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Contents May 2017 | Volume 17 Issue 3

Regulars

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14

Features

26

EDITOR’S DESK

BIOPHARMA Bosch focus on quality and safety

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31

ANALYSIS

SERIALISATION

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38

REGULATORY AFFAIRS

22

Looking at the critical role packaging plays

Natoli examines sticking and picking issues

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25 37 OPINION

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41 PACKAGING

ON THE COVER

SPOTLIGHT ON INNOVATION

What lessons should we learn from the US

GENOMICS

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EPM reporter delves into the latest developments

head office Carlton House, Sandpiper Way, Chester Business Park, Chester, CH4 9QE. Tel. +44 (0)1244 680222 Fax. +44 (0)1244 671074 Web: www.epmmagazine.com

editorial editor felicity thomas felicity.thomas@rapidnews.com deputy group editor dave gray david.g@rapidnews.com group editor lu rahman, lu.rahman@rapidnews.com reporter reece armstrong reece.armstrong@rapidnews.com publisher duncan wood

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European Pharmaceutical Manufacturer is published by Rapid Life Sciences Ltd. European Pharmaceutical Manufacturer is distributed in electronic and print formats to a combined readership of 14,000 pharmaceutical manufacturing professionals.

Volume 17 Issue 3 © May 2017 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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COME AND BREATHE DIGITAL INTERPACK 2017  HALL 17

editor’s desk

As the industry realigns itself to some major changes, EPM magazine also has a shake up As the UK is going through the motions of leaving the EU, now that Article 50 has been triggered, and the pharmaceutical industry worldwide is experiencing vast changes, we at EPM magazine have also experienced a shake-up (of sorts)!

Also, we must consider where the EMA will be based in the future.

From Italy to Sweden and possibly the Republic of Ireland, there are many contenders applying to be EMA’s new home. This decision, however, is firmly in the hands of EU member states.

Firstly, I would like to introduce myself, Felicity Thomas, as the new editor for the publication. With an extensive background in scientific B2B publishing, I hope to continue the thought-provoking and well-rounded nature of the content that you, as the readers, have come to enjoy and look forward to each issue. I would also like to welcome any comments and opinions you may have on this issue and potential features and stories that you would like to see covered in future issues.

Although the certainty of location is, as of yet, unknown, what we are sure about is that with the departure of the EMA from London the UK pharma industry will be affected. With increasing regulation and scrutiny of drug efficacy and the new set of regulatory changes coming into force to combat counterfeiting these effects must be compounded.

Obviously, a huge discussion point currently hitting headlines is that of Brexit. How will the UK pharma industry adjust to this departure and what changes might the rest of Europe encounter?

One question highlighted by the New Statesman is what will happen to the EMA? Since beginning operations in the mid 90s, the EMA — a decentralised agency of the EU based in London — has been responsible for scientifically evaluating and monitoring the safety of medicines developed by pharmaceutical companies to be distributed within the EU. With patients in Europe generally able to access medicines about six months to a year sooner than patients in Australia and Canada, there is concern over how the departure of the EMA from the UK will affect British treatment waiting times and drug prices. If the UK decides to go completely independent from the EMA, creating its own guidelines and standards, how will pharma companies from other EU based countries manage these extra complexities or will they simply decide to overlook the UK altogether?

This brings us to the EU Falsified Medicines Directive (EU FMD) to be brought into full force across all EU countries by February 2019. Although the UK government has asserted that Brexit will not affect the implementation of the EU FMD, potential repeals and amendments to EU guidance and regulations post-exit have been highlighted as a positive outcome of the UK’s departure by Brexit campaigners. If the UK does decide to create independent regulations surrounding these issues then we must anticipate effects on global distribution of medicines manufactured within the UK and a potential withdrawal of other EU manufacturers from the British market.

Either way, these coming months of negotiations are vital for both UK and European pharmaceutical companies and most definitely the patients requiring treatments.

We will have to wait and see what the next few years hold, but it will surely be exciting to see the situation unfold and EPM will be there to provide a resource to guide you through the ups and downs.

Felicity Thomas

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ANALYSIS

BIG data BIG data

How pharma R&D can make the most of the big data revolution

The big data hype train has been gaining momentum for a number of years and its rise has been well documented.

However, pharma companies are still perplexed by the scope of what big data can do, and why, how and where they should use big data tools to their advantage.

With focus moving away from sheer volume of data and inherent variability and complexity of large unstructured datasets towards user-friendly analytic tools that can help businesses plan for the future, now is the time for big, small and medium size pharma to seize the ‘big data’ opportunity.

Trailing behind Despite being a sector priding itself on innovation, pharma has trailed behind when it comes to adopting new technology. For example, the timid approach that pharma has taken with social and new media (due in part to regulations and the industry’s code of conduct) and in the selection of clinical research partners. pharma has

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trailed behind when it comes to adopting new technology.

Programme teams are still relying heavily on their existing networks or CRO partnerships, rather than tapping into the vast amount of data out there on scientific expertise and patient populations.

Nevertheless, data analytics can open a whole new world of possibilities in the research of new compounds with the power to radically improve multiple stages of the drug discovery process.

”

In clinical development, phase II–IV, new technologies have emerged ‘en masse’ since the early nineties, but only a handful have attempted to go beyond the value proposition of merely smart reporting of in-clinic

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generated data within controlled and randomized clinical trials.

This is not surprising given that the data entering the pharmaceutical data hub is unstructured and messy, including many duplicates or errors. The formidable challenge here is to clean and link the data, building a consistent and reliable foundation upon which any model of value-adding analytics can be developed. Once that hurdle is taken, data can become a fertile ground for deriving intelligence. This is the fundamental proposition that big data offers; to speed up process and improve decision making.

What is meant by ‘analytics’?

Algorithms and statistics can start making ‘models’ of real world activity, which can be tested according to real world measurements. Machine learning takes this activity one step further — rather than handcrafting a relatively simple model, a model with up to hundreds of parameters is ‘trained’ using large amounts of input data. Everyday examples of machine learning, intrinsically linked to computational power, are face or fingerprint recognition, tumour cell classification and analysis of microarrays.

The concepts of analytics have also been extensively applied in the linking of information related to clinical trial metrics, investigational site locations, patient recruitment metrics, investigator and medical expert identification.

Unifying data on multiple parameters, when combined and semantically matched, helps to connect the dots for efficient clinical trial planning and patient recruitment.

Whereas teams used to perform manual searches on publicly available sources (such as publications, trial registries and conferences) automated analysis can now provide companies with an improved picture on drug development programmes to assist business decision making.

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External vendor support Despite considerable investments in data science analytics teams, more pharma companies are using external vendors to support the implementation of a big data strategy. One such tool, ta-Scan, founded 10 years ago

by MDCPartners has been employed by global pharma companies to change the way companies use data.

One of the elements that has been most sought What is clear is after has been the ability to consolidate public and that big data is internal unstructured data here to stay and from the large data silos will continue to that still reside in pharma have a growing companies.

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influence

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The quality of data output from tools such as ta-Scan that analyse vast public data repositories has earned the trust from big pharma and has piqued their curiosity to expand the analysis to their internal silos and real world data. It has been purported that real world data can cost in excess of $20 million with no clear measurable or KPI to evaluate the impact of interventions on patient cohorts.

Indeed, opening the lid on this internal data and providing it to experienced data companies may reveal valuable analyses that can translate data to information, guiding business intelligence and initiating alternative strategic objectives.

What is clear is that big data is here to stay and will continue to have a growing influence in terms of its impact to business decision making across a number of sectors. Some of those in pharma are firmly grasping the opportunity that analytics-based decision making can bring… And those that aren’t will need to catch up before they lose out.

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ANALYSIS

John Culkin, director of information management, Crown Records Management, reveals why pharma companies should still prepare for the EU GDPR regardless of Brexit.

P

harmaceutical companies are being told to think twice before cancelling or delaying preparations for the forthcoming EU General Data Protection Regulation (GDPR), as the UK pushes ahead with Brexit.

Businesses across the country have been studying implications of the new regulation, set to be in force in May 2018, which aims to create a ‘one-stop shop’ for data protection across the EU. Some of the key aspects of the bill include huge fines for data breaches, new rules around the collection of personal data and new rights for European citizens to ask for data to be deleted or edited. Many firms will also be required to appoint a data protection officer.

However, as a result of the Brexit vote and the recent triggering of Article 50 by Prime Minister, Theresa May, the UK is already in the process of leaving the EU before the new regulation has come into force.

So, what does this mean for businesses, including pharmaceutical companies, in the UK currently preparing for the new regulation and updating their policies and processes in the New Year?

Here are some of the answers to commonly asked questions: 1. Will the EU GDPR still apply to post-Brexit UK businesses?

It is tempting for businesses to think that because the UK is leaving the EU this regulation will not apply. In fact, that isn’t the case. Although an independent Britain will not be part of the regulation, in reality it will still be impossible to avoid its implications.

The regulation governs the personal data of all European citizens, providing them with greater control and more rights over information held about them. So, any company holding identifiable information of an EU citizen, no matter where it is based, needs to be aware. With

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millions of EU citizens living in the UK, too, it’s hard to imagine that many businesses based in the UK will be unaffected.

The same applies to data breaches involving the personal data of European citizens. Therefore, it will still be vital to have a watertight information management system in place which allows businesses to know what information they have, where it is, how it can be edited and who is responsible for it.

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With a total footprint of 1100 m2, the GPSC epitomizes the state-of-the-art in oral solid dosage (OSD) form testing, development, and optimization, and offers a full range of batch and continuous manufacturing technologies. From product development and process enhancement to real-life simulations and test and loan machines, we provide a comprehensive range of services that are designed to improve production efficiency and expedite time to market.

The GPSC offers • customer demonstrations and trials on our batch and continuous equipment • training sessions and classes • hands-on laboratory experience • pharmaceutical product development assistance • CQAs evaluation • testing of new concepts (equipment and advanced controls) • scale-up from laboratory to production • process development/refinement to increase the understanding and capability of GEA equipment.

2. Why should businesses push ahead with data reforms regardless of Brexit?

Businesses should be thinking about the benefits of good information governance rather than hesitating because of what could happen in the future.

There is no point putting in place systems that ignore privacy by design, for instance, when that is good procedure — no matter what happens after the UK becomes fully independent. The same is true of measures to

protect a business from data breaches, which have reputational as well as financial implications — no matter who imposes the fine.

As for personal data, citizens in the UK are only going to be more demanding about how their data is collected, stored and edited in future — the genie is out of the bottle and it’s not sensible to think that leaving the EU will change it. Preparing for a modern data world is not only about the GDPR.

3. What regulations will affect UK business once Brexit has been completed?

Even though the UK has voted to leave the EU, data in Great Britain & Northern Ireland will continue to be regulated by the current Data Protection Act, which was passed in 1998. It will remain in place after exit, at least until parliament decides to introduce a new law or amend it.

It’s worth noting that the UK’s data protection laws precede EU legislation by more than a decade, and go beyond the current requirements set out

by the EU, for instance with the power given to the ICO to issue fines.

So, if businesses think that leaving the EU is suddenly going to change the agenda, it is a dangerous stance to take.

Failing to prepare for the regulation could leave businesses open to fines, loss of reputation and — just as importantly — see them miss out on a chance to make the most of their data.

4. How might UK data regulation differ in future from those in Europe?

It’s pretty hard to see data regulation in the UK varying much from the essence of the EU GDPR which, after all, we have been heavily involved in drafting over the last few years. Having clear laws with safeguards in

place is more important than ever in the modern world with a growing digital economy that relies on the safe sharing of data.

5. What are the benefits of the EU GDPR? Could we be missing out on by leaving?

The political debate has its own arena and that is for people to make up their own minds on. However, in terms of the GDPR this is a regulation designed to make things easier for businesses that work with the personal data of EU citizens. A one-stop shop for data protection, for instance, is long overdue.

Trying to regulate a rapidly-evolving digital world with legislation dating from 20 years ago does not make sense. Any regulation which encourages businesses to have strong and robust information management systems in place should be a good thing.

6. What could be the benefits of being outside the EU GDPR? There are certain requirements of the GDPR that may no longer apply, such as a requirement to appoint a data protection officer for some companies. So, there could be cost savings in the short-term. The reality, however, is that the general principles of the regulation are pretty universal and likely to influence legislation and best practice in other areas of the world.

The best advice for businesses is to embrace those principles and prepare accordingly. Undertaking a data audit in 2017 and re-assessing data protection and information management processes will help prepare for all eventualities — whether that is strengthening data protection compliance, building confidence for the brand or making the most of data assets.

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Preparing for a modern data world is not only about the GDPR.

”

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ANALYSIS

Integral automation

A

utomation is an integral part of biopharmaceutical production, playing a central role in manufacturing coordination, control and documentation and replacing many manual operations.

Not only do processes need to be flexible regarding the size of batches but also must comply with strict regulatory guidelines while also keeping costs down. Therefore, automating hardware alone is not sufficient in today’s market.

As a result of this demand GE Healthcare Life Sciences has completed a strategic minority investment of technology company, Zenith Technologies, which delivers manufacturing software systems to global life sciences companies. This enhancement to the existing partnership will see Zenith’s automation expertise being applied to GE Healthcare’s consumer base and will also increase automation capabilities for product development.

“Zenith has grown significantly over the last number of years and now has over 700 people globally. Zenith are engaged with the top 10 life science companies and we are looking forward to continuing to work with GE Healthcare and the next-generation of manufacturing solutions,” said Brendan O'Regan, Executive Chairman and Founder, Zenith Technologies. “This investment by GE will further enhance our recent partnership and collaboration, and will enable an acceleration of growth for Zenith.”

“In a complex and highly regulated industry, automation is critical for our customers, who want to establish biomanufacturing capacity quickly and at a lower cost. This is often in challenging markets, where the access to life-saving therapies is limited,” added Jan Makela, General Manager, Bioprocess, GE Healthcare Life Sciences. “With many years of experience in a wide diversity of customer applications, Zenith Technologies can strengthen our end-to-end solutions even further. This is a significant strategic investment by GE and the next step in developing our marketchanging FlexFactory and KUBio manufacturing solutions.”

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Filling the cell therapy space Additionally, GE Healthcare has acquired a specialist in cryochain technology for sensitive cellular therapies, Asymptote. This acquisition will fill the space in GE Healthcare’s end-to-end ecosystem of products and services for cell therapy production.

Cellular therapies are fast becoming a revolutionary aspect of the healthcare landscape as a result of the potential they offer in treatments and cures for challenging conditions.

As this market develops so will the demand for manufacturing and clinical delivery of cellular In a complex therapeutic solutions.

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and highly

“Asymptote’s high-quality offering takes us another regulated industry, step forward in our vision to industrialize cell therapy, and in providing reliable and high-quality services automation is for our customers and patients around the world,” critical for our explained Ger Brophy, general manager of GE customers Healthcare’s Cell Therapy business. “We want to improve the access to cellular therapies and tap the great potential that they have in curing some of our most difficult diseases.

Finding ambitious technologies and partners like Asymptote, we are one step closer to realizing that goal.”

This acquisition further increases GE Healthcare’s investments in cell therapy and regenerative medicine. Over the past 12 months the company has also acquired Biosafe — a supplier of integrated cell bioprocessing systems — Virtuvian Networks — a GE Ventures and Mayo Clinic collaboration, providing cloud-based software systems and manufacturing services for cell and gene therapies — and BirdGE@ CCRM Cell Therapy Centre of Excellence — a US and Canadian government co-investment project to promote new technologies in cellular therapies production in Toronto.

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AD VE O RT RI AL

Productive R&D drives intelligent drug delivery Phillips-Medisize and Medicom Innovation Partner argue that strategic development of a drug delivery device boosts pharmaceutical industry R&D productivity, shortening development lead times while providing enhanced value for all stakeholders.

Pharmaceutical companies face higher price pressure on better – but more highly priced – products as healthcare costs strain national economies increasingly. Phillips-Medisize’s chief technology officer Bill Welch and Kevin Deane, executive vice-president at Medicom Innovation Partner, observe that strategically developed drug delivery devices will drive improve patient outcomes, creating more value for the healthcare system, which in turn will improve pharmaceutical industry R&D productivity. For late-stage developments, the average yield on R&D expenditure has dropped from 10.1% in 2010 to 3.7% in 2016, as drug development costs rise.

Drugs are delivered to patients increasingly by complex devices, as opposed to traditional oral administration. As the number of internetconnected devices rises, the healthcare industry, and specifically drug delivery, will inevitably be caught up in this societal change, too, according to Welch and Deane.

stakeholder interviews, user research and client workshops. Rapidprototyped delivery devices can be a useful workshop tool, as well as a means of to identifying further opportunities.

