EPM October 2017

SIZE MATTERS SCHOTT DESCRIBES HOW SMALL AND FLEXIBLE MEANS FAST AND PROFITABLE IN PHARMA PACKAGING PLUS: OCTOBER 2017

• CPHI PREVIEW • INTO THE ‘DATA’ BREACH

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Contents October 2017 | Volume 17 Issue 7

Regulars 5

10

Features 27

EDITOR’S DESK

GRANULATION & MILLING, MIXING & BLENDING

As CPhI Worldwide returns to Frankfurt, we take a look at what makes the city such a great place for pharma.

Explaining how comprehensive, process relevant characterisation of wet granules can lead to control of tablet CQAs and help with design space definition.

7 ANALYSIS Discussing the future of biosimilars in the UK and the shocking results of a survey into the failure of pharma businesses to report data breaches.

12 OPINION Revealing some of the key challenges and opportunities facing the industry in the digital space and the top five reasons why quality management should be moved to the cloud.

16 REGULATORY AFFAIRS Looking at the practicalities of mastering IDMP compliance, the challenges the industry will be facing to meet forthcoming regulatory changes and the history and necessity of pharmacovigilance.

24 ON THE COVER SCHOTT makes the point that small and flexible means fast and profitable in pharma packaging and demonstrates how this shift will affect the industry and consumers.

66 LAB DIARY Evaluating data safety and cloud computing.

34

40

MEGA TRENDS IN PHARMA In this roundtable, four industry leaders reveal their thoughts on what the ‘mega trends’ are in the current pharma landscape.

37 IMAGE ANALYSIS

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

Describing a co-extrusion technique and how Raman imaging microscopy can be used to measure aspects of the outer shell of the extruded material.

production

40

advertising

APIs/EXCIPIENTS Highlighting the challenges in prefillable syringes and discussing a new method to tackle excipient selection challenges.

44 CPhI PREVIEW Previewing the forthcoming CPhI Worldwide event and briefly looking at some of the innovations to expect on the show floor.

64 48

START UP Revealing what life science start-ups should bear in mind when looking for funding.

50 SERIALISATION Overviewing how to best use the US DSCSA enforcement postponement and how a CDMO can help companies be serialisation compliant globally.

59 LABELLING Looking at the accessories that are available to meet various labelling needs.

62 DRUG DELIVERY Detailing some important design considerations in self-administered therapy solutions.

art robert wood

robert anderton tel: +44 (0)1244 680222, rob@rapidnews.com damien challenger tel: +44 (0)1244 680222, damien.challenger@rapidnews.com

subscriptions subscriptions@rapidnews.com qualifying readers Europe - Free, ROW - £249 outside qualifying criteria UK - FREE, ROW - £249 please subscribe online at www.epmmagazine.com Address changes should be emailed to subscriptions@rapidnews.com.

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

Volume 17 Issue 7 © October 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.

All rights for European Pharmaceutical Manufacturer are reserved and reproduction in part or whole without written permission is strictly prohibited.

64 LAB INNOVATIONS PREVIEW Running through what to look out for at the upcoming Lab Innovations event.

BPA Worldwide Membership ISSN No - 2052-4811

US requirement for TE-ring on ophthalmic dropper bottles | Dropper bottle System A now with a blocked TE-ring on the bottle | All dimensions, properties and material are kept the same | Design of TE-ring modified October 24 – 26, 2017 | Frankfurt

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editor’s desk A Frankfurt adventure As we fast approach CPhI Worldwide’s return to Frankfurt, we take a look at what makes the city such a great place for pharma.

T

his coming October I will not only venture to Frankfurt for the first time but this will also be my very first CPhI Worldwide! Although I have been to many places in Germany, I am quite looking forward to seeing the delights Frankfurt has to offer and am excited to see the vast Messe in all its glory, full to the brim with pharma movers and shakers.

Despite this being my first time, however, it has been a welcome location for the immense pharma event many times in the past. Following on from the success of last year’s event in Barcelona there is much anticipation about the continued growth in visitors, particularly in light of the fact that the industry is currently flourishing.

However, out of all the worldwide locations, what makes Frankfurt such a great place for pharma? Well, as the financial capital of Europe,1 there are obvious economic reasons that make the city attractive. As PricewaterhouseCoopers revealed in their 2017 Pharmaceutical and Life Sciences Industry Trends report,2 companies within the pharmaceutical and life sciences sectors are experiencing the challenges of a ‘New Health Economy’ – consolidation among providers, varying patient demands and expectations, pricing reform as a result of rising cost pressures from payors and more focus on rule-based, protocol-driven care.2 Within this new era, pharma companies will need to be more consumerfacing, so not only prioritising product sales but also delivering positive results for targeted populations.

One way in which pharma companies are already shifting to this new economic way of thinking, according to the report, is to “adopt new technologies for data analytics that can manage and assess the results of personalised medicine delivery and determine the direction of product development.”

Another factor companies will be considering is the distribution of products, as a result of the diversification of product types and variances in lifecycles that comes with a more personalised treatments and a rise in biopharma. It is in this area of logistics that we find another lucrative benefit Frankfurt can offer pharma.

The city has easy road, rail and river access that have long served as beneficial distribution routes in Europe but more recently air transportation hit the headlines for Frankfurt. In April last year, it was announced that plans surrounding the city’s airport, which is the largest in Germany and the busiest in Europe,3 to become the major pharma-hub for the continent had been reinforced.4 The aim was for a number of companies to achieve IATA Center of Excellence for Independent Validators in Pharmaceutical Logistics (CEIV-Pharma) certification with the support of the Air Cargo Community Frankfurt.

“With comprehensive certification of the entire process chain we will have independent confirmation and can recommend Frankfurt as the Pharma-Gateway for Europe,” explained Joachim von Winning, executive director of Air Cargo Community Frankfurt.4 “At the same time we also see the certification process as an opportunity to optimise services and processes. In doing so, we want to respond even better to the needs and requirements of freight forwarders and pharmaceutical companies. IATA CEIV Pharma provides the perfect setting…”

Nowadays, Frankfurt Airport is Europe’s leading pharma hub, followed

by Paris and Amsterdam, offering solutions for perishables and pharmaceutical products, which must be of great benefit to the 90+ pharma and biotech companies housed in the city and others just located beyond.

So, it is plain to see why the city is considered to be ‘pharma’tastic and will make a wonderful host for the forthcoming CPhI Worldwide. I can’t wait to take in the sights and sounds of the busy Messe and hope to see you there too, but for now…

Auf Wiedersehen und danke schön, Felicity

References: 1.

2.

3.

4.

https://www.frankfurt.de/sixcms/detail.php?id=stadtfrankfurt_eval01.c.317693.en https://www.strategyand.pwc.com/media/file/2017-Pharmaceuticals-and-Life-Sciences-Industry-Trends.pdf https://www.britannica.com/place/Frankfurt-am-Main https://www.internationalairportreview.com/news/22943/frankfurt-largest-pharma-hub-in-europe/

WWW.EPMMAGAZINE.COM

5

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6

ANALYSIS

Vive la révolution!

Harriet Lewis, ABPI’s Medicines Optimisation Lead, discusses the future of biosimilars in the UK asking the pertinent question: will they revolutionise healthcare?

T

he ABPI represents UK-based pharma companies researching the newest and most innovative medicines. Our members make both originator biological medicines and make biosimilar medicines so, for want of a better word, we have a foot in both camps.

Biosimilars are neither generic medicines nor novel treatments.

Definitive guidance from the European Commission sets out that they are in fact a ‘version of an active substance’ within an already approved medicine.

We work to support the introduction of biosimilars but also work to ensure there is a sustainable and active competitive market. To understand why we talk about biosimilars and the biosimilar market in a unique way, it is important to take a step back.

Biosimilars are

Manufacturers must convincingly demonstrate the similar nature of these products. Regulators require biosimilars to demonstrate a comparable clinical effectiveness to originator products. The European Medicines Agency (EMA) goes so far as to say that the ‘concept of biosimilarity is applicable to any biological medicinal product’.

“

neither generic medicines nor novel treatments

I am a pharmacist – not a scientist – so I am constantly amazed by the science behind biosimilar medicines that is both fascinating and complex. Put simply, biosimilar medicines are made from living cells and since living cells are all slightly different, there are also variations between biosimilar medicines. This so-called heterogeneity is part and parcel of biological medicines: chemical difference that do not affect the clinical effectiveness of the medicine.

”

When producing biological medicines, companies must demonstrate the reproducibility of their drugs time-after-time and within certain parameters.

Before they even get to the point of clinical trials in humans they are required to demonstrate successful reproducibility. As a result of the complexity of manufacturing and regulation, bringing these products to market is time-consuming and expensive.

One of the early key discussion points around biosimilars is how they should be defined and therefore how they should be treated.

Just as with any medicines, there are class-based risks associated with a biosimilar medicine’s pharmacology, potency or bioavailabilty over time, and these are monitored on an ongoing basis. Pharmacovigilance is a necessary component to the success of biosimilars and ensures that regulators can trace where biosimilar medicines are used to track immunogenic side effects should they arise.

We can only know so much about any medicine, including biosimilars, before they are licensed. Information and our understanding of how they work in patient populations is continually built-upon once the medicine become available to patients: pre-authorisation clinical studies are often insufficient in highlighting all adverse effects. Across Europe, the pharmacovigilence regulation requires that all adverse events for biologics are reported by brand name and batch number. In England, prescribers are encouraged to prescribe by brand name and NHS providers to record product name and batch number to provide an audit trial for product identification and traceability.

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The impact of biosimilar competition and what comes next The European biosimilars market has grown exponentially since the first medicine was launched back in 2006; there was a sudden uptick from 2012 and if you look at any timeline outlining the number of medicines launched what is abundantly clear among the many …switching successes are also a number of failures.

“

to biosimilar medicines may release savings in health systems that should be reinvested in patient care…

Once you have started manufacturing a biosimilar medicine, it isn't a done deal that you'll have a successful medicine. In that respect, biosimiliars are indistinguishable from originator products.

There are also strict regulatory challenges for biosimilar medicines and regulators take time to assess and approve them. This is unlike generic medicines, which are often licensed relatively quickly and are made available to patients on much shorter timescales.

While we are seeing a fast-growing market in biosimilars in all areas, it is also becoming apparent that they might not always be commercially viable.

”

It has become clear from the rapid expansion of the biosimilars market, according to the QuintilesIMS European study ‘The Impact of Biosimilar Competition in Europe’,1 competition drives down price. The report also shows there is a relatively weak correlation between biosimilars market share and price; this is a fast-growing market that will inevitably provide complex medicines at more affordable prices, switching to biosimilar medicines may release savings in health systems that should be reinvested in patient care and not used to plug financial deficits.

We know that switching from originator projects to biosimilars is being heralded by the NHS as the next step in delivering savings to health systems, although the predicted savings on the scale suggested have yet to be delivered. Actually, it's not switching per se but the introduction of competition, in which both the biosimilar producers and originator biologic manufacturers compete (as the IMS Health study has demonstrated).

Regardless, the decision to switch should be clinically-led: considerations must be made to ensure patient access to innovative new medicines and that those are made between patients, clinicians and doctors.

8

There is also a burden associated with switching to biosimilar medicines both in the financial sense but also as a burden on the clinical support staff that need to manage the change. Education is a key part of these decisions. To support clinicians considering switch programmes there are a number of important documents setting out the process for clinician and patient engagement, including ‘Considerations for physicians on switching decisions regarding biosimilars’ a joint document from European Biopharmaceutical Enterprises (EBE) European Federation of Pharmaceutical Industries and Associations (EFPIA) and International Federation of Pharmaceutical Manufacturers and Associations (IFPMA), but also on the EMA website, to show clinicians some of these toolkits available to make informed decisions about switching.2 At ABPI we are working closely with our partners: the BIA, the BGMA and the BBA, as well as the regulators, to make sure that we have a sustainable and active market so that patients do actually benefit from the innovation seen in this growing field of medicines.

We continue to work closely with NHS England on a range of activities to highlight how competition within the biologics market is beneficial for patients. The ABPI recently advised on a forthcoming NHS commissioning framework document which will provide guidance to NHS commissioners about biosimilar switching programmes. We look forward to seeing the final version and hope that our industry’s insight has been considered and that the benefits to patients of an effective biosimilars market here in the UK are included.

The phenomenally complex manufacturing process involved in making biosimilars is really leading contemporary science in this field and could potentially revolutionise the treatment of some conditions.

References: 1. http://www.abpi.org.uk/media-centre/Partner-organisation-statements/Pages/EBE-EFPIA-andIFPMA-launch-position-paper-on-biosimilar-switching-decisions.aspx 2. https://www.ifpma.org/wp-content/uploads/2017/03/Considerations-for-switchingdecisions_IFPMA-vF.pdf

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ANALYSIS

Into the ‘data’ breach A recent survey has revealed the extent to which pharma businesses are failing to report data breaches.

Here, Dominic Johnstone, head of Information Management Services at Crown Records Management, discusses the shocking results.

D

ata breaches have been hitting news headlines worldwide this year including high profile stories, such as that of the mobile phone company Three – where an employee’s password was stolen in March and the data of 200,000 customers compromised. Then in April, cybercriminals seized 250,000 customer records at Wonga – this Some of [the] data breach included bank account details. statistics really Probably the biggest are shocking and suggest that story for pharma was that of Merck, which fell data breaches victim to a ‘NotPetya’ may be far more cyber-attack in June, leading to a shutdown common and more widespread of its manufacturing operations.1,2

“

than many people realise.

”

However, it seems these stories may be only the tip of the iceberg! The real extent of the pharma sector’s problem with data breaches has been revealed by a survey which suggests a quarter of IT workers in the industry are keeping them quiet.

The Crown Records Management Survey, undertaken by Censuswide, polled 408 IT decision makers in companies of between 100 and 1,000 employees across the country.

It provided some shocking results, which suggest many of the UK’s data breaches are going unreported.

10

Some of the statistics for the pharmaceutical sector are highlighted below, with mixed results: • 23% have chosen not to report a breach to more senior management or the appropriate authorities.

• 15% don’t know who to report a breach to – only the retail sector polled worse.

• 23% know somebody in their company who hasn’t reported a data breach.

• However, nobody polled was unaware of what constituted a data breach – better than the national average of 8%.

A long way to go…

Whilst the pharmaceutical sector is doing better than most when it comes to understanding what entails a data breach, there is still a long way to go. The frequency of data breaches that go unreported is especially worrying in a sector such as pharma, which handles large quantities of sensitive data.

Some of these statistics really are shocking and suggest that data breaches may be far more common and more widespread than many people realise. These results also indicate a culture inside many companies that the best response to a breach is to ignore it or keep it quiet.

Perhaps this comes from a fear of the loss of reputation which can be experienced when breaches are publicised.

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Or perhaps it is simply down to lack of a clear procedures and information management in the business. Either way, the implications are serious, and the fact still remains that data breaches must legally be reported within 72 hours.

New legislation, such as the UK data bill and the forthcoming EU general data protection regulation, due to come into force in May 2018, include measures to tackle data breaches.

The latter will bring in huge fines for businesses that suffer breaches as a result of poor compliance. It also sets a strict timeframe for the reporting of breaches – with fines for those who do not meet them.

It is, therefore, absolutely vital that businesses tackle this culture of secrecy because in future unprotected data loss will simply not be acceptable. In fact, it shouldn’t be acceptable now.

Having a clear data protection and information management programme in place is vital for businesses to avoid these kind of problems. It should be very clear who is responsible for reporting breaches and who they should be reported to.

Until businesses grasp how much a breach can cost them – both financially and in terms of reputation – this problem is not going to go away.

References: 1. https://www.epmmagazine.com/news/global-cyberattack-affects-manyincluding-merck-and-may-be-w/ 2. https://www.reuters.com/article/us-merck-co-results/merck-says-cyberattack-halted-production-will-hurt-profits-idUSKBN1AD1AO

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8000

Molecule = Acetaminophen Human cross-over study in 24 subjects

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5000

Vcaps Plus Capsules

4000 3000 2000 1000 0

0

2

4

6

8

10

Nominal Hours (hrs) Post Dose

100 90 % Caffeine dissolved

80 70 60

pH 1.2 USP pH 6.8 USP pH 6.8 JP2 Simulated milk fluid pH 1.2 – 2 g KCI/L pH 1.2 – 9 g KCI/L

50 40 30 20 10 0

0

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6 9 12 15 18 21 24 27 30 35 40 45 50 55 60 75 Time in minutes

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OPINION

On cloud five!

Robert Gaertner, director of strategy for quality at Veeva Systems in Europe, reveals the top five reasons why quality management should be moved to the cloud.

M

any organisations around the world are making the transition to softwareas-a-service and embarking on new cloud technology initiatives. In fact, by 2020, more than $1 trillion in IT spending will be directly or indirectly affected by the shift to the cloud, according defining to Gartner.1

“

The attribute of a true cloud solution is multitenancy.

In life sciences, an industry that has lacked software innovation for decades, it is no different.

