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Contents Jan/Feb 2018 | Volume 18 Issue 1

Regulars

Features

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18

Looking at why the results of the current flu vaccine are variable and what one company has in clinical development that may offer a solution.

In this article, NSF International details the potential ramifications of Brexit may be on the regulatory landscape in pharma.

EDITOR’S DESK

LEGAL — REGULATORY

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ANALYSIS

DRUG DELIVERY

Discussing why organisations need to take the issue of operational downtime seriously.

Highlighting the technological advancements that are having an impact on R&D timelines and how they can be applied on a wider scale, as well as discussing how hot melt extrusion finds use in the continuous production of drug implants.

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OPINION Evaluating important considerations in managing the natural variability of plant-based pharma ingredients, listing five reasons why ecommerce is on the rise and looking at how measurement can help with the industrial strategy.

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REGULATORY AFFAIRS

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group editor lu rahman, lu.rahman@rapidnews.com reporter reece armstrong reece.armstrong@rapidnews.com publisher duncan wood

advertising

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Here, EPM sits down with Schott to discuss the impact of glass tubing on future packaging challenges.

IMA and BASF describe their recent study comparing three different coating technologies’ efficiency in a pellet coating process.

The first of our new series gives seven key tips that should be remembered when trying to implement a successful mHealth strategy.

deputy group editor dave gray david.g@rapidnews.com

This case study details SchubertPharma’s automated solution for a small-component packaging task.

PACKAGING

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TECH TALK

editorial editor felicity thomas felicity.thomas@rapidnews.com

production

THE YEAR AHEAD

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Tel. +44 (0)1244 680222 Fax. +44 (0)1244 671074 Web: www.epmmagazine.com

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Sharing some tips and insights on how to successfully implement solutions for serialisation and providing an update on the regulatory developments impacting pharma as a result of Brexit.

ON THE COVER

head office Carlton House, Sandpiper Way, Chester Business Park, Chester, CH4 9QE.

What to watch out for over the coming 12 months that should have an impact on the pharma landscape, according to some industry leaders…

OSD MANUFACTURING

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 18 Issue 1 © Jan/Feb 2018 While every attempt has been made to ensure that the information contained within European Pharmaceutical Manufacturer is accurate, the publisher accepts no liability for information published in error, or for views expressed.

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

BPA Worldwide Membership ISSN No - 2052-4811

editor’s desk Shot in the dark?

As we embark on a difficult flu season, I look at why infection rates vary so much year on year and the potential universal vaccine one company is progressing through the clinical development stages.

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s I sit in the office surrounded by coughing and spluttering, sneezing and wheezing, it came as no surprise to me to find out there has been a surge in flu cases this year. The signs and symptoms of a difficult season ahead for the northern hemisphere became clear after reports landed about the experiences of Australia and New Zealand where hospitals had struggled to cope.

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But, why, in this day and age of medical innovation, are we still encountering such variances in infection rates year to year from a seasonal virus and why can the vaccines’ efficacy be universal such a ‘shot in the dark’?

[The] flu vaccine… is unique from the traditional versions as it uses proteins that are housed within the core of the virus to stimulate the immune system…

Part of the reasoning as to why the efficacy of the flu vaccine varies is that the virus itself keeps mutating and there are multiple strains in circulation simultaneously.

However, another truth behind the variability is the science of how the flu vaccination is created, which some have described as ‘imprecise’.

Currently, vaccines to combat seasonal flu are created from viral strains that are deemed to be the most likely ones to be in circulation by the World Health Organisation (WHO) — this assessment is performed in February for the northern hemisphere and September for the southern hemisphere. Production of the vaccine is then started a month after the announcement so that it can be ready for the general population just before the winter season begins.

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Obviously, this approach means that there is an element of uncertainty about efficacy. If WHO predicts the correct strains then most people who receive the vaccination will be protected. However, if the strains are incorrect, then the proportion of people protected becomes much lower.

