EPM January/February 2019

THE YEAR AHEAD

DATA AND THE SUPPLY CHAIN

PACKAGING FOCUS

January/February 2019

TAKING THE ADVANCED APPROACH

Nemera examines the design features that help improve adherence for patients using nasal spray devices

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Contents

January/February 2019 | Volume 19 Issue 1 REGULARS 5 EDITOR’S DESK

Between multi-million-pound mergers and the ongoing implications that Brexit could place on the industry, pharma firms are now cautiously waiting to see what 2019 has in store for them.

6 A SMALL DOSE

A brief round-up of some of the latest developments in the industry, including a collaboration driving the discovery of cancer drugs and the pharma company keeping on top of their social media game.

9 NEWS ANALYSIS

Is the Industrial Strategy the shining light amongst Brexit?

12 OPINION

How life science companies are embracing digital transformation.

16 COVER STORY

How Nemera is innovating in the drug delivery space to improve adherence for nasal spray patients.

FEATURES 14 SINGLE-USE TECHNOLOGY

Why patients are the ultimate beneficiaries when pharma manufacturers implement single-use systems.

18 IMPROVING OPERATIONS

Looking at the growing importance of Advanced Planning and Scheduling (APS) systems.

20 DRUG DELIVERY

How powder testing helps manufacturers define standards and a drug delivery technology that could help reduce opioid dependence.

24 PACKAGING

Brexit implications in pharma, using suitable adsorbents to reduce moisture and odour, and the latest developments in smart packaging.

30 THE YEAR AHEAD

Major names in pharma look ahead to see what 2019 has in store for the industry.

33 SOLID DOSE MANUFACTURING

An in-depth case study looking at the challenges of tablet production and the technology used to rectify capping issues.

36 AMReview

Reece Armstrong sits down with biopharma group Helperby on how it’s helping tackle anti-microbial resistance (AMR).

39 INDUSTRY 4.0

The steps needed by pharma manufacturers towards digitisation.

42 GENOMICS

How this personalised risk assessment test could improve breast cancer diagnosis.

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A CHANGING LANDSCAPE

T

he start of 2019 has seen its fair share of interesting developments for the pharma industry.

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Between multi-million-pound mergers and the ongoing implications that Brexit could place on the industry, pharma firms are now cautiously waiting to see what 2019 has in store for them.

EDITORIAL editor reece armstrong reece.armstrong@rapidnews.com group editor dave gray david.gray@rapidnews.com

Here in the UK, the government’s actions towards ensuring a steady and indeed safe supply of medicines draws parallels with hoarding money in your mattress in case the banks close down - except in our case it’s the ports which are at risk of shutting down.

head of content, life sciences lu rahman, lu.rahman@rapidnews.com assistant editor Ian Bolland ian.bolland@rapidnews.com publisher duncan wood

PRODUCTION head of studio and production sam hamlyn design robert wood

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

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Volume 19 Issue 1 © January/February 2019

While every attempt has been made to ensure that the information contained within European Pharmaceutical Manufacturer is accurate, the publisher accepts no liability for information published in error, or for views expressed.

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Between multi-millionpound mergers and the ongoing implications that Brexit could place on the industry, pharma firms are now cautiously waiting to see what 2019 has in store for them.

Well, shutting down might be a bit of an overstatement but health secretary Matt Hancock’s statement about a potential delay of six months across Dover and Folkestone does nothing to stem worries about access to potentially life-saving drugs after we leave the EU. I apologise if this column doesn’t take you into the New Year with a positive attitude, but the pharma industry’s scepticism surrounding Brexit should highlight the precarious situation the government and most importantly patients find themselves in.

EDITOR’S DESK This isn’t hyperbole. The European Federation of Pharmaceutical Industries and Associations (EFPIA) has said that a ‘no deal’ Brexit presents “very real, tangible and immediate threats to patient safety and public health in both the UK and across Europe.”

“Now is the time for policy makers in the UK and the EU to put politics aside and put

measures in place to prevent patients being harmed by the consequences of Brexit,” according to EFPIA director general Nathalie Moll. “In particular from disruption to the supply of medicines including from transport delays at the border and where the development, manufacture, packaging, safety testing and regulation of the medicine no longer benefits from mutual recognition.”

However, despite Brexit it’s not all bad news.

According to the latest report from Pharmapack Europe, the industry is entering the golden age of innovation for research & development, making 2019 the perfect year for companies wanting to bring their innovations to patients.

A stronger focus on patients seems to be a key driver for companies innovating within the industry. Personalised medicine and genomics are just some of the developments driving the industry towards patientspecific treatments, but changes are happening throughout all sectors.

Take smart packaging for instance. Products utilising printed electronics allow companies to track and monitor how patients are adhering to their medication and even give them reminders if they forget to take a dose.

It isn’t just so-called ‘big pharma’ leading the way. Now we’re seeing a holistic industry effort, from SMEs, start-ups and spinouts, not to mention academia, all acting as exciting players within pharma. And as evidenced by the recent spate of acquisitions, pharma companies are now actively searching for the latest innovative companies and their ‘game-changing’ portfolios.

I’m sure Pharmapack Europe will play host to many of these innovations when it opens its doors in February. I’m certainly looking forward to seeing all the industry players together under one roof. It also gives me the chance to escape the UK’s Brexit woes, if only for a couple of days.

6

A small dose

BLOCKCHAIN

can reduce supply chain costs for pharma, survey says

EUROPEAN TEAM-UP TARGETS AUTOIMMUNE DISEASES Blockchain technology has the potential to improve cost efficiency within the supply chain for pharmaceutical manufacturers, according to a new report by Pharma Logistics IQ. The report highlights that 50% of pharma businesses are spending too much money on temperature-controlled logistics and that blockchain technology has the potential to reduce supply chain costs while also improving data capture and traceability tools.

Respondents stated that they think personalised

medicines will have a significant effect on the supply chain over the next decade, making shipment consolidation and outsourcing more challenging. More so, respondents said that modern supply chain planning must take into consideration things like third-party logistics, data loggers and a variety of passive and active containers.

Over a third of respondents said that their biggest ‘pain point’ over the next year was reducing supply chain costs, and almost half blamed this on complex business operations.

The topic of supply chains was recently discussed at the Temperature Controlled Logistics (TCL) event.

Katherine Gordon, programme director for TCL 2019, said: “These results suggest that there is not a single area of the supply chain which is particularly cost inefficient, and the challenges of maintaining cost efficiency can vary between organisations, making the problem personalised and therefore harder to combat for the market as a whole.”

Life sciences spin-out Velabs Therapeutics has partnered with the BioMed X Innovation Centre to provide its microfluidics technology to assist T-cell screening research.

The BioMed X Innovation Center is a collaborative effort for research that works with academia and industry. Through the partnership, BioMed X will use the Velabs platform to support research for the rapid identification of autoantigens in autoimmune diseases.

The research team will use high-throughput microfluidic screening approaches to couple

T-cell receptor specificity with auto-antigens. The screening platform can test millions of correctly paired immunoglobulins from humans and mice for therapeutic effects, rather than just for binding, with results being obtained much faster than other technologies.

“In order to address the central challenge of screening and characterising different immune cells at large scale, the research team chose Velabs’ technology as the most suitable and promising microfluidic screening platform available”, says Christian Tidona, founder and managing director of BioMed X.

7

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PAREXEL LAUNCHES NEW DIVISION TO HELP EMERGING BIOTECHS Biopharmaceutical services provider Parexel has launched a dedicated division to help emerging biotech companies reach their drug development and commercialisation goals.

New collaboration hopes to drive discovery of cancer medicines Major biopharma company AstraZeneca has announced it will work with Cancer Research UK to open a centre of excellence for accelerating the discovery of new cancer medicines.

The Functional Genomics Centre will use CRISPR technology to create biological models that better reflect the disease and will analyse large datasets using advanced computational approaches. The research undertaken at the centre could help clinicians better understand tumour disease and resistance mechanisms, enabling scientists to more accurately select the right drug for patients, increasing the probability of success.

Located at the Milner Therapeutics Institute at the University of Cambridge, scientists from AstraZeneca and Cancer Research UK will work alongside each other to facilitate collaboration. There they will have access to CRISPR libraries for silencing or activating every gene in the genome.

Mene Pangalos, executive vice president, innovative medicines & early development, AstraZeneca, said: “The best science doesn’t happen in isolation which is why AstraZeneca is committed to advancing innovative science through collaboration. This new centre of excellence with Cancer Research UK will combine our expertise in functional genomics and CRISPR technology to identify new biological pathways driving disease

and will accelerate the development of new cancer medicines for patients.”

Dr Iain Foulkes, Cancer Research UK’s executive director of research and innovation, said: “We’re delighted to collaborate with AstraZeneca on this exciting new initiative which will give leading Cancer Research UK scientists and our alliance partners access to the latest in CRISPR technology. As we move into an era of personalised medicine, we’ve reached a turning point in our ability to harness powerful technologies in the pursuit of targeted cancer therapies. We hope that this will translate into urgently needed new therapies for patients with hard to treat cancers such as lung, pancreatic, oesophageal and brain tumours.”