Phillips-Medisize starts each development path with a strategy stage, with market differentiation, execution and constraints-to-execution phases. The company says its approach achieves shorter lead times than conventional ones, which omit the strategy stage, plunging straight into development.

The lack of a strong device strategy means the drug risks becoming a ‘me too’ solution; in this instance investing up front in a sound strategy generates a solid return.

All development team members are involved with the entire project, saving time that would otherwise be consumed in transferring knowledge from one team member to another.

Maximum value Addressing productivity, Welch and Deane say pharmaceutical R&D productivity should be enhanced by focusing less on efficiency and more on effectiveness, with patients benefiting from the greater value offered by more innovative drugs and better information.

Modern drug delivery devices achieve maximum value within each individual therapy strategy, ensuring more effective treatment, potentially also reducing documentation. Medicom is proud of its approach to identify how specific delivery devices can support patients and obtain improved care results.

Welch and Deane suggest drug delivery device producers should approach the market with differentiated, rather than lower-value ‘me too’ solutions that simply replicate others’ achievements. Only then can plans be drawn up for launch and further development of identified high-value therapies.

Strategy development should be completed within two or three months and should use existing approaches as building blocks, supported by

Time is also saved by handling device development parallel with development of technology platforms that provide the required technology.

Welch and Deane say early planning of specific drug delivery devices for individual types of therapy “will often hold the key to unlocking greater value”, creating better understanding and benefiting patients and the support they obtain from the various stakeholders – with potential spinoffs into more differentiated products. Integration of drug and device development and manufacturing is the key holistic approach and the driver towards obtaining significant improvements in R&D productivity, they conclude.

Intelligent multiple sclerosis solution Medicom gives an injection delivery device designed for treatment of multiple sclerosis as an example of a product developed with the company’s drug delivery strategy approach that maximises added values. It is a solution that improves ‘event-driven’ patient interaction and information sharing with healthcare professionals (HPCs) on specific MS therapy needs, to an extent that “off-theshelf devices are simply not able to deliver”.

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GENETIC LEVEL MEDICINE

G(e)nome and trolls Healthcare expert and partner at BLM, Greg McEwan, discusses DNA sequencing and the future risks it may pose.

T

ypically, when we talk about futuristic technologies in healthcare, it’s often hard to anticipate how quickly society will make the bridge between science fiction and mainstream medical practice.

That was almost certainly the case in the early noughties when scientists were at work developing the publication of the first complete genome in an effort to provide a DNA bible by which future medicine would abide. However, just 14 years on from the big Biological data breakthrough in 2003, is becoming DNA sequencing is making increasingly itself uncompromisingly known in the daily lives of important as health practitioners in some technology of the most important fields provides us with of treatment.

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greater access to what makes us human.

2017 was intended to be a landmark year for the development of ‘genomic services’ — a term coined by the Department for Health when it launched the 100,000 Genomes project in 2012, intending to sequence 100,000 genomes from NHS patients within the space of five years.

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While the initial deadline has been shifted by a year, all signs are pointing to DNA sequencing becoming this century’s defining revolution in mainstream treatment as it creates a sprawling mass of new data with which to develop treatments for previously untouchable diseases.

Risk assessment required The future looks bright but, as with any new development, there is a level of risk that needs to be assessed and

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medical insurers are rightly doing their due diligence for current and future policy. Interestingly, while insurers might have once been concerned with issues of negligence and malpractice in treatment, the threat profile is following general insurance practice and moving in the direction of the IT department.

Biological data is becoming increasingly important as technology provides us with greater access to what makes us human.

What begins with the issue of access can often lead to questions of ownership. Is our genetic information ‘property’? One of the co-discoverers of the BRCA1 and BRCA2 genes (which signal an increased risk of developing breast cancer) sought to patent its discovery in the US. A US court held that the genetic information already existed in nature and that naturally occurring compositions are (at least in the US) incapable of being patented.

Elsewhere in the world, companies have been able to patent naturally occurring genetic information. As the usual aim of obtaining a patent is to allow an invention to be exploited commercially, this raises the spectre of the testing and treatment for certain genetic conditions being available only to those with deep enough pockets.

In the UK, our genetic data satisfies the definition of sensitive personal data within the Data Protection Act 1998, consisting of information regarding our ‘physical or mental health’. Such data must be held and processed within the strict provisions of the act, in recognition of its value and sensitivity and the potential for it to be exploited.

For example, how would we feel about the idea of an employer, or an insurer, having access to our genetic data? This gives rise to the potential for decision making (potentially discriminatory decision making) on genetic grounds — not necessarily for what is, but for what might be. Insurance premiums could be raised for those with

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certain genetic markers, jobs offered to those with more ‘favourable’ genetic profiles.

Huge potential and significant risk The uses to which our genetic data might be put are many and varied. There is huge potential for medical advancement, such as bespoke cancer treatments. There is also the risk of significant harm.

In 2013, the US FDA determined that a particular genotyping test was intended for the ‘diagnosis of disease… or in the cure, mitigation, treatment or prevention of disease’ and warned of the potential consequences of false positive or false negative results.

The raw data from one genome alone amounts to around 200 GB, with every genome offering millions of variants from a reference model. The data generated by the NHS’s 100,000 Genomes project alone is therefore significant and all of it needs to be protected from those wanting to exploit it for the wrong reasons. All of this points to something of a big data headache.

As technology makes the data easier and cheaper to obtain, obvious questions arise — how is my genetic data held? How securely, by whom and to what end?

The potential for DNA sequencing, both the positive and negative, is clearly huge and it’s a door we’re unlikely to close again. When you consider that the cost of discovering your genetic make-up costs less than a new iPhone, it’s not hard to believe this could very quickly become an industry in itself.

As with any industry, insurers will need to be ready to pick up the pieces.

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REGULATORY AFFAIRS

Early access to medicines Lini Subin, director — regulatory affairs, ELC Group, highlights EMA’s regulatory tools and support pathways that are available during development.

I

n recent years, the pharmaceutical world has been witnessing huge demand to serve unmet health needs and deliver early access to medications. Many companies are focusing on R&D innovation to meet these needs, however, the regulatory pathway for early access to medicines is always a challenge globally.

for medicines which fulfil unmet medical needs and where the benefit of immediate availability for patients is greater than the risk of less comprehensive data than is normally required. Pending data is generated based on the agreed timeframe post-authorisation.

With significant developments in regulatory tools, and in approaches towards regulatory routes and access of medicines, the EMA plays a central role in the global development of medicines. The EMA approval system is based chiefly on benefit-risk assessment. Early access to medicines and assessment are particularly challenging because of the limited clinical evidence available.

A product is eligible for CMA if it belongs to one of the following categories:

Within the EMA there are different regulatory tools and support available for the earlier access of medicines for unmet medical needs, or where there is a major public health interest. The main regulatory tools and pathways include accelerated assessment procedure, conditional marketing authorisation, compassionate use, PRIME scheme and adaptive medicines pathway.

CMAs are granted for a one year period and can be renewed annually.

Stricter post-authorisation monitoring and fulfilment of obligations from the side of the applicant are applicable. Upon availability of the data, the authorisation converts to a standard MA with a validity of five years.

• Seriously debilitating or life-threatening diseases.

• Use in emergency situations.

• Medicines for rare diseases.

In the absence of comprehensive data, under exceptional circumstances the agency may grant an MA if the applicant cannot obtain comprehensive data in the agreed timeline.

Accelerated assessment procedure This regulatory tool reduces the overall timeframe for the assessment of a marketing authorisation of a centralised procedure (CP) from 210 days to 150 days (excluding the clock stops for products with major interest for public health and therapeutic innovation). Marketing authorisation holders have to submit the request for accelerated assessment to the Committee for Medicinal Products for Human Use (CHMP) two to three months before the planned submission of the application, justifying the major public health interest of the product.

Though the overall timeframe would be reduced, standard requirements for the marketing authorisation application are still applicable. A pre-submission meeting could be requested six to seven months in advance of the submission date. Early confirmation of the possibility of accelerated assessment is now feasible during the clinical development phase, since the EMA’s launch of the PRIME scheme in 2016.

Conditional marketing authorisation (CMA) The EMA grants the conditional marketing authorisation in the interest of public health, providing early EU access to medicines based on some conditions before completed data are available. It is granted

Similarly to standard marketing authorisation applications, applicants can seek early stage advice and assistance in the clinical development stage. The intention to acquire conditional marketing approval could be discussed in the early stage advice meeting. However, the request for the application is submitted along with marketing authorisation application. Under the conditional marketing authorisation route, it is also possible to obtain the privileges of the accelerated assessment scheme under the provision of applicable legislation.

On 23 January 2017, the EMA published a 10-year evaluation report based on data collected from 2006 – the start of CMAs – to 2016, and the EMA’s experience gained during the period on the success rate of conditional marketing authorisation applications. According to this report, the EMA recognises conditional marketing authorisations as an important tool for ensuring timely access to medicines in the areas of unmet medical need, and provides an in-depth analysis of the positive impact of this regulatory approach.

Based on the statistical results for which the obligations were fulfilled by companies, it was shown that the regulatory approval granted by CMA was, on average, four years earlier than standard marketing authorisation procedures. In the last decade, the EMA granted 30 continued overleaf >

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CMAs, of which 24 are targeting debilitating or life-threatening conditions, 14 are rare medicines and 3 address the medicines for emergency situations. Seventeen of these medicines were oncology medicines. With respect to fulfilment of obligations and success rate, the report shows that 90% of the holders fulfilled the obligation without changing the scope and 70% did not request for extension.

Engaging in early stage dialogues with different stake holders [the EMA and other key parties such as health technology assessment (HTA) bodies] plus careful planning is required to deliver early stage approvals and access to medicines for patients.

Other emerging initiatives Adaptive medicines licensing Adaptive licensing is an emerging scientific concept from the EMA which enables early and progressive patient access to medicines that are expected to have a significant therapeutic effect. This concept is based on these core principles: • A prospectively designed iterative, developmental plan.

• Real-world data to complement randomised clinical trials in the post-authorisation phase.

• Early involvement of HTA and other downstream decisionmakers, enabling market access.

Compassionate use

This regulatory tool allows access to an unauthorised medicine, The concept is based on the existing regulatory framework of scientific which is under development or entered into a marketing authorisation advice, conditional marketing authorisation, patient registries process. Patient groups with life-threatening, long-lasting or seriously and pharmacovigilance tools for collection of real-world data, debilitating illnesses, which cannot compassionate use and so on. Though be treated satisfactorily with currently this is an emerging concept, there are available drugs and who cannot lot of uncertainties — particularly enter in clinical trials, can benefit from significant improvement and on the real-world data, early access transparency is needed to help foster timeline and reimbursement process, this process.

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effective development and to ensure stakeholder involvement and so on.

On the request of national competent early access of these medicines to authorities, the EMA provides The European Commission and EMA patient groups. recommendations through CHMP on organised a workshop on adaptive the use of such medicines, whereby the pathways in December 2016. Postnational patient access programmes can consider this opinion before workshop reports show that the EMA addressed the challenging areas making a decision. This opinion cannot be requested by applicants of adaptive licensing and discussed the limitations and strengths of the themselves. The benefits of this programme are co-ordinated and observational studies. The EMA and EC will further assess the different implemented by national competent authorities. views expressed at the workshop, and we may expect the action plan in

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the coming months. Early collaboration between industry, regulators and HTA is essential to achieve the objective of the adaptive licensing pathway.

PRIME scheme (priority medicines scheme) PRIME is a new voluntary scheme launched by the EMA in 2016, and based on the existing regulatory framework fostering the early dialogue and accelerated assessment of medicines with unmet medical needs. Products that demonstrate significant medical benefit over existing therapies and patients with no treatment options can benefit here. Products that are eligible for this scheme can also gain an advantage from the accelerated assessment tool. The scheme promotes efficient development and robust data generation.

Based on preliminary clinical evidence, applicants can request PRIME eligibility, which is open to all companies. The agency will respond within 40 days. Once selected, applicants will have access to: • Feasibility for accelerated assessment confirmed at the very early stage • Early rapporteur appointment by the EMA to provide continuous support and help to build knowledge ahead of a dossier submission.

• Kick-off meeting with expert CHMP/CAT rapporteur and guidance on overall regulatory strategy and development.

• Scientific advice and regulatory support at major milestones.

• Dedicated project manager within the EMA.

Parallel consultation – EMA and HTA bodies To overcome the complexity of market access issues, the EMA also offers scientific advice and protocol assistance in parallel with HTA bodies.

Are these early access tools exclusive?

Early access tools are not mutually exclusive. It is possible to use these in combination within the scope of defined criteria. As an example, products which are benefiting from PRIME can have conditional marketing authorisation granted before comprehensive data are available.

Conclusion Although the EMA has introduced many regulatory tools since 2005 to support early access of medicines, significant improvement and transparency is needed to help foster effective development and to ensure early access of these medicines to patient groups. In particular, greater clarity is required with respect to the disease condition and criteria for each regulatory category. Early stage dialogue with regulators and other stake holders is therefore strongly recommended to avoid any gaps in the development.

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REGULATORY AFFAIRS

Challenging scale In this article, Mark Usher of Solidsoft Reply, explains the challenges of deploying multiple connected national systems for the large-scale European pharmaceutical industry.

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omputer systems are never simple but when the application needs to scale to facilitate the entire EU it needs a special kind of management, especially if this applies to falsified medicines, which have been infiltrating the supply chain for years.

by the fact that many medicines are licensed to be sold in multiple markets: Luxembourg is an example where the majority of their medicines are imported from markets other than their own.

Both the Solidsoft Reply European hub and their national blueprint system have been built to create enterprise class application that automatically scale to meet the demands of the users. The system has been built as a modern application suite using micro services, creating a robust, always-on service. In addition, the application is restricted to run only on Microsoft data centres within the EU boundary to comply with the EEU directive.

Fighting back — the EU FMD

Falsified or counterfeit medicines represent a serious threat to public health and target those in society who are already in need. The pharmaceutical industry has decided to fight back and has created a stakeholder model that has been enshrined in law by an EU delegated regulation to a falsified medicines directive that was finally published in The delegated regulation places February 2016. a number of obligations on all

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stakeholders in the The delegated regulation places a number of obligations on all stakeholders in the supply chain, including the requirement to add tamper proof safety features to all prescription medicines and to establish a European wide verification system that will allow the authenticity of the medicine to be determined before dispensing to the public.

European hub

Key to the success of the system rollout is Solidsoft Reply’s partnership approach with existing pharmaceutical supply chain… and wholesaler IT system vendor, as it was important to not disrupt an already mature ecosystem of IT system providers in each country. The implemented system allows the verification functionality to be accessed via a secure interface, and the current IT system suppliers are an integral part of the nation’s programme. It is important to ensure that they have all the technical resources they need to adapt their existing applications.

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NMVO implementation

To fight the problem, Solidsoft Reply on behalf of the European Medicines Verification Organisation, NMVO, decided to build a European hub — a data hub where medicine manufacturers and parallel traders can upload their product, batch and pack data. The hub’s responsibility is to route the data to all the connected national systems in which the product is licensed to be sold. Solidsoft Reply are also one of three national blueprint system providers that have been endorsed by the NMVO and are able to provide the national repository systems to the individual EU nation states.

One of the main challenges is that the hub alone needs to process over 10 billion packs of medicines on an annual basis and distributes this data to over 25 national systems. The system is further complicated

Each EU nation will create its own national medicines verification organisation (NMVO). It’s the responsibility of the NMVO’s to select a blueprint supplier and to ensure that the stakeholders adopt the system. The delegated regulation mandate that each nation must be fully operational by 9 February 2019. Solidsoft Reply’s implementation programme includes a pilot period before ramping up adoption, to ensure that the newly formed operation is running smoothly.

Solidsoft Reply are also participating jointly with NMVO’s to promote awareness of the national programme to all stakeholders to ensure everyone understands their role in what is a significant undertaking across all of the EU.

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COVER STORY

Sticky situation?

Dr Charles Kettler, director Natoli Scientific analyses common sticking and picking issues in tablet manufacturing and how a little homework can go a long way in avoiding potential issues before they arise.

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ablet sticking and picking problems are ubiquitous in the tablet manufacturing industry whether pharmaceutical, nutraceutical or confectionery. Often, in the regulated world of drug-product manufacturing, there is a sense of urgency to the development of a new molecule offerings. However, this urgency can result in hasty decisions to enter clinical trials or submit for regulatory approval with a formulation that ultimately results in unanticipated compression scale-up problems.