A key area that can benefit from modernisation with cloudbased technology is quality management. In line with IHC Q10 guidance for more holistic and effective quality systems, organisations are looking to simplify and improve access for better visibility and control of GxP-critical processes.

As a result, organisations are replacing outdated technology with modern cloud solutions to improve productivity and reduce quality risks.

”

When it comes to modernising quality management, key aspects such as a single source of truth, data integrity across multiple sites, and external collaboration are highly valued in the life sciences industry. However, many solutions on the market masquerading as ‘cloud’ aren’t truly cloud or purpose-built for GxP areas. In reality, these solutions are often existing applications simply offered in an online hosted model. In other words, these applications are online versions of legacy software, and therefore do not deliver all the benefits of an industry cloud.

What’s the difference?

The defining attribute of a true cloud solution is multitenancy. Multitenancy enables the secure deployment of only one version of cloud software to all customers. It supports quick, ongoing innovation that minimises the IT and validation burden. In contrast, legacy software hosted online requires the application supplier to maintain multiple versions of the software, which can result in infrequent upgrades that are time consuming for customers to implement.

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Here are five characteristics of an industry cloud solution that address today’s needs for manufacturing quality.

users consistently working within the system, helping to drive quality and improving return on investment.

1. Complete

5. Accurate

A unified cloud-based suite brings together multiple solutions, such as quality management system (QMS) and document management for improved control, visibility and partner collaboration. Harmonising globally on a single system means processes and document templates can be standardised, reducing the risk of errors or duplication.

Users can easily view the real-time status of activities and conduct ongoing analyses to identify areas for improvement with a unified cloudbased quality management system. This makes it easier to generate recurring regulatory reports or satisfy the upcoming need for submitting quality metrics. For example, companies can run reports on a wide range of QMS metrics across their enterprises so they can anticipate potential bottlenecks or compliance risks well in advance. This shifts an organisation from reactive to proactive and can positively impact business areas beyond compliance.

2. Inclusive Organisations can bring external stakeholders into internal business processes easily and securely to reduce manual efforts and improve collaboration. A multitenant cloud solution gives any authorised user access from any device, at any time, from anywhere, which enables harmonisation of different business processes.

For example, with a unified cloud-based QMS and document control solution, when changes are made, all parties are involved and can collaboratively solve the problem.

3. Innovative With a multitenant cloud solution, the provider makes continual investments to deliver ongoing application updates and keep up with the latest industry best practices. This increases the agility of business and IT and shifts the focus to finetuning the applications to align to the business needs. In addition, industry cloud solutions for GxP areas means all applicable regulations, such as 21 CFR Part 11 and EU-GMP Annex 11 are fulfilled, including a full validation program.

4. Intuitive Multitenant cloud applications are intuitive and easy to use. For example, managing document lifecycle and taking documents from draft through review, revision, approval, issuance and training is simplified with an industry cloud solution, which encourages user adoption.

A good user experience in turn will result in

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Ready for an industry cloud solution?

The transition to the GxP-regulated cloud will continue to gain momentum. With multiple cloud options available, at first glance it may seem difficult to decide on the best solution.

However, a true multitenant industry cloud solution purpose built for life sciences has unmistaken benefits that can’t be matched by online legacy applications.

With all users working on the same platform, in a system that allows for secure collaboration and increased visibility, the productivity and efficiency gains are considerable. And it is the cloud solution provider who manages software updates and ensures the applications stay current with regulations. This means you can realise true change – without needing to upgrade your software first.

Reference: 1. http://www.gartner.com/newsroom/id/3384720

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OPINION

As people search for healthcare information online more frequently and the digital market keeps growing the boundary between offline and online is becoming more blurred for pharma.

Here, Jake Holyoak from Mediaworks details some of the key challenges and opportunities facing the industry.

I

n the past, pharmaceutical brands have operated in an exclusively offline market. However, with the growth of digital and the increasing numbers of people actively searching online for healthcare information, these boundaries have become blurred, triggering a rapid race for pharmaceutical brands to establish a digital presence.

Now that the vast majority of them have some form of digital presence, pharmaceutical companies are vying to improve their websites in order to better capture their target audience. One in every 20 Google searches is for health-related information. With their core audience already harnessing the power of digital, it’s vital that these brands further improve and build their digital presence.

Digital marketing agency Mediaworks has created a white paper titled Pharmaceuticals: The Digital Forecast,1 which contains predictions for the key trends expected to impact this sector in the coming months. Below I’ve broken down some of the key challenges and opportunities facing the brands outlined in this paper:

Create content for all stages of the user journey Content has huge potential within the pharmaceuticals sector, given the multi-faceted user behaviour pathway. For example, users will turn to the search engines to conduct research prior to being diagnosed, as well as after diagnosis, before treatment and after treatment.

As such, brands need to create content to target all user intents if they are to position themselves as a digital leader. This can be done by writing in-depth, informative pieces around key search topics to target a number of keywords and variations.

Stay ahead of RankBrain RankBrain, Google’s machine-learning artificial intelligence system, is helping Google get smarter. Used to establish the most relevant 14

results for a particular search phrase, RankBrain is so advanced it is difficult to optimise for, unlike other SEO ranking factors. However, through concentrating on creating high-quality content, you can maximise your ranking potential.

Pharmaceutical brands are encouraged to regularly update their content and monitor its performance, as RankBrain looks for both relevancy and site performance.

Protect your brand Like many other sectors, digital has opened pharmaceutical brands to a whole new world of information- and opinion-sharing. Traditionally, these brands have kept tight control on how products are perceived though controlling the information released to the media. Digital has weakened this grip, providing a wealth of platforms for independent information sharing – both positive and negative. In order to safeguard your brand in a notoriously delicate sector, online reputation management is essential.

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“

digital has opened pharmaceutical brands to a whole new world of information- and opinion-sharing.

Realise the potential of an app

”

Health apps are huge – you’ll likely have at least one on your smartphone or tablet. By being localised on a user’s device, they’re ideal for helping you better connect with your target audience – but, with app stores fit to burst, launching a successful app can be difficult.

To ensure the success of your own, make sure it has a clear purpose and usability benefits. Ask yourself, why would someone need or use this?

Perfect the user experience and keep personal details secure to give your app the best chance of succeeding.

Reference: 1. https://www.mediaworks.co.uk/whitepapers/downloadpharmaceutical-digital-forecast-white-paper/

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REGULATORY AFFAIRS

The impact of pharmacovigilance Pharmacovigilance is a dynamic clinical and scientific discipline that has had an important impact on the public health environment. Madalina Huruba, manager (Pharmacovigilance), ELC Group, goes into the history of the discipline and the necessity of an effective pharmacovigilance system.

W

ith a history of more than 40 years, pharmacovigilance is defined by the World Health Organisation (WHO) as ‘the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other possible drug-related problems’.

From a regulatory point of view, a need for robust settlements has been identified as a way to build a strong, sustainable system for medicine safety and for public confidence in medicines. The provision of good quality, safe and effective medicines – as well as ensuring their appropriate use – is the responsibility of national governments and is a responsibility that has grown as the industry has expanded. The global pharmaceutical industry, universities and non-governmental organisations (NGOs) now, more than ever, need to join forces to educate rational use of medicines and pharmacotherapy monitoring.

Once a drug reaches the point where it is authorised to be placed on the market, it leaves the secure and protected scientific environment of clinical trials to be used by the general population. At this point, all the data we have on the medicine is gathered from short-term monitoring of a limited number of subjects with limited to no health issues.

As a consequence, the need to monitor the effectiveness and safety of the medicine under real-life conditions post-release – with an emphasis on specific population groups and polytherapy – becomes imperative, thus turning effective pharmacovigilance into an essential tool when it comes to patients’ safety.

Indeed, the aims of pharmacovigilance, as noted by the WHO, span improving patient care and safety in relation to the use of medicines,

16

contributing to the assessment of benefit, harm, effectiveness and risk of medicines, encouraging their safe, rational and more effective (including cost-effective) use, as well as promoting understanding, education and clinical training in pharmacovigilance and its effective communication to health professionals and the public.

effects are now considered in the context of a sustainable pharmacovigilance system. Basic characteristics and distinction of the medicines are taken into account, aiming to contribute to a system that is generally applicable, and also serves as an educational structure for a better understanding of the complex issues that could arise during drug treatment.

Despite its substantial history, pharmacovigilance remains a dynamic clinical and scientific discipline. It is essential that adverse effects and toxicity correlated with the use of medicines are reported, and subject to robust analysis. The trade-off between the benefits and the potential for harm must always be acknowledged and discussed. Pharmacovigilance has therefore had an important impact on the public health environment. Thanks to good guidance and training programmes for healthcare workers, aspects such as exposure to risks linked to medication error and/or preventable ADRs are now acknowledged and managed.

Risks linked with diseases, population characteristics, medicine, healthcare systems, empirical treatment and the aftermath are now closely monitored throughout different pharmacovigilance approaches.

Pharmacovigilance best practices also allow the documentation and addressing of issues such as counterfeit drugs, substandard medicines, quality standards of donated medicines, as well as ADRs due to medicine interactions, and inappropriate use or dosage.

One key challenge that has emerged is the issue of monitoring the safe use of medicines in countries with no active regulatory or safety monitoring system in place. In this scenario, the use of medicines in specific communities, such as the treatment of diseases like malaria, leishmaniasis and schistosomiasis, or HIV/AIDS and tuberculosis, becomes a matter of great concern and the subject of coordinated efforts to reduce the risks.

Today, a number of major categories of medicine-related problems are recognised and assessed. Issues including dependence and addiction, tolerance and rebound, overdose and poisoning as well as indirect adverse

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Registers and databases are being created and used as a foundation for statistics that allow medical care providers to oversee potential risks and minimise them. The success or failure of any pharmacovigilance activity depends on the reporting of suspected adverse reactions.

WHO has played a vital role in promoting the safety of medicinal products as a clinical and public health issue. Duly, the data collected through spontaneous reporting, national pharmacovigilance centres, and the WHO Programme for International Drug Monitoring has led to changes in the labelling of medicines.

Pharmacovigilance has become an essential tool in providing the necessary infrastructure for drugs programmes. Furthermore, the cost of an effective pharmacovigilance system is notably smaller when compared to the national expenditure on medicines or the cost of managing ADRs.

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REGULATORY AFFAIRS

The IDMP journey should have already started, or should have at least entered an assessment phase, where the data preparation task is scoped. Companies who leave their preparations too late in the process are likely to find that, in their haste to meet the IDMP compliance deadline, they sacrifice broader potential wins. Taking steps now to get the business’ master product data in order will pay dividends later.

Prepare once, re-use ad infinitum The next aim should be to progress from the initial IDMP data analysis to a broader plan for ‘master data management’ (MDM), that will set the company in good stead for wider transformation, not least by strengthening transparency across the different business operations.

Mastering IDMP Master data management promises an efficient, definitive way to address the demands of the forthcoming ISO IDMP standards for product information recording.

What is involved in practice though, and how can companies ensure the investment pays off?

AMPLEXOR International’s Sonia Monahan explains more…

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s the life sciences industry appears to have grasped, ISO IDMP compliance is more than just another regulatory hurdle to straddle. It also promotes the kind of structure and discipline needed if organisations want to break new ground and take their businesses forward. It is an essential facilitator for digital transformation and for exploiting new technologies such as artificial intelligence. All the surrounding ambitions begin with data, and with assumptions about its quality, completeness and reliability as an accurate record of operations.

As EMA’s IDMP requirements near finalisation, the scale of the standards’ impact on managing regulatory data becomes more apparent. The transition from the current xEVMPD submission requirement to the more extensive and rounded demands of IDMP will involve extensive work.

Data is extracted from a wider range of sources than just regulatory affairs (i.e., also across chemistry, manufacturing, and controls; clinical; pharmacovigilance; and manufacturing). The same high levels of data integrity and data quality need to extend across all of these business areas, so that the combined data can be relied upon as a definitive reflection of product reality.

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EMA’s own ambition for ISO IDMP supports this effort to improve the data’s quality and integrity, thereby increasing its value. This requires getting the underlying data (the master data) in order, using agreed upon standards. The reason ISO IDMP has taken so long to materialise as a set of confirmed definitions is that so much groundwork has gone into getting the detail rights; it’s also why there are five standards in total, rather than just one.1 This is intended to be a comprehensive definitive structure for data management.

Companies can enhance and add to this source data for their own internal purposes. The idea is that building on the right foundations and using agreed upon terminology will make the complete data set more meaningful and easier to repurpose. This applies consistently, whether for publishing, pharmacovigilance, resource planning, or artwork preparation. If the underlying data is trusted, the subsequent stages can happen much more efficiently and Data stewardship will effectively.

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be critical in extracting value from MDM and IDMP investments.

Beyond compliance requirements, companies should be striving for a 360-degree view of product data. This includes a global, integrated view of product information, which supports business processes throughout the product lifecycle and provides a definitive master data set servicing multiple applications. The data doesn’t have to be confined to product information either. Agreed upon identifiers can be used to define other core business entities such as customers, patients, partners, suppliers, locations and employees. Ultimately, controlling master data will change the standard operating practices for life sciences firms.

Defining MDM best practice What might MDM best practice look like? Jens Olaf Vanggaard, a senior life sciences R&D consultant at HighPoint Solutions and a member of the ISO IDMP SPOR Task Force Referentials sub-group, provided a useful analysis at AMPLEXOR’s recent annual customer conference.

He noted that a single, finished product takes three forms from an IDMP perspective, including: the pharmaceutical product as administered; the

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authorised medical product; and the packaged product that ships to market. This is just one indication of the complexity that systems need to be able to cope with to keep data correct and in sync. Below these higher-level definitions are the more intricate product details.

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“The set of processes and solutions used to acquire, enhance and share product data across the enterprise are the key tenets of master data management,� stated Vanggaard.

IDMP compliance will require solid data governance and use of MDM principles and processes for data stewardship, irrespective of whether an organisation plans to implement MDM technology to support IDMP or not.

Further parameters include ‘reference data’, the set of permissible values to be used by other (master or transaction) data fields.

This data is typically non-volatile (slow to change). However, managing the processes and solutions used to acquire, manage and share this reference data across the enterprise will become increasingly important with the introduction of IDMP.

Vanggaard believes the journey to MDM should be viewed as an evolutionary one, though the scale of the transition could be construed as daunting. The important thing, he notes, is that companies start somewhere and treat developments as a continuum – with people, processes and technology brought on in parallel.

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down into a number of clear steps, from initial data profiling/discovery/ scoping, and data modelling, to data cleansing, profiling, enriching, matching, consolidating and relating.

Data matching and consolidation stages involve comparing overlapping data across the company to arrive at the best version of the truth, keeping full cross-references to enable un-linking if needed. Data relating allows records to be grouped logically for management and analysis.

MDM checklist A checklist of stages companies can expect to go through on the transition to MDM will look something like this, according to Vanggaard: Identify stakeholders (roles and responsibilities) Define data dictionary Define data sources Define target data model Define data quality rules Conduct data pilot Document and communicate pilot learnings Update data dictionary, data sources, data model and data quality rules

Without good governance, chaos will ensue The starting point should be data governance, Vanggaard says, warning that “without good data governance, [companies] are likely to fail – no matter what technology [they] implement.� As long as there is inconsistency in data quality and definitions, the value of the system and its potential ROI is eroded, because the data simply isn’t sufficiently dependable.

With this in mind, it is important to establish early on how quality and consistency will be managed, who owns the data, and who is accountable for its quality and integrity. “Establishing clear communication channels will enable stakeholders to have a say in the data management process, increasing stakeholder acceptance and ownership of the data across the different functions,� Vanggaard advises.

Another early priority must be to author a data strategy, which defines how the company will increase the value, timeliness and reliability of data assets, perhaps by including external data sources which can augment and improve data quality and completeness.

Data policies and processes should then provide the documented guidelines, procedures and tasks to direct data stewards and other stakeholders, enabling them to ensure the integrity, consistency and sharing of enterprise data resources.

Data stewardship will be critical in extracting value from MDM and IDMP investments. This involves proactive management and oversight of an organisation’s data assets. Operationally, the remit can be broken

Prepare business case for implementation phase

Given that life sciences companies will have to do much of this groundwork anyway to fulfil the needs of ISO IDMP, it is strongly in their interests to invest the time in getting this right and deriving the maximum business benefit, while future-proofing any investment. Other new regulatory demands will be much easier to meet once the core data structure is in place. Research by Gens & Associates suggests that companies using a common model for regulatory information management are 3.5 times more likely to realise business benefits, are 18% more efficient, and have 2.5 times more confidence in data quality levels.2 The potential gains grow exponentially when we broaden this approach to more comprehensive product and operational information.

IDMP compliance will require solid data governance and use of MDM principles and processes for data stewardship, irrespective of whether an organisation plans to implement MDM technology to support IDMP or not. Ultimately, ISO IDMP’s main focus is master data. As such, it makes business sense to harness this master data for maximum effect.