The Parexel Biotech division will work with emerging biotech companies, consulting with teams throughout the various stages of drug development to help reach commercialisation.

The division will offer a range of services, including patient recruitment services for clinical trials, trial execution services, China Advisory Services, quantitative clinical development and genomic medicines services, and real-world evidence programmes.

“Today’s emerging biotech companies have an increasingly critical role in identifying and developing new medicines that truly serve as the innovative arm of the industry,” said James Anthony, global head of biotech and co-leader of the

new division. “However, these companies face significant pressures and challenges in terms of timelines, resources and funding to succeed.”

“Parexel has been working to support biotech companies across the globe with clinical research services and regulatory consulting for many years, successfully accomplishing more than 650 projects in this space and developing a deep understanding of the needs of these companies,” said Peyton Howell, chief commercial and strategy officer for Parexel.

“To build on our commitment to biotech success, we have grown our capabilities to include management and strategy consulting, pipeline development, value substantiation and evidence vetting.

This enables us to provide experience, expertise and partnership throughout the biotech journey, and bring even greater value to this sector,” Howell added.

8

A small dose

MERCK WINS AWARD FOR BEST USE OF SOCIAL MEDIA Global science company Merck has won the 2018 Life Science Industry Award for best use of social media.

Awarded by market intelligence supplier Bioinformatics, the award recognises the way companies engage customers and stakeholders through the use of social media platforms.

One example raised in relation to Merck was the company’s employee

advocacy program, which encourages employees to share their industry expertise on social media, and which has helped raise the global visibility of the business.

executing a top-notch social and digital strategy that clearly is working to engage our customers with content that educates and inspires them to solve their toughest problems.”

Renee Connolly, head of communications & corporate responsibility, life science, at Merck said: “Congratulations to our global life science communications and digital marketing teams for creating and

DISCOVERY PARK LOOKS FOR DRUG DEVELOPMENT TENANT A leading UK science campus is looking for an anchor tenant for its 24,000 square foot pilot scale manufacturing facility.

Situated in the South East of England, Discovery Park is looking for an ambitious drug development company to take up space on its campus, as part of its 2019 business development plans.

The campus’ building 518 was formerly occupied by a global respiratory drugs

manufacturer and is ideal for pilot scale small molecule drug development although it could be modified for biologicals manufacture.

Discovery Park also states that its building 500, which was the former home of Pfizer R&D and manufacturing, is available and includes flexible office space plus chemistry and laboratory space.

Mayer Schreiber, CEO of Discovery Park, said: “2018 was

an important year for Discovery Park, with appointment of Martino Picardo as chairman and further development of our strategy. In starting 2019 with a focus on an anchor tenant for the building 518 manufacturing facility, as well as further occupiers for building 500, the evolution of the park continues.

We look forward to welcoming new companies to our vibrant community here over the coming months.”

Orphan disease specialist extends European activity Specialist drug developer for orphan diseases Minoryx Therapeutics has extended its activities in Europe through the creation of a subsidiary in Belgium.

The company’s new office, located in Brussels, will leverage the local biotech ecosystem to help research and develop Minoryx Therapeutics’ new drug (MIN-102).

Designed to treat central nervous system-related diseases, MIN-102 is a novel, orally bioavailable and selective PPAR gamma agonist. The drug is currently in phase 2 of a clinical trial with results expected at the end of 2020.

“We are very excited to be expanding our operations to Belgium, benefitting from local experience in growing biotech companies as well as starting a relationship with Belgian VCs and public investors,” said Marc Martinell, CEO of Minoryx. “With major Belgian investors participating in our recent €21.3M Series B funding round, we believe that we have an excellent opportunity to tap into a very attractive biotech ecosystem and reinforce our growth.”

9

NEWS ANALYSIS

Shining a light on life sciences in 2019 Mark Street-Docherty, CEO of Elucigene Diagnostics, explains why the UK’s Industrial Strategy is the shining light amongst the shambles of Brexit.

As refreshing as it would be to look past the obvious, there’s no avoiding it.

The one topic universally keeping the UK scientific community awake as we start 2019 in earnest is Brexit. Six months ago, a no-deal exit was a nightmarish prospect – if an unlikely one.

But with Theresa May’s deal rejected by parliament, we have to brace for the everincreasing possibility of leaving the EU without one. The cabinet reportedly began contingency planning in mid-December.

Pragmatic UK-headquartered firms in the medical device and diagnostics industry were one step ahead of them.

Many companies have been looking at how quickly they could establish a European operation or authorised representation, to run alongside their domestic business, for some time now. For those which rely on self-declared CE Marking, as is the case for the majority of IVDs in the market – leaving without a deal may pose serious challenges to business continuity.

UK companies which depend entirely on Europe for trade, and have yet to establish themselves in further-flung markets like Canada and Australia, could find themselves in even choppier waters.

There’s precious little time to register new products through Notified Bodies with the dual rights which would ensure products could move freely onto the continent after 29 March.

If the government can reach an accord, even a less than perfect one, then this cliff edge scenario can hopefully be averted, with the UK able to operate under a transition period for at least two years.

But while the government’s approach to Brexit leaves something to be desired, quietly rumbling along in the background is the well-thought-out Industrial Strategy. It may be somewhat deprived of oxygen due to political firefighting, but it’s still heading in the right direction.

Last month we received an update in the form of Life Science Sector Deal 2. News that Roche is to invest £20m over three years in a precision cancer research partnership with the Christie NHS Foundation Trust in Manchester is a huge vote of confidence for both the city and the UK. It further cements our growing reputation as an international destination of note for genomics and evidences the shift towards increasingly personalised oncology.

Other announcements in the deal were focused around facilitating

the adoption of software and artificial intelligence (AI).

The increased integration of these technologies with traditional chemical and diagnostics pathways will be key as the year unfolds, and beyond.

Whitehall has laudable aspirations for the UK to become a global leader in these fields. Alongside rendering the country an attractive destination for global corporations and inward investment, they can also be part of the solution to the challenges facing the NHS. Harnessing cutting-edge diagnostics, be they AI-driven, biomarker, or genetic, will enable the earlier diagnosis of diseases including cancer, cardiovascular disease, inflammatory and neurological disorders. This positive move can be compounded by an increased use of companion diagnostics to ensure drugs are used judiciously and effectively.

The net result? Vastly improved patient outcomes and a more efficient use of the healthcare budget.

2019 will also see the acceleration of a trend that’s seen multiple life science sectors converge, with progressive firms within them collaborating far earlier in the research and development cycle than they traditionally have.

10

NEWS ANALYSIS

The triangular relationship between molecular diagnostics, pharma and contract research organisations is not an inherently new concept. But the drug and diagnostic development landscape is evolving. There’s a growing expectation that companion diagnostics will be developed alongside new drugs from day one, replacing the model of retro-fitting them to old treatments.

On the one hand this is driven by pharma companies. That drug discovery is a costly and long process is news to no-one. Pharma firms of all sizes are now embracing that if use of their drugs can be guided by companion technologies, there’s a far greater chance of payer and market acceptance.

But demand-side factors also play a part. Healthcare providers and increasingly-informed patients rightly expect a standard of care that is worlds apart from the trial and error approach of yesterday’s medicine.

When innovative technology is enabling customers to have bespoke shopping, dining and leisure experiences, it should surprise no one that patients are becoming more discerning and demanding more from their healthcare treatment.

This shift shows no signs of slowing down. The growth in the precision and personalised medicine it is fuelling will continue to drive a robust market for entrepreneurial and resilient companies focused on the right areas, both in the year ahead, and beyond.

But while the government’s approach to Brexit leaves something to be desired, quietly rumbling along in the background is the well-thought-out Industrial Strategy. It may be somewhat deprived of oxygen due to political firefighting, but it’s still heading in the right direction.

The Reality of Continuous Pharmaceutical Manufacturing 26–28 March 2019, near Newcastle, UK

GEA, Siemens and Perceptive Engineering will host an inaugural three-day conference to examine the fact and fiction of continuous manufacturing (CM) in the pharmaceutical industry, addressing user experiences and the current status of continuous pharmaceutical processing.

Confirmed speakers include representatives from AstraZeneca, Bayer, CMAC, GSK, Janssen, Merck, RCPE, UCB Pharma, University of Sheffield.

For more information and to register for the event gea.com/events

12

Opinion

To make a digital transformation happen successfully, there needs to be complete alignment - from the board and executive team through the whole organisation.

HOW DIGITAL TRANSFORMATION IS ACCELERATING CHANGE

It is no secret that the pharmaceutical industry has faced some challenges when it comes to modernising its platforms, processes and practices, but recent trends suggest the industry is tackling this head on. In this piece Christian Hebenstreit, general manager & senior vice president EMEA, Medidata Solutions explores the steps life sciences and healthcare companies are taking to embrace digital transformation.

A

host of new technologies are transforming the pharmaceutical sector today, helping life sciences, healthcare, biotech, and medical device organisations make data-driven business decisions so that new drugs can be brought to market faster and more efficiently.

This explains why, in just a short space of time, an increasing number of innovative organisations in the life sciences and healthcare sector are embracing digital transformation and IOT (Internet of Things) strategies.

These companies have prioritised the shift – despite the challenges it represents – and are seeing the benefit in terms of reducing risk and delivering positive business outcomes.