The design process for an oral solid dosage form often overlooks some of the seemingly minor details of tablet design. This can result in tablet defects as the manufacturing scale-up increases from clinical to full patient-population supply. Pharmaceutical company marketing departments’ desires for certain tablet shapes and logos to enhance brand recognition are a source of design constraints, often resulting in post-approval manufacturing complications.

Compression tooling manufacturers can often identify potential sticking and picking issues before tablet and tool designs have been finalised, reducing the challenge shared by the tablet manufacturer and the tooling vendor.

Sticking and picking issues generally arise from either formulation or tablet design inadequacies. Both emerge because of the differences in physical properties of the formulation excipients and drug substance. The process of blending components of a formulation results in a powder that will either consolidate and compress, or not. As failure to compress into a tablet is a separate issue, we will only consider powders that will compress.

Cohesive forces: Forming a solid dose tablet

Simple Considerations to Alleviate Sticking and Picking

Formation of a compact is the result of chemical dispersive and mechanical forces joining particles to form a solid of measurable density and porosity.

The cohesive forces binding the particles together can be assessed through a series of studies, outlined previously in this publication, to determine whether problems with tablet compaction can be anticipated.1 Compaction profiles and strain rate studies are important to development projects. These studies ensure that the probability for successful scale-up and technical transfer is high. Therefore, market supply is not impacted because technical due diligence was overlooked.

Remediation of picking and sticking does not always mean changing the tools used for tablet manufacturing. When powder sticks in the embossed letters, one of the first things to check is the moisture level of the formulation. Excess formulation moisture or excessive humidity in the compression suite can initiate picking. Insufficient compression force is also a potential source of picking because the compaction of the powder is not complete. This means the adhesive forces can readily overcome the cohesive forces of the improperly compressed tablet.

Tablet particles are bound by cohesive forces. However, during the compression process the cohesive forces binding the particles are challenged by the adhesive forces of the punch cup and the embossing within the punch cup. The first stage of a sticking problem occurs when the adhesive force of the punch cup can pull even a single particle away from the tablet. A recent publication indicates this is principally caused by the physical properties of the active pharmaceutical ingredient (API) and the mechanism and kinetics can be successfully modelled.2 The problem of formulation sticking in the letters and characters of punch embossing is typically referred to as picking. Picking is a type of sticking often rooted in an inferior tablet design. Picking issues can normally be resolved, but are rarely predictable and often not detected until transferring product from the research and development environment to the production setting. Among the typical sources of picking issues is the selection of the proper font and the engraving cut design for character islands and character peninsulas.

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Another potential solution is to try increasing the amount of lubricant used in the formulation slightly. This will impart greater release of the compressed tablet from the punch cup surface. Careful inspection of the punch cups is also essential to ensure there are no surface scratches to capture very small particles of formulation. These scratches will lead to filming, a slow form of sticking, often due to excess moisture in the granulation. If surface scratches are identified, punches should be polished. A specialized polishing compound can be used to impart greater lubricity and better product release properties as well.

Reducing picking with font selection When simple fixes, as mentioned above, are not enough, a full tablet and tooling design review may be necessary. Font selection is often a battle of form versus function. An ornate or decorative font, while pleasing to the eye, will likely cause picking problems and tablet defects.

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Figure 1 illustrates an impractical font selection. The variation in engraving width, as well as the isolated and unnecessary peninsulas of the letters, are impediments to even powder compaction. This variation often leads to powder picking away from the compressed tablet core, thus remaining in the punch cup, as indicated by the shaded areas.

Fig. 1

Figure 2 illustrates the same embossing using a more practical font that uses increased engraving and corner radii. The font modification minimizes picking opportunities, increases the opportunity for consistent powder compaction and yields the best possible cohesive forces for the tablet.

Fig. 2

Changing the engraving cut In addition to changes in the font selection, attention should be paid to the design of the engraving cut. Figure 3 illustrates a typical round tablet. The engraving of the ‘9’ cut into the tablet is illustrated with typical engraving cut width, depth and angle of 35 degrees. Most product formulations should be readily compressed into tablets using tools with this engraving design.

However, many formulations are not typical, and problems can still occur.

To reduce or eliminate problems with material picking in the centre island of the ‘9’ (Figure 3) pre-picking can be incorporated in the design. This is illustrated in Figure 4 where the depth for the island is reduced from 0.33 mm to 0.17 mm. This reduction is defined as a 50% pre-pick. The amount of reduction can range between 10 to 100%, depending on the extent of the picking problem. For branding or aesthetic purposes, consideration must be taken for tablets being coated post-compression, as excessive pre-pick will significantly reduce the clarity of the logo. The partial pre-pick concept is applicable to any letter or numeral with fully enclosed areas called ‘islands’ or ‘pads’.

Fig. 3

Fig. 4

Fig. 5

Materials of tooling construction If the sticking and picking has been discovered during the R&D stage, or if it is time to order the next set of punches for a product with known sticking and picking issues, another consideration is to have the punches made from a speciality steel. It is widely accepted that punch steel with a high concentration of chromium in the alloy chemistry, usually between 16 to 18%, enhances release of the compressed product. A reputable tool vendor will have multiple grades of high chrome steel available to use in manufacture of punches. There are also several other speciality steels available that can enhance the performance and service life of the punches and dies in regard to compressive strength, wear resistance and corrosion resistance.

As an alternative to using a speciality steel, some may choose to have a coating applied to their standard steel punches to enhance the release characteristics of the punch faces. The most common coatings are hard chrome (Cr) and chromium nitride (CrN). There are several other coatings available as well, depending on the unique characteristics of the blend to be compressed. However, it should be noted there is the possibility that the thin chrome coating layer may wear off over time, due to the abrasion of the formulation and polishing. Thus, the better choice may be a high chrome steel, without coating, for a long-term solution.

Discuss these issues with your tooling vendor early in the process to help reduce production issues and additional costs. Your tooling vendor should be able to explain the unique properties and advantages of the various steels and coatings available for your tooling.

In conclusion

Many other somewhat complex characters that do not have fully enclosed areas are also prone to picking. Letters like E, S, K and M, and numerals like 2, 3 and 5 all contain these partially enclosed areas that are described as peninsulas. For these areas, we employ a feature called ‘tapering’ or ‘ramping’ to prevent picking. Starting on the tablet surface at the open end of the peninsula, this feature tapers downwards, toward the enclosed end of the peninsula by a percentage of the engraving depth. It is usual to have peninsulas tapered between 10 to 50% of engraving depth, with 30% the most common. An example of 50% taper is illustrated on the right side of Figure 5.

Ultimately, there are several remedies to help speed a new drug to market, ranging from slight formulation changes to major tablet design and tooling modifications. When developing a to-market strategy, it is often best to consult with your tooling vendor early. Their insights will benefit the final product and assist in creating a tablet that is accepted by both the manufacturer and the end-consumer. Discussing all unique physical properties with your tool vendor during the tablet design phase will often eliminate sticking and picking issues before they occur.

References: 1. Sedlock, R., European Pharmaceutical Manufacturer, 2016:16(2);16-17.

2. Paul, S., et al., J. Pharm. Sci., 2017:106(1);151–158.

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Known for its focused profile Chemspec Europe is the place to be for international experts of the fine and speciality chemicals industry. Purchasers and agents looking for highly specialised products and bespoke solutions will find leading companies from all over the world presenting a maximum range of fine and speciality chemicals.

Benefit from excellent networking opportunities and be inspired by the latest results in research and development at top-class conferences.

Top-class conferences Agrochemical Outlook Conference Chemspec Careers Clinic Pharmaceutical Update Conference Pharma Outsourcing Best Practices Panel REACHReady Regulatory Services Conference RSC Symposium

Chemspec Europe 2017 – The driving force for tomorrow’s business!

Exhibition Conference Networking

31 May – 1 June 2017 Munich Trade Fair Centre, Germany

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Organisers:

SPOTLIGHT ON INNOVATION

It’s the thought that counts Thanks to ongoing research and development in pharmaceuticals, the sector is benefitting from ongoing innovation which is helping break new boundaries in healthcare. Lu Rahman explains.

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he decline of the blockbuster drug means that pharmaceutical companies have been keen to exploit new revenue streams and opportunities. Innovation has become key to the continued success of businesses involved in the manufacture of drugs and medicines. And while the market may not be flooded with single molecule launches, the industry is at the forefront of new healthcare processes and systems which are already becoming potential game changers in the pharmaceutical supply chain.

3D printing in pharma

The role of digital health in pharma

One of the most exciting new areas of innovation is 3D printing. This technology has become widely used in the manufacturing sector, but its use in pharmaceuticals is still relatively new.

The uses of digital health on the pharmaceutical sector are varied and offer potential for both drug manufactures and the wider healthcare sector.

Two years ago University College London set up a spinout company – FabRx – to 3D print drugs, recognising its potential to change the way medicine is manufactured and delivered. The team printed tablets for the treatment of inflammatory bowel disease and antibacterial polymers suitable for wound dressings.

Earlier this year researchers from the UCL School of Pharmacy began looking for participants to take part in a study examining how 3D-printed pills are handled and swallowed, particularly among paediatric and geriatric members of society.

In the US, Aprecia Pharmaceuticals has already taken a product to market. Last year, the FDA approved the first medicine manufactured using 3D printing. Spritam disintegrates in the mouth with a sip of liquid and is designed to offer a new option for patients, including those who may struggle to take their medicine.

Ali Moiyed, Aerobit chief executive said: “We are delighted to be working with Eularis. By combining our expertise, we are able to offer pharmas valuable intelligence relating to asthma. This offers great potential to guide product development and improve the quality of lives for the 5 million asthma sufferers within the UK alone.”

Last summer, GSK launched a study into rheumatoid arthritis in the US, where participants used iPhones.

The idea behind this Patient Rheumatoid Arthritis Data from the Real World (PARADE) study – wasn’t to test a new medicine but to “bring patients into the center of research so we can better understand the disease and its impact” according to the company.

The company used Apple’s ResearchKit and claimed to be the first in the industry to use it in research, in this case, looking at the impact a patient’s disease has on their day-to-day life. Presumably this information will feed back into the supply chain to benefit future drug development.

Data is king

“As we explored potential applications for our 3D printing technology in prescription drug products, it was important that we identified disease areas with a real need for patient-friendly forms of medication,” said Don Wetherhold, CEO of Aprecia.

One of the key benefits that digital health brings to the pharmaceutical sector is data. Last year Aerobit, provider of a smart respiratory device, teamed up with artificial intelligence (AI) expert, Eularis, with the aim of unlocking the potential of big data and gain a deeper understanding of patient needs, drug efficacy and adherence, and real world data to drive accelerated growth for asthma drugs.

“Spritam is designed to transform what it is like to take epilepsy medication, and is the first in a line of products we are developing to provide patients and their caregivers with additional treatment options.”

To more effectively manage asthma care, Aerobit introduced a smart inhaler tracking medication use and recording each time an inhaler is taken by an asthma patient.

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Clinical trials and digital health Clinical trials have benefitted hugely from the digital health explosion. Earlier this year contract research organisation (CRO) INC Research Holdings and clinical technology and analytics provider Medidata announced a partnership to help life sciences researchers increase the speed and improve the cost and accuracy of clinical trials.

INC Research will use Medidata CSA’s machine-learning capabilities to help sponsors identify clinical trial data anomalies. This will allow the company to prioritise resources around patient safety, data quality and integrity.

Medidata’s chief operating officer, Mike Capone said: “Medidata’s partnership with INC Research reflects our shared, long-term commitment to improving clinical trial processes and helping sponsors deliver scientific and medical breakthroughs to patients. We’re proud to be INC’s cloud-based, clinical technology platform of choice, and we look forward to celebrating the continued success of our life sciences customers together.”

Innovation in the pharmaceutical sector is ongoing and varied. As technology opens the door to opportunities, the way in which drug companies seize upon to develop products that benefit the healthcare sector while adding to their bottom line, is exciting to say the least.

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BIOPHARMA

Key changes Quality and safety are in focus as industry advancements force a change, writes chief pharma expert at Bosch Packaging Technology, Johannes Rauschnable, PhD.

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he market for pharmaceuticals is growing at an astonishingly rapid pace. According to a market report by the QuintilesIMS Institute, expenses for drugs will amount to $1.5 trillion globally in 2021. The reasons are obvious: global population is increasing (by 1.24% per year until 2030) and ageing at the same time. Increasing urbanization and a growing middle class are making drugs available and affordable for more people, while leading to a higher demand for medication.

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Megatrend biologics

Targeting illnesses more precisely

While the demand for common medication is increasing in the ‘pharmerging’ markets, completely new forms of treatment are emerging in industrialized countries.

Medicine is also advancing rapidly in the area of vaccines, where targeted campaigns are promoted strongly for instance by WHO or UNICEF. Pharmaceutical companies are committed to providing cost-efficient solutions for the development of new vaccines to fight malaria, HIV, Zika or Ebola — diseases which have now also made their way to the industrialized nations. Two aspects are at the centre of attention — making these vaccines available for a large population, and simplifying their administration.

Now, the patents of some large biotechnical molecules have expired and the production of biosimilars has begun.

Groundbreaking changes are occurring in the area of biological agents, for instance regarding the treatment of cancer, autoimmune diseases, as well as rare illnesses.

In the still relatively new cancer immunotherapy, for instance, the body’s own immune system is stimulated to fight against tumour cells. Monoclonal antibodies attach themselves to the characteristic structures on the tumour surface and mark the cells for macrophages or induce cell death. A further breakthrough in cancer therapy was achieved with checkpoint inhibitors.

A highly promising research and application area deals with antibody-drug conjugates (ADCs). These biopharmaceuticals connect a certain substance to an antibody, which binds to a target structure, such as an antigen, on the surface of a tumour cell. This way, cytostatic agents can get to the centre of the tumour cell like a Trojan horse, and can unfold their chemotherapeutical effect.

Molecular diagnostics serve to identify the genotype of a patient, thus predicting the efficacy and compatibility of each drug. This not only raises effectiveness, it also leads to less side-effects following the adaptation of the dose to a specific genotype.

Kinase inhibitors also range among the increasingly used targeted cancer therapies. They are able to slow down unrestrained cell growth, for example in chronic myeloid leukaemia, by blocking the signal cascade that triggers cell growth.

Before new pharmaceutical products can be introduced to the market, they undergo long and expensive research and development processes. At the same time, producers depend upon a fast market entry to make full use of their exclusivity during the limited patent protection timeframe.

Less expensive solutions for the masses

The keyword is ‘scale-up’, meaning the transfer from laboratory to production scale. Parameters and recipes must be precisely conveyed from laboratory equipment to larger machines, always in line with good manufacturing practice (GMP). Here, new simulation tools help to calculate the required process conditions and save a significant amount of time.

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For several years, the pharmaceutical industry was awaiting the biopharma patent cliff with a certain concern. Now, the patents of some large biotechnical molecules have expired and the production of biosimilars has begun. The first biosimilars have already been approved, for instance for the treatment of neutropaenia or rheumatoid arthritis.

Moreover, approximately 15 replicas of the monoclonal antibody bevacizumab are currently being tested. Patent rights for the reference product will expire in 2019 in the US and in 2022 in Europe. For patients, this development is a great progress, as many drugs are now produced in larger quantities and are sold at significantly lower prices.

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The next step towards an even more targeted treatment consists in the use of stratified medicine. As opposed to cytostatic drugs, which kill both abnormal and healthy cells with a high division speed and can stop hair growth or lead to hair loss, stratified medicine follows a different approach by addressing patient groups with the same genetic preconditions.

From laboratory to production

Speed is especially important for the production of generics in both pharmerging and industrialized nations. The latter are facing constantly rising cost pressure, while the pharmerging markets require affordable medication for a large population. Prerequisites are sophisticated, robust technologies with easy handling as well as short cleaning and changeover times.

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Biosimilars are produced in both small and large volumes.

Whenever frequent product changeovers are on the agenda, pre-sterilized single-use systems offer a solution with hardly any preparation time. They combine high filling accuracy with maximum safety — and omit the need for time-consuming cleaning, sterilization and validation of product contact parts.

Continuous processing The production of complex pharmaceuticals also focuses on cost-efficiency. A concept that favours this approach is ‘continuous processing’, and has already been applied in the food or chemical industry for some years. In contrast to batch production, continuous processing implies the production and processing of materials in an uninterrupted process.

© Bosch Packaging Technology

The KLV series platform can inspect up to 600 standing glass containers per minute in special inspection chambers — testing either individually or in groups.

In spring 2015, Dr Janet Woodcock, director of the FDA’s Center of Drug Evaluation and Research, raised the question why this method was not yet more widely used in the pharmaceutical industry. Despite a slow development pace, the climate has changed over the past years — leading technology companies are currently working on new continuous technologies for solid pharmaceuticals, which above all aim at reducing costs and enhancing efficiency.

