attendees are invited to login online and use the Live Pharma Connect one-to-one business match making tool which allows

visitors and exhibitors to prearrange their meetings. The system automatically finds the best matches — ensuring key contacts are made by all. Additional event planning tools available online can be utilised for a smoother experience. Remember to download the CPhI Worldwide App which provides exhibitors and attendees with a timetable of the day’s activities, a list of exhibitors and their hall location. AWARDING EXCELLENCE Following the incredible success and popularity of last year’s awards, a greatly expanded CPhI Pharma Awards Gala Dinner (Tuesday, 9 October) will take place at the Eurostar Madrid Tower, with 500 inﬂuential pharma guests expected. Among the most famed accolades in the pharma industry, former winners of the CPhI Awards feature a ‘who’s who’ of pharma executives. Last year, over 200 applications were received, and a total of 17

commendations will be awarded to celebrate the innovation and skill shown in the pharma industry today. AND FINALLY… Hosted in the landscape of one of Europe’s burgeoning biotech and pharma hubs, Madrid, CPhI Worldwide promises to be an unmissable opportunity to discover the latest and most innovative advancements, catch up with old contacts and form vital new partnerships that will push the industry to the next level.

Hosted in the landscape of one of Europe’s burgeoning biotech and pharma hubs, Madrid, CPhI Worldwide promises to be an unmissable opportunity to discover the latest and most innovative advancements…

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DIGITAL HEALTH

Tech on trial Recruitment into clinical trials can be a testing task, leading to a push more recently into patient-centric approaches. Technology is a major resource in this respect but there are some important aspects to consider as Mike Novotny, founder and CEO of Medrio, discusses further.

great deal of recent research has looked into the top challenges the clinical research industry faces today, and the conclusion always seems to be the same: Patient recruitment is among the greatest obstacles, if not the number one, that researchers say stands in the way of clinical trial success. As a result, the industry has seen a great push, in recent years, to make clinical research more patientcentric, expand eligibility criteria, and thereby shore up enrolment numbers enough to keep their studies moving.

as conversation continues to swirl around mHealth and wearables in clinical trials, one can’t help but wonder about the patientcentricity value of these methods of remote data collection

Technology has been a major resource for organisations who have embarked on these endeavours. How does technology play a role in patient centricity, and what do organisations need to consider as they begin to take advantage of it? MEETING THE NEEDS OF PATIENTS Among the greatest factors behind the recruitment and retention struggles the industry faces are a wariness of unproven treatments (often referred to as the ‘guinea pig fear’) and the fact that, for many potential clinical trial subjects, committing to regular site visits over a period of months or years is inconvenient or simply unfeasible. In this light, it will be interesting to see to what extent

organisations utilise advancing technology to mitigate these challenges. As patient reported outcomes, for example, go electronic, researchers are empowered to better demonstrate an investment in the patient experience and ensure patient safety and comfort. And as conversation continues to swirl around mHealth and wearables in clinical trials, one can’t help but wonder about the patient-centricity value of these methods of remote data collection: The ability to collect data remotely, without a site visit, could significantly reduce the burden of clinical trial participation. It’s necessary, however, to keep any optimism cautious. For the use of next-generation technology to truly be feasible, there are some important considerations. For one, any technological platform in use for remote data collection will need to be able to transmit that data to the central EDC or other eClinical system in use in the study; APIs will need to be in place to streamline integration, so that manual data transfer doesn’t slow down study timelines. It’s not enough for a wealth of technological solutions simply to exist; they need to be able to work with one another, as well — and until they do, it won’t be feasible to harness them for patient centricity or any other purpose.

WHAT DO REGULATORS HAVE TO SAY? Then, of course, there’s the regulatory question. During technological boom times, the creation of innovative solutions can outpace the evolution of the regulatory frameworks that govern their use. In an industry as sensitive to regulations as clinical research, this is an essential consideration. The good news, however, is that major regulatory bodies have recognised the promise of innovative clinical trial technology, and have moved to announce their encouragement and develop guidance around it. Since 2013, the FDA has been oﬃcially in favour of eSource; just in the last year or so, institutions ranging from government, nonprofits and the private sector have collaborated to hash out guidance and recommendations for the use of mHealth technology in clinical trials.

DIGITAL HEALTH

Get connected!