That said, a transformation like this is never easy. Furthermore, it can’t happen overnight, nor is it necessarily a process that ‘ends’ - it will be an ongoing ‘work in progress’ for every organisation that embraces it. There is also no single template for success - every engagement we’ve had with leaders in the life sciences industry tells us that to get digital transformation moving in the right direction, organisations will need to embrace three key considerations: operations, infrastructure and culture.

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RE-IMAGINING THE OPERATIONAL MODEL An effective digital strategy defines where a business sits today, where it is going in the future and how it will get there. But more important than the “where” and the “how” is the “why” i.e. the reason a company exists today despite all the disruption that is occurring around us. Each business leader embarking on digital transformation must start with a simple question: how can I utilise digital to reimagine the business model of the future?

Digital transformation demands a radical rethink of business operational models and where an organisation exists within its industry. For example, where can an organisation play to win in the nearto-medium term? How will a digital transformation programme add new value for customers, streamline the supply chain or support business outcomes?

New models of care are emerging in the health and life sciences sector as digital enables activities, such as remote monitoring, and data exchanges between clinicians and patients. Together with these new models of care, new economic models are being created as insurers, governments and healthcare providers innovate and build new revenue models. Similar to every other industry, life sciences is being impacted globally with digitalisation, specifically from smart devices.

Subsequently, real-world data streams from patients’ smart devices is generating massive amounts of data, providing more accurate insights into patients’ conditions.

To embrace these new technologies, the organisation operational model from the supply chains, the manufacturing process, the delivery model as well as the interaction with the physicians and the patients will have to change. These radical changes and digital technologies are what will really enable digital transformation. The devices will inevitably give greater visibility and transparency at the patient level but the supportive models that are coming out of this are also equally as transformational.

In today’s digital age, every life science and healthcare organisation will need to approach business like a strategy house, innovate like a start-up, design like a tech giant and scale like a venture capitalist. Only then can they really shift to a digital model.

REFRESHING EXISTING INFRASTRUCTURE Due to the growing data volumes involved in life sciences research and the need for speedy analysis, traditional IT infrastructures can no longer

deliver what is required. The reason being that such infrastructures are hard to scale or struggle to deliver the needed performance, and as a result can be an obstacle to research progress and investigative success.

What is needed is an infrastructure that can accommodate large volumes of data in such a way so that high-throughput computational workflows can be sustained to quicken the pace of research.

This must be accomplished in an economical manner that does not require IT staff to invest large amounts of time managing and operating systems.

Life science companies also will often be working with multiple technology vendors, on an array of different platforms, resulting in a complex IT environment. When this is combined with the necessary and painful management of ageing physical IT infrastructure, it is not difficult to see how workflows could be interrupted and processes slowed. This is where the migration to consolidated platforms – and in particular the cloud – can have a dramatic impact.

RETHINKING THE ORGANISATIONAL CULTURE Many companies already have a strategy of continuous improvement in their businesses and operations globally. Digital transformation will demand changes to strategy, technology, processes, and organisational structure but culture change is the glue that will bring it all together.

Changing the internal culture is often one of the biggest barriers to digital transformation. Culture is everyone’s responsibility, and digital leaders must constantly educate about cultural changes that will help shift their organisation towards a digital culture that is customer-focused, innovative, agile and collaborative. That said culture change is a slow process and must be handled patiently, with understanding and persistence. Some changes are gradual and evolve toward an end goal, which becomes clear over time and some such as acquisitions, investments, partnerships, or other external activity or statements can be more immediate.

The role of the board in a digital business is key yet very different from the role of the board in a legacy business. To make a digital transformation happen successfully, there needs to be complete alignment from the board and executive team through the whole organisation. To this end, there is a new generation of board director emerging that is much more handson, with a more entrepreneurial background actively striving to make digital transformation a reality.

13

14

SINGLE-USE TECHNOLOGY

REALISING THE POTENTIAL OF SINGLE-USE TECHNOLOGY David Staunton, global director services at Zenith Technologies and Scott Ripley, global marketing director at GE Healthcare, discuss the benefits of single-use technology and how patients are the ultimate beneficiaries.

BENEFITS OF SINGLE-USE IMPLEMENTATION STRATEGY Both upstream and downstream manufacturing processes benefit from single-use systems. They allow manufacturers to quickly add capacity at lower costs.

They also make multi-product GMP manufacturing easier to implement, allowing facilities to respond quickly to changing supply demands.

When a comparison is drawn against stainless steel, the benefits of single-use technology are numerous. They include lower capital cost, greater flexibility, lower environmental impact as well as more efficient and quicker manufacturing practices. Singleuse technology adoption has led to reductions in capital investment by as much as 25-30% in some cases and increased speed to market by as much as 60%.

Contrary to common perception, the environmental footprint of single-use technology is also lower because of the reduced consumption of water, energy and chemicals used primarily in cleaning and sterilising stainless steel equipment.

The manual nature of singleuse can make automation a challenge in GMP manufacturing environments. However, there are significant automation efficiencies created by having suppliers like GE deliver pre-validated and tested Manufacturing Control System

(MCS) software with the equipment.

This GMP MCS software, complete with design specifications and executed test protocols, reduces commissioning time on site by avoiding the need to rediscover knowledge from project to project.

We are getting close as an industry to being able to purchase ‘out of the box’ not only the MCS with the single-use equipment train but also a standard Manufacturing Execution System (MES), digital dashboards and data analytics platform. This will lead to improved regulatory submissions, more effective GMP Non-Conformance (NC) investigations and increased production capacity.

Increasingly, full upstream and downstream single-use manufacturing trains are being deployed by GMP manufacturers.

These entire facilities include the delivery of the building fabric, production equipment, utilities and automation as one package – such as GE Healthcare’s prefabricated KuBio manufacturing facility.

END-TO-END SUPPORT As with traditional GMP manufacturing equipment, it is vital to plan to reduce downtime when implementing an integrated single-use production train.

Rapid GMP incident response processes, planned preventative maintenance and on-site rapid response teams should be part of the overall design.

PATIENT IMPACT Beyond the benefits for GMP manufacturers, the success of single-use is having a much broader impact. The lower cost and ease of use gives market access to start-ups who may not have the capital to invest in contract services or traditional manufacturing sites.

These companies are almost universally developing and manufacturing innovative and precision therapies, often targeting orphan and rare diseases, where no treatment has previously been available.

The flexibility and speed to market associated with single-use is also enabling entry into new markets for larger manufacturers and bringing increased capacity to others. Three biopharmaceutical manufacturers have quickly entered the Chinese biosimilar and biologics market by deploying a single-use biomanufacturing process in one of GE’s KUBio modular facilities. Additionally, contract manufacturers have realised the benefits of standardising their single-use production process and automation software to gain efficiencies in both tech transfer and production.

Ultimately, single-use is an agile technology that offers patients around the world better access to existing medicine and enables manufacturers to deliver these therapies faster.

16

COVER STORY

TAKING THE ADVANCED APPROACH Pascale Farjas, global category manager for drug delivery company Nemera examines the design features that help improve adherence for patients using nasal spray devices.

N

emera develops and manufactures devices that truly improve patients’ daily use.

In particular, we provide millions of nasal sprays all over the world. We work every day to develop new features to improve patients’ lives.

This is why we periodically organise user studies, to test our devices and get feedback and insights from users’ experience.

Recently, we conducted a nasal user study at Nermera’s La Verpillière site which aimed at receiving feedback to help better understand patients’ nasal care habits.

The study, which featured 20 users aged between 20 and 60, was important as we wanted to better understand what users are expecting from their nasal spray.

Unsurprisingly, over half of the users (57%) said that ease of use is the most important point, followed by size and ease of transport in relation to nasal spray devices.

The study also highlighted another interesting point: people generally don’t read the instructions for use.

Only 25% of respondents always read them, but over 50% read them only occasionally.

REFERENCE: 1 Yokel RA1. Bloodbrain barrier flux of aluminum, manganese, iron and other metals suspected to contribute to metal-induced neurodegeneration. J Alzheimers Dis. 2006 Nov;10(2-3):223-53.

This last point is very important to be considered, as it could explain how, in some cases, compliance rate is poor. Patient adherence is key for both therapy efficacy and avoidance of dangerous consequences using potent drugs.

HOW CAN A NASAL SPRAY IMPROVE PATIENTS’ ADHERENCE? Realising the challenges nasal spray users experience when using their devices, Nemera developed a platform designed to improve the level of patient adherence. Patient non-adherence with their drug could result in non-effective therapy or even dangerous consequences for potent drugs.

they are quite happy with what’s existing today but would like even easier-to-use/transport devices.

Advancia has been designed with a number of features to ensure an increased level of adherence and ease of use for the patient.

That’s why engineering considerations during Advancia development were based on ergonomy and convenience on the design side. For instance, the snap-on version is easier to handle and avoids accidental actuation when being transported.

Moreover, this overcap is more hygienic and protects the actuator from dust/ external environment, which is much appreciated and corresponds to the patient lifestyle nowadays.