The highest safety for humans and products Biologic processes are becoming more complex and guidelines surrounding them stricter. The highly potent ADCs, which consist of a biologic part (the antibody), a linker and a small active molecule, are toxic to the operator.

At the same time, humans also pose the greatest contamination risk to these products. The effective protection of humans and products from each other requires suitable containment technology.

In the manufacture of liquid pharmaceuticals, isolators are the enclosure of choice. The development of new pre-filled, sterile primary packaging solutions such as pre-sterilized syringes, vials or cartridges has paved the way for the development of new line concepts. To protect ADCs from external influences, they are mostly freeze-dried in vials after filling. The substances are preserved until usage and have a much longer shelf life than their liquid counterpart. This requires a very exact integrity test of the packaging material.

© Bosch Packaging Technology

CCI inspection of sterile products will also be one of many topics during the revision of the ‘EU GMP Guideline for Manufacture of Sterile Medical Products Annex 1’. This revision will certainly introduce the most significant changes to Annex 1 since its first publication in 1972.

Pharma en route towards industry 4.0?

Further regulatory changes have already occurred or must be implemented in the near future. For instance, the unambiguous serialization of pharmaceutical packaging requires a data matrix code to be printed on folding cartons. Software solutions should be able to manage the allocation of serial numbers through to the last aggregation step. They should also connect single components and third-party equipment, packaging lines, own or third-party IT systems and entire production facilities.

This calls for increasing connectivity and digitization — or what is nowadays called ‘industry 4.0’. In fact, the holistic pharmaceutical serialization is a first step towards an increasing connectivity of production processes.

Compared to other industries, pharmaceutical production is still in quite an early stage — just as it is with continuous processing. However, digitisation developments are advancing here, too.

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In the course of all these advances, the role of equipment manufacturers has also changed.

Amongst others, software modules help to control and monitor production and quality data as well as logistic processes flexibly according to customer requirements.

Easy-to-handle user interfaces not only facilitate the operator’s work but also allow current machine and production status to be clearly visualized from the global level down to a single machine. Apps ensure that a transparent overview of machine data is delivered to mobile devices — no matter where the operator or line manager is within the production facility.

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Changing role concepts In the course of all these advances, the role of equipment manufacturers has also changed. Suppliers have become partners, who accompany the entire process with profound market knowledge and technological expertise before, during and after project implementation, thus ensuring a fast time-to-market of new pharmaceuticals. This also includes analysing the market carefully, identifying future demands and implementing customer experience in new developments.

A simulation of a complete line for liquid pharmaceuticals.

New regulations are changing the pharma industry Container closure integrity (CCI) is extremely important to ensure the sterility and stability — and thus quality and safety — also of lyophilised products. It requires the inspection of a large number of parameters. The US Pharmacopeia has therefore revised its general chapter 1207, demanding more quantitative, non-destructive CCI test methods. Examples are high-voltage leak detection (HVLD) or headspace analysis (HSA).

Which regulations must be implemented until when? Which laws will be changed in the coming years, which effects will they have on the production process? Which technologies are needed to instantly fulfil these requirements — and how can they be seamlessly integrated into the overall process?

Whoever is able to answer all these questions and at the same time provide the corresponding technical solutions is ready to take on exactly this partner-like role.

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LOGISTICS & DISTRIBUTION

The extra mile ‘Last mile’ transportation and subsequent user storage conditions present unique challenges when it comes to ensuring the safe and effective use of pharmaceutical products.

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emperature monitoring group Berlinger says the industry faces a need for improved temperature management of drugs, especially vaccines and biologics, during and after the final stages of transportation to the user.

The firm has also released a whitepaper entitled “Beyond the Cold Chain” that discusses the temperature-related problems associated with the delivery and storage of drugs after they leave the primary supply chain.

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may result in the product becoming dangerous due to the production of toxic degradation compounds. This is because once a pharma product leaves the controlled-temperature environment of the primary supply chain it tends to enter a ‘grey area‘ where little might be known about the correct handling and storage of sensitive drugs and even less may be known about the consequences of taking thermallycompromised medicines.

It looks at typical domestic storage conditions for medicines and the circumstances found in under-developed countries and during humanitarian relief efforts.

The results of a recent study of real end-user storage conditions were startling, according to Berlinger. Out of 255 participants in the study less than 10% had stored their medication within the recommended temperature range.

According to the author, there is significant risk of therapeutic loss or impairment in the event of unacceptable temperature exposures. In some cases such temperature deviation might not only result in a loss of potency, in some cases it

The white paper goes on to consider the need for cold as well as hot temperature monitoring and the role of the latest generation of micro monitoring devices that can be physically attached to primary packaging.

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Poor last-mile temperature management has huge implications for the industry as Berlinger’s chief operation officer, Corneliu Tobescu, explained: “How many drugs are thrown away due to being judged unfit for human consumption at point of use? How many drugs are consumed that are outside the official margins for safety? These are serious issues that to a large degree can be addressed through equipping individual medicine containers with inexpensive, electronic temperature indicators that are accurate, reliable and easy-to-use.

Such a safety feature will reduce unnecessary waste and improve curative outcomes.”

The whitepaper comes as a new initiative, TeamUp, is launched to encourage the uptake of technology to improve pharmaceutical logistics.

Speaking at the recent IQPC Coldchain Logistics Summit in Toronto, Team-Up’s Alan Kennedy stressed the need for the pharma sector to embrace some of the supply chain

concepts that have proved transformational in other industries.

Introducing the initiative, which is a collaborative project, Kennedy pressed his proposition by describing some of the approaches to logistics that are the business signatures of leading companies such as Amazon, Apple and Inditex.

“The common denominator in all these ground-breaking supply chain platforms is collaboration,” Kennedy said. “By taking a lead and driving supply chain integration, pharma

companies can position themselves to better assimilate technology, drive efficiency, facilitate transparency and, ultimately, deliver improved, safer, outcomes for patients.

“The sector lacks a common platform to underpin collaborative working and enable supply chain integration”, Kennedy went on to describe how the TEAM-UP pharma-logistics collaboration program has been designed to fill this need.

Based around three ‘pillars’ (community, resources and accreditation) Team-Up has been

conceived as a not-for-profit body fostering winwin collaboration and integration between all stakeholders in the pharma-logistics supply chain.

Co-presenting with Kennedy at the IQPC event was Andy Akrouche, MD of the Institute of Collaborative Working in Canada. Akrouche acquainted the audience with the new ISO 44001 international standard for collaborative working. “The Team-Up program is aligned with the new ISO standard and provides pharma companies and their logistics partners with a structured route to its operational execution.”

Bigger is better!

Vetter starts operations in its expanded Center for Visual Inspection and Logistics.

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s industry-specific requirements in final product inspection are ever increasing from both customers and regulatory bodies, the site capacity of contract development and manufacturing organisations (CDMOs) needs to be bigger to be able to accommodate these needs. In lieu of these sorts of demands, global CDMO company Vetter has expanded its Visual Inspection and Logistics Center, located in Ravensburg, Germany.

This new expanded facility has bundled together the company’s capacity for final product inspection and logistics into one site.

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This new expanded facility has bundled together the company's capacity for final product inspection and logistics into one site. Finalisation of this second construction stage, which was initially put into operation five years ago, will more than double the prior capacity for quality control, cold storage and room temperature storage.

A substantial investment

This new site is the result of approximately 100 million ($107 million) investment by Vetter and will be referred to as Ravensburg Vetter West. Located on about 50,000 square metres (538,000 square feet) of floor space, it offers a 35,000 pallet warehouse capacity for storing pharmaceuticals in refrigeration or room temperature conditions.

The capacities for chest freezers, incubation chambers and constant climate chambers have also increased, along with the visual inspection capacities of filled units that can be realised in either manual or automatic mode.

Moreover, the centre also contains a support materials warehouse with corresponding safety installations as well as a new packaging-check laboratory and the company's central archive. The number of office workspaces were also increased at the new site.

Positive business development “At Vetter, we continually invest in meeting the needs of our customers. The requirements regarding final product inspection as well as transportation and storage of (bio-)pharmaceutical materials are ever-increasing,” said Vetter’s managing director, Thomas Otto. “Concentrating our supply chain processes in one site enables bundled resources for even more efficient and highly-secured logistic and quality control procedures.”

Vetter reported a successful year in 2016 and the global market for contract pharmaceutical manufacturing is anticipated to continue expanding in 2017. Furthermore, the demand of customers in the areas of clinical development, commercial production and final packaging is continuing to increase.

By the end of 2017, the CDMO will relinquish its existing Holbeinstrasse site for visual inspection and logistics. Its employees and departments will gradually be relocated to Ravensburg Vetter West, resulting in a working staff of approximately 800 employees. Globally, the company will see an increase in its employee numbers from 3,600 to 4,100 operating in its production sites and sales subsidiaries.

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SERIALISATION

Shabbir Dahod, president and CEO of TraceLink, highlights insights to take from DSCSA to help with EU FMD.

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atisfying the requirements of track and trace regulations in the world’s two largest pharmaceutical markets isn’t easy. With the US serialisation mandate fast approaching, and the EU deadline coming in February 2019, businesses across the supply chain are working to determine how best to navigate through uncharted territory.

The good news is that earlier serialisation deadlines for the US Drug Supply Chain Security Act (DSCSA) offer lessons and insights that can be mined to help global and EU manufacturers prepare for serialisation under the EU Falsified Medicines Directive (FMD).

Insights from DSCSA While many companies thought that DSCSA lot-level traceability would be easy to implement, it was far more challenging than anticipated.

In fact, our findings from the TraceLink 2016 Global Drug Supply, Safety and Traceability Report confirmed that the complexity of the requirements prevented some companies from achieving lot-level compliance altogether.

The reality is that lot-level compliance in the US required a more significant investment in IT infrastructure and staff resources than expected, and the level of connectivity for customers and suppliers to exchange data was much more complicated than estimated.

The lack of a single standard around data formats and exchange also opened the door for trade partners to make unique demands on each other. With trading networks of dozens to hundreds or thousands of partners, some companies found that accommodating so many unique requests greatly magnified the burden of compliance and challenged business relationships.

So, how can we apply this knowledge to EU FMD preparation? Despite the variations in US and EU regulations, companies can expect similar complexities with serialisation, whether they are selling product outside or inside the EU. One such complication is the challenge of managing and exchanging massive amounts of data that comes with serialising product down to the unit level. Another is the burden of adapting to the particular business preferences of partners across the supply chain. Let’s take a closer look at these specific challenges.

Data exchange and processing: Ever more complex Companies that have already invested heavily in serialisation have been surprised by the level of commitment required. In addition to higher capital costs is the complexity of data integration, and beyond that, the networking and data exchange aspects of serialisation. Both the US and EU serialisation regulations require some sharing of data across the supply chain, an entirely new concept for the life sciences industry. Under DSCSA, the data that is exchanged moves from the seller to the buyer whenever a change of ownership occurs.

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PROCESSES AND PACKAGING LEADING TRADE FAIR

JULIUS HESLET CO-FOUNDER & CEO PUREPHARMA

Messe Düsseldorf GmbH Postfach 10 10 06 _ 40001 Düsseldorf _ Germany Tel. + 49(0)2 11/ 45 60-01 _ Fax + 49(0)2 11/ 45 60-6 68

www.messe-duesseldorf.de

2017-01-10 interpack 2017_International_Pure Pharma_220 x 156_European Pharmaceutical Manufacturer_4c_5494 2017-01-10 interpack 2017_International_Pure Pharma_220 x 156_European Pharmaceutical Manufacturer_4c_5494.indd 1

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13.01.17 13:14

While no data will be exchanged directly between all supply chain trading partners under EU FMD, manufacturers that use CMOs will need to exchange serial number data with one another because manufacturers must report to the European hub, which in turn passes the information to national repositories so that verification can take place at the point of dispensation.

Along with introducing data sharing where none existed before, serialisation compliance is going to ramp up data and transaction volumes steeply and quickly. The computer power needed to process the exponential increase in data transactions is often misunderstood, and if not addressed early on can result in stopped shipments — a devastating outcome for any drug manufacturer.

To give an idea of the magnitude: In the US, before serialisation, processing a single batch of 10,000 units required a mere 2 KB of DBMS storage and just four transactions [batch created, then the pallet picked and shipped, and an advanced shipping notice (ASN) sent]. With serialisation, processing that same batch could take 11 MB of DBMS storage and at least 60,000 transactions because of the processing done at the unit level.

It can’t be emphasized enough, that underestimating data exchange and processing requirements will present significant business risk to any prescription drug marketing authorization holder (MAH) that serves the EU market.

Trade partner demands: Unpredictable expectations As compliance requires a new level of collaboration across supply chain business relationships, it naturally introduces the opportunity for trading partners to place additional information demands on one another.

Findings from the 2016 Global Drug Supply, Safety and Traceability Report show that companies gearing up to meet the first DSCSA regulation deadlines were not prepared for these unforeseen trade partner demands. Of the pharmaceutical companies surveyed*, more than 50% had to modify their A key piece systems to meet customers’ data requirements and 44% of them asked at least one customer to make modifications of advice — start preparing to their systems to accommodate unique data requests.

“ now.

Though these early learnings are based on DSCSA lot-level compliance, it’s clear that custom demands from trade partners greatly magnify the burden of compliance. Failing to recognize this potential outcome will introduce even more risk, as companies prepare for meeting EU FMD requirements.

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Final thoughts: How to prepare Companies that are complying with DSCSA lot-level regulations, and who have started the journey toward serialisation, understand that the complex implementation process will have a ripple effect throughout their operations. Serialisation will introduce enormous data and transaction volumes, a magnitude unlike we’ve ever seen before, driving the need for a smart strategy and long lead time.

A key piece of advice — start preparing now. Planning and executing a successful strategy will take longer than you think, and you will need the time to have crucial conversations with trade partners about how serialisation and regulatory data will be managed; what their specific serialisation needs are; when upgrades should begin; and how financial responsibilities will be divided. All of these critical decisions can take months to resolve, so open and clear lines of communication between you and your trade partners will be paramount to achieving success.

The decisions you make today will impact your operational performance.

Pharmaceutical and contract manufacturers that demonstrate seamless integration with each other will move forward without incident — while those who are unprepared may lose valuable business.

New tasks that didn’t exist before, such as provisioning, commissioning, and potentially aggregating serial numbers — plus the regular pick, pack and ship tasks — introduce tens of thousands of new transactions.

The increase in storage requirements from 2 KB to 11 MB for this single shipment is unprecedented.

In Europe, where medicines are generally packaged and sold at the ‘unit of use’ level (as opposed to in the US, where the saleable unit is distributed in larger bulk quantities), the volume of product and the magnitude of transactions for serialisation will be five to seven times what companies will handle in the US. Any operations that rely on traditional application architectures for enterprise-class problems involving far fewer transactions will not be able to scale to meet the new demands.

By the year 2020, more than 50 countries around the world will have set standards and deadlines for item-level pharmaceutical serialisation and traceability. Every day, we’re learning more and more about the challenges the industry faces implementing such critical standards in a very short time frame. Now is the time to use the learnings from early adopters to successfully move into a serialised and electronic world. One thing is for certain — everyone’s serialisation readiness is critical to the industry’s success in ensuring that medicines flow safely through the supply chain to patients without interruption. *A survey of 331 industry professionals, which took place in the 1st quarter of 2016, examined the experiences of companies across the supply chain that had a DSCSA lot-level requirement.

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EU FMD

Is Europe compliance ready?

Christoph Krähenbühl, Senior Director at 3C Excellis Europe, talks to EPM about Europe’s readiness for the EU falsified medicines directive (EU FMD).

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lawmakers to move the compliance deadline when it becomes clear that industry will not be ready in time, something that happened with serialisation requirements in other markets.

From that date, pharmaceutical companies can no longer sell products in Europe unless they comply with the three critical ‘safety features’ requirements — that every pack of medicines is tamper-evidenced, carries a 2D data matrix with a unique identifier (UI) and that the UI has been uploaded to a European repository system for systematic check-out at pharmacies.

However, there are no indications to support this assumption. The ‘Directive and Delegated Regulation’ are very clear about the date, stating: “This regulation shall enter into force on the twentieth day following that of its publication in the Official Journal of the European Union. It shall apply from 9 February 2019” and neither the Q&A published on the European Commission website nor any public statements give any support to the assumption that a change of compliance date is being considered.

his month sees an important milestone for all pharmaceutical manufacturers supplying the European market and their supply chain partners: 9 February 2017 marks the beginning of the two-year countdown until the EU FMD comes into force across Europe.

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The question is: How realistic is the prospect that Europe will be ready in February 2019? To answer this question, let us consider the different areas of work in turn.