John Rush subject matter expert — HVAC, from specialist cleanroom design and construction provider BES, discusses strategies for designing more energy eﬃcient cleanrooms.

harmaceutical makers have a patient engagement problem. Wearable makers have a user engagement problem. Each could be the other’s solution. But first they need to understand exactly what they need to oﬀer patients. It may be heresy, but clinical outcomes may not be the top priority. Studying employer driven programmes suggests wearable adoption today is not necessarily driven by clinical results, but rather for engagement. And the foundation of engagement is community. Adherence software company Adherium’s vice president of marketing, Vik Panda recently noted: “Combining community and technology to support health goals is not a new discovery, as the combination deserves credit for the massive success of fitness companies like Strava, Aaptiv and Peloton. Data about your health is good, but you need a community to put it to work.” New or not, community needs to be central.

REFERENCE: 1. https://www.pgeu.eu/en/ policy/5-adherence.html

PHARMA HUNGERS FOR WEARABLES’ ENGAGEMENT AND DATA For drugmakers wearables are a tantalising option to address adherence. In industrialised countries therapy adherence can average at about 50%. Nonadherence represents an estimated $100 to $300 billion annual burden on the US healthcare system alone and according to the Pharmaceutical Group of the European Union it is estimated to cost the EU €125 billion per year.1

Pharma companies also want access to patient data in as many forms as are available, beyond clinical trials. But therapy makers have historically been the furthest away from patients and their data, trying to peer over the heads of providers and payers in the front row seats. Roche’s $2 billion acquisition of Flatiron Health takes this on, acquiring a sophisticated data team working with 265 cancer clinics and six research centres. Connected devices are of special interest. In clinical trials Adherium’s Hailie asthma and COPD solution — based around a sensor and nudges that integrate with inhalers — was found to support improved adherence by children by 180%. Overall an 80% reduction of acute asthma attacks was achieved. This can represent a boon for drug companies, but wearables have many suiters. PROVIDERS ENTER THE WEARABLES MARKET Klue, a software company focused on behaviour tracking and change, recently announced a partnership with Crossover Health in the latter’s clinics. Klue’s new Mindful Eating Messenger shows the power of artificial intelligence by recognising when, how fast and how much a person consumes through the nuanced movements of their wrist. Personalised, actionable micro-nudges to adopt specific consumption behaviour can be oﬀered to empower users to create and hold onto new habits. The ability of hospitals to manage this kind of data is turning a corner.

Gray Matter Analytics announced the launch of its CoreTechs Analytics as a Service solution for providers. It leverages advanced machine learning to continuously improve data quality and allow providers to work with clean, dirty, structured and unstructured data — accelerating innovation. ….AND THEN THE PAYERS Most important are carriers. Insurtech startup Zipari has launched an insurance member Mobile App to enhance the health plan onboarding experience with biometric login verification, reduce administrative costs with chatbots that guide members through a rich self-service user interface, help members find doctors and hospitals with integrated geolocation, and drive wellness initiatives. The core of Zipari’s software uses predictive analytics to provide customer profiles based on consumer interactions including through wearables. Spurring this along is an eﬀort to build a standard data ecosystem for insurance — including for formularies and potentially extending out to wearables data. Vericred is a healthcare data services company serving as a data translation layer between insurance carriers and insurtech companies. Today, they deliver plan design, rate, provider network and key formulary data for medical insurance product lines. As health insurance formularies become more restrictive, knowing if a drug is covered and how much a consumer will pay for that drug, is critical when shopping for a health plan.

The shifts are dramatic. But in the end if drugmakers, wearables makers, providers and payers are to succeed, as the employer data shows, community will be key.

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Pharma companies have to work to collaborate from a position of strength. Wearables are the unique thread through it all with their ability to provide live streams, sitting on the wrist throughout the day. But wearable makers are having some diﬃculty keeping wearables on wrists, and they are looking to health. WEARABLE MAKERS SEE HEALTH AS THE SOLUTION Wearables businesses are working to be more than providers of novelties that are used for a few months and then end up in the gadget drawer. Some have seemed nervous about health, Nokia sold its digital health business back to its founder. But many more are noting the enthusiasm of employers for building wellness programmes around wearables. According to consultancy Endeavors Partners, this year