As we noticed from our last userstudy, main expectations from nasal spray users are about size (compact format), ease of use and ease of transport. Most of the time,

As snap-on is the standard today for preservative-free nasal pumps, we differentiated Advancia through a patented specific snap-on system, with a full overcap. This allows one-

17

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step assembly during drug filling and is intended to facilitate device assembly onto different containers (plastic or glass).

More so, the platform’s preservative-free version, Advancia PF avoids the need for preservatives in the drug, preventing bacterial contamination over the duration of treatment. This is achieved thanks to Nemera’s PureFlow technology, which filters air entry by permeation through a silicone membrane.

Another beneficial feature for patients is Advancia’s reliance on a new technology pump engine, which guarantees the dose in 100% delivered. For the user, Advancia’s actuation profile makes it feel like they’re having the full dose delivered, no matter how they use the device.

This consistency for example makes Advancia suitable for drugs with infrequent treatment needs, as the patient does not have to re-prime the system after several weeks of non-use.

Also, some drug formulations/ active ingredients can oxidise in contact with metallic parts and potentially become toxic, it was important that the device ensured there is no metal in contact with the drug formulation. Oxidation reactions can also alter and degrade metallic parts, potentially liberating toxic particles for the brain1. Also, some deterging agents can be used during the manufacturing process of metallic parts, with the possibility to migrate into the drug formulation. That’s why, in general but for some drugs in particular, it is recommended the fluid pathway is metallic-free.

One feature that users may not notice is the device’s anti-clogging actuator.

The mechanical closing tip ensures that no contamination can enter through the actuator orifice, providing protection from crystallisation and clogging issues, ensuring patient have a spray for each delivery.

When coming to problems encountered with some devices today, we realised that improving the design features of Advancia could help the patient in their daily use and overall satisfaction of the device. That’s why Advancia is a mix of different benefits for the patient, but in particular user- independence.

Patient adherence is key for both therapy efficacy and avoidance of dangerous consequences using potent drugs.

18

IMPROVING OPERATIONS

Driving data forward Rod Schregardus, supply chain specialist at Access Group, looks at the growing importance of Advanced Planning and Scheduling (APS) systems in pharmaceuticals.

W

ith production costs growing, partly as a result of complex treatments and competition in the market, pharmaceutical manufacturers are well aware of the need to drive operational efficiencies.

Spreadsheets have long presented issues, even when production was more straightforward. We know that documents can corrupt, updating them is time-consuming and employees sometimes develop their own formulae.

Admittedly few pharmaceutical companies depend entirely on spreadsheets – yet many choose basic Enterprise Resource Planning (ERP) solutions over Advanced Planning and Scheduling (APS) systems that offer real-time visibility of all manufacturing processes. This allows teams to match complex production processes to tasks like purchase orders, which can improve on-time-in-full document (OTIF) delivery and maintain strong customer relations.

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OTIF is essential in the tightlycontrolled pharma sector, where drugs could be rendered ineffective or dangerous if production is behind schedule. In the case of biologic drugs, entire batches may need to be destroyed if maintenance work has not been factored into the schedule.

As well as making existing operations more efficient, planning and scheduling software can also be used to perform a capacity analysis before production begins.

This was crucial to a US project involving a leading pharmaceutical company our team worked on.

Needing to prove that a new $1 billion facility could provide enough vaccine for half the US population in the event of a ‘flu pandemic’, a manual capacity analysis was clearly unsuitable.

Given the requirements of the job the team could not key in data from the first batch runs into a spreadsheet.

Deploying our software, they were able to build a detailed ‘what-if’ model in less than two weeks. By showing how long every batch run would take and where equipment could be used more effectively, the model provided proof to stakeholders that the facility could deliver.

It went beyond reporting on issues to showing what action could be taken, with 10 remediation areas highlighted and ranked for importance. With the improvements complete, the company could reduce the time taken to perform tasks by three weeks – reassuring stakeholders that the facility

would be ‘pandemic-ready’ if it completed the necessary strategic improvements projects.

The software was implemented across the company for tasks such as quality control, sample management, day-to-day planning and scheduling, and shutdown/turnaround planning and maintenance.

With hour-by-hour data at their fingertips, production teams on the shop floor are continually optimising tasks, while senior management has the insights it needs to make strategic decisions. Everyone has benefitted from reduced administration and up-to-date information, without a time lag in reporting. This is partly down to the company’s ‘one schedule’ culture that promotes data sharing across teams.

APS systems are not the only example of how digital technology is transforming the pharmaceutical supply chain. Another is warehouse management systems (WMS), increasingly being used to tackle ongoing challenges such as traceability, including the problem of counterfeit drugs.

The commercial challenges facing pharmaceuticals companies will undoubtedly intensify further in the coming years, as demand for complex treatments is compounded by regulation and squeezed margins. Given the missioncritical nature of pharmaceuticals, manufacturers cannot afford to relegate planning and scheduling to spreadsheets. Considering the investments made in R&D, it is vital that the tools needed for the final stage of production can also deliver.

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20

DRUG DELIVERY

Powder testing – a powerful tool for the healthcare industry Thought Leader Q&A with Todd Mollner, global product owner, respiratory powders, GSK. WHY DO YOU THINK POWDER TESTING IS SO IMPORTANT IN THE MANUFACTURE OF HEALTHCARE PRODUCTS?

WHAT TECHNIQUES AND INSTRUMENTATION HAVE YOU FOUND PARTICULARLY HELPFUL AND WHY?

One of the challenges we face is establishing the supply chain needed to safeguard product consistency within a global marketplace that can change rapidly. The best defence is to have multiple-suppliers that make active ingredients, and key excipients, to the same high standards.

The powder tester I use most is our powder rheometer (FT4 Powder Rheometer, Freeman Technology) because we can run a whole gamut of tests with it, and we have, for just about every powder we use. It allows me to investigate flow properties, aeration behaviour and permeability, compressibility and to generate shear data which are particularly helpful for hopper troubleshooting. And it’s easy to use as the instrument pretty much defines what you need to do.

For us powder testing is central to defining those standards and determining which materials to use.

Obviously, a new supplier will meet the market specification for a product but in terms of how that material will process that’s no guarantee of consistency.

With the right powder testing strategy, it is possible to determine which properties define performance in any given process and the specifications of powders that will work well. With established specifications for powders that work well it’s far easier to identify alternative suppliers and build a robust supply chain – instead of failing in validation or having to run under compromised operating conditions. The other reason that powder testing is critical is that it more generally supports efficient manufacturing.

Why I particularly like this tester is that it puts a lot of power into the hands of the ‘average Joe’, the person solving the problems.

For example, we had an issue with segregation through a vacuum transfer process that necessitated the use of a subsequent stabalisation period. This was less than ideal, and to check whether it was really necessary we took some external advice. There are some good powder handling consultants available and we received sound advice, based on the use of traditional testing techniques, after a couple of weeks. Now though I would carry out aeration testing and get to the same answer in around half a day. With this

instrument I have the speed and independence to tackle problems as they arise.

CAN YOU GIVE SOME EXAMPLES OF PROBLEMS THAT YOU’VE ADDRESSED? I have a good example that illustrates how variable the ‘same’ material can be and what this can mean for processing.

One of the actives we use in a roller compaction process typically has a compressibility of around 5%.

When we looked at the compressibility of alternative supplies we found one at 10% which was easily accommodated by increasing compaction force, within the established operating window.

Then we tested a new supply and it had a compressibility of 25% so the expectation was that this would be quite interesting to process and result in some extremely hard granules. However, with the existing process we couldn’t apply sufficient force to make the powder stick together, or, in fact make any granules at all.

Here then, powder testing made it possible to differentiate between supplies we could work with and more importantly those we couldn’t.

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A good example on the troubleshooting side is a problem we had with segregation in a hopper. At low hopper levels the product became inconsistent suggesting that the hopper design was leading to segregation under certain circumstances.

To solve this problem, I checked out the design by carrying out some shear cell testing with the FT4 Powder Rheometer and running the results through the integrated hopper design software.

The answers suggested a significantly different design to the existing one with a 55% larger volume, and a different half angle and outlet size.

Videos from inside both hoppers clearly show the difference between them and why the new one solves the issue. In the old hopper there is evidence of funnel flow where the powder is flowing in the centre but not at the sides, providing a rationale for rolling segregation associated with interaction with the hopper walls.

The new hopper, in contrast, maintains a ‘first in first out’ consistent mass flow regime with no edge effect, right until the point of complete emptying. And despite being larger it empties more rapidly, a much-improved solution.

CAN YOU PUT ANY VALUE ON EFFECTIVE POWDER PROPERTY MEASUREMENT? Yes, and it’s significant. So, taking that last hopper example, our previous solution resulted in wastage which we’ve been able to eliminate with the new hopper design. This has produced an 8% reduction in waste.

Furthermore, it can be too easy to lose sight of just how much it's costing to be sub-optimal with respect to raw materials.

For example, we had a legacy product that came with the advice “don’t change any of the materials”.

Over time that became impractical and as a result tabletting rates had steadily decreased by around 50%.

When powder testing unlocks throughput gains like this it can easily deliver savings of up to 50 – 100 times the cost of the instrument.