References: 1. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_ content_000645.jsp 2. http://gens-associates.com/wordpress/wp-content/uploads/2016/09/Executive_World_ Class_RIM_Whitepaper_Summer_2016_Edition.pdf

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REGULATORY AFFAIRS

The regulatory

With the forthcoming regulatory changes set to come into force over the next couple of years in pharma, management practices will surely be tested.

In this article, Tom Nichols, senior director, Pharmacovigilance at Quanticate, details some of the challenges the industry will face.

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ince the introduction in 2012 of good pharmacovigilance practices (GVPs) in the European Union (EU), the industry has experienced rapid changes and it is showing no sign of slowing. The next two years are looking to be no exception, with 2019 scheduled to be a year that will really test companies’ change management practices.

Eudravigilance launch and GVP revisions On 22 November 2017, we will see the launch of not only the new EudraVigilance system1 but also the updated GVP Module2 VI that covers the collection, management and submission of reports on suspected adverse reactions to medicinal products.

Standard operating procedures (SOPs) and Standard operating best working practices must procedures (SOPs) therefore be fully reviewed and best working to ensure they address all practices must be fully aspects of new functionality of EudraVigilance but reviewed to ensure they also the practical issues address all aspects of resulting from changes new functionality of to data collection EudraVigilance but also requirements, not least the practical issues the need to receive cases electronically in the new resulting from changes E2B(R3) format. to data collection

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requirements

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The increase in data fields in E2B(R3) expected in Individual Case Safety Reports (ICSRs) will require comprehensive retraining of staff and potentially increased resourcing for departments, due to the prolonged processing time of these cases.

For larger companies, where separate teams may deal with EudraVigilance and case processing, cross-functional working groups must be formed to ensure that decisions are being made centrally. For smaller companies, challenges lie in the perceived scale of the changes to be adopted and with such time constraints too. To assist the industry as it continues to respond to these regulatory changes, the European Medicines Agency (EMA) has provided guidance with a EudraVigilance stakeholder change management plan.

The updated GVP Module IX (signal management), another major GVP revision, links to the new EudraVigilance system and is also due to come into effect in 2019.

The EudraVigilance Data Analysis System (EVDAS)3 will allow marketing authorisation holders (MAHs) to view reports on their active substances to aid and enhance signal detection activities. Again, this will require coordination between groups overseeing EudraVigilance and those responsible for signal detection activities within a company. Most pressingly, the EMA has published a list of timeslots for companies to register for the system and failure to meet the assigned slot may lead to significant delays, which would have subsequent knock-on effects to managing the change control process.

Clinical trial regulation The 2014 Clinical Trial Regulation (CTR) (Eu No. 536/2014) was scheduled to be introduced in 2018.4 However, delays in confirming the functionality of the EU portal and database means that this is now

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expected to be introduced in 2019. Application of the regulation will be six-months after the functionality of portal and database are confirmed via an independent audit.

In isolation, PV in the new CTR is not particularly In isolation, PV in the new different from the existing CTR is not particularly requirements, but this different from the existing does not mean that PV departments do not need requirements, but this to react.

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does not mean that PV departments do not need to react.

Once again, crossfunctional teams will be needed to ensure changes in working practices all continue to remain cohesive. This may be particularly relevant where PV departments deal with both clinical and post-marketing responsibilities and have many processes. Any necessary divergence in these needs to be identified and addressed, potentially leading to a much more split system.

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IDMP standards Tied in with the E2B(R3) data standards, are the Identification of Medicinal Products (IDMP) standards.5 The objective of this is to standardise and support identification of medicinal products in all International Conference on Harmonisation (ICH) regions. It is based on the four domains of master If companies are not data in pharmaceutical ready with compliant regulatory processes: substance, product, databases and processes organisation and referential from day one of the new (SPOR) data. This has huge Eudravigilance database implications for ICSRs in in November 2017, they both clinical and postwill need to move from marketing settings, case evaluation and signal temporary solutions to detection. SPOR data also a more robust solution. applies to both human and veterinary products.

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Unlike the other changes discussed, which are focussed very much on changes in processes of departments, Brexit will affect companies and sponsors at a wider business level. Boardroom discussions will likely be dominated by where companies and staff should be based and the economic outlook. Therefore, it is down to PV departments to be proactive in not only planning for the necessary changes, but to also make sure they are not lost within company decision-making processes.

Busy time ahead As discussed, the next two years are expected to be an incredibly busy time with many changes for PV in the EU, culminating in a surge in activity expected in 2019. Some of the changes, such as E2B(R3) are clearly defined and can be addressed immediately, allowing for a smoother transition.

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The industry will no doubt experience a challenging time ahead that will test both technical expertise and the ability to deal with change, but ultimately this period will lead to a stronger and more harmonised PV system within the EU.

References: 1. https://eudravigilance.ema.europa.eu/Decommissioned/Decommissioned.html 2. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/ document_listing_000345.jsp 3. http://www.ema.europa.eu/docs/en_GB/document_library/Other/2017/05/ WC500227997.pdf 4. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_ content_000629.jsp 5. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_ content_000645.jsp&mid=WC0b01ac058078fbe2

The SPOR project will call for transition from the eXtended EudraVigilance Medicinal Product Dictionary (XEVMPD) and the Article 57 database.

Once this transition has been finalised, E2B(R3) reporting in the EU will also become fully mandatory.

Therefore, companies need to remain ahead of the curve on E2B(R3) compliance and adopt new systems as early as possible, so that both major changes are not being introduced simultaneously. If companies are not ready with compliant databases and processes from day one of the new Eudravigilance database in November 2017, they will need to move from temporary solutions to a more robust solution.

Brexit The biggest shadow hanging over PV in the EU in 2019, however is Brexit. As it stands, from 30 March 2019, the UK will no longer be a part of the EU and the EMA is currently working on the assumption that the UK will become a third country. Although there is a long way to go with the Brexit negotiations, there is very little time to prepare for what the pharmaceutical industry post-Brexit will look like. As such, companies and sponsors should carefully monitor any output from the EMA on the progress of its working groups and the direction of discussions.

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The industry will no doubt experience a challenging time ahead that will test both technical expertise and the ability to deal with change…

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COVER STORY

Size matters Gregor Deutschle, global business development manager for SCHOTT, speaks about how small and flexible means fast and profitable in pharma packaging and he reveals what this shift in manufacturing means for the industry and consumers.

O

ver the past decade, pharmaceutical companies have seen their drug development pipelines turn from firehoses to dripping faucets. While the days of blockbuster drugs seem to be in the past, each drop from the faucet has surged in value.

High value products – often biologics, targeted medicines for patients susceptible to specialized drugs, and treatments for rare diseases have replaced the blockbuster injectables that kept pharma’s balance sheets healthy. These treatments target smaller populations. And that’s uncovered a glaring issue with their filling lines. In short, they are too big and inflexible.

Consequently, pharma manufacturers are engaged in a fairly massive shift away from bulk filling toward smaller and faster finish-and-fill operations. By relying on proven standards known from syringe filling, the industry can simplify its supply chains and reduce the cost and the number of variables involved in the selection of optimized drug delivery devices. In fact, this tried-and-true nest-and-tub system that has been used by the pharmaceutical industry for decades is the key to true flexibility.

The need to adapt There’s a continuing trend from small molecule, traditional medicine to large molecule, biotech drugs. A lot of these treatments are targeted. They are not so much the ‘one-drug-fits-all-patients’ blockbuster approach, but a more targeted treatment to address parts of the patient population.

As these therapies are targeted, production runs will inevitably be smaller.

This in turn leads to a requirement for pharma manufacturers to adapt their focus on smaller batch sizes.

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pharma manufacturers are engaged in a fairly massive shift away from bulk filling toward smaller and faster finish-and-fill operations.

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On a large production line, a changeover that takes one or two days isn’t significant because the ratio of downtime to production is fairly reasonable.

Filling smaller orders, however, is less cost effective on a big line, because the changeover time may be longer than the time it takes to fill the order.

Previously, for example, there might have been a drug that was made in the tens of millions of pieces. Targeted medicines, however, might have dosage and delivery recommendations that differ according to genetic tests. For one part of the patient population, the company might need to fill a 6-R vial, and then for another patient population or target market, you need to fill a cartridge, and the next one would get a syringe.

Switching from one batch to the next takes time.

Sizeable challenges!

Nest and tub solution Let’s say you have a traditional filling line, one capable of filling 400 vials per minute. That’s a big line, and while it’s filling product, it doesn’t run anything else. When that run is done and it’s time to make another drug, it might take several shifts to change out all the paths that a vial takes throughout the system.

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To assist with the necessary adaptation to smaller production runs and more flexible processes, we at SCHOTT have harmonised the packaging components already in use. In basic terms, offering ready-to-use products in a nest that sits in a tub.

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The nest and tub is sealed and one or two bags are sealed around it. When they are transferred into the sterile filling suite, the tubs must be debagged. The lid is removed from the tubs and the nest from the tub. The machine then fills each vial. By making sure the nest and tub are universal to all machines and thus ensuring maximum compatibility, all these steps are easy and thus production efficient.

Large manufacturing lines can also work with nest and tub systems, but they are even more important for small and flexible lines. The nest keeps the glass vials separate, and reduces the need for human operator intervention. Both can introduce contamination or breakage. These smaller batched medicines tend to be far more expensive than mass market injectables, maybe $500 per dose or more.

Even with the standard industry loss rate of 1%, the cost of broken and contaminated medicines adds up.

Credits: Vanrx

Flexibility is key Pharmaceutical lines need ready-to-use syringes, vials and cartridges. Pre-filled syringes have been around for decades. Vials rose to prominence in the last five years or so. The International Standards Organisation has standardised the system for ready-to-use syringes.

Rather than develop a whole new standard for vials and cartridges, our nest and tub system relies on the existing one. When we developed our adaptiQ system for nested vials, we worked with the world’s leading manufacturers to develop packaging that is compatible to their existing machinery as well as new cutting-edge developments.

By offering flexible fill & finish machines, we can help accelerate drugs to the clinical trial stage because they provide drug manufacturers with a pathway to create a small batch of injectable treatments. Additionally, these offerings will also serve the growing market of biologics’ use.

However, we also foresee another future, one in which pharmaceutical manufacturers have small and even regional facilities that can instantly respond to changing market demand and adjust their production schedules accordingly. SCHOTT’s solution is well positioned for that as well!

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GRANULATION & MILLING, MIXING & BLENDING

Watch this design space Jamie Clayton, operations director at Freeman Technology, explains how comprehensive, process relevant characterisation of wet granules can lead to control of tablet CQAs and assist design space definition in the manufacture of an OTC medicine.

T

he adoption of a quality by design (QbD) approach to wet granulation requires manufacturers to fully understand the relationship between process variables – such as powder properties and equipment settings – and critical quality attributes (CQA) of the resulting product.

Manufacturers need to develop a design space by understanding the impact that variations within the process have on the properties of the resulting granulate and the influence they, in turn, have on final product quality.

Furthermore, a robust design space allows process variables to be controlled and manipulated to produce quality assured tablets with targeted properties.

Dynamic characterisation for QbD Variations in material properties, as well as process settings, offer both challenge and opportunity to the manufacturer. Knowledge of how materials, that may themselves vary across batches, behave within a manufacturing process, where conditions may also vary, enable the operator to develop a design space within which to operate.

The ability to convert a challenge into an opportunity when working with powders is greatly enhanced if the characterisation techniques employed deliver results that are repeatable, reliable and relate specifically to conditions within the process. Unlike many other established powder flow testing techniques, such as tapped density, angle of repose and shear cells, dynamic test methods simulate typical process conditions and therefore deliver information on materials’ properties that are more likely to influence final product quality.

Evaluating wet granules Dynamic testing using a powder rheometer can be used to evaluate the characteristics of wet granules by measuring the resistance that the granulate exerts on a blade, as it traverses through a sample. This resistance is expressed as a ‘flow energy’, which is calculated from direct measurements of rotational torque and axial force during the blade’s traverse.

Flow energy is influenced by many properties including inter-particular friction and mechanical interlocking, strength of capillary bonds and cohesion between particles. In high shear wet granulation (HSWG), the addition of water and work (shear) results in larger, denser, more adhesive granules that typically generate a higher flow energy as these larger, denser granules are harder to displace using the blade, as well as being less compressible.

Flow energy, often presented as basic flowability energy or BFE, is therefore a function of solid to water ratio, impeller speed and binder temperature, and this robust relationship between flow energy and process settings allows critical process parameters to be identified and a design space to be determined. The ability to test in a wet state allows this approach to be applied as early as possible in the manufacturing process.

The following case study shows how a fully functional design space, based on dynamic flow properties, can be defined for a wet granulation process enabling CQAs of the final tablet to be targeted.

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CASE STUDY: Defining wet granulation by granule quality Two aspects of design space definition were investigated for manufacturing an OTC medicine.1 First, the relationship between granulator variables and the resulting granule quality, as quantified by the rheological properties, was investigated. Granules were generated using a pilot-scale HSWG process, then dried using a fluidised bed dryer before being milled, lubricated and finally tabletted. Immediately following the HSWG step, the dynamic, bulk and shear properties of the wet granules were measured using an FT4 Powder Rheometer (Freeman Technology, UK).

The results of the first phase of the study (Figure 1) show that BFE of the wet granules can be predicted from knowledge of the process parameters, in particular solid-to-water ratio and impeller speed. By adjusting these parameters operators can therefore attain a desired BFE value.

Figure 2: Tablet hardness with respect to BFE of wet granules.

Developing a design space to achieve CQA Each stage of a process, from granulation to compression must function effectively to produce a quality product. Uncontrolled variation at any point in the manufacturing process can result in product failures and operational downtime. Robust design space definition provides operators with the opportunity to adjust settings to maintain quality.

In this example, the BFE of wet granules has been shown to link directly to tablet quality. With sufficient understanding of the relevant material properties and critical process parameters, it is possible to employ a QbD/ design space approach to batch granulation and tablet manufacture, and convert potentially problematic upstream variation into an opportunity to optimise process performance and product quality.

Figure 1: Actual versus predicted basic flowability energy (BFE) values of wet granules.

A second investigation was then performed to determine how granule properties influenced CQAs of the resulting tablets.

References: 1. Freeman, T., et al., Evaluating the Design Space for the Batch Manufacture of an OTC Medicine, Freeman Technology, Pfizer Inc. 2. Freeman, T., et al., A QbD Approach to Continuous Tablet Manufacture, Procedia Engineering, 2015;102: pp.443–449.

Tablet hardness will depend on die fill depth, blend permeability and press pressure which are in turn influenced by variations in granule density, flow properties, compressibility and operating speed, among other things.

To isolate the relationship between granule properties and tablet quality, an adjusted measure of the tablet hardness was adopted for this study to compensate for differences in process parameters.

Adjusted Hardness =

Hardness Thickness x Pressure x Weight

Analysis of the tabletting data (Figure 2) shows a strong relationship between BFE of the wet granules and adjusted hardness. The two studies combined therefore illustrate how CQAs of tablets can be achieved by controlling critical process parameters.

Previous studies have also demonstrated the relationship between process variables and CQAs as well as how this approach can be applied to a continuous wet granulation process.2

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AD VE

,

Results demonstrated the feasibility of all the three different configurations for freeze drying process and the benefits obtained by using vials in nest and tub.

The freeze-drying processes were performed on 4R and 10R EZ-fill® vials, each format was tested in two Lyophilisation runs, filled at half capacity in order to obtain a height of 16mm for both cases. The rubber stoppers were placed and the EZ-fill® vials were loaded into the freeze dryer following the same loading scheme of the freeze dryer shelves. Two different placebo formulations were used for the tests: 6% sucrose in purified water (w/w) (cycle 2) and 6% sucrose in purified water (w/w) plus 40 mM sodium chloride (NaCl) (cycle 1).

The addition of NaCl in latter formulation results in a higher risk of collapse, so it is more challenging to freeze-dry.

Both runs were designed as modern single step drying cycles with primary and secondary drying performed under identical conditions in respect to pressure and shelf temperature. The shelf temperatures of the primary/secondary drying were 35° C and 40° C, respectively for the first and the second run.

The results were evaluated from different perspectives: the outcomes related to process parameters and the ones related to the quality of the product.

Results related to process parameters for both the runs demonstrated a behavior that could be considered as superimposable between 4R directly on shelf versus the nested ones for what concerns drying duration.

In both runs – from start to finish of sublimation –, the total cycle time of 4R and 10R vials in nest and tub was slightly prolonged in comparison to the variant in shelf due to the steric footprint; but the quality of the nest and tub 4R Lyophilisate was significantly improved as reported below, while the quality of the Lyophilisate 10R on shelf showed clear defects.

Results related to the quality of the product were assessed through different analytical methods based on: Visual Examination, Scanning Electron Microscopy (SEM) and Karl Fischer titration.

The Visual Examination of the Lyo cake proved that vials on shelf, for all the formats and in all the runs, showed deformed areas at the bottom of the Lyophilisates due to local overheating.

Meanwhile, cake cross section resultive from the first run demonstrated that the 4R vials in nest and tub had a more homogeneous structure of the Lyophilisate, if compared to vials on shelf (See Figure). In fact, in the Lyo cake of vials dried on shelf, both for 4R and 10R, shrinkage occurred.