This universal flu vaccine, which has already been successfully tested for safety in 145 people, is unique from the traditional versions as it uses proteins that are housed within the core of the virus to stimulate the immune system to boost influenza-specific T-cells rather than antibodies. According to the company,2 previous research has demonstrated that these T-cells can help the body to fight more than one type of influenza virus, which in turn should mean more people are protected after receiving the vaccine.

More than 2,000 people aged 65 years and older have been registered at six general practices to take part in the trial over the course of the winter season. Those who participate will be randomised to either receive the current vaccine in addition to a placebo jab or the new universal flu shot. It is expected to be completed in 2019.

“If we get positive data that shows we can affect rates of hospitalisation and illness with influenza then there is no question in my mind that a partner would take this on,” said Vaccitech chief executive, Tom Evans when speaking with Reuters.3 “This could be a game-changer in a very competitive market.”

Although this is not the only universal vaccine for influenza out there, it is the first one that has made it into the second phase of clinical study.

So, as we brace ourselves for a rough flu season, this exciting progression offers some hope for a future where less injections are needed and more people can rest easy with greater protection against the virus.

For now, stay healthy and hope you enjoy the issue, Felicity

So, if there is always an amount of uncertainty with this method, is there another approach that could be used in the creation of a seasonal flu vaccine?

References:

Well, an Oxford University spinout company, Vaccitech, says ‘yes there is’! It has recently secured funding from multiple investors (including the venture capital arm of Google parent company Alphabet, GV) and has already begun its two-year Phase II clinical trial of a universal flu vaccine.1

1. https://www.vaccitech.co.uk/vaccitech-secures-20m-series-gv-osi-sequoia-china/ 2. https://www.vaccitech.co.uk/world-first-nhs-trial-for-universal-flu-vaccine/ 3. https://www.reuters.com/article/us-health-flu-vaccine/google-venture-arm-backs-uk-universalflu-vaccine-company-idUSKBN1F400H

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5

ANALYSIS

Time to get serious Avoiding operational downtime is a major issue for all organisations, as the related disruption and financial consequences can prove catastrophic. Following the publication of a major new report on the subject of energy resilience, Tim Wynn-Jones, head of distributed energy solutions sales at Centrica Business Solutions, suggests that organisations need to start taking it seriously.

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hese are uncertain and worrying times for the business world. While the threat from cybercrime, for example, is serious and widely recognised, it’s not the only issue that should be It is only on the minds of those charged when a failure with ensuring their organisations occurs that the remain operational at all times. operational In fact, security and continuity of energy supply is perhaps a more vulnerabilities pervasive and immediate issue, of a business are and resilience should, therefore, revealed, and be at the centre of any business the need for a continuity strategy.

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secure source of energy becomes apparent.

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Defining moment

Resilience is perhaps best defined as ‘The ability to prepare for and adapt to changing conditions and withstand and recover rapidly from disruption and other outside factors. Resilience includes the ability to withstand and recover from deliberate attacks, accidents, or naturally occurring threats or incidents’.

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currently a disparity between the threat posed by energy-related failures and the priority that businesses are giving to putting an energy resilience strategy in place.

Financial times No business can fully mitigate its business risks without ensuring that there is a secure and reliable energy supply. However, Centrica’s survey reveals that nearly one in three (32%) of organisations do not have any form of energy resilience strategy in place.

Despite this, more than one in two (52%) of energy decision-makers believe they will experience an energy-related failure within the next year, with one in three organisations claiming to be unprepared for a disruption to their energy supply from a temporary grid failure.

It is only when a failure occurs that the operational vulnerabilities of a business are revealed, and the need for a secure source of energy becomes apparent. Energy resilience helps companies reduce the risk of operational failures and reduce commercial risk, and it’s important that organisations take steps towards implementing a strategy.

While many acknowledge the reality of the threats to their energy supply, a phenomenon of ‘unrealistic optimism’ may have taken hold, whereby organisations think it can either never happen to them, or that someone else will take care of the problem. The implications of a power outage in somewhere like a hospital could literally be life-threatening. But there are numerous examples where outages have occurred in factories, data centres and other missioncritical environments with devastating effect.