WHAT ARE THE KEY LESSONS THAT YOU THINK YOUR INDUSTRY NEEDS TO LEARN ABOUT POWDER TESTING? The supply chains associated with healthcare products are global and complex. Making them robust and secure is critical and relies on being able to identify what it is about a raw material that makes it optimal for any given application.

I believe powder testing is a key part of that.

The other point I’d make is that powder testing doesn’t have to be the preserve of experts.

With a well-chosen instrument you can access the information you need quickly and easily and build the in-house competence needed to combine excellent product quality with competitive manufacturing costs. The right powder tester isn’t just something for the lab to get excited about, it’s a worthwhile company investment that can return many times its cost.

A longer version of this interview will be available on https://www.epmmagazine.com/

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The supply chains associated with healthcare products are global and complex. Making them robust and secure is critical and relies on being able to identify what it is about a raw material that makes it optimal for any given application. I believe powder testing is a key part of that.

23

DRUG DELIVERY

PROLONGED DELIVERY The method of administration of a medication may result in suboptimal exposure profiles and poor treatment compliance, which negatively affects treatment outcomes.

Here, pharmaceutical company Camurus explains how the company’s latest technology aims to improve clinical outcomes and potentially reduce opioid dependence.

TRANSFORMING OPIOID DEPENDENCE TREATMENT In November 2018, Camurus received EU approval for weekly and monthly Buvidal – the first long-acting medicine approved in the EU for the treatment of opioid dependence in adults and adolescents.

Buvidal is a lipid-based solution containing buprenorphine in a pre-filled syringe which is injected subcutaneously once weekly or once monthly using a conventional syringe with a thin needle.

Current established buprenorphine medications, which are the most frequently used treatment for opioid dependence globally, are taken every day as a sublingual tablet or film. However, this form of administration has a number of drawbacks – including the risk of diversion (the unlawful channeling of prescription drugs to the black market), misuse (use by people for whom the drug has not been prescribed), and accidental ingestion by children. Furthermore, daily treatment increases the risk of suboptimal compliance leading to relapse and increased costs to payers and the healthcare system.

The way Buvidal functions is dependent on Camurus’ FluidCrystal injection depot technology, which aims to improve therapeutic performance, treatment adherence and clinical outcomes – and ultimately the patient’s quality of life. Designed as a versatile drug delivery technology, FluidCrystal is used to create convenient, long-acting treatments.

The technology uses combinations of endogenous polar lipids that spontaneously self-aggregate to form well-defined gel-like liquid crystal nanostructures in aqueous environments – such as at tissue surfaces or in the body. The time it takes for the structures to break down can be controlled by adjusting the formulation’s composition. Camurus is combining these lipids with active pharmaceutical ingredients which have proven efficacy and safety profiles, to develop new medicines which extend and reinforce treatment efficacy.

In Buvidal for instance, FluidCrystal injection depot technology enables the depot to biodegrade at a controlled rate over time, releasing the buprenorphine which blocks the drug-liking effect of opioids in the brain and reduces withdrawal, craving and patient’s use of illicit opioids.

More so, the simplicity of the FluidCrystal technology – which can be adapted to prefilled syringes and autoinjectors - eliminates complicated manufacturing procedures and the need for mixing (reconstitution) prior to administration.

With the approval of weekly or monthly Buvidal, which is administered by a healthcare professional, there is the potential to increase treatment adherence and also reduce the risks of diversion, abuse, misuse and accidental paediatric exposure, as clinicians can be confident that the medication is being used by the person for whom it was intended.

The time it takes for the structures to break down can be controlled by adjusting the formulation’s composition.

24

PACKAGING

The Brexit implications for the UK pharma packaging industry Rich Quelch, global head of marketing, Origin, looks at how Brexit will affect regulatory bodies in the UK and how this impacts pharmaceutical packagers.

L

ike every industry, the pharma sector is poised on the edge of its seat in anticipation of a final agreement on Brexit.

The UK will officially leave the European Union on March 29th (if all goes to plan) and the terms of the exit will dictate how British pharma firms can trade with and market their products to Member States and the rest of the world.

Marketing authorisation for products in the EU is currently governed by the European Medicines Agency (EMA), based in London. The immediate consequence of Brexit is that the EMA will relocate to the Netherlands, with the likelihood of losing key members of staff and adding complexities when it comes to remits and responsibilities.

The EMA is currently working on the eventuality of a no-deal Brexit, which would leave the UK classed a ‘third country’, meaning they’ll no longer be able to engage as a ‘co-rapporteur’ in the marketing authorisation process of products in the EU. The UK currently contributes heavily to the regulation of EU medicine approval - used as a reference Member State in 45% of decentralised EU medicine approvals – so, Brexit will see the supply chain impacted. Plus, the UK exports a significant amount of products to the EU, and a nodeal eventuality would impact the £11.9 billion of medicinal exports and put the EU market under strain.

A no-deal agreement would also see the responsibility for human medication marketing in the UK fall on the Medicines and Healthcare Products Regulatory Agency (MRHA). It would require new laws and systems for packaging, labelling and patient information leaflets to ensure high standards and safety, putting stress on regulatory bodies to ensure they’re prepared.

The problem is, the MRHA approval process is largely industry-funded and would struggle to sustain itself on only the fees paid for the review of medicine in the UK. It could see the number of authorisations granted drop, unless funding could be secured from the health budget or public funding.

It will, however, provide a platform for the MHRA to establish itself as a global leader in medicine regulation, including marketing authorisation and packaging.

The MHRA already contributes heavily to the EU workload and will look to grow its authority as it undertakes greater responsibility in the case of a no deal Brexit, where the UK looks to begin trading in new markets.

Alone, the UK is a much less appealing market though, representing just 3% of the global pharmaceutical market compared with the EU’s 22%. As the UK looks to expand its trading opportunities it may struggle, with attractive

countries like USA, China and Russia signing mutual recognition agreements with the EU. The UK government is preparing for future customs arrangements with the EU, hoping to minimise disruption post-Brexit. However, Brexit will inevitably add costs which could cause businesses to move elsewhere and result in damaging border delays. This will cause serious problems for timesensitive medicines which require delivery in as little as 24 hours in many cases, potentially leaving patients without vital medication.

Patient-focused drug delivery devices Drug Delivery Devices Innovative developments Customized solutions GMP contract manufacturing

www.nemera.net information@nemera.net Phone: +33 (0)4 74 94 06 54

26

PACKAGING

Move it odour!

While moisture in pharmaceutical packaging can have negative or even dangerous effects on its content, unpleasant odours are especially repellent to patients. Here, Ursula Hahn, head of product management, Sanner, Germany, looks at how both can be systematically prevented using suitable adsorbents – provided the right aspects are taken into account.

M

any pharmaceutical products are sensitive to moisture, the effects of which are manifold and often pose a high risk to both drugs and patients. In the case of tablets, powders and effervescent tablets, the properties and texture may change, whereas gel capsules might dissolve, and blood or urine test strips may produce false or misleading results. In the worst case, the efficacy of drugs is reduced, or the analytical results are falsified, which can lead to an incorrect medication and impede successful therapy. In addition, many pharmaceuticals, especially analgesics such as acetylsalicylic acid, release specific molecules into the ambient air inside the packaging that can develop very unpleasant odors.

ONLY REAL DATA PROVIDES RELIABLE RESULTS The amount of humidity that penetrates the packaging is decisive for the stability of a moisture-sensitive drug. Around 65% of humidity ingress can be attributed to the packaging. Weak spots can be the packaging wall, the sealing surfaces between containers and closures, as well as the sealing seams of blister packs.

Hence the choice of the primary packaging depends mainly on maintaining the optimum climate inside the packaging to ensure the required shelf life.

A holistic approach that considers all aspects of moisture ingress into a pharmaceutical packaging

is indispensable. Relevant parameters such as material type, wall thickness, product moisture and production conditions, as well as differing climatic conditions and consumer behaviour must be observed when designing the packaging. To obtain reliable data, tests should always be conducted with the actual packaging. Material datasheets or databases provide data determined under very specific and ideal conditions.

These cannot be transferred 1:1 to a specific packaging. Consequently, only real data and realistic analysis avoid unnecessary durability tests.

DESICCANTS: SILICA GEL OR MOLECULAR SIEVES Depending on the area of application, different desiccants such as silica gel or molecular sieves can be used. Hygroscopic desiccants attract moisture and keep it away from the content. The most common desiccant, silica gel, contains small interconnected channels that open into pores on the surface and can absorb up to 36% of their own weight without altering their structure. The higher the relative ambient humidity, the higher the adsorption capacity.

Molecular sieves, on the other hand, are synthetically produced zeolites with a uniform pore diameter and a crystalline structure.

Molecular sieves adsorb moisture corresponding to between 2022% of their own weight, almost independently of the relative ambient humidity. While silica gel

brings moisture to a certain level, molecular sieves can achieve a climate of close to 0% relative humidity inside a closed packaging.

ACTIVATED CARBON: FAR MORE THAN ODOUR ADSORPTION When it comes to odour adsorption, activated carbon is particularly efficient: the surface of just one kilogram of activated carbon equals a 160-kilometre two-line highway. Activated carbon is made of organic material with high carbon content such as peat, wood or coconut shell.