it’s believed US employers will integrate more than 13 million wearable devices into wellness programmes and even in light of updated privacy laws in Europe there is still growth in workplacebased fitness tracking. When employers prioritise goals for wearables, 77% said they want to increase employee engagement with their health, a close second is the lower bar of wanting to add a fun element to a wellness programme, coming in at 74%. After that 62% said they want to see improvements in employee health, which is a higher expectation with the potential for clinical measures. The problem of wearables’ waning novelty seems to recede when integrated into a community like that of a workplace. Fifty-four percent of employers said the majority of employees were using the wearables they were provided six months after programme

launch and 95% said they would continue oﬀering wearables. On demand like this, the smartwatch market is expected to hit nearly $18 billion in 2020, according to IDC. Fitbit recently unveiled health-focused features with a heart-rate monitor and a sensor to estimate blood oxygen levels. It is launching audio coaching sessions and virtual trainers that can organise personalised fitness routines. The company has also expanded toward guided wellness programmes that counsel users to eat and sleep healthier. Apple and Xiaomi, plus Alphabet’s Android are making aggressive moves in health as well. The shifts are dramatic. But in the end if drugmakers, wearables makers, providers and payers are to succeed, as the employer data shows, community will be key.

for medical devices, pharmaceutical manufacturing and digital health. Keep up to date with key developments that matter.

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TECH TALK

Trustworthy transactions This time in Tech Talk, Dr Neil Polwart, Novarum founder and BBI Group head of mobile, looks at blockchain technology in mHealth.

here can be few people working on a mobile health (mHealth) concept who haven’t been asked: ‘Are you using blockchain?’ Blockchain technology is the underlying principle behind virtual currencies such as Bitcoin. The idea is simple, elegant and solves a key problem with currency transactions — yet, how can you trust the transaction without relying on a central authority to authenticate it? So, does blockchain have a role to play in mHealth? Possibly. However, it certainly isn’t a panacea and, likely in many implementations, does little to actually solve security or privacy issues. The idea behind blockchain is simple, each time a transaction is performed it is passed through an algorithm which generates a seemingly random string of letters and numbers — known as a cryptographic hash. Change any of the inputs to the algorithm, even slightly, and a totally diﬀerent hash is returned, but if you enter exactly the same inputs, you will receive exactly the same output and so it is easy to verify whether content has been altered. One of the inputs to the algorithm is the hash from the previous transaction in the chain and this continues all the way to the original transaction. As a result, it becomes impossible to alter any individual record without also updating every other record in the chain.

If the list of transactions (often referred to as a ledger) is stored in multiple locations (a distributed ledger) and rules are in place to resolve conﬂicts between the multiple copies, it becomes possible to authenticate a transaction without relying on a central trustworthy source. The downside of blockchain is inherent within its design. The computational eﬀort and complexity in generating blockchains are what brings the inherent robustness, but also uses huge amounts of electrical power and so their green credentials are poor. Moreover, the concept that transactions can be checked implies that their contents must be visible or accessible to others. One solution is a ‘private blockchain’ held by the institution — however, that brings little benefit over a classic secure database. Conceptually, some medical records could be held by and only decrypted by the individuals involved, in some ways mimicking how people ‘hold’ Bitcoins. However, if you lose your credentials you lose the value of the coins — a mistake some people have found very expensive. Not many of us can say that we have never forgotten a password or lost a file which we forgot to back-up. Now, what if the consequences of that were the loss of medical records? Given that many patients are the most vulnerable in society — expecting them to manage a technological solution may be impossible.

One of the main benefits of blockchain is the ability to move away from a single trusted central authority. That benefit is primarily of importance where there is a risk that a central authority might intentionally manipulate data. However, if we have lost faith in our medical providers not to modify our data then we have a trust issue, which seems way more fundamental than data storage. It is clear society and its lawmakers still trust medical professionals with extremely sensitive data, with the recent GDPR regulations having special carve outs for data where doctor-patient confidentiality could be assumed for example. The greatest vulnerabilities to medical data security come from two completely diﬀerent extremes — firstly, poor user compliance and secondly, in system-wide security vulnerability that enables hackers to access data. Rather than jumping on the blockchain bandwagon as a marketing stunt to suggest we have unparalleled security, we would be better investing our eﬀorts in good userexperience to help avoid people using bad practice, adding features such as two-factor authentication and designing infrastructure and software that is robust to attack and kept up-to-date. So, I suggest if you are asked; ‘Are you using blockchain?’, ask yourself what problem you are trying to solve first.

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