...out of an estimated 2,500 manufacturers that will need to be on-board, only 50 are currently connected or in the process.

Pharmaceutical manufacturers The first major area covers the obligation on all pharma manufacturers supplying Europe to routinely serialise their products, to apply tamper-evidence and to implement the necessary systems and processes.

Progress in this area must raise big concerns: The latest update published on the European Medicines Verification Organisation’s (EMVO) website shows that out of an estimated 2,500 manufacturers that will need to be on-board, only 50 are currently connected or in the process. With just over 100 weeks to go, this low number chimes with other anecdotal evidence — many manufacturers are taking an overly optimistic view and delaying their implementation, especially in the sector of mid-size to smaller companies. This is worrying because even major companies with well-established projects (driven partly by serialisation requirements in other markets) are still reporting concerns about their readiness for February 2019.

”

Why so many companies are risking their European business is open for speculation. One argument is that companies expect the

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Europe-wide repository systems Then there is the work of setting up the Europe-wide infrastructure of ‘repository systems’, delegated by the directive to the industry stakeholders.

This is a significant effort that includes not just the design, build and implementation of interconnected systems to cover the whole of Europe from manufacturer to end use but also the set-up of the supporting organisation structures and business processes, at a European as well as a national level, in each of the participating 32 countries. Despite the monumental task, indications are that one can be cautiously optimistic about progress. Stakeholders from all parts of the industry (with their competing and often conflicting interests) have been actively collaborating since before the publication of the directive in 2011. As of February 2017, the EMVO has been in existence for two years and a growing number of countries — 15 at the time of writing —have also set up their National Medicines Verification Organisations (NMVOs) or are close to the point of achieving this major milestone.

Progress has also been made on the technical side: The central piece of this infrastructure, the European hub, into which manufacturers can connect to upload the UI data, was implemented in 2014. It has been connected to the first national system — Germany’s SecurPharm — since mid-2015 and other countries are also making progress

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towards the establishment of their national systems, helped by the ‘Blueprint’ approach: A shortlist of three providers favoured (and pre-checked) by EMVO to achieve consistency and interoperability as well as cost-efficiency.

Eight countries have so far completed their vendor selection or are very close to it, and while that number may seem low at this point, the Blueprint approach provides a strong foundation for a rapid rollout following the successful establishment of the organisational underpinning. It is therefore safe to assume that the organisational and systems infrastructure will almost certainly be ready and operational Europe wide by February 2019.

Wholesalers and pharmacists Apart from manufacturers, wholesalers are also required to establish technical capabilities to handle serialised products, because there are a number of scenarios where they will need to scan UIs against the repositories for verification — or even checkout, such as risk-based verification, export from Europe and early dispense in certain situations.

The estimated 10,000 pharmaceutical wholesalers are likely to be ahead of the curve, given that other regulations like the 2013 guideline on ‘Good Distribution Practice of Medicinal Products for Human Use’ have raised the bar on process and system requirements that they need to comply with. The EU FMD adds to these requirements, setting out a number of scenarios where UIs need to be scanned against the repositories for verification or even check-out, such as risk-based verification, export from Europe and dispense at the point of supply (DR article 22 ad 23).

While compliance will require effort and investment, many wholesalers and distributors are making good progress towards establishing systems that will allow them to comply with their regulatory obligations, including the readiness to connect to the national systems as and when these come online.

The third stakeholder group that needs to implement new technology are the approximately 150,000 pharmacists who will be legally obliged to scan every pack of medicines dispensed to the public.

This is a tough call, because pharmacists have been less exposed to serialisation and traceability requirements compared with manufacturers and as such are further back along the adoption curve. However, in many European member states they are now engaging with the other stakeholders and getting increasingly involved and committed to progress at a national level. A sign of this progress are the full-scale pilots involving community pharmacies planned in several countries for 2017. In parallel, extensive engagement with the pharmacy systems’ IT providers is underway, to ensure that ‘the last mile’ of the technical end-to-end system provision is in place to meet the implementation timeline of 2019 readiness.

So, are we ready?

“

It is safe to assume that the organisational and systems infrastructure will almost certainly be ready and operational Europe wide by February 2019.

The EU FMD is an ambitious requirement and the practical challenges of implementation across 32 countries with their diverse backgrounds, practices and requirements are daunting. While it is true that there are still many details to be worked through, the basic requirements are very clear and have been published for over half a decade now.

”

The roadmap for achieving EU FMD readiness should be well known and in some areas, notably the work area to establish the medicines verification infrastructure consisting of the European hub and national systems, good progress has been made. It now remains for all other stakeholders to step up to the challenge and do their bit.

The anniversary of the publication of the delegated regulation is a good reminder that time flies and everyone involved in the supply of pharmaceutical products to patients in Europe will need to focus on the ultimate goal, to be achieved in just over 100 weeks, ensuring the provision of safe medicines to every European citizen.

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TIME IS SHORT – SERIALIZE NOW !

More and more government regulations are demanding that drugs be serialized and accompanied by track & trace processes. Legislation to this effect will soon be coming into force in both the EU and the USA – serialization is already compulsory in China.

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MedTracker

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OPINION

Innovation formulation Simon Hill, CEO and co-founder of Wazoku, examines the formula for great innovation.

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oming up with new ideas when you are running a business of any size is a challenge. Whose responsibility is it to be innovative and where can you find inspiration are just two questions over which business leaders scratch their heads.

However, for most companies the answer is staring them in the face — ideas come from people and from good communication, so you have to engage the army of potential innovators that every company has at its disposal.

Pharma stands out

Start with quick wins

To all intents and purposes, given its long list of momentous medical achievements, the pharmaceutical industry stands out in innovation terms. What’s interesting, however, is that even now those remarkable successes are often the result of efforts by individuals or small teams working separately, rather than as part of a systematic company-wide innovation strategy.

As with any process change it is important to manage the change and deliver it pragmatically. No organisation should be afraid to fail.

This is part of the process as long as it provides useful lessons and the organisation can shake itself off and start again. It’s important to see that the actions being taken will provide a positive impact in a way that will move the company closer to the overall innovation vision.

Pharma is not the only sector in which, despite the implementation of processes to streamline almost every other business operation, innovation is far too frequently the result of a one-off good idea or a fortunate coincidence.

When choosing the first projects it’s worth considering the working environment. Does it support and enable the innovation goals? If not, there are some ways around this, such as organising an ideation challenge with prizes for successful ideas or perhaps engaging the team to come up with a rapid prototype, or alternatively, get involved in one of the many ‘hackathons’ that are set up to create and test proof of concept solutions.

This approach will not sustain the industry in the long-term. Developing a new medication is increasingly difficult, as evidenced by the US FDA approving only 22 new medicines in 2016.

A report by PricewaterhouseCoopers (PwC)1 into managing pharmaceutical innovation points out that companies will need to ramp up innovation to maintain the level of good results that shareholders demand. It also highlights the huge returns on effective innovation, referencing research amongst c-suite and executive level respondents from the pharma sector, which showed that the most innovative 20% in its study grew at a rate 16% higher than the least innovative.

Where to start?

All too often it’s not the lack of ideas that is the problem, but finding a formula for processing, filtering and seeing them through from suggestion to execution. Implementing an innovation strategy can be daunting, so it’s crucial to set overall objectives that justify the effort being put in.

The other important aim is to create an environment in which innovation is part of everyone’s job, in every role and every department, every day.

For pharmaceutical companies, innovation is as likely to be about internal efficiencies as it is about developing new medical products. Whatever the objectives, they do need to be shared with the entire business and all stakeholders, who can give a sharp assessment of the organisation’s innovation capabilities.

The next step The next step is to measure the impact of what is being done as it evolves, and this is quite challenging. It is important to ensure activities are aligned to overall business objectives, to maintain collaboration opportunities and keep employees engaged. As part of the innovation formula, a consistent set of evaluation metrics needs to be put in place that consider all aspects of the innovation process including the culture shift occurring in the organisation.

Some companies set up innovation programmes in-house, others outsource to consultants, but increasingly companies are using idea management software platforms to provide them with the effective formula for innovation success. These platforms deliver a structure to capture, evaluate, prioritise and select ideas, a home for all the creative and innovative thinking, regardless of whether it relates to new drug trials, or to process improvements.

In fact, having the right tools and processes is part of an innovation strategy, providing valuable insight into areas for focus and improvement.

Whichever method and formula is used, one thing is certain, those who get it right will emerge as next generation organisations where real competitive advantage is driven by ‘everyday’ innovation.

Reference: 1. https://www.pwc.com/gx/en/pharma-life-sciences/assets/pwc-managing-innovation-pharma.pdf

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SMART FINANCE

Flexibly financing Chris Wilkinson, head of sales for Healthcare and Public Sector for Siemens Financial Services, UK, writes

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he pharmaceutical industry contributes significantly to the UK economy. Pharmaceutical production has contributed almost 10% of the UK’s GDP, doubling since 1995. The industry has consistently produced a trade surplus, totalling £3 billion in 2014.1 Similarly, investment in the sector continues to boom; the pharmaceutical industry is responsible for 25% of the total expenditure on research and development by UK businesses.2 In addition to benefiting the UK economy, the pharmaceutical industry also delivers improved health outcomes for patients. Medicines developed by the pharmaceutical industry have helped in the fight to prevent and cure diseases. However, tackling contemporary challenges such as an ageing population, which fundamentally impact the healthcare landscape, will require further research efforts.

If the pharmaceutical sector is to attempt to meet such challenges, it firstly needs to keep up with new phases of the technological revolution.

Investment opportunities Companies involved in all aspects of the development and manufacture of pharmaceutical products can invest in technologies to increase productivity and efficiency. For instance, in the manufacturing process, improved technologies such as capsule filling machines can help to reduce waste and increase speed of production, resulting in faster output.

Similarly, companies can acquire highly modern and sophisticated test equipment for laboratory analysis. These immunoassay systems improve test productivity, accuracy and detail though optimal sample processing. Used in the early stages of drug development, this technology can assist with workflow, operational efficiency and patient care.3 Harnessing technological innovations can help produce cost savings while ensuring high-quality outputs and waste reduction. Nevertheless, keeping pace with technological advancements requires considerable capital expenditure. More often than not, businesses have to preserve their cash flow

and lines of credit to support other working capital requirements. Moreover, access to bank credit has become more restricted following the financial crisis.4 For smaller-sized pharmaceutical companies where funds can be scarcer and restrictions on funds tighter, investing in new technology can prove particularly challenging. With downward pressure on drug prices across the world and, specifically, changes to the 2014 Pharmaceutical Price Regulation Scheme,5 smaller businesses are likely to feel the squeeze further

Asset finance techniques This explains why asset finance techniques such as leasing are gaining popularity as a cost-effective investment-enabler. Such financing solutions spread the cost of the equipment over an agreed financing period, with regular finance payments arranged to align with the expected benefit of its use, such as efficiency gains. This removes the need for a large initial outlay, thereby increasing the funds available for operating expenditure.

Asset finance allows pharmaceutical companies access to the latest technologies, without having to commit scarce capital or use traditional lines of credit. Fixed finance payments also eliminate the volatility of interest rates, inflation and credit conditions while assisting with long-term budgeting.

In addition, financing arrangements can incorporate other costs such as installation, as well as introduce the possibility of technology upgrades in broad line with developments.

Such tailored, all-encompassing financing packages tend to be offered by specialist financiers who have an in-depth understanding of sector technology and its applications. They are therefore more inclined and more able to create customised financing packages that fit the specific requirements of a business — for instance, flexing the financing period to suit the customer’s cash flow. This contrasts with the standard financing terms usually available from generalist financiers.

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Flexible financing for the future If companies in the UK’s pharmaceutical industry want to remain competitive and keep pace with industry growth, acquiring the latest sector technology is a crucial step. UK pharmaceutical companies should exploit the enhanced potential offered by advanced equipment and modern Instead of tying up precious technology.

“

Investment, however, capital in should be undertaken equipment under the premise of acquisition, sustainable financing. pharmaceutical Instead of tying up companies can precious capital in use flexible equipment acquisition, asset financing pharmaceutical companies can use techniques. flexible asset financing techniques. This means available financial resources can be deployed more effectively in research and development — a crucial area that underpins the sector’s ability to make a vital contribution to raising healthcare service quality.

”

References: 1. Roberts, H., and Salvatore, V. (2016). What would BREXIT mean for pharma?, Pharmafile.

2. ONS, Business Enterprise Research and Development, 2012, (November 2013) 3. Siemens Financial Services, International clinical laboratory science specialist acquires state-of-the-art immunoassay system 4. Siemens Financial Services, Taking the Pulse (February 2016) 5. A 5-year voluntary scheme agreed between government and the Association of the British Pharmaceutical Industry effective from 1 January 2014. The 2014 Pharmaceutical Price Regulation Scheme (PPRS) will provide assurance on almost all of the branded medicines bill for the NHS. The bill will stay flat over the first 2 years of the scheme and will grow slowly after that. The industry will make payments to the Department of Health (DH) if NHS spending on branded medicines exceeds the allowed growth rate.

For more information see: Department of Health, Pharmaceutical price regulation scheme 2014 (21 December 2015).

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PACKAGING

Two for one

Schubert-Pharma combines both thermoforming and cartoning in one TLM system

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he increasing complexity of packaging solutions, changes to the way in which customers’ order, as well as the trend towards smaller batch sizes pose new challenges to production technology and has led IDT Biologika to implement a new manufacturing strategy in the field of assembly.

A long-term solution The packaging applications at IDT include cartoning vials of various sizes, numbers and configurations, with or without partitions, as well as blistered syringes and combination packages of syringes and vials, which are combined into kits. A recently added application is to package and carton medical devices in thermoform packages.

“We want to achieve greater flexibility with fewer packaging lines over the long-term, while increasing capacity,” explained Raimund Merkel from Klocke Holding.

Karin Kleinbach from Sales and Project Engineering at Schubert-Pharma stated, “The decisive factor for Schubert-Pharma was its ability to realise the required processing operations within a single line. Other suppliers could not offer a system concept in which all the necessary functionality was available in one machine from one manufacturer. As IDT is a contract packer, more and more formats are continuously added to the required production portfolio. Creativity and flexibility were required from all involved parties and this is what made the project especially exciting.”

Added value with a small footprint In spite of the complexity and the numerous applications and formats, the machine is very compact. When packaging the devices, the thermoform trays are first produced in Schubert’s thermoforming module. A mother tray is formed with a defined number of individual trays, which are only separated later in the process.

In the area of product feeding, the grouping processes of the products to be packaged are already performed on transport robots, called Transmoduls, using F4 picker robots. A vision scanner positioned above the product belt transmits the position and number of the products of the delivered trays to the F4 picker robots. These then pick up the individual products and place them in the thermoform trays. Subsequently, the trays are mechanically separated and the product is loaded into a top-load carton.

The vials are conveyed to the labeller in a standing position either by means of a turntable or a belt and then transferred to the product belt.

This belt is positioned in the working area of the F4 picker robots, so the vials are pre-grouped by the same robots, which also process the devices.

“This gives the customer a highly flexible and space-saving solution,” said Kleinbach.

Automated line clearance As IDT Biologika packs a wide range of products on the line, proper line clearance between batches is an absolute requirement. “Intermingling must be entirely ruled out,” Merkel stated. This process runs automatically in the TLM machine and offers the customer time savings, thereby increasing the system availability.

System control is handled by Schubert’s own VMS packaging machine control system. Through confirmations and counter-checks, there is assurance that no products from the previous production are still on the line. A sensor automatically checks whether all transporters are empty and passes this information on to the machine operator.

“This guarantees maximum safety and security for the manufacturer — eliminating any potential for cross-contamination,” explained Kleinbach.

“Furthermore, this process enables a reduction of manual documentation, leading to faster batch changes.”

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PACKAGING

Critical design

Pharmaceutical packaging plays an important role in increasing patient adherence, with Essentra’s Design Hub manufacturers can identify areas to add adherenceincreasing features.

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t may seem that packaging design is only important for FMCG brands that need to fight for shelf space and customer attention, but, in fact, it is something that must be carefully considered in many industries.

In the pharmaceutical and healthcare sectors, for example, packaging design is crucial.

Ultimately, customers are patients who need medicines to improve their lives in some way and, therefore, packaging must be convenient to use, simple to open and easily distinguishable to ensure it is used appropriately.

Packaging plays an important role in increasing patient adherence: the extent to which a person’s behaviour — for example taking medication, following a diet, or executing lifestyle changes — corresponds with agreed recommendations from a healthcare provider.

Indeed, patient adherence is currently one of the biggest challenges that the pharmaceutical and healthcare industries are facing. In fact, research shows that patients not taking their medicines properly is costing the NHS £500 million a year.