This material is slowly heated in an oxygen-depleted or oxygen-free environment to remove water and impurities. The surface increases significantly through further physical and chemical processing and creates a submicroscopic network of pores.

The extremely hygroscopic surface molecules actively search for other molecules they can bind to.

Activated carbon attracts numerous chemical compounds by adsorption and thus binds bad odors.

Moreover, activated carbon can adsorb residual solvents as well as organic and inorganic impurities that reach the headspace of bottles by evaporation.

DROP-IN SACHETS: ELIMINATING RISKS RIGHT FROM THE START There are many ways to equip packaging with the right type and amount of desiccants and/or activated carbon. The fundamental difference is how adsorbents

27

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While silica gel brings moisture to a certain level, molecular sieves can achieve a climate of close to 0% relative humidity inside a closed packaging. are inserted into the packaging.

More cost-intensive, integrated desiccants are found within the cap of a tablet tube or as a desiccant chamber in the package bottom or in the wall. Drop-in desiccant solutions are added directly into bottles or containers in different forms.

Desiccant sachets are particularly soft and flexible. They can be placed anywhere in the container without any risk of damaging the drugs and patients can easily distinguish the sachets from the drug, leading to a low risk of accidental ingestion. Sachet packs are ideally made of Tyvek, which offers both durability and breathability. It is also particularly tear-resistant and puncture-proof, eliminating the risk of product contamination due to desiccant leakage during filling or usage.

DESICCANT CAPSULES FOR 360° MOISTURE PROTECTION Desiccant capsules are small, cylindrical containers made of plastic and sealed with a cardboard disc. Desiccant canisters have a similar shape but are made entirely of plastic.

Desiccant capsules that provide 360° moisture absorption are rarely to be found on the market.

Thanks to the unique grid structure in the capsule wall, moisture adsorption is ensured without losing effectiveness, even if the capsule ends up on the cardboard side after filling.

These capsules can adsorb up to 30% more moisture than conventional capsules and their tactile grid structure prevents confusion with drugs and ultimately accidental ingestion.

Drop-in capsules or canisters are available in different sizes and with different filling material.

Depending on the moisture protection requirements of certain drugs, silica gel, molecular sieves or a combination of both can be used. A mixture of silica gel and activated carbon is the best choice for pharmaceuticals that require both odour adsorption and moisture protection.

HOLISTIC APPROACH FOR ULTIMATE PRODUCT PROTECTION Regardless whether a product is to be protected against moisture by using silica gel, molecular sieves or a combination of both, or whether additional activated carbon is used for odour adsorption: all solutions must always be tested regarding suitability and regulatory compliance.

Moreover, a holistic view based on real data is crucial. It is the only way to implement all technical and regulatory aspects quickly, efficiently and with high quality. Individual, integrated or drop-in – all desiccant packaging solutions must be smoothly integrated into existing processes of pharmaceutical manufacturers.

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29

PACKAGING

THINKING OUTSIDE THE BOX Dale Pittock, sales director of pharmacy consumables provider Valley Northern, explores the latest developments in the smart packaging market.

I

magine if a packet of antibiotics could tell a patient whether it had been opened and which pill had been taken and at what time. Then, imagine if things could be taken a step further and the medication could alert patients when it was time to take the next one, then feed this information back to their doctor as part of a healthcare management system.

The pharmaceutical industry isn’t far off this point, and improving patient compliance is just one of many benefits that smart packaging will be able to offer.

SETTING A REMINDER Smart packaging can provide patients with a better understanding of their medication, and how to take it safely. By implementing a radiofrequency identification (RFID) that communicates with Wi-Fi enabled devices, packaging could remind patients when to take their medication and supply a dosage schedule to help them get the most out of it.

This data could then be transmitted to the patient’s GP or pharmacist, enabling them to monitor treatment plans without frequent face-to-face follow ups. The ability to provide patients with the information they require to safely take their medication could decrease unnecessary appointments, providing some breathing space for already overburdened health service practitioners.

Data also has the potential to re-define the supply chain.

Tapping into digitalisation could allow pharmacists to better track the medication that has been dispensed, and when it’s time to re-order. This would mean that healthcare facilities are only supplied with medication that is needed, which would be particularly beneficial in terms of seasonality, such as hay fever or flu medication.

THE FIGHT AGAINST FRAUD There are known problems with drugs being tampered with, swapped for cheaper, less effective alternatives, and subjected to non-compliant storage and handling. Sensors could provide the possibility to mitigate against counterfeit drugs and prevent medication tampering.

For instance, by changing colour if medication has been opened or if temperatures suddenly change, sensors on smart packaging can help indicate whether its contents has been spoiled, switched or replaced with an unwanted counterfeit.

The Falsified Medicines Directive (FMD) will come into place in 2019, meaning all new packs of prescription medicines in Europe will have to include two new safety features: an anti-tampering device and a unique identifier in the form of a barcode. Smart packaging with scannable features holds the potential make this process run smoothly for pharmacists, while ensuring medicine safety.

THE BENEFITS OF BESPOKE For these innovations to take place, current packaging needs to adapt.

Digital additions to packaging seem to be the way forward, but at the same time they cannot simply be placed over the important information already on a box or label. Instead, a bespoke packaging design would allow pharmaceutical manufacturers to reap the benefits of smart packaging while the medicine’s original information isn’t interfered with.

As digital developments become integrated into the market, pharmaceutical packaging will mean more than just boxes and bags. Smart packaging will not only optimise production on a manufacturing level, it will also help to ensure that patients get the most out of their medicine.

30

THE YEAR AHEAD

Pharma’s focus in 2019 The start of 2019 has already seen some major developments in the pharma world. Huge acquisitions between Bristol-Myers Squibb and Celgene, or GSK’s consumer healthcare business merger with Pfizer are just two examples of the changing landscape in pharma. The very real prospect of a ‘no deal’ Brexit is causing consternation for UK pharma firms and the introduction of the Falsified Medicines Directive in February aims to strengthen supply chains across pharma.

Here, editor Reece Armstrong catches up with some of pharma’s leading names to see what else is in store for 2019.

ALEX BUNTING - I HOLLAND MARKETING MANAGER “The requirement for solid dosage continues to grow and with it increases the pressure on manufacturers to get a quality product out quickly and cost-effectively. At I Holland we are continually working on innovative solutions to help to satisfy this demand in tablet manufacture. A particular area of concentration for I Holland in 2019 will be continuing to develop high quality training and support that we have been known for globally for many decades. By delivering education and guidance through flexible channels, advice can be implemented quickly, therefore impacting deliverables.

We envisage that multi-media tools that enable businesses to receive expert knowledge at the touch of a button are the future. This style of training, delivered alongside our extensive programme of face-to-face seminars, hosted by recognised experts in the field focus on specific elements within tablet manufacture and provide the appropriate information to the individual.”

BEN WYLIE - SENIOR PRODUCT MANAGER, CHARGEPOINT TECHNOLOGY “Pharmaceutical manufacturing using highly potent active pharmaceutical ingredients (HPAPIs) and sterile manufacturing certainly doesn’t appear to be declining into 2019 and manufacturers across the pharma and biopharma industries need to respond to containment challenges if they are to benefit from this continued growth.

Better ways to achieve operator safety and prevent cross contamination of products has been widely discussed during 2018 and as we enter into 2019, we are seeing more innovative containment strategies entering the market. Smart wireless monitoring technology was introduced last year to give manufacturers increased confidence in their containment strategies enabling users to receive crucial equipment usage data quickly and remotely if needed, giving confidence in the health status of the equipment.”

www.epmmagazine.com

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PAUL CIANCIOLO, SVP, BUSINESS MANAGEMENT, TRACELINK “In 2019, I anticipate that the pharmaceutical industry will progress towards ensuring a more efficient global supply chain focused on increasing patient safety and medicine availability. With the launch of the European Union’s Falsified Medicines Directive (FMD), and the passage of many more serialisation and track-and-trace laws across the globe, clinicians, patients, and caregivers should have more confidence than ever in the quality of medicine products. Additionally, as 2019 progresses, I expect to see significant developments centred on digital information sharing among pharmaceutical industry trading partners to enhance supply chain business processes and patient-centric engagement programmes.”

NICK GIUFFRIDA, SALES DIRECTOR AT FUTURMASTER - IOT AND A CONNECTED SUPPLY CHAIN “Connected objects and the internet of things (IoT) will undoubtedly have an increasing impact on the supply chain, due in part to the falling costs of wireless tracking devices and the ubiquity of internet connectivity.

This will profoundly benefit the monitoring and flow of goods from the manufacturer to the retailer and ultimately on to the end-consumer. Take-up, so far, has been confined mostly to more expensive items, such as in the apparel and pharmaceutical industries; but adoption will be become much more widespread in 2019 and beyond.”

JIM STREETER - GLOBAL VICE PRESIDENT LIFE SCIENCES PRODUCT STRATEGY ORACLE HEALTH SCIENCES “Artificial Intelligence (AI) will become more mainstream in clinical research, starting with drug safety reporting.

As the sheer volume of data in clinical trials increases, humans will no longer be able to handle it manually, and AI will need to be leveraged to automate some of the work.