W W W. E Z - F I L L . C O M

In summary, it can be concluded that nested vials freeze dried either in nest or in nest and tub provide a more homogeneous heat flow to the drug product by radiation compared to vials with direct contact of the vial bottom to the Lyo-shelf. The insulation of the vial bottom against direct heat flux by conductivity avoids local overheating and allows for more efficient Lyophilisation cycles without jeopardizing the pharmaceutical quality of the Lyophilisate itself.

Authors: Lorenza Bonaldi Product Specialist Strategic Support (lorenza.bonaldi@stevanatogroup.com) Odra Pinato SG Lab Analytics Manager (odra.pinato@stevanatogroup.com)

References: 1. W. Y. Kuu et al. Gap-Freezing Approach for shortening the Lyophilization Cycle Time of Pharmaceutical Formulations – Demonstration of the Concept, 2013.

Journal of Pharmaceuticals Sciences, Vol. 102, 8.

2. Matejtschuk P. (2007) Lyophilization of Proteins.

In: Day J.G., Stacey G.N. (eds) Cryopreservation and Freeze-Drying Protocols. Methods in Molecular Biology™, vol 368. Humana Press

AL

OMPI, supported by an External Supplier, studied the performances of freeze-drying processes comparing EZ-fill® vials in three different configurations: one with the vial bottom directly in contact with the Lyo-shelf according to prior art, one Lyophilised in nest and the last Lyophilised in the nest and tub.

Residual moisture determined

by Karl-Fischer titration revealed no significant difference between the variants. All values of all variants were well below 1% residual moisture.

RI

M

In the second run, the appearance of the Lyophilisate obtained starting from the different placebo formulation without sodium chloride, generally showed a homogeneous structure.

Hence, the quality outcomes were deeply analyzed by SEM at 15x and 100x magnification. SEM images showed large cavities in the interior cross section and defects on the top surface of 4R variants dried directly on shelf and minor collapse zones within 4R variants dried in nest. All 10R variants and 4R variants dried in nest and tub revealed intact structure without collapse in the interiors.

any aqueous pharmaceutical formulations are lyophilized to promote product stability1. Lyophilisation (or freeze-drying), the removal of the majority of the water in a sample under conditions of low temperature and vacuum, is a widely used technique in the pharmaceutical, biotechnological and food industry2. Safety, efficacy and quality of the drug are the drivers of freeze-drying process focused to maintain product quality consistent not only within the batch but also from batch to batch. Since Freeze-drying is an expensive and time consuming process, productivity plays a crucial role in the pharmaceutical industry for process optimization.

O RT

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CASE STUDY: Granulation & milling, mixing & blending Who:

IMA Active and Zambon

What:

Formulation and blending

How:

IMA-designed tumble bin blender

Scale transfer and uniformity The companies Established in Vicenza in 1906, Zambon is now headquartered in Bresso and operates on three continents – Europe, South America and Asia – it employs 2,800 people in 15 countries. In addition to in-house research, an Open Innovation perspective, Zambon collaborates with external partners, research institutes, start-up companies, technology transfer and biotech companies.

The pharma technology department handles in-house pharmaceutical development, which includes pharmaceutical research devoted to formulation and process development in laboratory scale as well as analytical development, and pharmaceutical development and industrialisation for pilot scale and industrial transfer.

Established in 1961, IMA is a designer and manufacturer of automatic machines for the processing and packaging of pharmaceutical products.

IMA Active, a division of the pharma group, provides solutions for its partners in the field of solid dose processing and manufacturing.

The project Organisation is imperative in the development of a formulation and process, which interacts with analytical development and industrial perspective. This is particularly true when following recommended guidelines, such as ICH Q8, and for quality by design (QbD).

It is in this context that the project was originated, leading the pharmaceutical research facility of Zambon's pharma technology department to purchase an IMA blender with which to tackle the formulation and process study starting from the laboratory scale.

of small blenders that, due to their structural characteristics, facilitate the formation of segregation areas, which are harmful to the process.

The IMA blender is compact and mounted on wheels for laboratory scale, which has been designed in accordance with GMP. It is consistent with larger scale systems and features a highly innovative bin-coupling system.

Moreover, since the shape and movement of traditional equipment differs from that adopted in pilot and industrial scale, it does not allow the studying of directly scalable processes. Cyclops ensures blending uniformity and scale transfer at the same time.

Cyclops – tumble bin blender

Cyclops meets the pre-defined double and single tilting working requirements, modulating the rotating speed and stop time, selecting the rotating direction and changing it even during the rotation cycle, and has been equipped with bins of increasing capacities (5, 10, 20 litres) suitable both for the production of small trial batches and the systematic study of the blending process.

Due to its features, similar both in laboratory scale and in pilot and industrial scale, Cyclops optimises the scale-up steps. In general, laboratory scale blending is performed in bags or, alternatively, by means

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This project, with Zambon, is part of the process analytical technologies (PAT) implementation – the powder container was coupled to a NIR spectrometer for the in-line monitoring of the blending process. IMA verified cyclops suitability to support the weight and bulk of a rotating spectrometer in collaboration with Zambon Pharmaceutical Research through computer simulations. All bins have the same neck in order to use a modified cover, with the addition of a sapphire window to house the NIR spectrometer. Moreover, the cover has been fitted with inlets for the powder sampling probes. IMA and Zambon ran the FAT and SAT tests together on the blender coupled to the spectrometer.

The NIR spectrometer can perform a chemometric analysis through the continuous acquisition of spectra, evaluating their change according to blending uniformity. This is exactly where the real innovation of the Zambon project comes into play: setting up a PAT system that, being applicable both to laboratory scale and industrial scale, allows the achieving of a rational and correlated blending profile.

A study was conducted both on the formulation (optimisation of excipients, evaluation of active substances from different suppliers) and on the process parameters (blending speed and time). In the first part of the study, preliminary scale-down of the reference product was performed in order to correlate the industrial scale blending process with laboratory bins. Using a mathematical approach (based on Froude Number) and the in-line control with the NIR spectrometer, it was possible to obtain the starting parameters scaled by the industrial reference process, confirmed by the off-line analysis with UPLC on samples taken from the bin in different points (Figure 1) to determine blending uniformity. These parameters, preliminarily tested with the new formula, provided the expected NIR profile and the appropriate physical characteristics of the blend.

In the second part of the study, the effect of the critical variables (active substances from different suppliers and addition of an excipient having a different composition) was examined, through design of experiment, on the chemical-physical characteristics of the new blend, keeping constant the operating conditions specified by the NIR in the previous study.

The interpretation of data obtained through the qualitative/quantitative analysis (NIR profile/UPLC analysis) and the statistical evaluation of the various responses such as blending uniformity, flowability (Carr Index, %), repose angle and density have shown that the blend's flowability depended on the particle size of the active substance used. As expected, active substances from different suppliers have different physical properties that lead to different behaviours of the final blend.

Moreover, the variability of the physical properties has no impact on attaining blending uniformity, which is ensured even while significantly prolonging blending time, thus confirming the reliability of the screening study. As such, it was possible to correlate the NIR profile with powder flowability and type of active substances used, and this information was used in the next industrial scale up stage.

The high degree of innovation with which this study was conducted allowed Zambon to register its product without any observations on behalf of the examiners.

The solution: Formulation and process optimisation Reformulating a product in sachets with the aim of improving patient compliance (palatability), by applying a novel, patented taste masking approach, led Zambon Pharmaceutical Research to change the composition of a blend in which flow optimisation was critical, not only to ensure the uniformity of the content of the active substance and the ingredients responsible for the taste masking, but also to improve efficiency during the packaging of the pre-existing product.

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MEGA TRENDS IN PHARMA

Table talk In this roundtable, four industry leaders from Symbiosis Pharmaceutical Services, Recipharm, Sterling Pharma Solutions and Idifarma, reveal their thoughts on what the ‘mega trends’ are in the current pharma landscape.

The biotech BOOM! The biotech industry has experienced phenomenal growth in recent years. This has been largely driven by an increase in funding which is, in turn, driving the demand for parenteral manufacturing as biopharma companies continue to advance new drug products to market in what some people It can be confidently would argue is a progressively more argued that the contract efficient way.

“

services industry has directly facilitated the rapid expansion of the emerging biopharma sector, and the ‘biotech boom’…

In turn, that demand is fuelling an increase in outsourcing to contract manufacturing organisations (CMOs) like Symbiosis with the capability to aseptically manufacture parenteral drugs for use in clinical trials. It can be confidently argued that the contract services industry has directly facilitated the rapid expansion of the emerging biopharma sector, and the ‘biotech boom’, given that 80% of approved parenteral drug products are manufactured

by CMOs for those drug developing companies.

”

As a result, there is a demand for CMO partners who can deliver projects on tight timescales and therefore meet both investor and drug developer expectations. In the area of parenterals, we have witnessed increased demand from biotech companies for flexible, small-scale and specialist aseptic manufacturing capabilities to support first-in-man clinical studies with very stringent timelines and similarly tight budgets.

In addition, we see the US biotech market as particularly buoyant.

Symbiosis has experienced significant revenue growth in the US in recent years, and we foresee that continuing as there is an ongoing need to reflect the demand from US-based biotechnology firms looking for smallscale aseptic manufacturing resource. This need is driven by the growing number of active clinical trials that is representative of US-based biotech firms’ collective financial good health, which gives them the means to advance more potential medicines.

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Finally, we fully expect the shift towards the development of personalised medicines among emerging biotech companies to continue, bringing with it increasing demand for cytotoxic and specialist biologic products, and therefore, a greater need than ever before for specialist CMOs that can rapidly manufacture small (and often technically demanding) batches for small patient populations. Symbiosis has therefore positioned itself over the last few years to be at the forefront of providing world class sterile GMP manufacturing for small volume commercial medicines which may be patient-specific.

Colin MacKay, CEO, Symbiosis Pharmaceutical Services

Consolidation in contract services One of the biggest trends that is currently shaping the pharmaceutical contract services landscape is consolidation. The sector is extremely fragmented, with lots of small-scale contract manufacturing organisations (CMOs) operating with very few contracts and slim margins, however these types of companies will not be able to survive in the long-term and will most likely be acquired by larger players and consolidators.

There have also been a few large-scale consolidations in the space with larger companies coming together to take advantage of both cost and perceived commercial synergies. I expect this to continue too especially as much of the industry is private equity owned and, by definition, always for sale.

“

Regulatory changes such as serialisation are also likely to have an impact on the consolidation trend as the large investment that needs to be made may simply be too much for smaller players.

From a customer perspective, we are increasingly seeing a search for full service providers that can offer support from development to commercial

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”

manufacturing, helping to simplify the supply chain. In addition, I also think that customers are beginning to look for a more global solution from their partners. CMOs that can provide solutions across the globe, including supporting market access restrictions such as those in Russia, Turkey and some other countries, are well positioned for growth.

Regulatory changes such as serialisation are also likely to have an impact on the consolidation trend as the large investment that needs to be made may simply be too much for smaller players. Following the implementation of the European Falsified Medicines Directive (FMD) in February 2019, this will result in loss of business in key markets and the need to join forces with larger players to ensure compliance.

Mark Quick, executive vice president of corporate development, Recipharm

East-to-West: Manufacturing movements

“

The rise of niche service providers The growing trend for outsourcing in the pharma industry will lead to continued demand for niche service providers.

In particular, the growth in the number of products for orphan indications, alongside oncology treatments requiring small quantities and highly potent APIs, are fuelling the need for more niche contract partners, with specialist capabilities.

For example, high potency drug development and manufacturing requires specialist facilities, which are capital intensive and bring strict regulation.

Because of this, it is often more economical and practical for pharmaceutical companies to work alongside niche service providers to develop and manufacture their products in a more efficient manner.

“

choose a niche service provider that is independent, clientorientated and without conflicts of interest and it will continue to be an effective business strategy for long-term success.

Quality has always been the core concern of pharmaceutical manufacturers and regulations continue to tighten to ensure the industry delivers.

As well as the practical and technical capabilities, niche service providers are also experts in their field and offer the flexibility, responsiveness and reliability that are so important when dealing with this type of product.

In the past, we have seen companies move their manufacturing operations, particularly active pharmaceutical ingredient (API) production, to emerging markets, such as India, in order to generate cost savings. However, quality concerns surrounding the APIs produced in these markets are driving many sponsors to bring their operations back to the west.

I see the demand for niche service providers remaining high as long as pharmaceutical companies choose their partners well – choose a niche service provider that is independent, client-orientated and without conflicts of interest and it will continue to be an effective business strategy for long-term success.

western facilities that are able to demonstrate a comprehensive quality and compliance track record, coupled with exceptional service delivery, will dominate the innovator product contract manufacturing sector.

”

Manuel Leal – business development director, Idifarma

”

While the initial cost savings that can be generated as a result of manufacturing in the eastern market were attractive to many pharmaceutical companies, they are now finding that it is more expensive in the long-run.

Frequent failures to meet quality standards and the long lead times required to deliver the product to market means the overall price of manufacturing and distributing products from an eastern facility is continuing to rise, as their western counterparts find ways to become more competitive.

Whilst the eastern companies will resolve these quality issues over time, going forward I believe western facilities that are able to demonstrate a comprehensive quality and compliance track record, coupled with exceptional service delivery, will dominate the innovator product contract manufacturing sector.

Kevin Cook – CEO, Sterling Pharma Solutions

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Messe Frankfurt, Germany BOOTH # 10.2D13

IMAGE ANALYSIS

Imaging quality In this article, Katharina Paulsen, Ines Ruff, Dirk Leister, Jennifer Ramirez and Robert Heintz from Thermo Fisher Scientific, describe a co-extrusion technique and how Raman imaging microscopy was used to measure the thickness, quality and continuity of the outer shell of the extruded material.

“

Raman microscopy imaging was found to be an ideal tool to determine the shell layer thickness and to visualise any chemical and physical defects of the outer shell.

”

H

ot melt extrusion is a process used to produce a broad range of pharmaceutics. It can be used for oral applications, implants or patches. In oral solid dosage forms it can be either used to increase the bioavailability of poorly soluble active pharmaceutical ingredients (API) in immediate and sustained release formulations or even in combination of different release behaviours.1,2 To produce a combination of different release profiles and/or different drugs in fixed-dose combinations, it can be extruded in a multi-layer system. With co-extrusion, the production of an inner core and an outer shell will be achieved in one single step. The most important parameter is a precise inner core and outer layer to achieve the desired drug content and release. For quality control, we employed Raman imaging microscopy.

od ls and meth ia r te a m e h T trusion: Hot melt ex

re r – inner co ce each laye u d ro d p se u to e ired re, w er was requ r the inner co Fo n.

6 o 1 One extrud si f ru o xt -e meter yer – for co a screw dia ith w , er re d and outer la o u tr ef ex ed, ther g twin-screw hput is need g u ro th er a co-rotatin et er w m lo dia outer layer a a with a screw mm. For the crew extruder -s in tw g tin -rota xtrusion we used a co ders for co-e b -screw extru in tw of p . m t-u e of 11 m Fig. 1. Se 4 mm for th an insert of ith w d ed lle pp ro equi cont sion die was uter layer was The co-extru ess of the o kn ic er phase. th ut o e th e yed al analysis: er and r and th ne in e re we emplo th f total diamet o tion, Therm si w o o fl p ° ss 0 a 9 of the inner co m a e e at in th st f s o lid er so tio ud e tr th by the ra h anged the ex nted from To be able to determine sion, we arr r extruder orie etry (DSC). ye la rim lo er ut ca o For co-extru e ng th ni an ith sc w – ic m 1 dyna Figure as shown in . ht rig e th the left to of the inner pectroscopy se feed rates ci re p d n imaging ve win Raman s ie iT ch in a M e c w ri used Rama re et e su m w vi en s ra to te g , a o d lly a 532 nm co-extru loyed tw Additiona llected using cterise the se, we emp a co ra h a e p er ch r w te u a To o tr and a 10x an spec and the y.i The Ram age pixel size p im o sc s. µm ro er ic 0 1 m ed a d 025 s and powder fe mW power an time was 0.0 re su po ex laser with 10 e ns. Th the reference n objective le we collected , lly na o iti magnificatio dd 00. A ld with f scans was 1 Materials: the number o as Itraconazo w r nents. ye po la m r co ne er layer spectra of the single for our in ut o ed e us Th e w r. ie ug a carr The model dr polymerf as ut API. PVP/PVA co nd a lymerg witho e po se co o e at lact yl cr ha et a cationic m consisted of

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37

Results Determination of the solid state In theory, the crystalline Itraconazol should be transferred into a solid solution by the hot melt extrusion process to increase the solub ility and, consequently, the bioavailability.

The result of the DSC measurement in Figur e 2 demonstrated only one glass transition of the sample of the inner core, which mean s that a solid solution was achieved.

Fig. 2: DSC scan of the crystalline Itraconazol (green) and the extruded product (blue).