To ascertain just how seriously organisations in the UK and Ireland are taking the issue, Centrica Business Solutions recently surveyed 301 decision makers, across a range of industries, who have responsibility for energy and operational effectiveness. The findings of The Resilience Report make for uncomfortable reading,1 and it’s quite clear that there is

Importantly, while those who had not experienced a serious energy failure predicted the cost of any failure to their business would be seven percent of their annual revenue, in reality, this figure is much higher — estimated at 17%. For the typical medium-sized business, this equates to £2.8 million each year in damages and lost opportunities.

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An interruption in supply doesn’t need to go on for long for it to have a long-lasting impact.

18% of respondents said that an outage of only one day would be catastrophic for their businesses, while the amount of damage caused rises steeply the longer the outage lasts. Consequently, 23% of businesses have suffered equipment damage, with 14% reported having lost inventory.

Tools of the trade Although blackouts are obvious threats to on-site equipment, other conditions can also cause problems. Brownouts occur when the mains supply cannot cope with its overall load and the voltage levels reduce, in extreme cases for periods measured in hours. Mains power can also sag, or drop in voltage level for a few cycles, usually after a large load such as air conditioning or rotating machinery is switched on.

Disruption of power to a single component may only cause a brief outage but result in a lengthy restart, taking hours to return to an operational state. And, despite great strides in technologies such as uninterruptible power supplies (UPS) and generators, they are often not specified, installed and maintained correctly. For example, as a minimum, backup power technologies must be sized to meet critical loads, and priorities for keeping specific systems energised must also be built into operating strategies. Existing on-site generation equipment, such as combined heat and power (CHP) plant, typically shuts down upon loss of grid power, but could be reconfigured to run in ‘island mode’ and improve overall resilience.

that 88% of businesses surveyed for The Resilience Report stated it was important and 58% said it is becoming critical for businesses to be energy resilient.

Furthermore, the prognosis on this issue is not a positive one, as 27% of businesses expect energy-related failures to become more frequent over the next five years, with four percent of the view that the number of failures will increase significantly.

Cause and effect The damage caused by an unplanned power outage goes beyond inventory and equipment though, with 18% of businesses claiming that outages have damaged their The damage brands and 19% of the opinion that relationships with individual caused by an unplanned power customers have soured as a consequence. The alarming outage goes truth here is that the value of beyond inventory a business is being eroded and equipment… in ways that are not directly attributable to their causes.

Finally, there is the human cost to consider — employees of 11% of businesses have been put in dangerous or life-threatening situations as the result of energyrelated failures. This is clearly unacceptable.

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Action plan Most organisations clearly identify the importance of energy resilience as a means of securing a reliable energy supply, and to prepare for an energy landscape that is undergoing massive change. It is clear, therefore, that businesses need to have an energy resilience strategy in place to address the risks and protect themselves.

Businesses need support in evaluating their options and developing the business case for change within their organisation, and there is now a diverse range of help available. Centrica has created an online benchmarking tool so users can quickly see how their energy resilience

measures up against industry standards and also offers a range of advice about how to develop an action plan based on the whole lifecycle including build, maintenance, measurement and financial planning.2 Without an energy resilience strategy, organisations can only be as successful as their energy supply allows and there are also additional tangible benefits to having a plan in place. Organisations that do so are 13 percentage points more likely to have a good brand reputation and seemingly have a 34 percentage points better chance of achieving strong financial performance.

Protect and survive Regardless of the sector an organisation operates in, energy means more than just keeping the lights on. It means allowing staff to do their jobs uninterrupted, maintaining profit, keeping customers happy and even ensuring that people are kept safe. The poor state of energy resilience today must be addressed, and businesses must implement a more secure future by forming a comprehensive and strategic plan to protect against outages, market fluctuations and equipment failure.

References: 1. https://www.centrica.com/news/uk-resilience-report 2. http://www.centricabusinesssolutions.com/resilience

Given that more than eight out of 10 businesses (81%) have experienced at least one energy-related failure in the last 12 months and 51% consider it likely that they will experience an event within the Without an energy resilience next year, the lack of strategy, action in organisations ensuring can only be as resilience in some successful as quarters their energy is simply supply allows baffling.