Safety case management is an area that is leading the way into the adoption of AI. Some of the immediate areas that AI features may be incorporated into pharmacovigilance include: source document processing, case report narrative processing, call centre log adverse event flagging, product label processing, literature screening for adverse events, and signal detection.”

PAUL BROOKS, EXECUTIVE DIRECTOR, RAPS “With less than 100 days to go, pharmaceutical companies still do not know how they will be impacted by Brexit.

A ‘no deal’ Brexit, if it happens, is predicted by many experts to risk huge social and economic impact that will change and burden how all industries that move materials and goods across borders, not least the pharmaceutical and medical device sectors, do business. RAPS is closely monitoring this period of uncertainty and transition and is committed to informing regulatory professionals with the latest news and insights as they develop.”

MED-TECH INNOVATION EXPO 15 - 16 MAY 2019 NEC | BIRMINGHAM | UK medtech | digital healthtech | medical plastics | manufacturing software | inspection and metrology | regulation | design early stage innovations | pharmaceutical manufacturing

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SOLID DOSE MANUFACTURING

Who: I Holland What: Capping and delamination

Case study

How: Die bore ringing

33

THE RIGHT TOOL FOR THE JOB Michael Oxford, research & design engineer from tablet manufacturer I Holland explains how the company recently helped pharma company Accord Healthcare improve tablet production.

O

ne of the products Accord Healthcare manufactures is a 12.5mm Flat Bevelled Edged tablet embossed with central break-line.

Previously, Accord Healthcare used standard Tungsten Carbide dies to compress this product but due to ‘black spots’ appearing on the tablet walls after compression, the usage of the dies were suspended in 2008 and over the years either premium steel dies or powder metallurgy dies were used to compress the product.

At the time it was believed the problem was being caused through the added resistance during tablet ejection, or through a reaction with the tooling material itself.

Although Tungsten Carbide is a common tooling material used within the pharmaceutical industry, it typically uses Cobalt as a binding material.

This can have reactive properties with acids and certain materials found within formulations causing corrosion resulting in black spots.

I Holland has developed a Tungsten Carbide grade that uses a special binder in replacement of cobalt. It has exceptional corrosion resistance making it an excellent option if both corrosion protection and resistance to abrasive wear are required.

During manufacture, an additional problem experienced was capping (tablet separation) and delamination (tablet splitting) of the tablets.

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35

SOLID DOSE MANUFACTURING

The Investigation

Solution 1

In order to find resolutions to the problems, I Holland undertook a trial using their new nonmarking HPG-TC (Tungsten Carbide) dies.

After the trial using the new dies, no black marks were found on the tablet side walls.

Analysis on-site showed that the dies and punch tips had sufficient clearance when fitted to the press. The temperature influence (27.3°C at full speed compression) was checked during the site visit and determined not to contribute to the cause of the capping and delamination or black marks on the tablets (i.e. there was no heat created through friction that could have melted the granule). The press produced 240,000 tablets per hour with a batch size of 1.6 million tablets.

Sample dies from several sets (ranging from 2007-2018) were supplied for analysis.

The first step was to use dimensional analysis of the dies through the ‘Approve’ system. This works by using a combination of technologies/measuring equipment to accurately determine the dimensions of punches and dies to micron level.

The reports confirmed that the clearance between the punch tip outer diameters and die bores were well within specification.

This eliminated this as a cause of the delamination.

The next process was to use surface finish analysis. A form Talysurf was used to measure the surface finish of the die bores to ensure they were manufactured to Eurostandard specifications.

It was found the die bore surface finish was in specification for all the measured dies, so a ‘roughening’ of the die bore was not a cause of the issues.

Finally, analysis of the sample tooling took place using iNSPECT 2.0. Punches and dies should be visually inspected to establish if the tablet production process is running well and identify whether any tooling maintenance is required. Carrying out an assessment will establish if the production process is working as it should, giving clues to problems with the tablet press or tooling itself, and if any tooling maintenance is required.

The Trial A compression trial was undertaken on-site at Accord Healthcare using I Holland’s newly developed special grade of Tungsten Carbide.

The trial included manufacturing four batches of tablets with a production time of around five hours and 1.6 million tablets per batch.

Inspection of five specific dies took place after each batch to monitor any change in die bore appearance, for example, signs of wear.

Solution 2 Following extensive analysis of the supplied dies, I Holland recognised that the main cause for the capping and delamination was through die bore ringing. The rings can either be in the form of one ring which is caused by an abrasive granule, or by two rings which indicates tip deflection. ‘Die bore ringing’, takes place in the die bore where the tablet is compacted. The wear appears as a double ring due the upper and lower punch tips flexing and bending within the clearance between the tips and the die bores during full compaction.

The tablet when formed within these rings can have issues when being ejected from the die causing capping and delamination of the tablet.

Analysis of the rings on the old dies revealed that the depth of the die bore ringing varied between three and 17 microns, the deeper depth being with Premium HPG steel dies as opposed to the HPG Powder Metallurgy Dies.

These use a specialist powder metallurgy grade steel with uniform carbide distribution and small carbide size giving extremely high wear resistance over and above that of premium steel, but it is less wear resistant than Tungsten Carbide.

Analysis has shown that the life expectancy of the dies has always been inadequate due to the compromise of material selection required to overcome the black marks.

This has necessitated in sets of dies being discarded due to capping and delamination problems with the tablets.

CONCLUSION Compressing these tablets brought with it many issues, however through the use of advanced analysis and assessment processes and trialling innovative new tooling material, in this case I Holland’s HPG-TC, problems like ‘black spots’ and capping and delamination caused through wear were eliminated from production.

36

AMReview

It takes two Antimicrobial resistance AMR) is one of the biggest threats facing the world but arguably not enough is being done by both pharma companies and governments. Last year, biopharmaceutical company Helperby announced a collaboration with the University of California to develop the next generation of combination antibiotics.

H

ere, Reece Armstrong speaks to founder and chief scientific officer of Helperby, professor Anthony Coates, on how the recent collaboration can help combat AMR. RA: COULD YOU TELL ME ABOUT HELPERBY’S RECENT COLLABORATION WITH UCLA? AC: Helperby are collaborating with Dr Pamela Yeh and the UCLA. We are concentrating on the use of antibiotics in combinations to target antimicrobial resistant bacteria which are rapidly threatening the efficacy of existing antibiotic therapies. I believe that Dr Yeh’s research on the phenomenon of emergent synergy of combining two or more existing antibiotics and their efficacy against pathogenic Escherichia coli1 (E-coli) is an important breakthrough to combat AMR. We will work closely to explore the commercial opportunity of additional, new, combination therapies. The collaboration will include the sharing of data, expertise and research methodology. The work is based on the observation that major disease areas like tuberculosis, AIDS & cancer benefitted from combination therapies but that antibiotics continued to be single molecule therapies.

RA: WHAT DO YOU HOPE TO ACHIEVE FROM THE COLLABORATION WITH UCLA? AC: Ultimately for there to be more existing data which supports the benefits of combination antibiotics.

We want to help other companies to make their antibiotics more effective against resistant bacteria.

The ‘one drug, one target’ model has limited viability and there is evidence that combination therapy is the norm in the treatment of many cancers, viral infections such as HIV and tuberculosis treatment. It is a viable alternative to the development of totally new antibiotics that take at least 30 years or more to develop.

For there to be more investment in these combined strategies will keep mankind ahead of antimicrobial resistance and is crucial in order to preserve a world where simple infections do not routinely kill healthy people.

Finally, I see potential in this being the first long-term renewable solution to the antibiotic crisis RA: WHY IS DR YEH’S RESEARCH SO IMPORTANT? AC: Antimicrobial resistance is recognised by the World Health Organisation as most pressing global threats to health. It was previously held that the risks of combining antibiotic drugs often outweighed the benefit because of adverse interactions. But

Dr Yeh’s team found the direct opposite, and reported that as more drugs were combined, an elevated frequency of synergy was observed. This is a breakthrough and could be the information we need for a potentially longterm renewable solution to the antibiotic crisis. Without effective antibiotics, much of the success of modern medicine, such as the levels of unprecedented survival rates from major surgery or super effective, chemotherapy treatment, would be totally compromised.

RA: DO YOU THINK ENOUGH IS BEING DONE BY GOVERNMENTS TO TACKLE AMR? AC: No, I don’t think so. Of the 10 recommendations in Jim O’Neill’s AMR Report (2016) for the UK government, only a minority are progressing fast enough to have a major impact. Jim O’Neill pointed out this lack of progress in 2018 and thinks that his predictions of 10 million deaths per year in 2050 due to AMR may be on the low side if more is not done faster than at present. This is something that I definitely agree with.

RA: WHY DO YOU THINK SO MANY BIG PHARMA COMPANIES HAVE LEFT THE AMR SPACE FOR DEVELOPING NEW THERAPIES? AC: Most companies favour a focus on more incremental increases in innovation in chronic

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disease areas, over the more unpredictable leaps needed to keep up with the development of bacterial mutation. The high risk of creating a new chemical entity deters large pharmaceutical operations. This leaves the fight for antibiotic survival, arguably one of the most urgent fields of drug development, to smaller, more nimble biopharmaceutical companies. Due to these reasons there is a lack of investment for wide spread development of combination therapies. Hopefully the fact that research is very much alive in the benefits of combining existing antibiotics to create new super resistant combination therapies means that there will be more financial support.