Quality control measurements of the two layers Determination of the shell thickness and the quality of the shell was performed using Raman imaging microscopy. Through using chemical imaging, we were able to visualise the thickness of the shell layer s more easily, which would be more difficult or impossible with light micro scopy. Furthermore, any defects in the layers can be easily determined (Figu re 3).

Fig. 3: Cross section of a co-extrudate with a clear defect of the outer shell layer.

This method was also used to determine if there was any migration of the Itraconazol from the inner core to the outer shell, which would be reflected in the Raman spectra obtained from the outer shell. We found no migration.

Impact of extrusion parameters on the co-e xtrudate During a stable process the appearance of the co-extrudate was very homogeneous, and the surface was witho ut any defects. The Raman microscopy images given in Figure 4 clear ly show that the shell had a very homogeneous thickness, and there was no migration of the Itraconazol into the outer layer.

The total diameter of the strand was defined by the die insert used.

By varying feed rates different shell thick nesses were generated.

With an increased feed rate for the inner core the outer shell became thinner. By doubling the feed rate of the inner core, the thickness of the outer layer was reduced by half the thickn ess [Figure 4(a) and (b)].

Different process temperatures and, there fore, different viscosities of the different layers do not have an impact on the layer thickness. In the case of the co-extrudate shown in Figure 4c the process temperature of the extruder for the outer layer was incre ased 25 K compared to the co-extrudate process in Figure 4b, resul ting in no change in outer layer thickness.

Fig. 4a

Fig. 4b Fig. 4c Fig. 4a–c: Cross section of co-extrudates, produced with different process parameters: from a to b the throughput of the inner core result the thickness of the shell in b is only is doubled and as a half the size; from b to c the process temp erature of the extruder producing the outer 25 K, and the layer thickness stays the same shell was increased by .

References:

n Conclusio

ms layer syste uce multid ro ith p w s to e form e used cal dosag ti sion can b u e ru se c xt o a e -d lt rm e d e pha r fixe Hot m API or fo to produc e n n o o si r ru fo xt r by co-e behaviou issolution d t APIs. different d enous an of differen s n o ti a in ry homog e v s a comb w ness shell thick ughput. ing outer lt su g the thro re in e ry h a T v y ol to b ly si an ideal to ried ea nd to be can be va u ical fo m s e a h w c imaging alise any y su p vi o sc to d ro ic an Raman m r thickness e shell laye th shell. e r in te u rm o dete ts of the c fe e d l a and physic

1. Crowley et al., ‘Pharmaceutical applications of Hot melt extrusion’, Drug Development and Industrial Pharmacy, 2007.

2. Dierickx et al., ‘Co-extrusion as manufacturing technique for multi-layer mini-matrices with dual drug release’, European Journal of Pharmaceutics and Biopharmaceutics, 2013.

Product/materials list: a. Thermo Scientific Pharma 16 Twin-Screw Extruder, Thermo Fisher Scientific, Karlsruhe, Germany. b. Thermo Scientific Process 11 extruder, Thermo Fisher Scientific, Karlsruhe, Germany. c. Brabender Technology, Duisburg, Germany. d. Itraconazol, BASF, Ludwigshafen, Germany. e. GranuLac, Meggle, Germany. f. Kollidon VA 64, BASF, Ludwigshafen, Germany. g. Eudragit E, Evonik, Darmstadt, Germany. h. DSC 204 F1 Phoenix; Netzsch-Geratebau GmbH, Selb, Germany. i. Thermo Scientific DXRxi Raman Imaging Microscope, Thermo Fisher Scientific, Madison, USA.

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Targeting Innovation Colorcon Excipients - The Art of Perfection It’s what you do - you apply knowledge and technology to formulate and innovate, meet performance requirements and protect the integrity of your final dosage form. At Colorcon, it’s what we do too. We formulate, we innovate -- and we focus our excipients exclusively for pharmaceutical and nutritional oral solid dosages.

That’s why, when you set out to select the right coating or excipient for your formulation, be sure to partner with the leading company that brings you innovative products plus specialized technical support when and where you need it. Be confident with your choice. Contact us to find out more.

From Core to Coating Your Supplier of Choice

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APIs/EXCIPIENTS

The prefillable solution The field of prefillable syringes is constantly changing, driven by the innovations in active ingredients and patient safety at affordable costs.

Here Bernd Zeiss, manager technical support medical systems, business development at Gerresheimer reveals the challenges and how packaging solutions can help.

P

refilled syringes have been around for several years and has a reasonably mature market within Europe, being worth around $300 million and growing between eight and 10% each year.1 However, the field of prefillable syringes is constantly turning up new trends and developments, the requirements placed largely driven by the innovations in active on the syringe as an ingredients available and a desire for ‘interface’ between the patient safety at affordable costs.

“

medication and the patient are becoming increasingly demanding.

”

There are many uses for prefillable syringes within various sectors and the delivery devices are increasing in popularity due to the advantages they hold over the more traditional delivery device.2

Within pharma, customers are interested in syringe systems that fulfil extremely strict requirements in terms of quality and can be filled without any problem. An important advantage of prefillable syringes for a pharmaceutical company is the reduction in drug waste – if using vials it is common for manufacturers to overfill by 25% to ensure the end user gets the correct dose. In the advent of biotech drugs, which can be more expensive, this will be truly beneficial to the manufacturer.

However, with these advantages a drug manufacturer must also consider the challenges they will face when trying to incorporate a drug product into a prefillable syringe and what packaging solutions are available to overcome these.

The modern combination Modern injectables in prefilled syringes are classed as ‘combination products’ – most of which are relatively expensive and produced using complex biotechnological processes.

Current approaches being adopted include ways of adapting syringe systems to the requirements of new formulations. The additional therapeutic value for this process is closely linked in order to ensure the injectable and the syringe system work together smoothly. Development is focusing on facilitating higher dosage volumes per injection, dealing with higher viscosities and overcoming the sensitivity that the liquid formulation has to some of the syringe’s individual components.

2.25 mL needle syringe

Bearing this in mind, we at Gerresheimer have extensively investigated the functionality – the break-off and slipping forces – with a number of stoppers to help pharmaceutical customers choose the appropriate injection system. Functionality of the syringe is also essential to its integration in automatic injection systems, a factor which is becoming increasingly important.

Properties and production Patient safety when using the syringe system is always at the forefront of all research: Properties of the medications such as viscosity and technical properties such as break resistance and reliable force regulation when emptying the syringe are deal-breakers, especially when it comes to integration in automatic injection systems.

Highly viscous medications Increasing numbers of biotechnologically produced medications are highly viscous. When the syringe is emptied into the tissue through the cannula, this leads to high backflow forces, making injection more difficult.

The aim of making injections quick and painless can be achieved using needles with a larger inside diameter: ‘thin-walled’ cannulas allow a higher flow rate per unit of time, at a lower pressure. They also reduce shearing forces, which can sometimes impair the often-sensitive liquid formulations.

G3 camera system for maximum quality

Additionally, the requirements placed on the syringe as an ‘interface’ between the medication and the patient are becoming increasingly demanding. The effective dosage needs to be injected safely.

With all these combined factors to consider it is vital to ensure the syringe itself is of consistently high quality – after all, it needs to be able to store the medication safely (primary packaging) and make the injection itself safe, patient-friendly and as painless as possible (injection device).

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To cater to the requirements of modern injectables, we have developed a range of thin-walled cannulas. In addition to the traditional 27G cannulas, we also have 29G, 26G and 25G and we offer a 23G thinwalled cannula for extremely viscous medications.

Among other products, Gerresheimer offers a 2.25 mL syringe that allows subcutaneous injection for such applications.

Minimising interactions with active ingredients

Modern production technology for glass forming, needle mounting and the ‘ready-to-fill’ (RTF) process is important in ensuring product quality. Using camera technology (G3 camera system) and transporting syringes individually during the RTF process to avoid glass-to-glass contact are just two Highly viscous and highexamples of the measures we take in order volume injections are to improve quality for our customers and just two examples of minimise rejection rates.

One of the challenges that developers need to consider is the potential interaction of the material the prefilled syringe is made from and the drug.

Two components of the syringe are of particular significance when it comes to interaction with sensitive medication: silicone oil, which is used as a lubricant in prefillable syringes and residual traces of tungsten, which can remain in the syringe from the manufacturing process for the glass body.

Silicone oil can be kept to a minimum using baked-on siliconisation, a process that Gerresheimer has offered for many years with its Bakedon RTF syringes. Traces of tungsten can be significantly reduced using a special washing process, or avoided completely by using a special ceramic as an alternative pin material.

Break resistance After performing extensive studies on the break resistance of glass syringes we have found that it is possible to improve the break resistance of the finger flange and also to significantly improve the stability of the shoulder area and the cone. Our newly developed Valor glass offers further improvements in terms of break resistance. High break tolerance and compact dimensions are important parameters for a prefilled syringe, especially when using automatic injection systems.

Production technology

“

Looking to the future

the developments in the administration of modern medication, and the solutions a packaging manufacturer can offer in this field.

Close collaboration with pharmaceutical customers is imperative in the further development and improvement of existing injection systems. Highly viscous and high-volume injections are just two examples of the developments in the administration of modern medication, and the solutions a packaging manufacturer can offer in this field.

Gerresheimer continually works with customers in its own labs to is constantly working in close collaboration with its pharmaceutical customers in its own labs to respond to the changing trends and demands of the pharmaceutical industry, doctors and nursing staff, and the patients themselves.

”

High-volume syringes In certain applications, a higher-volume syringe is becoming a more established product, with a move away from the ‘traditional’ 1 mm syringe and to a 2.25 mL syringe being witnessed.

Not only can this increased volume lead to fewer required injections but can also allow patients to be injected with medication that acts as a deposit for a long-term effect, or based on a number of reasons, for which higher concentrations are unfeasible or impossible. In all these cases, high-volume syringes represent a significant expansion in the therapies that can be offered by a physician.

References: 1. https://www.medica-tradefair.com/cgi-bin/md_medica/lib/pub/tt.cgi/Future_of_ Prefilled_Syringes_Manufacturer_s_Perspective_–_Challenges_and_Opportunities. html?oid=16672&lang=2&ticket=g_u_e_s_t 2. Makwana, S., et al., Int. J. Pham. Investig., 2011;1(4):200–206. https://www.ncbi.nlm.nih. gov/pmc/articles/PMC3465144/

RTF syringe production at Gerresheimer Bünde

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APIs/EXCIPIENTS

Take your pick Traditionally, excipient selection has been performed using trial-and-error based methodologies, which are time-consuming and expensive. In this article, Dr Amjad Alhalaweh, PhD, formulation scientist, Recipharm, discusses a new method, high-throughput screening (HTS), which can help to tackle excipient selection challenges.

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any companies are facing solubility challenges of new chemical entities (NCEs) during development processes.

The solubility of a compound is fundamental in reaching the necessary concentration for the required pharmacological response.

During the early stages of drug development, liquid formulations are created to help understand an NCE’s pharmacology, pharmacokinetics and toxicology.

Also, failure to adequately dissolve can have a negative impact on bioavailability and result in suboptimal drug delivery. Strategies to improve drug solubility are therefore of crucial importance, and usually compounds must be paired with excipients that can adequately solubilise them to achieve the required therapeutic response.1,2

The process of selecting excipients has relied on trial-and-error based methodologies, which are wellknown to be both time-consuming and expensive for sponsors. These challenges have readied the market for the introduction of a new high-throughput screen (HTS) method that can accelerate and rationalise the selection process.

The potential of a HTS approach A range of techniques are available to enhance solubility. These strategies include either solid form

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manipulation using amorphous, salt or cocrystal form, or solvation methods using materials that can solubilise the drug compound, such as co-solvents, surfactants or cyclodextrins.3,4 Solvent modification and carrier systems are used most frequently as they offer the ability to only impact the solvent characteristics of a drug rather than its solid-state properties.5 However, one of the limitations of current selection methods is that they risk missing the best excipient for a compound due to the high costs of traditional experimental procedures which rely on manual handling.

As a better alternative, a HTS approach has been developed to overcome the cost and time challenges of traditional techniques. The objective from the outset was to develop a robust, automatic platform that would use minimal amounts of a compound to provide conclusive information about a drug’s solubility and stability in a variety of solvents and excipients. To develop the methodology, a screening list of excipients was used, including water-soluble organic solvents, non-ionic surfactants, waterinsoluble lipids, organic liquids/ semi solids, cyclodextrins and phospholipids.6 Rather than testing every excipient manually, as has been required with previous approaches, the HTS methodology enables multiple tests to be undertaken concurrently.

It provides research scientists with insight into which excipients, or combination of excipients, are most appropriate for different drug delivery systems, such as those suitable for oral excipients and those best suited to injectables.

This insight is critical in ensuring patient safety as an incorrect number of excipients could result in unwanted side effects, such as pain, haemolysis, or inflammation following administration.

achieved using the HTS approach were not statistically different to those achieved using a manual approach. A t-test was used to verify this at a 95% confidence interval.

Testing the methodology

The HTS method offers a strategy to overcome the challenges associated with manual approaches. Not only has the technique proven to be more costeffective while using less materials, it can turnaround results in as little as 3–5 days per set of compounds.

Six commercial drugs with diverse chemical properties were tested for their solubility with 30 excipients.

These experiments ran in parallel in 96 well-plates, with each formulation being dispensed by a Tecan automated dispenser. The plates were shaken for 48 hours to ensure equilibrium. The results were compared with the solubility measurements achieved using a manual shake flask method. As well as proving understanding of the solubility of the various drugs in the different excipients, the process also determined any degradation.

The results The HTS platform has been shown to provide detailed insight on the solubilisation capacity of different compounds in a variety of excipients, while also providing information on the stability of a compound in the excipients tested.

During the experimental stage, it was found that the solubility levels

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Conclusion Low aqueous solubility is one of the most frustrating aspects of formulation development and there is a recognised need for more optimised techniques to inform the selection of appropriate excipients.

Adoption of a HTS approach will provide research scientists with an optimised pathway in understanding solubility behaviour, which will ultimately pave the way for more efficient formulation development processes.

References: 1. Li, P., and Zhao, L., International Journal of Pharmaceutics, 2007;341(1):1–19.

2. Dahan, A., et al., Advanced Drug Delivery Reviews, 2016;101:99–107.

3. Alhalaweh, A., et al., Journal of Controlled Release, 2016;229:172–182.

4. Miyako, Y., et al., International Journal of Pharmaceutics, 2010;393(1):48–54.

5. Alhalaweh, A., et al., Molecular Pharmaceutics, 2012;9(9):2605–2612 6. Strickley, R.G., Pharmaceutical Research, 2004;21(2):201–230.

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

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

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CPhI PREVIEW

A ‘Main’ of information It’s that time of year again, CPhI Worldwide is back and this time is taking place in the financial centre of Europe – Frankfurt-amMain, Germany. In this preview, the event organisers reveal what we can expect from this global and exciting pharma show.

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nce more, CPhI Worldwide is being hosted by Germany, a country which is perfectly placed in the centre of Europe and as such an ideal location for the development, production and sale of world-class pharmaceuticals – a market predicted to be worth $86 billion by 2021. This year’s event will be taking place at the Messe Frankfurt between 24 and 26 October.

Global reach The event returns in a year where global growth across the pharmaceutical industry is flourishing. It is a particularly strong time for outsourcing and ingredients, as well as an incredibly buoyant period for the pharmaceutical manufacturing industry. There is also a renewed confidence in the North American pharma market with the three hotbeds of biotechnology – San Diego, San Francisco and Boston – experiencing a notable resurgence.

However, this year has seen many exciting developments throughout the globe, with the new marketing authorisation holder (MAH) pilot in China providing huge innovation opportunities for Chinese biotechs, and generics expanding from Japan, US and Europe to the emerging markets.

In addition, all our global events have seen a surge in the number of bio and finished formulations attendees, again highlighting how strong these markets are.

It’s a truly dynamic time for the global pharma industry, and CPhI Worldwide provides an opportunity to come together and focus on the latest trends, technologies and insights. Above all else, it is a platform for the industry to drive forward new partnerships, do business and grow.

What to expect at the event The 2016 CPhI Worldwide event in Barcelona saw an all-time record attendance of over 42,000 people, with 2,550+ exhibitors from 156 countries. Building on this success, CPhI Worldwide 2017 will host over

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20 dedicated zones covering ingredients, APIs, excipients, contract services, packaging, biopharma, machinery and many more.

Running concurrently with the pharmaceutical ingredients halls are four other nearby brands, helping visitors quickly identify the right event for their business’s needs: ICSE – is an outsourcing focused event designed to connect the pharmaceutical community with contract providers from clinical trials, CROs, logistics providers, data management firms and CMOs, bringing the contract community together under one roof.

InnoPack – connects buyers and specifiers from the packaging and pharmaceutical industries, showcasing all the newest innovations in pharma packaging.

P-MEC Europe – features exhibitors from traditional large-scale capital equipment to companies focused on instrumental analysis, measuring and testing technologies, materials testing, laboratory and quality control.