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and there are also additional tangible benefits to having a plan in place.

”

This is especially the case considering

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OPINION

Insulin online?

All signs are that the life sciences and healthcare market is ripe for disruption, with ecommerce coming into its own in the sector. Scott Allison, president Life Sciences & Healthcare, DHL, lists five reasons as to why it is happening now.

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he push for online pharmaceuticals is underway with multibillion dollar ecommerce markets opening up as you read this. Very soon, The life sciences patients around the world will and healthcare have a genuine alternative to receiving drugs direct from their sector may prescribing doctor and having have been to wait in line to fill prescriptions late to adopt at their local pharmacy. digitisation, but Alongside these traditional ecommerce is channels, a burgeoning trend set to propel it in life sciences and healthcare ecommerce means patients are forward in the very near future. starting to receive insulin along with many other life-saving pharmaceuticals literally to their doorsteps.

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Why now? Firstly, consumers are changing and transactions are becoming increasingly digitised. This drives the demand for ecommerce solutions, with consumers ordering and receiving products at home. In addition, physical barriers to life sciences and healthcare ecommerce are being removed. We can now deliver essential temperature control and sensitive product monitoring throughout the end-to-end supply chain. Added to this, logistics companies have achieved both cost efficiency and sophistication in serving the so-called ‘last mile’ of delivery — the final part of the journey required to ensure an item is safely and securely handed over to the right person.

Today, I believe there are five key drivers for the intense growth of life sciences and healthcare ecommerce, all working together to change the face of our industry forever.

1. Profit-seeking Providing pharmaceutical products to patients is an extremely profitable business. Recent data from the US indicates that Walgreens and CVS make at least 70% of their profits from the pharmacy outlets, which are typically tucked away at the back of their stores. This kind of margin makes it attractive for different players to try and take a share.

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2. Cost-cutting In traditional distribution channels, multiple parties have always had a finger in the pharma pie: manufacturers, wholesalers, distributors, pharmacies, doctors and hospitals, even the insurance companies. Ecommerce can cut costs by creating a direct relationship between the manufacturer and the patient.

Governments and regulators can see this and, as pressure is on them to reduce healthcare cost, change seems inevitable.

Take for example the new two invoice policy in China. To keep a firm grip on pharmaceutical profiteering, this system allows a first invoice to be issued by the manufacturer to the distributor.

After this, the only other invoice is from the distributor to the medical service provider or institution. Cutting touchpoints is an effective way of cutting costs (and it speeds up cycle times too).

3. Customer demand Patients are also consumers. Across many countries of the world consumers are very familiar with the convenience of online purchasing and expect consistency in their omnichannel experience. Many of these consumers are already buying healthcare supplies online, and their demands are propelling life sciences and healthcare ecommerce growth.

In developing countries with an immature supply chain infrastructure, customer demand may even result in a technology skip. In the same way as Africa embraced mobile banking in the absence of accessible traditional banking services, developing countries may now leapfrog and welcome direct-to-patient delivery.

4. Rejection of protectionism As technology and progress are enabling new business models, lobby groups are very involved in protecting and bolstering the existing pharmaceutical channels of large companies. These companies must decide whether to ‘disrupt or be disrupted’. Failure to

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participate can mean missing out on valuable new opportunities as an e-pharmacy. Around the world there is rejection of protectionism in favour of open access and customer centricity.

5. Sheer momentum It’s not all just about prescription drugs. Many of the largest pharmaceutical companies have huge businesses that sell consumer healthcare and OTC products in vast quantities via the biggest online platforms. Medical device companies are already selling products online to business customers so why not direct to consumers too? Of course, prescription sales are highly regulated but, like the proverbial last bastion, this is sure to fall with the sheer momentum of the ecommerce movement.