RA: DO YOU AGREE WITH THE SENTIMENT THAT THE UK IS A POTENTIAL GLOBAL LEADER FOR FIGHTING AMR? AC: Yes, most definitely. Until 2016, the UK was a world AMR leader.

Recently, the country has not maintained this momentum, but has the potential to regain its position as a global AMR leader in the future.

RA: WHAT CAN THE GENERAL PUBLIC DO TO HELP AND HAS THERE BEEN ENOUGH AWARENESS RAISED OVER AMR? AC: AMR in common bacteria needs new antibiotics or new antibiotic combinations to save patients’ lives.

They need to be well tolerable, safe and if possible, prevent the emergence of resistance. Of course, other strategies also play their part: Irrational use of medicines is a serious global problem, good infection control, publicity about AMR, more effective vaccines, less use of antibiotics in agriculture,

fast diagnostic testing, more professionals working in the AMR field, more investment for clinical trials and a much higher unit price.

Establishment of national committee to monitor impact of antibiotic resistance and provide intersectoral co-ordination is required. Joint efforts from patients, prescribers and individuals to international regulators and policy makers are needed to fight against the globally spreading AMR. Investing in these combined strategies will keep mankind ahead of AMR and is crucial in order to preserve a world where simple infections do not routinely kill healthy people.

RA: DO YOU THINK UNIVERSITIES, SMES AND BIOPHARMA GROUPS LIKE HELPERBY ARE HAVING TO TAKE ON THE BRUNT OF THE WORK SURROUNDING AMR? AC: Yes. Big pharmaceutical companies have moved out of the field. For example, Novartis moved away in 2018. This leaves universities, SMEs and biopharma companies such as Helperby Therapeutics and other companies to bear the brunt of the work to, for example bring new antibiotics, new antibiotic combinations and new diagnostic tests to the market

We want to help other companies to make their antibiotics more eective against resistant bacteria.

37

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39

INDUSTRY 4.0

DIGITAL DRIVERS In the pharmaceutical industry, especially complex processes must be adhered to, and stringent requirements upheld. Here, a, project manager industry 4.0 pharma at Bosch Packaging Technology explains why the road to digitisation is multi-faceted.

PHARMA: A SPECIAL CASE Compared to many other industries, pharmaceutical production underlies more demanding regulations. Changes to production mean changes to the machines, processes and ultimately the product itself. To ensure consistently high product quality, authorities like the US FDA and the EU Commission issue strict guidelines, such as those on Good Manufacturing Practice (GMP).

Accordingly, companies have their fair share of reservations when it comes to implementing new and untried technologies.

Nevertheless, many pharmaceutical companies have already taken the first step toward digitisation and are now engaged in its implementation.

In this case, we are talking about serialisation based on Track and Trace applications – at least, if a holistic solution is used. To adhere to all relevant legal guidelines, it is not enough to simply print a data matrix code on the folding carton. A holistic serialisation and aggregation solution should include the connection between machines and software, ensuring that the entire process can be managed, and the data is constantly available.

Only this way manufacturers and distributors alike have a clear overview of all process steps.

GETTING STARTED STEP BY STEP The implementation of a serialisation solution alone represents a huge challenge.

However, in the next step, pharmaceutical companies face obstacles of a very different kind: while Track and Trace applications

focus on the packaging, other instruments directly affect the production or filling process.

Accordingly, pharmaceutical manufacturers have especially high demands when it comes to new industry 4.0 solutions. They need the security of knowing that a given solution can be or has already been successfully implemented in the market.

Digitisation projects can influence many processes and components.

Hence, no one party can or should try to implement them alone.

Instead, digitisation is about bundling the respective expertise and experience on a cross-project basis. This can include participating in nationwide initiatives. Above all, however, machine providers, software manufacturers and process experts need to work together closely to reap the maximum benefits of industry 4.0 for their customers. This does not mean they have to replace their entire machine park or abandon their current production philosophy.

A step-by-step approach is often the more sensible alternative.

MAKING USE OF EXISTING COMPETENCIES For this purpose, an introductory solution like Bosch’s Pharma i 4.0 Starter Edition is a good fit.

The package offers machine operators key functions for condition monitoring, event tracking and measuring Overall Equipment Effectiveness (OEE) on their PC or mobile device, including a complete audit trail for all user interactions. The data gathered by the software can be subsequently

analysed and used as the basis for targeted process optimisations.

This also includes historical data, which can be compared to realtime data and offers valuable insights into the development of central parameters, such as the OEE within a certain timeframe.

Thanks to the use of open standards, incorporating machines and lines from different brands does not mean reinventing the wheel. OPC-UA and the machine programming language PackML are primarily used as the standard for communication and data exchange. Adding further features, for instance the generation of Electronic Batch Records (EBR), is also possible. Here, too, all process steps are subject to strict regulations concerning electronic signatures, GMP-compliant processes and longterm data archiving.

FINDING BURIED TREASURE Once the data is available, the real challenge consists in identifying previously overlooked information and new potential for optimisation.

With the help of data analytics or data mining, huge amounts of data are assessed for effects and correlations using statistical methods. Usually, the data from two production batches is suďŹƒcient to draw initial conclusions. Yet the more data is evaluated, the more details come to light. The only equipment needed are sensors to gather the data, which can also be found on the majority of older machines, and the right tool for analysing the data. The most important aspect, however, is the combination of extensive process expertise and IT know-how.

40

INDUSTRY 4.0

FROM VISION TO REALITY In the near future, such recalibrations could be even easier, thanks to augmented reality and virtual reality (AR and VR). For example, AR applications can guide employees through the process step by step, and be used to display calibration instructions and spare parts.

This can considerably accelerate the process without the need for lengthy training. When more complex processes are involved that make training essential, it no longer has to take place in a classroom or on the shop floor.

VR applications produce 3D simulations of machines, which can be used under highly realistic conditions in virtual training sessions. Trainers can follow the simulation live and add helpful instructions as needed, while operators can practice safely and without stress, since any errors they make will have no direct consequences or interrupt the ongoing process.

Admittedly, some of these industry 4.0 applications are still in an early stage of development. Nonetheless, the digital future is within our grasp, as essential devices like sensors are getting smaller and smaller, and components are becoming more affordable. To gradually make the vision of a connected pharmaceutical industry a reality in day-to-day production, strong partnerships are called for. After all, the challenges posed by digitisation can only be successfully and sustainably overcome if machine manufacturers, software developers, process experts, and employees work hand in hand.

Many pharmaceutical companies have already taken the first step toward digitisation and are now engaged in its implementation.

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42

GENOMICS

From detection to prevention Assistant editor Ian Bolland explains how a genomics-based personalised risk assessment is aiming to improve screening programmes for breast cancer.

H

ealthtech company Sophia Genetics has developed a personalised risk assessment test for breast cancer called Prevent.

The test, a decision aid for health professionals, involves a saliva swab and questionnaire In the near future, which is supported using technology by over 10,000 breast cancer such as Prevent genomic profiles will quickly bring and 10 years of some of the promise research.

of personalised medicine into everyday use in the clinical setting.

The objective behind Prevent has been for women to receive breast cancer screening at an age they require it rather than the age range in which they qualify for it, with free screenings usually offered to women aged 50 and above.

It is thought that close to 50% of women diagnosed with breast cancer are not within the age range required to do a free screening.

It has been trialled at Imperial College London Healthcare NHS Foundation Trust under the guidance of Dr Jonathan Krell, consultant medical oncologist who says it has “potential to improve breast screening programmes, so women are checked when they actually need it.”

David Cox, a researcher and the clinical application product manager at Sophia Genetics explained to European Pharmaceutical Manufacturer how the product was put together by combining expertise in genetic epidemiology, statistics and user interfaces.

He said: “Prevent would not have been possible without the Human Genome Project, which was first published in 2003. Since then, there has been an explosion of our capacity to understand and use genetic variability for health purposes."

Prevent works by taking into account both genetic and nongenetic factors when assessing the risk for a patient.

“The genetic variations used are very common variants that only slightly influence risk individually.

However, when taken as a whole, they are powerful tools for risk stratification. The non-genetic factors are well established from decades of research and are mainly related to reproductive history and lifestyle,” Cox said.

Cox thinks that such screening technology will be used in the future when it comes to the detection of cancer. While

refining the risk estimate for a given woman and by increasing the precision with which risk is estimated, it can allow for more targeted steps towards prevention.

When it came to how the product may be developed in the future, he explained that up-do-date research and work is integral.

He said: “Including new results is paramount to our vision of Prevent. Being able to provide the most up to date, most relevant insights for physicians is a main goal of every Sophia Genetics product. In December, a paper was published from an international consortium of breast cancer studies proving association between over 300 variants and breast cancer risk.

We have designed Prevent to be able to rapidly adapt to such new knowledge, and will integrate this into our algorithms.

“Genomics is still a rapidly expanding and advancing field.

The potential to apply genomic solutions to health is enormous.

In the near future, using technology such as Prevent will quickly bring some of the promise of personalised medicine into everyday use in the clinical setting,” Cox concluded.

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