Finished Dosage Formulation – for every aspect of the finished dosage supply chain, from big pharma and CMO to in/out-licensing and dossier specialists.

Beyond the exhibition…

The Pharma Forum is CPhI’s go-to space for all pharmaceutical professionals looking to explore specialist areas and new business opportunities, as well as sourcing information on trends, innovations and developments – all in one location. The Pharma Forum includes the latest innovative products and services in the Innovation Galleries, free high value content at the Pharma Insight Briefings, and the chance to share your experiences and recharge your batteries in the Insight Lounge.

The second day of the event will see the Women in Leadership Forum return. Here, female executives will meet and discuss with their peers about

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promoting diversity in the workplace. It serves as a space to share their experiences, exchange expertise, and discuss effective leadership strategies.

Awarding excellence

The Pharma Insight Briefings will offer participants the chance to access a diverse range of content through succinct 45-minute sessions. All content is free to access and open to all visitors with topics covering pharmaceutical packaging, market entry, mergers & acquisitions, mHealth, new technological developments and the latest innovations in pharmaceutical ingredients and biologics.

The vastly expanded CPhI Pharma Awards returns to the show for its 14th year, with eight new categories – awarding an impressive 20 commendations in celebration of the most successful and innovative pharma achievements. The expanded awards have been created to give wider recognition to all the great advances and technologies coming out of the pharma industry. The winners will be announced live during the prestigious CPhI Pharma Awards Gala in Frankfurt, amongst over 250 of the industry’s most important executives and luminaries.

As well as the many free-to-attend industry seminars, the Innovation Gallery will provide a showcase for some of CPhI's most exciting new products. This is where visitors can see innovative pharmaceutical developments in ingredients, finished dosage formulations, contract services and packaging. Moreover, a team of pharma experts will also present visitors with the opportunity for guided Innovation Tours, which run across each of the three days at CPhI Worldwide. These one-hour bespoke tours are exclusively selected by CPhI’s partners to cover all sectors of the pharmaceutical industry. Registration however, is on a first come, first served basis.

Stay connected The Live Pharma Connect is an online business match and meet tool at CPhI Worldwide open to both visitors and exhibitors to pre-arrange their meetings. The system is very easy to use and automatically finds the best matches for both visitor and exhibitors needs, eliminating the need to manually search databases to find the right business connections.

Helping others CPhI is striving to encourage their partners to incorporate corporate social responsibility,1 and this year has chosen International Medical Corps UK as its official charity partner. There are a range of charity sponsorship options, with free promotions at the event and contributions going direct to International Medical Corps to sustain their global efforts.

International Medical Corps delivers lifesaving aid and healthcare in emergencies for people affected by disaster or conflict. They work around the clock to rebuild lives and communities in some of the most dangerous places on earth.

And finally…

At the event, don’t forget to use the official CPhI mobile app, providing exhibitors and attendees with a timetable of the day’s activities, a list of exhibitors and their hall location.

Early bird?

This year’s CPhI Pre-Connect Congress will take place on the 23 October, and offers its most exciting and comprehensive agenda to date. This platform gathers experts and thought leaders from the entire pharmaceutical supply chain to provide insights into the latest developments.

Held in the heart of Europe’s largest pharma market, this year’s event is an unmissable opportunity to network with existing contacts and engage vital new customers that will be invaluable in moving your business to the next level.

In particular, the first keynote will feature Samsung Biologics president & CEO, Dr Tae Han Kim. He will provide an in-depth presentation addressing uncertainty in the industry, as well as the future outlook for pharma.

The second regulatory keynote will be given by Ajaz Hussain, president, National Institute for Pharmaceutical Technology & Education, Inc. & former deputy director, Office for Pharmaceuticals, FDA. Hussain will give a special address covering the US and European regulator’s intention to mutually recognise one another’s pharmaceutical manufacturing inspection procedure, and the urgent need to reduce regulator heterogeneity in the cGMP inspection process.

This year’s conference will also examine engaging and forward thinking topics, such as an analysis of biosimilar uptake in the US and Europe, the future of continuous processing and discussions on innovative therapies such as CRISPR, immunotherapy and personalised medicines.

Market analysis Emphasizing that CPhI Worldwide is also a key opportunity to learn about new trends, business insights and prospects, the revered CPhI Annual Report launches its 5th edition. This eagerly anticipated collection of essays will provide thought leadership on the industry’s hottest topics and issues, with contributions by Ajaz Hussain, Emil Ciurczak and Alan Sheppard amongst others, and a contract services overview from Gil Roth of the PBOA. Reference: 1. https://www.cphi.com/charity-and-sustainability

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CPhI PREVIEW – SHOW FLOOR

From the floor Here, we feature a sneak peek preview of some of the companies that will exhibiting at this year’s CPhI event.

Addressing mega trends in drug delivery Drug delivery systems provider, Aptar Pharma, will be presenting key innovations during this year’s CPhI Worldwide, to address the mega trends in drug delivery.

Featuring an innovation area at the booth, Aptar Pharma will showcase seven healthcare technology mega trends, including a special connectivity hub, which will be dedicated to the growing field of connected healthcare solutions.

Additionally, the company will be presenting three Pharma Insight Briefings during the show: 1. ‘Innovative Respiratory Solutions for Expanding Your Product Portfolio’ Guenter Nadler, director of business development at Aptar Pharma, will deliver a talk on the company’s respiratory solutions and how they meet today’s need for compliant patient treatment.

Safe and customised solutions Raumedic has announced it will be presenting its innovative safety device for syringes, Rausafe, that protects from needlestick injuries.

Rausafe is suitable for many standard syringes and can be used intuitively.

Tuesday 24 October – 10.30 am at the Innopack Zone, G1A3 2. ‘Driving Better Patient Outcomes with Connectivity’ The second briefing will be presented by Sai Shankar, director business development – Connected Devices at Aptar Pharma. Among the topics to be presented during this briefing will be the findings of a recent study, conducted by the company, on its integrated connected pMDI, as well as its connected health devices portfolio that support respiratory treatment for patients.

Tuesday 24 October – 3.50 pm at the Innopack Zone, G1A3 3. ‘Setting New Standards for Coated Stoppers’

The safety device is activated straight after injection by a simple hand movement. As soon as the needle is completely enclosed by the protection unit, the system clicks into its final position.

Here, Arnaud Fournier, business support manager – Injectables at Aptar Pharma, will exclusively introduce PremiumCoat, a coated stopper that has been developed in response to the growing challenges of developing more sensitive drugs.

Wednesday 25 October – 10.30 am at the Innopack Zone, G1A3

Another focus for the company during the show, will be its development of customised products. “We accompany our customers from the initial idea through to series production according to the individual product specification,” added Ulrich Doppel, business development manager. “We would like to make this development process one of our central themes in Frankfurt.”

Hall: 4.2 Booth: 42F10 www.pharma.aptar.com/en-us

Hall: 4.2 Booth number: 42L74 www.raumedic.com

Integrated safety system

First joint appearance

During this year’s CPhI Worldwide event, Gerresheimer will present an integrated safety system for syringes to prevent needlestick injuries.

Uniting heat-sealing technology with die-cut packaging formats, Romaco Siebler is taking advantage of the CPhI Worldwide event to make its first joint appearance with Constantia Flexibiles, which has been a collaborative partner to Romaco in R&D for many years.

The Gx InnoSafe is installed like a standard seal in the cleanroom on Gx RTF glass syringes during the manufacturing process. The syringe body itself remains completely visible, so that the presence, filling level and state of the active ingredient, as well as the injection procedure can be inspected without visual hindrance.

Accidental activation of the safety system is not possible as the mechanism is completely relaxed prior to injection. Once the cannula is in use, the safety system is automatically activated and once the syringe is removed from the injection point the safety mechanism is locked. In this way, the cannula is reliably covered and renewed use of the syringes is impossible.

For their joint appearance, the companies will be presenting various solutions, such as die-cut strip packaging machine – HM 1 series – which can be configured to manufacture die-cut strips on a custom basis. These individualised strips can be manufactured using the Romaco-Siebler HM 1-350 series, which is equipped with a continuous cutting station.

Gx InnoSafe syringes are packed in perforated trays and tubs and then sterilised with ethylene oxide gas. They can be processed on existing filling lines without additional preparation and assembly steps.

Additionally, an integral part of the solution is the correct heat-sealing foil, which has been a key factor of the collaboration between Romaco and Constantia Flexibles.

Performing numerous joint feasibility studies and tests, the companies offer combined experience in this area to produce adaptable yet stable pharma packaging.

Hall: 4.2 Booth: 42D02 www.gerresheimer.com

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Hall: 4.2 Booth: 42H51 www.romaco.com

www.cflex.com

9th 8th Pre-Connect Congress

October 23, 2017 | Portalhaus, Frankfurt Messe

Explore the Future of Pharma

VIEW THE AGENDA:

http://gotocphi.com/pre-connect-agenda

Organised by:

START UP

Natural selection Here, Giovanni Rizzo, PhD, MBA, chief of Innovation Division, Z-Cube, reveals what life science start-ups should bear in mind when looking for funding.

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t is an often-repeated statistic, that 90% of all start-ups fail within the first year,1 however, it is in everyone’s interests that the most innovative and creative life science start-ups succeed.

off for investors as it found that private equity houses believe that some key business skills such as IT management and marketing are generally sub-par in the businesses they acquire.5

type of support is offered by different types of investors, being careful not to underestimate the importance of access to mentors and advisors that can show them the ropes when it comes to the practicalities of setting up a business. So, while the

An ageing population, the need to invest in new-generation, digitalised technology, a rise in patient demand of service and value for money, will see life sciences drive a medical revolution as the scientific discoveries of recent years are translated into patient treatments and products.2

Raising money for a new company also relies on a person’s ability to relate their vision and network, but securing the right exposure – being in front of the right people at the right time – is no easy task with many businesses finding this is one challenge too-many.

Choosing an accelerator that operates in the right niche can help the start-up connect with advisors and peers that understand the business, its processes and can help devise a plan for future growth that avoids many of the obstacles and pitfalls that typical of the industry. The right match accelerator will expose your business to investors that are a good fit to your business and can help it to grow to maturity and to becoming even more valuable.

Learning from other industries is one way to improve the chances of a start-up’s success. A recent study found that 33% of founders who are mentored by successful entrepreneurs went on to become top performers. This is more than three times better than the performance of other companies.3 In the UK, roughly 60 new life science startups are formed each year with University spin-offs accounting for 34% of these.4 This finding highlights that start-ups in life sciences are very often composed and set up by visionary academics who, unfortunately, would probably not hesitate to describe themselves as inexperienced with the practicalities of setting up a business such as composing a robust business plan, sourcing a reliable supply chain, managing partners, tax and staffing issues. Yet all these key business activities need to be fleshed out and accounted for if early stage companies wish to impress investors and secure funding.

This environment, which sees early-stage often academic start-ups struggling to get funding, translates into a Catch-22 situation, where the only people knowledgeable enough to innovate are denied access to funding because they lack business experience and only firms that have already received funding are able to access more. Such an environment is damaging to the whole life science sector as it stifles innovation, discourages entrepreneurial initiative and ultimately suppresses important developments that could improve patient health.

A recent report by MindMetre Research confirms that a lack of key skills is a turn-

Life science early-stage start-ups should, therefore, consider wisely what

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without significant funding. To solve this, many businesses are going public too early by commentators’ standards at the risk of undervaluing their business.

initial draw to a particular accelerator programme might be the availability of funding, not all programmes are set up to provide structured growth opportunities and counsel.

Reports show that the global life science sector is set to grow to the value of $447.5 billion by 2020,6 but early-stage life science start-ups are often largely cut-out of this bounty with large-scale M&A activity accounting for most investment. The European life science start-up panorama is in fact blighted by a critical inconsistency: businesses typically tend to get funding when they have reached relative maturity, and yet they are unable to reach maturity

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References: 1. Forbes, 90% Of Startups Fail: Here’s What You Need To Know About The 10% 2. PwC, the economic contribution of the UK Life Science industry, March 2017, http://www.abpi. org.uk/our-work/library/industry/Documents/ The_economic_contribution_of_the_UK_Life_ Sciences_industry.pdf 3. Techcrunch, Mentors are the secret weapons, March 2015, https://techcrunch. com/2015/03/22/mentors-are-the-secretweapons-of-successful-startups/ 4. Life Science Network, Life Science Startups in the UK, 27th December 2016.

5. MindMetre Research, Mind the (skills) Gap, June 2015.

6. EP Vantage data

SERIALISATION

On serialisation, don’t delay!

Savvy pharma companies will use the US DSCSA enforcement postponement for enhanced – not deferred – implementation of track & trace systems. Dave Harty, head of Professional Services for Adents, tells us more…

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rocrastination is human nature. All of us hem, haw and actively avoid responsibilities at times. This is especially true for things we are told to do, rather than those we choose to do. And when there’s plenty of time to do something, it’s easy to justify putting it off another day… until it isn’t!

In a nutshell that is why, in late June, the US FDA announced a one-year postponement on enforcing the Drug Supply Chain Security Act – a regulation which, among other mandates, necessitates printing unique product identification codes on all Rx units of sale and homogenous cases distributed domestically. Simply put, the FDA’s hand was forced: an alarmingly high number of pharmaceutical manufacturers and CMOs did not have serialisation solutions in place sufficient to meet the original deadline of 27 November 2017.

This shouldn’t happen again – and it won’t. Note the term ‘enforcement postponement’. The FDA isn’t delaying the law’s enactment – it is still slated to become official US law this November (changing the law would, in fact, require a formal act of congress). Rather, it is extending a penalty-free grace period for those in violation of the law. Make no mistake: unit-level serialisation is here to stay, and laws inevitably tend to… well… get enforced.

Coincidentally, the US enforcement postponement places pharma companies in the US and Europe – who, of course, frequently produce products distributed in each other’s markets – in roughly the same boat.

The deadline for serialisation implementation in the EU is 9 February 2019, about two months after the DSCSA will start being formally enforced by the FDA here in the US. That said, track & trace solutions meant to address the newly practicable US deadline of November 2018 should also conform to the EU’s similar standards, and vice versa.

With the clock is still ticking, it’s time for the pharmaceutical industry to quickly recover from its collective sigh of relief. Need some antiprocrastination motivation? How’s this, with the extra time, pharma companies can stop, catch their breath after a mercifully paused sprint to compliance, and move toward implementing forward-thinking serialisation solutions that actually help their business rather than merely allow them to stay in business.

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In other words, pharma companies have a golden opportunity to introduce track & trace systems that are truly remarkable rather than restrictively remedial.

The need for this next-level thinking is becoming increasingly evident. As awareness grows of the complexity and interconnectivity of the serialisation process, pharma manufacturers are realising the importance of modularity and flexibility in the solutions they choose. The enforcement postponement provides valuable time for pharmaceutical manufacturers to look beyond short-term compliance needs and consider long-term solution viability.

Considering what remains a muddied landscape, idyllic systems now trend toward more flexible, hardware-agnostic serialisation solutions that can adapt or scale up to meet future track & trace mandates, as well as help improve business practices. For those who had been rushing toward compliance, then, the postponement affords time to rethink the overall process, such as incorporating tools that can better use – for the sake of production improvements and personnel allocation – the troves of data that serialisation mandates be tracked and stored for reporting purposes.

To help pharma companies and CMOs take full advantage of the DSCSA enforcement suspension, here are three considerations toward implementing a more comprehensive, beyond-compliance serialisation system.

Be honest about buyer’s remorse The DSCSA postponement provides a chance for those spearheading serialisation initiatives to reassess their overall strategy. For those companies who’d been rushing toward compliance via the most basic, expedient routes available, the time is now for some honest soul-searching.

The big question is this – is the solution a marriage of convenience, or a truly happy one? Scenarios like these exemplify the adage that ‘speed kills’. Amidst the sprint to meet the original November 2017 deadline, did you feel the need to do some ‘settling’ in terms of what was achievable in a fast-narrowing timeframe?

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In my experience, the most common flaw with many serialisation solutions currently being embraced is that they are inherently short-sighted and, as a result, will be obsolete sooner rather than later. It is worth remembering that the initial DSCSA mandate for unit-level serialisation will be followed, in subsequent years, by increasingly stringent requirements ending with full supply chain traceability in 2023.

Why invest in a technology that will need to be replaced in five years?

The yearlong enforcement suspension gives pharma companies and CMOs enough time to reimagine their serialisation solutions into scalable systems that can address rolling deadlines with phased-in requirements… if they don’t procrastinate.

The important question is this – to what degree? In my experience, too many pharma companies have realised too late that their chosen serialisation solutions are significantly diminishing production output, and are expressing an urgent need to mitigate this drop-off.

Unfortunately, some are already in too deep, having installed on a multi-site, company-wide basis, systems that, in order to be significantly improved upon in terms of speed or other matters of import, essentially need to be ripped out and replaced. That’s tens of millions of dollars in infrastructure alone – an investment simply not possible for many manufacturers.

Here, two key buzzwords (or shall we say ‘buzz phrases’) are ‘hardwareagnosticism’ and ‘beyond-compliance return on investment’.