Essentra’s recently opened ‘Design Hub’ — a facility that combines the creativity of brand designers with the technical expertise of packaging manufacturing teams — allows the research and creation of patient adherenceenhancing packaging. By recognising that packaging plays multiple roles in a product’s journey — from containment, protection and communication, to security and transportation — the Design Hub has started to identify areas where manufacturers can add patient adherence-increasing features.

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Packaging has a critical role to play in communicating all the information needed for patients to take their medicines correctly.

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Containment and accessibility

Protection and transportation

On a basic level, packaging is a means of containing and delivering a product to a user. Successful packaging should allow the intended user to easily open, access and re-pack the medicines, ensuring that the product and related information stay together. This gives the patient confidence as they have all the materials required to support proper usage, even over long periods of time.

In addition, packaging plays a key role in protection and transportation, ensuring that medicines can be efficiently and safely delivered from the manufacturer through the supply chain. Simple factors, such as shape and structure, can help immensely when packing large quantities of product to be shipped.

Communication and information Packaging has a critical role to play in communicating all the information needed for patients to take their medicines correctly. To ensure that this data is as clear as possible, pharmaceuticals need to provide detailed literature that caters to multiple audiences such as availability in multiple languages. Text should be printed in an easy-to-read font face and size, and colours can be used if appropriate.

To aid understanding and reassure patients, information should be delivered in an easily-digestible format, using features such as graphs or infographics. Images are particularly important for those who are illiterate; according to the UNESCO Institute of Statistics, in 2013 the global illiteracy rate was 15.9%, approximately one in six people.

In addition, braille can be used to support patients that are partially or fully blind to take medications in line with guidance.

If there is not sufficient space on the carton or bottle to supply the volume of information required, manufacturers can employ features such as booklet labels or booklet leaflets, allowing customers to easily navigate supplementary material.

On a more sophisticated level, intricate structural elements can be installed. For fragile medical instruments such as vials, packaging may need to include ‘crumple zones’ that are shaped to the contents’ form, ensuring that they are protected when in transit.

Pharmaceutical companies must also recognise that protection extends to the full journey of the medicine. Even when the drugs have been successfully delivered to the patient, consumers must be able to store the product safely when at home. For example, manufacturers can use thermochromic inks that are activated by high or low temperatures to help patients monitor their storage conditions.

Summary Every one of these basic elements has the ability to add value and increase patient adherence by using intelligent, targeted design practices. Though these design tools may not completely solve the issue of patient nonadherence, employing these practices should not be underestimated.

Secondary packaging components are materials that are already delivered and amending these have been proven to make a noticeable difference in adherence.

Developing a successful product should not end with the product itself — manufacturers must always think of the complete offering, including its packaging, delivery and after care, to provide their consumers with a holistic solution.

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SINGLE-USE

Risky business Dr Sade Mokuolu, group compliance manager, WatsonMarlow Fluid Technology Group, examines the importance of risk assessment in qualifying SU components to ensure global adoption continues at an accelerated pace.

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he increased market value and small batch sizes of biologics has led to a boom in the employment of single use (SU) components for manufacturing therapeutics.

The prevalence of these technologies within biopharmaceutical manufacturing has been widely disclosed.1

SU components have gone from being niche devices used in upstream processing into widely deployed large scale options for downstream and fill/finish operations. In the mature SU market, there has been a shift from technological innovation to establishing the safety of the materials used in the components.

An important aspect is how drug manufacturers qualify these components for use within their manufacturing processes.

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BPOG extractables standardisation protocol and elements of this approach which is now finding its way into the new chapter, United States Pharmcopeia (USP) 665.2

Qualification/Validation of SU components As yet there is no regulatory guidance specific to SU components. However, the USP are publishing a new guidance, USP 665, Plastic components and systems used in pharmaceutical manufacturing systems (draft). In the meantime, there are industry expectations based on documents used in the medical devices industry and guidance on good manufacturing practice (GMP) for ensuring the safety, quality and efficacy of the drug products in contact with plastic packaging materials and container closure systems.

The method by which SU components are qualified and validated has been a source of contention between the end user and supplier groups. More recently, there has been increased collaboration between the industry groups such as Bio Process Systems Alliance (BPSA), Biophorum Operations Group (BPOG), American Society for Testing and Materials International (ASTM), International Society of Pharmaceutical Engineering (ISPE), American Society of Mechanical Engineers-Bioprocessing Equipment (ASME-BPE) in providing strategies on what determines whether a SU component has been sufficiently and appropriately qualified by a vendor.

Materials qualification should generate data on the safety of the plastics used in pharmaceutical manufacturing. A series of tests used to demonstrate biocompatibility or biological safety are those detailed in USP 88 and 87.3 USP 88 describes the set of biological reactivity tests, in vivo. These tests are designed to determine the biological response of animals to elastomers, plastics and other polymeric material. Additional tests are described in USP 87. These tests are used to determine biological response of plastics in contact with cell culture.

Collaboration between these industry bodies has led to a number of benefits, as it allows the industry to effectively police itself, by providing best practice approaches which may then be incorporated eventually into regulatory guidance. One example of this is the recent

As detailed in USP 661.1, passing the biocompatibility tests is not sufficient for a complete risk assessment to be performed.

Understanding not just the material but the propensity for the material to leach unwanted and unknown chemicals into a drug product

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has been a requirement of the industry in recent times. This has been principally achieved through extractables testing.

Extractables are chemical compounds with the potential to migrate from product contact material under exaggerated conditions of time and temperature. Leachables are compounds that may migrate into the actual drug product under normal processing conditions and may be found in the final drug product. Leachables could be a subset of extractables, as long as the conditions used to generate the extractables are a reasonable worst case and adequately reflect the extremes of the process conditions, such as temperature, time, surface area to volume ratio and so on. However, additional leachables may be formed on the reaction of an extractable and a drug product constituent.

Historically, assessment of extractables has been determined using tests listed in the USP 661. The main tests were non-volatile residue (NVR) and total organic carbon (TOC). NVR is the determination of weight of semi-volatile and non-volatile extractables after evaporation of the extraction fluid. TOC, is a non-specific test that provides information about the amount of carbon in solution. Using NVR and TOC, it is not possible to determine the identity of any extractables.

As the analytical technologies have advanced, the techniques used to assess extractables and potential leachables has become highly developed. The analytical instruments are extremely sensitive and are able to detect the presence of compounds at levels in parts per billion (ppb). These technologies are a far cry from the wet chemistry tests reported in the previous compendia.

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Risk assessment is an important activity to ensure that there is sufficient information to qualify the SU fluid pathway as being suitable for use.

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By providing the level of technical/validation data about the component material to the drug manufacturer early on facilitates the adoption of SU technologies into drug processes faster.

The new USP 665 although in draft serves as the first guidance in this area, allowing for the alignment of supplier and industry expectations.

In the draft USP 665, one of the fluids recommended for extraction of plastic components used in the manufacture of drug products is a 50% ethanol/50% water solution.

The use of 50% ethanol solution as an extraction fluid could be viewed as a worst case model solvent in comparison to the extraction ability of a mostly aqueous drug product.

In light of upcoming guidance, it is the SU suppliers — who understand the challenging market and regulatory environment for the drug manufacturers and are able to provide them with necessary technical data to prove that their drug products are unaffected by the SU components — who may be best placed to provide assistance for validation purposes.

Risk assessment tools — the TTC approach Risk assessment is an important activity to ensure that there is sufficient information to qualify the SU fluid pathway as being suitable for use. Although the onus of this activity as detailed in regulatory documents is the sole responsibility of the drug manufacturer, it could be shortened in part by having good technical data provided upfront by the SU vendor. Additionally, a degree of knowledge is required to understand how the data could be used to illustrate that the component material will not adversely affect the drug product.

In terms of risk assessment of extractables data, there are no specific limits on extractables.

However, it is required to demonstrate that any potential leachables found within a drug product is at a level low enough not to be of safety concern over the duration of treatment and at the dosage levels that the drug product will be administered.

The threshold of toxicological concern (TTC) approach is a risk assessment tool for evaluating substances with little or no toxicity data with a low level of exposure.4 The TTC was developed to provide an acceptable intake of any unstudied chemical that poses a negligible risk of carcinogenic effects or toxicity.

For the assessment of acceptable limits of mutagenic impurities in drug substances and drug products, a value of 1.5 micrograms per day has been set as an arbitrary limit.

This corresponds to a 1 in 100,000 increased probability of cancer due to the presence of genotoxic impurity in a drug product. However, this level is associated with a lifetime dosing regime of the drug product. ICH has established limits based on less than lifetime (LFL) dosages.

However, there is a small group of compounds which are known to be highly potent mutagens even at very small concentrations and it is not possible to risk assess these particular compounds. Compounds such as N-nitrosamines, aflatoxin-like compounds, azoxy like compounds, dibenzodioxins and dibenzofurans are excluded from the TTC approach. For these highly potent compounds, the best form of control is to ensure that they are not present in the materials used in SU systems. This is demonstrated by good control and knowledge of the materials supply chain.

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Supplier validation packages As described above, risk assessment to determine the material safety can be complex when looking at SU systems comprising of several different materials. Often the supplier may be best placed to offer information on the component materials for the drug manufacturer to make an assessment that there are no compounds of a safety concern or that the extracted compounds are of a low enough concentration not to pose any risk.

Conclusion Adequate risk assessment and risk mitigation approaches when it comes to validation and qualification of the disposable equipment is the only way to ensure that global adoption of SU systems and hybrid facilities continues at its accelerated pace. The overarching goal is that well qualified manufacturing systems can only lead to benefits in the availability of safe medicines for patients.

References: 1. Rader, R.A., BioProcess Int., 2007, 29.

2. USP 661.3 (665) – Plastic components and systems used in pharmaceutical manufacturing systems, 2016 (draft).

3. United States Pharmacopeial Convention, chapter <88>/<87>, Biological reactivity tests, In vivo,/ in vitro 2008.

4. Kroes, R., et al., Food Technol. Toxicol. Lett., 2004;42:65–83.

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OUTSOURCING

Trending towards a strategic future Strategic outsourcing is trending within the pharmaceutical industry with companies relying on trusted and preferred suppliers in an integrated supply model, notes Justin Schroeder, executive director, Marketing, Business Development & Design at PCI Pharma Services.

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This trend towards strategic outsourcing is the driving force of change […] increasingly drug companies are relying on preferred and trusted suppliers in an integrated supply model.

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utsourcing in the pharmaceutical industry, once viewed with a certain degree of scepticism, is now accepted practice and is being bolstered by the trend toward strategic outsourcing with a focus on core competencies. The rise in emerging companies with ’virtual’ supply models is also leading to outsourcing growth and is seen by many as the trend for the future.

Outsourcing partnership

In the past pharmaceutical companies have competed on the grounds of product innovation. Taking into account the high cost of R&D — combined with heightened regulatory scrutiny, increased internal diligence, and the economic and political pressures for better end product pricing — finding ways to reduce overall costs is now critical.

The next step is to work with an outsourcing partner so that understanding is shared and risk minimised by clearly defining who is responsible for what, how and when. To that end, high performing and experienced providers such as PCI Pharma Services are being regarded more as strategic partners rather than just tactical outsourcing vendors.

Outsourcing has not only helped to increase company product ranges, it has also reduced the time taken for a product to reach the market and this has become a vital factor in maintaining profitability. Furthermore, as the pharmaceutical market is increasingly global in nature, outsourcing with select CMOs can provide highly specialist experience and insight to access nuanced emerging markets.

As an outsourcing partner, there is an inherent requirement to deliver tangible value. Such ‘value’ may include cost savings or cost mitigation, but also may include ways to improve product quality and safety or reduce risk. It might also deliver ways to improve the patient experience or provide a means of improving the supply chain, or it may include any other initiative that enhances the overall performance of the client and provides competitive advantage in the demanding global healthcare market.

In the make-or-buy decision process, pharmaceutical and biotech companies have to evaluate six key areas: capital investment, resource, risk, regulatory considerations, expertise, and experience. Drug companies are increasingly looking to select CMOs in a more strategic and inclusive fashion which provides the better option and frees them to devote resources to better pursuits.

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Working closely with an outsourcing expert who understands the business and products and who can advise on those processes that can be transferred, while minimising any risk, provides pharma companies with a means of safely going down the outsourcing route.

Progressive minded companies have developed scoring systems to evaluate strategic suppliers on this total performance metric — providing a methodology to measure intangibles such as innovation, risk mitigation, quality, loss/scrap reduction, price, performance and even facets such as environmental sustainability.

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The supplier is expected to do more for the relationship than what is expected in a traditional tactical sourcing model, and the benefit is stable, secure product demand, information sharing and long-term commitment in the relationship.

Strategic partnership model In a partnership model, not only is this value creation an expectation of the pharmaceutical company for supplier performance, but it also works as a motivation to the vendor partner — what is good for one party is mutually beneficial to the other, ultimately resulting in shared successful outcomes for both.

The other expectation in a strategic partnership model is the role of the supplier in anticipating, identifying and acting upon market factors and trends, translating them into strategies and service offerings that increase competitiveness for the client in both the current market environment, as well as the future.

A good example of PCI’s effective strategic partnerships is the way the company has worked with leading pharmaceutical companies and developer Capsugel to bring forth a fully contained Xcelodose unit in support of potent compound development.

This allows PCI to work with clients on developmental services for potent compounds that expedite clinical development and at the same time maintain all the safe and effective handling of these powerful therapies.

This expertise and value creation has allowed clients to achieve speed-tomarket in the highly attractive oncology market and considerably reduce costs in early phase development.

David O’Connell, PCI’s director of Pharmaceutical Development, explained, “Housed within the new containment facility at Tredegar, South Wales, the Xcelodose microdosing unit enables us to offer a premium service to our clients. PCI is continually investigating and investing in ways in which we can accelerate the manufacture of our clients’ products, while maintaining our uncompromising commitment to safety and quality.

“By involving our experts early in the strategic development of a client’s new product, we can assist in optimising the process, ensuring that regulatory hurdles are minimised and that the most efficient routes to clinic are delivered.”

Industrial evolution As the pharmaceutical industry continues to evolve and rethink its strategies and tactics, there will be a greater reliance on outsourced service providers and the adoption of new logistical models. As a result, PCI is actively investing in its geographical presence for clinical trial supply.

“We have been very fortunate to be present for much of the dialogue around strategic outsourcing with our clients. It really is an industry shift as they reconcile their market competiveness and identify what is core to their business,” said Bill Mitchell, president and CEO of PCI Pharma Services.

“Pharma companies are rethinking their pipeline development strategies and tactics and adopting new logistical models. PCI is focused on providing advanced solutions for our clients that help them achieve both optimal supply as well as more effective execution.

“Our expert staff and the substantial investments we have made in infrastructure across our North American and European operations allow us to provide our clients with a more dynamic supply model. The customers that we work with tend to want to have companies that have a footprint not just in the US, but in other major global markets. That has been our strategy from day one and we continue to pursue it.”

Driving force of change This trend towards strategic outsourcing is the driving force of change.

Where the market had once been very transactional and tactical in nature, increasingly drug companies are relying on preferred and trusted suppliers in an integrated supply model.

With continued merger and acquisition activity in the pharmaceutical segment, coupled with large-scale vendor reduction initiatives, PCI sees this trend ever increasing. Pharmaceutical and biotech companies have been vocal of their desire to partner with leading service providers who can offer a multitude of development and commercialisation services, developed from a broad client base and deep specialist experience.

Mitchell sees tremendous value in this partnership model, stating, “At PCI, our number one commitment is to provide the industry’s leading customer experience. That singular focus translates into our own strategies and specific investments being very much aligned to the key insights and both current and future needs shared by our customers.”

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CURING DISEASE

Head to toe A quick review of some recent treatment approvals, clinical studies and general news in curing diseases, affecting patients from top to bottom.

Head and neck above the rest A late clinical-stage nanomedicine company, Nanobiotix, is extending its head and neck cancer programme with its lead product NBTXR3.

Head and neck cancer is an aggressive form of the disease and although highly curable if detected early, more advanced forms may require surgery in combination with chemotherapy and radiotherapy. However, surgical intervention can lead to severely debilitating side effects

as a result of the area involved, such as swallowing or breathing issues post-op.

NBTXR3 is an aqueous suspension of specially coated nanoparticles that has been designed to enhance radiotherapy energy in tumour tissue. Based on the value of Phase I/II clinical data, being presented in June, the company will determine the fastest pathway to both the US and European markets.

Penetrating the brain Funding was awarded to Cypralis by the Alzheimer’s Drug Discovery Foundation (ADDF) to assist in the development of new cyclophilin inhibitors for neurodegenerative diseases.