Consider lessons learned Fact: As someone charged with implementing a workable track & trace solution – and with the business’ entire viability at stake, no less – you know more about serialisation now than at the inception of the process. The postponement gives you the opportunity to employ that newfound knowledge.

A real-world example: One of my customers needed to add bundling operations on seven packaging lines. A huge problem arose when they realised that a few of the lines couldn’t be updated using the existing serialisation solution they’d been using. I won’t name names, but that’s alarmingly inadequate, and the customer is fortunate to have discovered this limitation early enough to correct it – an onerous exercise involving costly downtime and the requisite validation that any system used in the pharma industry must complete.

Another typical issue here lies with cyber-security. As we move toward enterprise-level serialisation, solutions will need to be interconnected in a way that, in our age of the Internet of Things, can expose vulnerabilities. As the widespread grief caused by the aptly named WannaCry ransomware attacks exemplifies, it’s become all too easy for criminals to take the cyber-backdoor into the networks of large companies and, once inside, wreak havoc.

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

Operational costs and beyond-compliance ROI It’s inevitable the vast majority of serialisation solutions are going to reduce overall productivity. Whenever a new step is introduced to an extended process, such as pharma packaging, there will be some degree of slowdown.

Simply put, hardware-agnostic solutions are less likely to become obsolete, and are more suited to making a https://image.shutterstock. com/z/stock-photo-blurred-abstract-background-inside-pharmacystore-with-arranged-variation-of-pharmaceutical-and-677496022. jpg djustments as production needs change or evolve. A process as intricate as serialisation requires an outsized number of components to ‘play nice’ with each other; these sorts of ongoing transactional relationships are best mediated by software.

Finally, beyond-compliance ROI alludes to ways of using the massive amount of data generated by serialisation efforts to improve business practices (including the potential to reduce or even eliminate production slowdown caused by the system’s line incorporation).

Solutions now exist that open up new horizons beyond regulatory compliance in terms of data analysis and machine learning tools, among other capabilities.

Indeed, the data pharma companies are required to gather, store and report to regulatory authorities can be as valuable as they choose to make it. For example, tools exist that monitor overall equipment efficiency (OEE) to pinpoint potential production bottlenecks. Associated systems track and predict production scenarios that allow companies to allocate the proper personnel for specific projects, maximising individual fortes while limiting unnecessary overtime.

Conclusion The DSCSA enforcement postponement gives pharma companies an opportunity to address both current and emerging regulations while also minimising impact on production processes and productivity. The time is now to move toward solutions that are flexible, scalable and relatively painless to deploy. Often, this means hardware agnostic systems compatible with a wide range of equipment, and ‘smart factory’ solutions that allow for data-driven business practice improvements.

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SERIALISATION

A fighting chance Packaging is integral to the fight against counterfeit medicines and serialisation of packaging is an essential tool with which companies and customers can use to verify drug products. Here, Mario Scigliano, serialisation & automation manager, and Christian Ahlmark, associate director, sales & key account management, CordenPharma, discuss how a CDMO can help give companies a fighting chance to be globally serialisation compliant.

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ackaging is the key to combatting the worldwide drug counterfeiting problem. Nearly 10 years ago, the primary target for drug counterfeiters were lifestyle drugs, such as Viagra. Now, commonlyused and lifesaving medications, including insulin, cancer drugs and cardiovascular medicines, have fallen victim to phony Packaging manufacturers. This poses a pressing danger to consumer health. The World Health Organisation (WHO) estimates is the key to that the rise in counterfeit drugs is responsible for up to combatting the one million deaths annually, and that 1 in 10 medicines worldwide drug sold worldwide is counterfeit, a figure that can reach up counterfeiting to 7 of 10 in some countries.1

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problem

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Medicines need to be packaged in a way that allows counterfeits to be quickly and easily identified, preventing their circulation and/or eliminating drug recalls. Essential to this is package serialisation, which establishes a unique identifier that assures each member of the supply chain (from manufacturer to patient) the drug product is not counterfeit.

This November, US pharmaceutical companies must meet new serialisation compliance deadlines aimed at combatting global counterfeiting efforts.

The criticality of serialisation should rather be viewed as a clear benefit for patient safety, which can also be turned into a competitive advantage for the pharmaceutical industry.

If your manufacturing is outsourced to a contract development and manufacturing organisation (CDMO), they must understand the functionality and necessity for serialisation and help navigate through the myriad of global serialisation guidelines.

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As a full-service global CDMO, CordenPharma determined that in order to better service pharma customers, the drugs produced must comply with multiple market requirements worldwide. China, for example, made serialisation mandatory for certain pharmaceuticals in 2008.

Serialisation in the supply chain So how can these counterfeit medicines avoid detection in such a highly regulated and scrutinised industry? The Achilles heel of the pharmaceutical industry lies in the supply chain, with almost 40% of the drugs that supply the US market being manufactured overseas, and the active pharmaceutical ingredient (API) itself being imported from over 150 different countries.2 This supply chain is incredibly complex, with some drugs passing through 10 or more points of contact before reaching the patient. All stages of drug manufacturing and supply are vulnerable to drug counterfeiters.

Supply chain players are working together to integrate serialised anticounterfeit features into pharmaceutical packaging. Serialisation is a unique identifier issued for a particular manufacturer and a specific product. Some serialisation techniques include: • microscopic RFID tags, • security labels, • invisible inks, • track-and-trace technologies.

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More than 55 countries have chosen to implement serialisation and track-and-trace measures to prevent counterfeit drugs from reaching the market.3 By 2018, while more than 75% of the world’s prescription medications will be protected by serialisation, no two countries have passed exactly the same legislation, thus complicating the implementation process.

Each country determines its own specifications in terms of serialisation and anti-counterfeiting.

A CDMO can implement aggregation as part of its serialisation system. Through harmonising production lines, it is possible to make them capable, efficient and able to support full aggregation. The aggregation data then enables improvement of internal visibility into product movement, inventory, warehousing and shipping.

Additionally, any rework, recalls, or returns can be handled in a more controlled environment because the serialisation and aggregation data allows for quicker access to the drug product.

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The benefits of partnering with a CDMO When it comes to choosing a CDMO to handle your serialisation efforts, be certain that the partner will: • Guarantee secure packing for each product shipped. Assurance that each product is reliably protected against transportation and environmental stress. Advanced materials and packing technologies are deployed for special products, such as oncological products.

• Safeguard the patient from counterfeit medicines using systems applied to prevent the opening of the drug product and ensuring the product quality.

• Manage large quantities of data throughout the supply chain. Use current technology to monitor the drug product location at any time.

• Have processes and procedures in place for handling exceptions, rework, repackaging, returns etc. that could impact the integrity of the associative drug company parent-child hierarchy.

One language, multiple markets Each country determines its own specifications in terms of serialisation and anti-counterfeiting. The guidelines in some countries are limited, and leave manufacturers to decide on the information content. Fortunately, a standard language for communicating serialised information already exists. The foundation of this language is a GS1 standard, called Electronic Product Code Information Services (EPCIS). The serialisation and traceability industry is aligned, using EPCIS as the de facto standard, allowing an effective and efficient communication format.4

• Adapt to the most current standards and be flexible in transposing regulatory market requirements, while providing customers the utmost level of support. The goal is to keep patients safe.

At CordenPharma, for example, we employ a team to standardise processes and logistics while also maintaining the integrity of the data according to the specifications issued by various ministries of health and GS1. Countries that are using GS1 standards give the consumer confidence that their drug product is kept safe and secure throughout the supply chain. Countries that do not apply such standards will continue to have counterfeiting issues.

2. Hand, S., MSc, Will Pharmaceutical Serialization Solve All of Our Drug Counterfeiting Problems? 22 March 2017, http://xtalks.com/Pharmaceutical-Serialization-Drug-Counterfeiting. ashx.

References: 1. Fighting counterfeit drugs starts with knowing it exists, 17 May 2017, http://mediaroom. sanofi.com/fighting-counterfeit-drugs-starts-with-knowing-it-exists/.

3. Widengren, S., Serialization: The Final Countdown, Supplement to Pharmaceutical Technology, 41(2) February 2017, http://www.pharmtech.com/serialization-final-countdown?pageID=1.

4. Kamal, H., GS1 standards are vital for pharma serialization, 5 April 2017, http:// pharmaceuticalcommerce.com/manufacturing-and-packaging/gs1-standards-vital-pharmaserialization/

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CASE STUDY: Serialisation Who:

Atlantic Zeiser and Schaper & Brümmer

What:

Serialisation with Chinese codes

How:

MEDTRACKER control software

The language of serialisation The companies Headquartered in Emmingen-Liptingen, Germany, Atlantic Zeiser develops innovative and practice-proven systems, including hardware and software components. Its product portfolio includes sophisticated serialisation, personalisation, customisation and track & trace solutions.

Schaper & Brümmer, headquartered in Salzgitter-Ringelheim, Germany, is a mid-sized pharmaceutical company that produces non-prescription, naturally-based medication for the modern market.

The challenge As one of the first manufacturers of phytopharmaceuticals in Germany, Schaper & Brümmer exports its plant-based medicines to more than 40 countries and generates 45% of its total turnover from foreign business.

After receiving marketing authorisation in 1994 for the Chinese market, this export region has become one of the company’s most important for phytopharmaceuticals – including products such as the common-cold

The mark and verify unit applies the code for China to the individual packs, verifies them and automatically rejects non-compliant items. These process stages are controlled by the higher-level MEDTRACKER software from Atlantic Zeiser.

treatment Esberitox and menopause preparation Remifimin.

The rules that have been introduced progressively since 2013 for specified

The solution

preparations now apply to all medicines sold on the Chinese market: they must be provided with the special Electronic Drug Monitoring Code (EDMC) to meet Chinese requirements. The coding system stipulates serialisation and aggregation and thus ensures transparency and traceability – and therefore drug security – in the supply chain. The requirements of the Chinese code go right to the heart of companies’ existing processes and are far from easy to implement.

“To be able to continue serving the Chinese market after 1 January 2016, we had to start production in 2015. We ruled out the use of a packaging service provider owing to insufficient free capacities for the large batch sizes we need. We therefore decided to convert an existing packaging line, an investment with a high six-figure volume and a project start date of January 2014,” recalled Dr Martin Tegtmeier, head of manufacturing at Schaper & Brümmer.

The MEDTRACKER software solution from Atlantic Zeiser has a modular structure, can be implemented in existing or new facilities and is a flexible and audit-proof solution for generating, distributing, printing, aggregating and tracking codes for all current international regulations. Additionally, it includes a full track & trace capability for e-pedigree applications, as needed for the US for instance.

Should the range of requirements change, the software can be adapted.

In this way – if configured accordingly – it can cover the requirements of different markets, while forthcoming, as yet unknown, criteria can be implemented in a straightforward way without the need to purchase new software. Furthermore, the modular design of Atlantic Zeiser’s MEDTRACKER also allows the implementation of track & trace for parts of a line, entire lines, production facilities or whole companies – overall, therefore, it is a solution that can expand to accommodate growing requirements.

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by higher-level software that ensures audit-proof generation, printing, management and storage of the serialisation codes.

“We were converting a high-performance line set to produce 240 packs per minute – that is four packs per second. The requisite control software therefore had to be capable of processing very large quantities of data in an extremely short time,” Tegtmeier emphasized. “A further challenge was the integration of hardware components supplied by other manufacturers in the plant concept. This aspect, together with the high data processing performance we needed, could be satisfied only

by MEDTRACKER software.”

The benefits Does what it says on the tin: MEDTRACKER software effortlessly interconnects and controls hardware components from Atlantic Zeiser — they are MEDTRACKER compatible. On demand also equipment from other manufacturers can be interfaced.

“This was an important consideration when we decided in favour of the MEDTRACKER solution. Actually, apart from serialisation in China, similar programmes are currently being launched and rolled out all over the world. Given that we export to more than 40 countries, we will undoubtedly have to respond to further regulations in our target markets,” explained Tegtmeier. “Although, as a manufacturer of non-prescription medicines, we are currently exempt from the delegated regulation concerning the falsified medicines directive that will be transposed into national law in Europe in the coming years, it looks almost certain that we will have to address this issue in future. Thanks to the MEDTRACKER solution from Atlantic Zeiser, we are prepared for it when it comes.”

“Serialisation for the Chinese market was not just a new undertaking for us, but also a key investment in the future and made us one of the first mid-size phytopharmaceutical manufacturers to take this step,” Tegtmeier said. “Working together with our trusted partners, we were able to bring this project to a successful conclusion. Thanks to the versatile software solution provided by Atlantic Zeiser in particular, we will be able to fulfil new and changing requirements in the future too and so can safeguard our market position.”

The process To produce an initial plant concept, an interdisciplinary team of IT, production, purchasing and sales specialists discussed the fundamental issues. They were joined by those responsible for compliance with drugrelated legislation. Their aim was to define actual requirements, to analyse existing and planned processes and, on this basis, to determine overall plant effectiveness with a focus on the desired availability, performance and quality of the envisaged plant.

In parallel the project team acquired relevant expert knowledge about serialisation for China, appropriate coding and camera technologies, tamper-proof packaging and IT issues. This was collated in the user requirement specification (URS), which stipulated the criteria that were to be met by external services and suppliers and the conditions that had to be ensured internally – both in normal situations and in exceptional circumstances or in the event of a malfunction.

Once serialised, the packs are bundled and placed in cases by the case packer. Every item code is recognised for the generation of the next aggregation hierarchy, non-compliant packs or bundles are identified and rejected for manual rework.

As an active member of the Bonn-based Federal Association of Pharmaceutical Manufacturers, Schaper & Brümmer has shared its experience during the project with other companies interested in serialisation for the Chinese market and has used its converted packaging line in Salzgitter as an example. “Because of the complexity of the requirements, which must be incorporated with extremely individual, company-specific needs, we would strongly recommend getting to grips with the subject as early as possible,” summarised Tegtmeier.

In describing the advantages of this in-house approach Tegtmeier stated: “We were able to make informed and therefore better decisions during the implementation phase. In addition, as those responsible for compliance with drug-related legislation, we have retained relevant knowledge internally even after the project’s completion and can act accordingly if needed.”

The existing packaging line was equipped with a track & trace unit that prints serialisation numbers on individual packs, verifies codes and automatically rejects units that are unusable – because of inadequate print quality for example. A case packer was incorporated in the packaging line as an additional hardware component. It places the previously bundled individual packs in cases and records the codes on the individual packs with a camera system.

Thereafter an aggregation code is printed and automatically applied to the case. Aggregation at pallet level is performed manually. The new hardware components supplied by different third parties are actuated

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The high-performance packaging line at Schaper & Brümmer converted for Chinese serialisation is 35 metres long.

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LABELLING

Necessary accessories?

Here, Shaun Baker, managing director, Newman Labelling Systems looks at the accessories that are available to meet various labelling needs.

I

n its simplest format, a labelling system applies a label securely to a product or container; everyone understands this straightforward concept. For example, in the food industry it could be a label that combines nutritional information with cosmetic appeal and branding. The label will include batch specific information In the pharmaceutical such as ‘best before’ and ‘use-by’ date.

It’s important the correct label is applied sector… the wrong label to the product and in such a way as to be might cause considerable readable and look good – not skewed or harm or even death to creased.

“

the person mistakenly taking it.

”

In the pharmaceutical sector, the application of labels to products is more regulated. Apply the wrong label and a product might cause considerable harm or even death to the person mistakenly taking it.

There can also be a lot of information to be included on a label for a pharmaceutical product yet the actual container is often small, resulting in a variety of different label types being used such as leaflet labels and hanging labels. Lastly, labels for a single product will require different information, from a code per batch through to individual identification for each and every label; in many cases that information needs to be validated.

‘Accessories’ is almost a misleading term – these system add-ons are often 100% essential – but I refer to them as such as these are selected in each case based on application requirements and customer preference.

In such instances accessories aren’t there to ‘promote and decorate’ a container, but provide the critical identification of the contents.

There are many labelling system accessories readily available that will enable you to comply with regulations and standards, provide security/ validation throughout the labelling process and increase line efficiency.

Suitability very much depends on the specific requirements of the application and the degree of automation required.

Verification and identification The first step is to verify that you are applying the correct label for the product line. It’s not just about ensuring product A has label A applied, as label A could come in different versions. For example, we have seen a case where a labelling line was running with English language labels and a German language version of the label was spliced on by the operator by mistake; the information on both was 100% correct for that product, but you can’t have German language labels in the UK and vice versa.

It’s important that any labelling system is easy to use, reliable and ensures high-quality application of labels. However, where identification of a label is critical to an industry, as in the case of the pharmaceutical sector, then a basic labelling machine is not enough; system accessories will be required to meet the needs of that industry and its stringent regulations.

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In the pharmaceutical industry label identification is typically achieved by identifying a pharmacode (an industry standard 2D barcode). There are a range of pharmacode readers on the market from those that are referred to as ‘read and decode’ which ensure the information correlates exactly to what it should be, through to simpler ‘show and go’ readers which don’t go as far as decoding the barcode but instead confirm the pattern the pharmacode matches.