This money will be used to extend Cypralis’ ‘hit-to-lead’ medicinal chemistry and broaden its library of novel brainpenetrant cyclophilin inhibitors while also continuing to partner with Janssen in the generation of a new class of CNS penetrant.

There is a lot of potential in cyclophilin D as a novel target for degenerative diseases but no group has published on compounds that combine sub-type selectivity and brain penetration, noted Dr Michael Peel, CSO of Cypralis.

“If data from the ADDF funding is encouraging, Cypralis would expect to initiate a lead optimisation campaign in early 2018 with the goal of generating a novel preclinical candidate for this extremely challenging and devastating disease.”

Orphan designation for inebilizumab Orphan designation was granted to AstraZeneca’s inebilizumab by the EMA for the treatment of neuromyelitis optica spectrum disorder (NMOSD).

nerves and spinal cord, resulting in severe damage. With no current cure or approved medicine for this condition there is a significant unmet need for NMOSD patients.

NMOSD is a rare-life-threatening autoimmune disease of the central nervous system in which the body’s immune system attacks healthy cells, most commonly un the optic

Developed by AstraZeneca’s global biologics research and development arm, MedImmune, inebilizumab is currently in Phase IIb of clinical development.

Keeping abreast with abemaciclib Lilly revealed Phase III results of its MONARCH 2 breast cancer study, evaluating abemaciclib in combination with fulvestrant in the treatment of advanced breast cancer.

Designed to evaluate the efficacy and safety of abemaciclib in combination with fulvestrant, in patients with advanced (locoregionally recurrent or metastatic) breast cancer, the primary endpoint of progression-free survival was met.

“We are excited about the outcome of our first Phase III study for abemaciclib. These data are an important milestone in our goal of bringing abemaciclib to patients with advanced breast cancer, and we look forward to our upcoming conversations with regulators,” said Dr Levi Garraway, PhD, senior vice president, global development and medical affairs, Lilly Oncology.

Progressing therapy for MS A new drug to treat multiple sclerosis (MS) was approved by the FDA. Ocrevus (ocrelizumab) is the first drug approved in the US for primary progressive MS. It is administered through intravenous infusion by a healthcare professional.

Research said, “This therapy not only provides another treatment option for those with relapsing MS, but for the first time provides an approved therapy for those with primary progressive MS.”

Dr Billy Dunn, director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and

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Eyes front Aura Biosciences has enrolled and dosed the first patient in its Phase Ib clinical trial of light-activated AU-011, a targeted therapy for the treatment of ocular melanoma.

Ocular melanoma is a rare and aggressive form of eye cancer with no current targeted therapies available. AU011 is administered through an intravitreal injection into the eye and once activated with an ophthalmic laser targets the membranes of tumour cells selectively.

The trial will evaluate the safety of two dose levels of AU011 for the treatment of patients with small-to-medium primary ocular melanoma. Patients enrolled in the trial must be treatment-naïve and have a confirmed ocular melanoma diagnosis.

This treatment has been granted fast track designation by the FDA.

Breathing easier Positive interim Phase II results were reported by Heat Biologics for its trial assessing HS-110 in combination with a checkpoint inhibitor in the treatment of lung cancer.

In the trial 12 of the 15 patients that completed the HS-110/nivolumab (Bristol-Myers Squibb anti-PD-1 checkpoint inhibitor Opdivo) combination treatment were evaluated with ELISPOT analysis. The results of the evaluation suggest that HS-110 is important in tumour reduction and may enhance the efficacy of checkpoint inhibitors in lung cancer patients.

“Our results appear to further validate the expected mechanism of action of our approach in combination with checkpoint inhibitors, with a continuing trend towards early and sustained T cell activation in the peripheral blood cells.

All patients who mounted a sustained immune response to HS-110 exhibited substantial tumour reduction,” said Jeff Hutchins, PhD, Heat’s chief scientific officer and senior vice president of preclinical development.

A diabetes cure?

Researchers from the University of California have released findings, published in New Scientist, that a daily dose of a new drug could effectively ‘cure’ type 2 diabetes.

The drug works by inhibiting an enzyme called low molecular weight protein tyrosine phosphatase (LMPTP), which is found in the liver and appears to cause cells to become resistant to insulin. Researchers administered the

drug orally to mice daily without incurring any side effects.

“This could lead to a new therapeutic strategy for treating type 2 diabetes,” said Stephanie Stanford, University of California, San Diego.

Emily Burns of Diabetes UK added, “If this new drug works as described, it could be used to reverse insulin resistance, but we need to know first if it does that safely in people.”

Implantable AIDS treatment The NIH has awarded a grant to researchers to the University of North Carolina at Chapel Hill for the development of a new implantable drug delivery system for the treatment of HIV/AIDS. This new system is in the form of an injectable formulation that contains an anti-HIV drug, a polymer and a solvent.

Once injected, the compounds solidify in the skin and then as the polymer slowly degrades the anti-HIV drugs gets released slowly into the patient’s system.

Current treatment to prevent HIV-infection is in the form of a pill taken once-daily, however, adherence is an issue.

An injectable implant would solve this issue.

APPROACHing success The Phase III APPROACH study of volanesoren met its primary endpoint of reducing triglyceride levels in patients with familial chylomicronaemia syndrome (FCS).

FCS is a severe, rare genetic disorder that is characterised by extremely high levels of triglycerides and the risk of recurrent, potentially fatal pancreatitis. Volanesoren is an antisense drug in development designed to reduce the production of ApoC-III (a protein produced in the liver that is important in the regulation of plasma triglycerides).

There are currently very few effective treatment options for patients with FCS. “The success of APPROACH represents an important milestone towards our first regulatory submissions for volanesoren in the US, Europe and Canada in 2017,” reported Dr Louis O’Dea, chief medical officer of Akcea Therapeutics. “We seek to bring this new treatment as expeditiously as possible to FCS patients who have a high unmet need with potentially life-threatening consequences.”

Never neglect your feet A Geneva-based non-profit R&D organisation (Drugs for Neglected Diseases initiative – DNDi) and Eisai are combining to tackle eumycetoma using a compound that is already available.

Eumycetoma is a fungal infection that causes swelling of the hands and feet and in severe cases can lead to

amputations. Although there is a current treatment for the condition it is ineffective and expensive.

Eisai will develop and manufacture an investigational reagent based on the active form of fosravuconazole.

DNDi will then conduct a comparative study with this agent and will publish the results in 2019.

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CPHI NORTH AMERICA

Streets of ‘Pharmadelphia’ This month, Philadelphia plays host to the inaugural CPhI North America, where attendees can access the full spectrum of the North American pharmaceutical supply chain. Here, Felicity Thomas previews some of the meeting’s highlights.

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he first CPhI North America is about to take place in Philadelphia, Pennsylvania. Infamous for its role as a meeting place for the Founding Fathers in the American Revolution, cheesesteak and of course ‘that scene’ from Rocky on the steps before the Philadelphia Museum of Art — the streets of Philadelphia will soon be pounded by thousands of pharma professionals.

Taking place at the Pennsylvania Convention Center from 16–18 May, attendees will have access to the complete North American pharmaceutical supply chain through an exhibition, conferences and educational sessions.

Fostering relationships

On the show floor

Designed to bring key business leaders together, CPhI North America’s inaugural show will foster business relationships spanning the full pharmaceutical eco-system. Dubbed as being the hub of North American innovation for the pharmaceutical industry, attendees will have access to the latest technological innovations as well as industry movers and shakers.

In the same way that the worldwide event is laid out the North American exhibition show floor will be organised into zones, allowing visitors to navigate the exhibition according to their business objectives and interests. Covering drug development, packaging, manufacturing ingredients and finished drug products, these zones will provide micro-communities in which like-minded people can gather.

The event will play host to more than 6000 attendees and over 450 global companies.

Additionally, the North American event will feature the matchmaking services that has been successful on the world stage over the last few years. This complimentary online tool allows badge holders to set meetings prior to reaching the event. Meeting requests can be sent based on individual business needs and the dedicated CPhI Matchmaking Area can offer an easy way of making connections.

On Tuesday 16 May, Expo Plus pass holders will also be invited to the Welcome Reception.

Located at the Pennsylvania Academy of Fine Arts, those attending will be able to meet with prospective suppliers and partners in a casual setting along with a drink or two.

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At this inaugural event, there are several features aimed at assisting with attendee engagement and education as well as facilitating navigation of the exhibitor booths: Exhibitor Showcases: These succinct presentations are accessible to all attendees and will be delivered by solution providers housed on the exhibition floor, providing an open platform to interact face-to-face with developers.

Insight Briefings: Offering visitors more of an in-depth view on technical and business topics, such as accelerated drug approval programmes, the digital transformation of the pharmaceutical industry and supply chain security advancements.

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Innovations & Product Gallery: A free-to-attend area that concentrates on the latest product developments and advancements for the future.

Supplier Finder: Touchscreen, interactive floorplans allowing users to search for specific products or solutions and navigate the show floor effectively.

BOND — Exclusive Meeting Service: A tool to facilitate meetings between solutions providers and solutions seekers based on compatible needs and capabilities.

Additionally, as a part of the CPhI Global Event Network, CPhI Online is a tool available that helps pharma suppliers and buyers connect.

Women in Leadership Forum The North American edition of the forum will offer a relaxed and open platform for female executives from across the global pharma network to share experiences, trade knowledge and build a community. In addition, attendees will have the opportunity to hear strategies for leadership and advice on overcoming workplace challenges from industry speakers.

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the hub of North American innovation for the pharmaceutical industry

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The two-hour forum will open with a half hour breakfast and networking opportunity followed by a welcome presentation from the chair. This will then be followed by a panel discussion and Q&A examining strategies for self-promotion from a female perspective. To finish the forum, Rosalie Harrison, consultant from Borderless will present on ‘Women in Leadership: Expect More’.

The opening keynote presentations for CPhI Connect will be ‘Partnering for Quality: A New Era’ by Ronald T. Piervincenzi, PhD, CEO of the US Pharmacopeial Convention, and ‘Discovery of Innovative Therapeutics — Today’s Realities and Tomorrow’s Vision’ by Magid Abou-Gharbia, PhD, FRSC, associate dean for research, Laura H. Carnell Professor of Medicinal Chemistry & director of the Moulder Center for Drug Discovery Research, School of Pharmacy, Temple University.

Connecting through conferences This show will introduce the Connect Conference.

Featuring two complete programmes, CPhI Connect and InformEx Connect, attendees will have access to more than 80 hours of educational content.

CPhI Connect: These sessions will cover drug development, drug manufacturing, quality and regulatory affairs as well as outsourcing.

Featured sessions will include, ‘Innovative Breakthrough Technologies for Drug Targets and Emerging Pathways’, ‘Case Studies in API Continuous Processing’ and ‘Economies of Capability vs Economies of Scale — Advancing CMO Decisions’.

InformEx Connect: This educational programme has been specifically designed for executives from the fine and speciality chemicals industry who are focused on innovations in their field, regulatory affairs and the future of the chemicals business. Featured sessions will include, ‘Discover the Latest Innovations in Green Chemistry’, ‘Mega Mergers and the Impact on Global Agricultural Sourcing — Managing Supply Chain Thru Consolidation’ and ‘Plant Operations to Efficiently Meet Regulatory Requirements for Multiple Markets’.

In the InformEx Connect programme there will be two keynote lectures and a keynote roundtable discussion. The lectures will be

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‘Accelerating Value Creation via Innovation and Transformation: Opportunity Beyond the Laboratory Beaker’ by John Foley, CEO, ORG Chemicals Holding, and ‘EPA State of Industry Address’ by Dr Jeffery Morris, director of United States Environmental Protection Agency’s Office of Pollution and Toxics. The roundtable discussion will be on ‘The State of Innovation and Industry Transformation’ and will be moderated

by Dr Sarah Harding, Speciality Chemical Magazine with Jack Drawdy, vice president — sales & business development, MFG, and Joe Dettinger, director EHS&S and government relations, Bimax.

To ensure the issues facing both the pharmaceutical and fine and speciality chemicals industries are addressed the event organisers have partnered with the American Chemical Society (ACS), the US Pharmacopeial Convention and the Society of Chemical Manufacturers and Affiliates (SOCMA) in the development of the conference schedule.

With these additional educational programmes attendees can access two conferences with a single pass!

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NEC BIRMINGHAM, UK | 26-28 SEPTEMBER 2017

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TABLET DESIGN

Design is key Steve Osborne, I Holland’s product design manager, looks at some of the important considerations to be taken before tablet production.

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ral solid dose is still one of the most popular forms of delivery and this is for a number of reasons from ease of use, portability, administration and accuracy in dosing. As so many billions of tablets need to be produced quickly and efficiently, the requirement for tablet manufacturers to look at design specifications prior to processing should be a primary consideration.

If the design is to be heavily embossed it is important to avoid tablet profiles with a deep cup, such as the ball or pill. Deep cup profiles can cause a softer core in the tablet which, in turn, can lead to sticking and/or erosion. It will also reduce the available space for the embossing itself.

Swallowability — do size and profile matter?

The ‘swallowability’ of the tablet can be affected by the design and profile of the form being produced. Difficulty swallowing tablets and capsules can be a problem for many. According to a survey1 conducted in 2014 on patients in Germany and the US, over 55% of people from all age groups and genders experience swallowing difficulties when taking tablets. Individuals who find it difficult to swallow tablets and capsules frequently cite the size as the main reason for the difficulty in swallowing.

Size and shape of tablets affects transit of the product and may directly affect a patient’s ability to swallow a particular drug product.2 With this in mind, it is important to pay attention to the design of the tablet before production, not only for the end-user, but it is also important to the final quality of the tablet and ease of production.

Tablets are becoming more complex in both shape and profile for brand identity and marketing purposes. As the tablets become more complicated, so does the tooling, increasing the demand upon tooling strength, durability and overall performance.

Tooling Performance Using a profile that is shallower, with a reduced cup depth, will allow for a larger embossing area.

Do you require a coating on the tablet? A coating may be aesthetic or intrinsic but can also help in swallowability, and so this requirement should be incorporated during the initial design. Successful coating is largely dependent on tablet profile. As discussed the centre of a tablet is normally softer, so during the coating process core erosion may take place. This vulnerability, caused by mechanical stress during coating, can be reduced by avoiding very deep concaves and ensuring a robust design.

The correct tablet shape and profile is key in finding a successful end product that can be easily manufactured.

There are two basic tablet shapes, round and non-round.

Non-round shapes are extremely varied and designs may require specialised tool manufacturing capability.

Choosing the wrong shape (or a shape that has been badly designed) can have a huge impact on the bottomline as problems like sticking and picking can result from this and will delay production.

Once a workable base shape has been decided, tablet size must be determined. Consideration should be given to the type of press available as this can limit the size of the tablet. Also, is it possible to produce the tablets using multi tip tooling? Multi tips can accommodate most tablet designs, but this is influenced by the press and tool type capabilities. You must look at the tablet size to evaluate the number of tips to fit the punch; some shapes can be more challenging to arrange so that they take off cleanly and efficiently.

Tablet profile is the next important consideration. The profile is affected by a variety of aspects, from the granule being used and the influence it has on the tooling, through to the embossing requirements, and coating process.

Several factors should be considered when incorporating a breakline. The tablet’s size and hardness should be addressed so the end-user can easily hold the table when breaking. Care should also be taken to ensure that the breaklines match on upper and lower punches.

Thought should also be given to branding as logos can have an influence on the breakline. Product identification should also be maintained to ensure brand integrity when the tablet is divided.

When looking at performance, consideration should be given to the tools’ ability to manufacture tablets that are representative of a manufacturer’s design requirements and product yield.

Selecting a design that is aesthetically pleasing but will not stand up to the demands of tablet production will waste time and money. Look at the choice of tooling material and coating, is it appropriate for the formulation being compressed? When a cycle is complete are the tool maintenance procedures optimised for ensuring prolonged tooling life? Can the design withstand prolonged cyclic loading and fatigue to produce a well compacted tablet?

This is even more important when specifying a requirement for multi-tip tooling.

All these questions are fundamental and should be advised by a quality tablet designer. Examination of any previous tablet production, tooling audit and management should also be considered.

Design is key The design of a tablet is crucial to a well-made end product. Without considering basic but important design processes like shape, profile and breakline, the tablet will simply not work. Professional tooling designers can take all these variables into account during the initial design and concept stage, resulting in an easily manufactured quality tablet.

Breaklines Breaklines that are used to divide a tablet must be both functional and effective. Uneven breaking of a tablet may result in significant fluctuations in the administered dose. The degree of inaccuracy may be associated with breakline design, tablet hardness and/or formulation.

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References: 1. http://www.hermes-pharma.com/about-us/news-events/detail-news/ article/conventional-tablets-may-no-longer-be-the-go-to-solution-pressrelease.html 2. https://www.fda.gov/downloads/drugs/guidances/ucm377938.pdf

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GENOMICS

Growing genomics The potential benefits of genomics are well documented in healthcare, European Pharmaceutical Manufacturer reporter Reece Armstrong examines the latest developments in the field.

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ver since the completion of the Human Genome Project in 2003, the benefits of DNA sequencing have been linked to an era of personalised medicine, where better treatments can be produced based on the genetic-makeups of individuals. Targeted therapies, preventative medicines and molecular diagnostics are just some of the benefits that genomics can offer healthcare.

At this year’s Wired Health Conference, healthtech company Sophia Genetics announced that it is set to reach its strategic goal of analysing the genomic profiles of 100,000 patients using its artificial intelligence SOPHiA. The system is currently being used in 250 healthcare institutions around the world to help analyse data produced by genome sequencing. These institutions pool their patients’ genomic data into a SaaS analytics platform powered by SOPHiA.

Global network SOPHiA’s global network of users means that it is continuously developed to identify key variants in patients’ genomic profiles. Following this the system can then turn this information into actionable insights, potentially allowing clinicians to make better informed decisions.

More so, by using SOPHiA, hospitals with little experience in genomics can get up to speed and analyse genomic data to identify disease-causing variants and match them with the most effective drugs that can be used to treat patients.

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Sophia Genetics’ latest approach to analysing patients’ genomic profiles is an example of the growing genomics market which is expected to reach1 almost $20 billion by 2020 at a CAGR of 9.9%.

Reducing costs Analysing genomics data has previously been a costly and lengthy process. According to the National Human Genome Research Institute2 (NIH) the cost of generating a DNA sequence in 2001 was almost $100 million. Due to advancements in next-generation sequencing (NGS) costs have fallen dramatically. In 2015, the costs of generating a sequence was estimated at just over $1,000, now healthcare companies are striving towards the $100 genome.

‘Bringing down this barrier’ as SOPHiA Genetics’ CEO Jurgi Camblong stated, “Will allow hospitals worldwide to embrace the clinical genomics revolution, to the ultimate benefits of patients.”

Personalised genomics The strive towards personalised genomic medicine would not be possible without access to large quantities of data. Sophia Genetics’ milestone of 100,000 patients’ genome sequences analysed is evident of how data can be used to the betterment of healthcare across the world.

Indeed, access to information produced by gene sequencing technologies is vital for researchers and clinicians to understand disease and genetic

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variations in the human population.3 The adoption of Sophia Genetics’ technology across the world is just one example of how information needs to be easily accessible in order for hospitals to treat patients with the most effective drugs.

Important initiatives

For drug manufacturers this means working towards a growing demand for personalised medicine, the market of which is predicted to be worth $149 billion by 2020.4 To do this pharmaceutical companies are having to move beyond the one-size-fits-all approach that has currently been the standard in drug manufacturing. Deloitte’s 2015 Life Sciences Supply Chain Benchmarking Survey5 confirmed the industry’s thoughts on a more personalised approach. When asked about what was expected out of the industry in the next 10 years, the majority of respondents (33%) said they expect supply chains to become far more segmented and specialised according to product.

In 20156 the country issued a single-pill therapy for HIV called efavirenz.

The drug was cheaper and easier than the previous three-drug cocktail used but it brought about a new set of problems. A gene variant found in many Zimbabweans slows their ability to break down efavirenz, causing side-effects such as hallucinations, depression and suicidal tendencies.

For instance, the NCIMATCH clinical trial in the US is one example of matching patients to existing drugs for the best effect. The trial is using genetic markers from cancer patients’ tumours to assign them to different treatments. NCI-MATCH is aiming to assess the effectiveness of different treatments according to patients’ genetic abnormalities. The trial opened for enrollment in 2015 and is estimated to be completed by 2022.

Speaking on the potential that the trial offers, Doug Lowy, NCI acting director said, “NCI-MATCH is a unique, ground-breaking trial. It is the first study in oncology that incorporates all of the tenets of precision medicine.

There are no other cancer clinical trials of this size and scope that truly bring the promise of targeted treatment to patients whose cancers have specific genetic abnormalities. It holds the potential to transform cancer care.”

Raising funds Over in the UK, Cambridge startup, Repositive, recently closed a £2.5 million Series A funding round bringing the total raised by the genomic research portal to £3.3 million.

Repositive’s goal is to speed up genetic diagnostics and research by improving access to available data around the world. The start-up’s online platform unites datasets from across the world in an easy-to-use portal. Researchers can search the portal for relevant data to help speed up their research.

The Repositive platform launched in 2016 and has since amassed over 1 million data sets which is continuing to grow. The company has also partnered with healthcare giants such as AstraZeneca, Merck Group and Horizon Discovery to develop a collaborative resource for oncology research data.

Both Repositive and Sophia Genetics realise that without widespread access to data, goals such as personalised medicine and better informed decision by clinicians are unlikely to be realised in an efficient manner.

These trials are promising examples of precision medicine being thought of as an attainable goal. While cuts to the National Institute of Health (NIH) in the US shine an uncertain light on precision medicine initiatives, the importance of it cannot be understated.

Take Africa for example where a drug used to treat HIV caused horrible side-effects for those with certain genetics in Zimbabwe.

The argument for precision medicine can be strongly made for populations where genetic variants make treatments ineffective or harmful. Realising this are researchers from the National Human Genome Research Institute (NHGRI)7 who examined genomic data in relation to the likelihood of obesity in African populations.

The researchers found that people with genomic differences in the semaphorin-4D gene were around six pounds heavier than those without the genomic variant. The research was the first of its kind to be conducted on an African population and highlights the importance of understanding genetic differences across global populations. For instance, the semaphorin-4D genomic variant is absent in European and Asian populations, meaning people of African ancestry have an increased risk of obesity.

Advancing precision Advancements in genomics have the potential to transform the way medicine is delivered to populations around the world. A move towards precision medicine is necessary if patients are to benefit from more effective drugs.

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Advancements in genomics have the potential to transform the way medicine is delivered to populations around the world.

Sophia Genetics understands that without global access to genomic data, researchers won’t be able to quickly and efficiently gain useable insights into the molecular causes behind diseases. The company’s AI platform has recently been deployed by hospitals in Africa. This achievement is evident of the company’s goal to democratise data-driven medicine and is one more benefit to healthcare across the world. A lot of progress has been made since the completion of the Human Genome Project and the work displayed in this article shows that precision medicine is an achievable reality.

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References: 1. http://www.marketsandmarkets.com/PressReleases/genomics.asp 2. https://www.genome.gov/images/content/costpergenome2015_4.jpg 3. Mattick, .J.S, et al., Med. J. Aust., 2014;201(1):17–20.

4. http://www.prnewswire.com/news-releases/personalized-medicine-market-worth-149-billionby-2020-covering-companion-diagnostic-and-targeted-therapeutics-568257891.html 5. https://www2.deloitte.com/content/dam/Deloitte/ie/Documents/Strategy/uk-deloitte-lshsupply-chain-logipharma-report-2015.pdf 6. http://www.nature.com/news/how-the-genomics-revolution-could-finally-help-africa-1.21767 7. https://www.nih.gov/news-events/news-releases/study-identifies-african-specific-genomicvariant-associated-obesity

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55

LABELLING

Surprise package Looking at how labelling can improve patient retention in clinical trials.

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s global healthcare grapples the problem of medicines adherence, C. Everett Koop’s famous observation has become a familiar retort: “drugs don’t work in patients who don’t take them.” The same concept applies in clinical studies. Trials don’t work when patients don’t take their meds. What’s more, if the cost of recruiting patients to clinical studies is high, the price of failing to keep them there is even higher.

covering more than 160 countries, all of which are enrolling patients today.

The globalisation of clinical trials has naturally brought with it a convergence of logistical, operational and cultural challenges. Moreover, it’s forced the pharmaceutical industry to adapt to an increasingly complex and evolving regulatory environment. A key component of this is the need to comply with variable local language labelling requirements, not least in the safe distribution of medicines for clinical trials.

Yet despite long-standing efforts to ensure patients remain engaged and motivated through the duration of studies, subject attrition is the norm not the exception. Studies show that attrition rates are commonly between 15–20%. They can sometimes exceed 30%. The factors that influence study drop-outs are varied but largely predictable. However, one significant barrier to patient retention is often overlooked: the label.

Yes, that’s right: the label.

With the global map for clinical studies now extensive, information to support the safe and effectual use of trial medicines must be coherent and understandable to the patients receiving them. It needs to speak their language.

The importance of labelling in clinical trials gets very little exposure. However, as the global war for patients intensifies in an increasingly competitive trial market, pharmaceutical companies are slowly discovering that the packaging of their products can be a key determinant of patient retention.

The revelation stimulates an interesting question: when did the packaging of a clinical trial product become more significant than the actual drug?

The answer? When the patient couldn’t understand it, and subsequently gave up. It sounds far-fetched. However, it’s happening every day on a global scale.

As the cost of drug development escalates, perhaps it’s time for industry to review its labelling infrastructure to alleviate the expense and implications of subject attrition.

Think global, speak local So how did we get here, and how do we solve the problem? As we know, the clinical trial market is not only global, it touches more markets than ever before. The US National Institute of Health’s clinical studies registry, Clinicaltrials.gov, currently lists registrations for over 225,000 trials

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That information is typically delivered through multipage booklets or IFUs (Information for Use), which have become key constituents in a burgeoning portfolio of packaging and labelling materials. In a global marketplace, these materials typically include information in multiple languages, combining patient-specific, product-specific and countryspecific content.

Much of this data is often stored in disparate local systems, spread across a global organisation — making the labelling process a complex one, fraught with inherent risks. A labelling error can have substantial financial, reputational and, sometimes, human costs.

Patient disengagement In the case of clinical trials, suboptimal labelling has ramifications that go beyond financial and regulatory risks. It’s a common, though unheralded, catalyst for subject attrition.

Typically, patients can find the trial process complex and distressing. Their ability to follow the right regimen and maintain the required frequency and dosage depends on a variety of factors, not least understanding how the product should be administered. Often, if patients are unsure or realise they have made a mistake, it’s easy for them to exclude themselves from the trial.

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For the pharmaceutical company, the implications are severe. Enrolling target patients is difficult enough, so to allow them to slip through your fingers because of poor labelling is both careless and costly.

Enrolling target patients is difficult enough, so to allow them to slip through your fingers because of poor labelling is both careless and costly.

Patient retention is a major cause of trial delays, with associated financial and operational costs. However, ineffective labelling is also a missed opportunity. For study sponsors, contact with patients on global trials can be very limited. The only interaction a company has with a subject is often through the product packaging itself.

In a pharma environment dominated by aspirations of patient-centricity, it’s easy to underestimate the important role packaging can play in patient engagement during clinical studies.

In many cases, the label is not just the primary touchpoint, it’s the only touchpoint — the sole means of influencing the patient or helping to make things easier for them.

What’s more, in many therapeutic areas, particularly with treatments for chronic disease, the packaging presents an early opportunity to drive long-term brand loyalty.

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It’s an opportunity that’s often squandered. In the worst examples, the information provided via multi-language booklets may do enough to satisfy regulatory requirements, but it relies on translations that fail to appreciate local, cultural and clinical nuances. In the process, patients become confused, disengaged and, ultimately, decide to quit their trial.

Local language challenges There are many reasons why local language labelling has always been difficult; outsourced translation services may not understand the context of clinical trial text, while dosage quantities and instructions typically rely on

complicated phrases. Similarly, where companies rely on native language specialists as part of label design and approval, processes can be slow, leading to increased costs and delays. Moreover, visual inspection of Asian and Arabic languages, which use unfamiliar symbols and fonts, can be difficult and labour-intensive.

The challenge of local language labelling, and of maximising the real estate of complex label designs, once again shines a light on the strategic importance of an effective labelling infrastructure. In an increasingly competitive global marketplace where drug development costs continue to rise, smart investment in innovative labelling technologies can lead to a significant reduction in the cost and operational impact of subject attrition.

The most effective systems will sit at the centre of an enterprise and take an integrated, data-driven approach to label lifecycle management. By focusing on the data, rather than simply the label, organisations can develop a 360° view of their master data assets, and enjoy the flexibility to adapt and tailor content to meet country-specific requirements, also ensuring local regulatory compliance. The smartest technologies will include language and phrase management tools that allow translations to be pre-agreed and pre-approved, and clinical trial-specific terminology to be specified and validated.

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clinical trials don’t work when patients drop out because they don’t understand how to comply.

In the same way that drugs don’t work in patients who don’t take them, clinical trials don’t work when patients drop out because they don’t understand how to comply. It’s a contentious suggestion that the packaging of a clinical trial product may be more significant than the drug itself — but if patients can’t confidently get beyond the packaging, the true benefits of high-value medicines will never be proven.

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There are many reasons why a patient may abandon a clinical trial — but the label doesn’t need to be one of them.

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O Diary entry #3

LAB DIARY

In the most recent entry, R&D software provider IDBS highlights four points to look out for when forming an outsourcing partnership.

Outsourcing to contract research/development and manufacturing organisations (CxOs) is a trend that has increased dramatically year-on-year in the pharmaceutical industry. There are many reasons why outsourcing continues to be so popular, despite some concerns within the industry.

Time and cost savings, along with access to specialist equipment and subject matter experts, are prime examples of key benefits, and Deloitte’s 2016 Global Outsourcing Survey revealed how 78% of respondents feel positively about their outsourcing relationships.

However, to ensure scientifically robust business-to-business collaboration, organisations need to be able to rely on a R&D informatics technology partner who is able to manage both the dynamic scientific and business critical data flow efficiently, securely and to regulatory standards.

There are four simple things to remember when looking for the right outsourcing technology partner:

1) Security Establishing a secure network when working with CxOs is essential, especially when sharing sensitive intellectual property (IP). Before starting any CxO collaboration process, sponsoring organisations should review their own data management systems and processes to ensure they are capable of sharing data outside the firewall. If they don’t allow for external sharing, organisations need to vet and assess the informatics solutions available.

There are several Software-as-a-Service (SaaS) solutions that enable secure data sharing outside the firewall, and operating in the cloud allows for fast onboarding of those all-important outsourcing partners. Ensuring all data and IP is safe from intentional or unintentional tampering will allow organisations to focus on selecting the best CxO for the job, without worrying about data flow and data security.

2) Systems integration and platform models CxOs tasks are assigned and this creates a steady stream of work, which is at the core of outsourcing, but eventually, all the data must be integrated into corporate systems to support downstream analysis, workflows and regulatory submissions.

Many organisations encounter difficulties integrating processes and data generated by their CxOs back into their own systems.

This can lead to sponsoring organizations feeling pigeon-holed into selecting CxOs based on their overall IT compatibly, rather than expertise and business drivers. This does not have to be the case — and SaaS platforms can be used to bridge IT systems in a cost-effective manner.

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Subscription pricing models also mean you only pay for what you use meaning better ROI. A further benefit is that bridging the informatics landscapes of the sponsor and CxO can also automate and streamline the integration processes of incoming data, shaving valuable time off the drug discovery and development process.

3) Compliance One of the benefits of outsourcing is having a global market of CxOs to choose from, although operating on a global scale raises regulation and compliance concerns. How can a sponsor organisation in the UK ensure a CxO in China is complying with EMEA regulations?

Advanced SaaS R&D informatics platform solutions allow sponsor organisations to define and embed business and master data management rules into their collaboration systems, ensuring the CxOs comply.

To avoid any compliance misconduct, sponsor organisations should identify what specific rules their CxO partner must comply with before collaboration begins. Communicating this through a scientifically robust informatics data management platform boosts the confidence in the data produced by CxOs.

4) Industry expertise and reliability Selecting the best CxO for a project requires visibility of a CxO’s accomplishments, credentials and expertise, and sponsoring organisations should thoroughly investigate potential CxOs before outsourcing any work. Similarly, sponsoring organisations need to select a technology partner that can support the complex, scientifically demanding, compliant workflows that are integral for drug R&D. Organisations that are collaborating should be working as one entity, where work is easily assigned and tracked. Data should be shared and traceable, auditability and compliance should be enforced across teams as required, and all people working on a given project should be visible and accountable.

All this needs to occur while also supporting the overall scientific workflows and reporting requirements through the diverse cross-domain boundaries of chemistry, biology, formulations and analytical sciences. Essentially, it should not matter if a company is outsourcing or not — the work process, data process and informatics systems should not be the barrier — they should be the enabler.

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