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Just as we need to confirm the label being applied is correct, we also need to confirm the container it is being applied to is the correct one. For example, this could be the identification of a specific colour container lid or even a small coloured ring on top of an ampoule. The different colours could indicate different strengths of the same drug, so it’s vital the colours are correctly identified. This will require the addition of a colour scanning unit on the infeed of the labelling machine. With tabletting lines the same can often be achieved by reading a 2D matrix code on the base of the bottle.

Printing know-how As we have already mentioned, the pharmaceutical industry requires different information to be applied to a label, whether it’s a batch code and expiry date or a different identification for each individual label.

Whilst the labels themselves are printed separately (there is an option to have integrated label printing, but this is higher cost and hasn’t had much traction in the industry), a printing device will be required to add coding and overprint information to each label.

There are many printer options, from the traditional hot stamp coder, through to thermal transfer coding, laser coding and thermal ink jet printers. The choice of printer will be determined by the following factors: the label material, the amount/variability of content to be printed on the label and the speed of operation.

Just as we have looked at accessories to identify correct labels and correct containers, we also need a suitable means of ensuring the correct information is printed on a label and is legible. Some markets will accept a simple contrast scanner to achieve this, but a full vision system is the norm.

As with pharmacode readers there are a variety of options when it comes to vision systems, from ‘show and go’ systems which look for a pattern match, to optical character verification (OCV)/optical character recognition (OCR) systems which look at each individual character and correctly match them to a database.

Rejecting faulty labels When a missing or faulty label has been identified, it needs to be positively rejected and removed from the production line, often at speed. Manufacturers have approached this in different ways. Many have designed their reject systems to remove the label from the web and place it on to a mandrel, but the problem with this is that the rejected labels are placed one on top of the other which makes it impossible to then perform batch reconciliation.

Other accessories Looking slightly further afield, there are other accessories that can be applied further up or down the packaging and labelling line that, whilst not a direct part of the overall labelling system, do have a benefit to the overall process.

For example, a rotary feeding or accumulation table will provide a buffer between different processes, balancing different machine speeds and enabling machines to be stopped and started without affecting the whole production line.

“

Online transfer of small glass containers such as vials, ampoules and cartridges are the more accessories you notoriously difficult to handle due to their add to your labelling the dimensions and instability. These types of containers are often manually transferred system the more expense to the labelling machine on trays, but this is you incur. It’s important both time consuming and costly. Thus, an to identify those that are accessory that is capable of automating this actually required is a welcome one! The traditional automated alternatives available typically utilise a synchronised screw transfer system, but these are prone to container breakage, have high change part costs and involve a lengthy changeover time. At Newman, we have our own container transfer system (CTS) which avoids the use of synchronised starwheels to feed screws, avoiding container breakage and providing an accumulation buffer between the upstream equipment and the labelling system.

”

A further recommendation is an accessory that will speed up label reel changeovers and enable them to take place without stopping production.

Newman’s Easisplice, for example, holds two reels of labels – one acts as the current label supply while the other is positioned to facilitate rapid splicing as soon as the first reel reaches the end. This system enables continuous label feed, thereby eliminating downtime of the labelling system.

Of course, the more accessories you add to your labelling the system the more expense you incur. It’s important to identify those that are actually required and the correct specification for each application.

Ultimately, you need to work with a labelling system supplier who has the right level of knowledge and experience in the pharmaceutical sector. They should be able to advise you what accessories you need for compliance and also ones that will prove commercially beneficial to you. They should also be able to seamlessly integrate such accessories into their labelling system, fully validated.

At Newman, we approached this differently with our Faulty Label Removal (FLR) system. In the event of missing or ‘bad’ overprint information, barcode or 2D matrix code, the FLR system will remove the faulty label from the label web prior to application onto the container. These faulty labels are then transferred to a paper roll for batch reconciliation and inspection.

A missing label on one single container could lead to a total batch product recall. An accessory to identify if the label is on the container following the labelling process is therefore important. The industry standard is to look for luminescence in the label using a UV sensor, although vision systems can perform the same task using a different method. It is then common practice to reject containers and/or stop the labelling system in the event that the container itself is out of specification, a faulty label is fitted or no label has been applied.

One accessory that is available at this stage of the process, but that I think should raise a red warning flag, is a vision system to measure label skew. A well-designed labelling system will apply labels precisely and repeatedly and should therefore make such an accessory redundant. This is one example where an accessory can easily be misapplied, adding unnecessary cost and complexity to the labelling system.

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DRUG DELIVERY

The trend of self-administered therapies is expected to grow, according to research, due to, in part, the increased incidences of chronic conditions and the development of biologics to treat these indications.

However, self-administrative devices need to be safe, intuitive and reliable with a design that supports patient adherence being vital. Here, SHL detail some important design considerations.

“

T

he growing emphasis on self-administered therapies has given rise to injectable drug delivery devices such as auto injectors and pen injectors. According to research, this trend is expected to grow at an annual rate of 7.6% until 2026.1

With self-administered auto injectors, patients can avoid expensive and time consuming visits to clinics and hospitals, and deliver the treatment themselves in the comfort of their own homes.

”

Important factors contributing to this growth are the increased incidence of a number of chronic conditions as well as the rapid development of biologic drugs to treat these indications, such as diabetes, autoimmune diseases and cancer. With self-administered auto injectors, patients can avoid expensive and time consuming visits to clinics and hospitals, and deliver the treatment themselves in the comfort of their own homes.

Nevertheless, as injections are administered without the supervision of healthcare professionals, designing a safe, intuitive and reliable drug delivery device that supports patient adherence is at the forefront of the development of any self-administered system.

Putting usability first The purpose of any medical device is to support treatment outcome.

Research has shown that reducing fear and anxiety can help improve

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patient adherence,2 as such, comfort and usability are fundamental to self-administered drug delivery. To meet this end, self-injection devices must be intuitive, safe and reliable so as to meet the unique challenges of every single disease. For example, patients with rheumatoid arthritis suffer from dexterity issues and often have difficulty gripping and holding onto objects. SHL’s auto injectors are designed taking this into consideration, improving usability with features such as enhancing the device’s grip, including a cap that is easier to remove, as well as incorporating simple and intuitive two-step or three-step operations.

A well-designed device, however, is not just about how one grips and holds a device; it is also about how the device is understood and accepted by the patient. Auto injectors should also include proper visual, audio and tactile feedbacks to help users gain a better understanding of what is going on both outside and inside the injector.

These feedback mechanisms help ensure the successful delivery of treatment, and also give the patients more confidence when selfadministering the injection.

Prescribing less frequent injections Today, with the development of the new generation of biologic drugs, there is a growing trend in the pharmaceutical industry to further optimise patient comfort with formulations that require less frequent dosing. Nevertheless, when formulating a biologic drug for this purpose, developers often face challenges with high viscosity, which may also lead to higher volumes.

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The question, therefore, is what position will self-treatment and auto injectors have on the development of these new drugs, and how will the method of delivery further benefit the patient?

The answer to the latter is clear. Using an auto injector, patients no longer need to be confined to hospital treatments; with less frequent injections, they will have even more freedom to lead normal lives while living with a chronic disease. However, as first generation auto injectors were developed for smaller volumes and lower viscosities, an auto injector capable of delivering high viscous/high volume formulations requires a more advanced technology. With this new technology in place, pharmaceutical companies can save time and costs reformulating their biologics and bring their products to market in a timely manner.

Building upon more than 10 years of experience with auto injectors for highly viscous drugs, SHL has developed the Rotaject, a constant force technology that makes the delivery of formulations with viscosities of up to several hundred centipoise possible within seconds. To meet the request for a wider range of volumes, the technology is also compatible with disposable auto injectors using either a 1.0 mL or a larger 2.25 mL syringe.

outcomes for patients with diabetes.3 In drug delivery, connected devices can support adherence through communication with a smartphone or a cloud-based system. At a basic level, connected systems can track injection records, send reminders for the next injection and provide additional services, such as in-app training, for patient support. Moreover, with the collected data, larger opportunities are opened-up for not only the patients, but also for healthcare professionals, payers, pharmaceutical companies and other stakeholders.

With an increasing number of biologic drugs being developed and the popularity of auto injectors continuing to grow, pharmaceutical companies have begun seeking differentiation for their drug delivery devices. While connected solutions can serve as a means to this end, to provide a truly valuable experience for patient and other stakeholders, drug delivery systems need to be developed with a weighted approach that is aimed at improving patient adherence and safeguarding treatment outcome. With near three decades of experience developing advanced drug delivery injection devices, SHL uses multilateral approaches to develop solutions that bring value for both patients and stakeholders alike.

Adherence and beyond References:

The challenge that comes with self-administering less frequently leads us back to adherence − helping patients administer their injections in a timely manner, and also ensuring that the injections are conducted correctly.

A study by Minnock shows that a simple add-on device with reminders about the time since last injection can significantly improve health

1. Global Autoinjectors Market 2016–2026. Roots Analysis, 2016.

2. Miller, T.A., Patient Educ. Couns., 2016;99:1079–1086.

3. Examining the Effects of an Insulin pen compliance device on HbA1C and lifestyle on Individuals living with Type 1 Diabetes Mellitus, Minnock, D., O’Donnell, S., Doyle, G., Canavan, R., O’Shea, D., Conference Paper https://www.researchgate.net/ publication/313800507_Examining_the_Effects_of_an_Insulin_pen_compliance_device_on_ HbA1C_and_lifestyle_in_Individuals_living_with_Type_1_Diabetes_Mellitus

A well-designed device must be intuitive, self-instructing and designed to meet various user needs.

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LAB INNOVATIONS PREVIEW

Dedicated to innovation A brief preview of the forthcoming Lab Innovations event, highlighting some key educational aspects the event will be offering and the opportunities the exhibition proposes.

R

eturning to the NEC in Birmingham, UK, for its sixth consecutive year is Lab Innovations — the UK’s only dedicated showcase for laboratory, analytical and biotech equipment.

As a global leader in research and development, the UK is an ideal location for companies to showcase the latest advances in technologies and product portfolios to help drive laboratory efficiency.

Organised by Easyfairs, this free-to-attend show will feature more than 150 manufacturers and suppliers of laboratory products and will be taking place between 1 and 2 November.

live theatres covering the latest trends in laboratory science.

Live Lab will feature demonstrations of a wide range of recently released products, complemented by the all new Insights and Innovations theatre, looking at the latest advances in food and drink technology, life sciences and pharma, laboratory sustainability, funding strategies in the face of Brexit, LIMS and the laboratory of the future. The panel discussion ‘Automation vs training’ is sure to raise some interesting questions; increasingly automated laboratories may well be the future of high output research, but at what cost of the training and availability of new scientists?

Everything the laboratory needs Lab Innovations has much to offer science professionals, from laboratory technicians, analytical scientists, engineers and managers, all the way up to chief executive officers. A diverse selection of exhibitors covers a wide range of sectors, including manufacturing, life sciences, chemical, pharmaceutical, food and drink, education, medical and healthcare, government, water and wastewater.

The exhibition offers the opportunity to take a step away from online or paper catalogues, and see the products up close and in person. With suppliers and manufacturers all under one roof, visitors will have the perfect chance to discover the latest developments and product releases, browsing the stands and discussing state-of-the art technologies as they wander around the exhibition hall.

New exhibitors for 2017 will include Microlit, Thermo Fisher Scientific, VWR International, GS Biotech, Alphatech and LabVantage Solutions, alongside companies such as Eppendorf, Shimadzu and Scientific Laboratory Supplies (SLS) that are returning for another year, providing the perfect environment for effective face-to-face business conversations.

An educational experience Lab Innovations continues its strong links with the scientific community, with partners for 2017 including GAMBICA, Laboratory News, the Science Council, the Royal Society of Chemistry, Innovation DB and UKSPA. Over the course of the two days, more than 35 hours will be dedicated to seminars and discussions focused on current hot topics, with a packed schedule spread across three 64

Continuing the long association between the Royal Society of Chemistry (RSC) and Lab Innovations, the RSC theatre returns with an engaging programme that will pique the interest of exhibitors and visitors alike. From artificial intelligence in drug discovery to automated laboratories, counterfeit pharmaceuticals and the medical potential of cannabis, there is something for everyone. In addition, the event will include sessions from the RSC’s careers service — ‘Get the skills to beat the robots’ — helping scientists future-proof their careers in light of the changing and complex labour market.

Keynote presentations make an important contribution to the conference arena, and the RSC has engaged two exceptional speakers; science writer and broadcaster Adam Rutherford, and award-winning product design engineer Jude Pullen. Adam will be speaking on ‘Pipetting in Hollywood: my life as a scientific advisor in films’, drawing on his experiences as a scientific adviser for the film industry and discussing the potential of blockbusters and popular culture to normalise science. On a different note, Pullen will be taking an anecdotal look into ‘Scratching the inventor's itch’, exploring the environment needed to foster scientific curiosity, and identifying what sets innovative companies apart.

A ‘must attend’ event With so much on offer, Lab Innovations has something for everyone. Come and hear inspiring speakers, find out about the latest product launches, network with fellow innovators, and get involved in interactive seminars and hands-on demonstrations. It’s an event not to be missed.

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Frankfurt, Germany, 14 – 17 November 2017 formnext.com

Simply limitless.

Engineers think like children. There are no limits, only possibilities.

Join us and be inspired at formnext powered by TCT, the international exhibition and conference for Additive Manufacturing and the next generation of intelligent industrial production.

Where ideas take shape.

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O Diary entry

LAB DIARY

#7

In this instalment, R&D software provider, IDBS evaluates data safety and cloud computing.

For pharma companies, nothing is more important than protecting their data and intellectual property (IP). If these were to fall into the wrong hands, the damage could be significant – both financially and in terms of reputation.

There are also other challenges. What happens when your contract terminates with your collaboration partner? Have the most recent versions been captured? Will they delete their inbox? Wait... you’re sending data via email? Really?

The average total cost of a data breach in the global healthcare industry, according to a 2016 survey by IBM,1 is $4 million – a 29% increase in total cost since 2013. With the price of getting it wrong so high, it’s only natural for organisations to take every measure possible to protect their data and their IP. But, instead of locking their data in an in-house Fort Knox, organisations are looking somewhere else entirely. They’re turning to the cloud.

When security should be paramount, too often collaborative projects see corners cut. By using a cloud-based system, organisations can provide partners with a neutral environment for collaboration, alongside the ability to restrict the access levels available to third parties, meaning private data remains inaccessible and secure.

On face value, concerns about data theft or loss might seem completely at odds with the industry moving towards cloud computing.

Despite this, 80% of enterprises globally are already using the cloud to store their data,2 and the use of cloud-based solutions is showing few signs of slowing. Why?

Ensuring overall security of data

More than simply cost-saving Cloud-based systems are increasingly popular with all kinds of businesses – they simplify deployment processes, they’re popular with IT teams who can use their time more productively elsewhere, they can be up and running pretty quickly and, ultimately, they can cut costs. That’s not the whole picture, though.

Threats to data have never been more evident. Earlier this year, the Swedish government was plunged into crisis after personal information was leaked to outsourcing IT contractors in other countries, who had not yet undergone security checks. In terms of scale, the loss of data was staggering: nearly every single Swedish citizen was affected.

So, what’s this got to do with lab data and the cloud?

Managing outsourcing partners The scientific landscape is changing, and more and more organisations are turning to external collaboration partners – like contract research organisations (CROs), joint ventures and academic partnerships. As the Swedish government learned, sharing data with organisations outside your firewall can be a messy business. Giving third parties access to your corporate systems by punching through your corporate firewall could make collaborating easier, but it’s not going to help your relationship with your CIO, and it’s definitely not going to keep your IP as secure as it should be.

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The cloud’s benefits don’t stop at ensuring collaboration projects are secure – and contrary to popular beliefs, an organisation’s business information can be far more secure in a cloud solution than in a traditional software on-premise situation.

Backed by a large web provider, data stored in the cloud can be protected by the most advanced security measures available, many of which are simply out of reach for organisations working on their own or using in-house or on-premise technology. Data centres are manned 24/7/365 (we did mention Fort Knox earlier…), access can be restricted to certain IP address ranges and intrusion detection systems can identify and block any malicious traffic.

The recent hurricanes in the Caribbean and Florida have also highlighted the importance of disaster recovery – if data is stored in one location, it risks being lost forever. By providing two separate geographical locations, cloud providers can store and identically mirror all data. And should anything happen to one of these locations, operations automatically pass to the secondary data centre, meaning no downtime and, more importantly, no data loss.

Organisations are right to be concerned about the safety and security of their data, and given the high stakes involved, it is only right for businesses to be vigilant (and even sceptical) when considering how and where to manage data – but when it comes to new technologies, staying away can sometimes be more damaging that staying put.

It might be time to change your perception of the cloud…

References: 1. https://www-01.ibm.com/common/ssi/cgi-bin/ssialias?htmlfid=SEL03094WWEN 2. https://dtr.thalesesecurity.com/insiderthreat/2015/

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