All signs are that the life sciences and healthcare market is ripe for disruption. Pharmaceutical companies and medical device manufacturers will continue to deliver in volume to wholesalers and distributors but they are now also embarking on direct-to-patient delivery. Ecommerce giant Amazon is hiring health professionals. There is a big slice of the healthcare market up for grabs — and the change is happening now.

Logistics is ready to respond with services tailored to different product types. For example, in big cities, essential insulin orders placed before 12-noon will be purchased with a fourhour delivery guarantee. Meanwhile, a supply of something less critical, such as aspirin, could arrive free of charge within a two- or threeday delivery window. When submitting online prescription orders for their patients, doctors will simply specify the delivery urgency in each case.

Patients will increasingly manage their own prescription medication online, as evidenced by the home delivery and pharmacy leader in ordering and refilling of prescription medicines, which embraces both a traditional pharmacy model and a home delivery model. The life sciences and healthcare sector may have been late to adopt digitisation, but ecommerce is set to propel it forward in the very near future.

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OPINION

Strategic measurements In this article, Michael Adeogun, head of Life Sciences and Health at NPL examines how and where measurement can help government and industry grasp the opportunities the Strategy and Sector Deal offer.

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ood measurement is vital to achieving the aim of the Life Sciences Industrial Strategy — to advance UK R&D to benefit the economy and society. As the UK’s National Measurement Institute, NPL helps to deliver the National Measurement System (NMS) A key theme of to provide the framework, facilities and expertise to enable the Life Sciences measurements to be reproduced with confidence, and with Industrial quantified uncertainty in the UK.

Strategy … is increased collaboration between the NHS and industry, to accelerate the adoption of new treatments.

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Many of the issues raised by the strategy, such as the need to accelerate access, foster growth of UK industry and ensure effective use of data, are priority areas for the NMS too. The NMS is also responding to the grand challenges identified in the Industrial Strategy white paper1 of supporting health ageing and leveraging the UK’s health data to improve health outcomes and UK leadership in life sciences.

Accelerating access

A key theme of the Life Sciences Industrial Strategy, which builds on the government’s Accelerated Access Review, is increased collaboration between the NHS and industry, to accelerate the adoption of new treatments.

Working in closer partnership is critical to drug attrition and ‘failing fast’ — to the benefit of industry and the patients. It takes the pharmaceutical industry 10-15 years and more than $1 billion to develop a drug to clinical trial stage,2 Phase II clinical programmes have the lowest success rate of the four development phases, with only ~30% of developmental candidates advancing to Phase III. With an improved measurement infrastructure in place, many drugs that go on to fail could be eliminated much earlier in the development process.

After receiving funding through the Industrial Strategy Challenge Fund NPL has strengthened its UK high-resolution mass spectrometry imaging facility to improve drug development and our understanding of disease states, which can be easily accessed by UK industry. The facility is supporting drug development through providing an understanding of where unlabelled drugs go in tissues and the changes induced by these treatments as well as better characterising disease tissue.

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The strategy also recognises the increasing role of physical sciences in the sector, and the value of interdisciplinary activity. An example of this can be seen in a current project NPL is working on, being funded by Cancer Research UK, which is aiming to revolutionise the prevention, diagnosis and treatment of cancer by creating a reproducible, standardised way to understand different tumours in greater detail. The team involved is multi-disciplinary, from a range of partner institutions, bringing new skills and approaches to an established problem.

Another aspect is reproducibility of research, which is vital in achieving scientific consensus earlier to help speed the uptake of discoveries. Standards provide certainty in the consistency of the product performance, which is crucial when deciding on the products that are to be commercialised by industry. Working with SynbiCITE at Imperial College London and in collaboration with LGC and NIBSC, NPL is establishing a new £7 million virtual lab to help the UK synthetic biology industry improve the manufacturing and adoption of new products through standardisation.

Fostering growth

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The need to nurture start-ups and encourage growth was also encouraged by the Life Sciences Industrial Strategy, as was the expansion of manufacturing in the sector.

The need to nurture start-ups and encourage growth was also encouraged by the Life Sciences Industrial Strategy, as was the expansion of manufacturing in the sector. As part of the strategy, the government announced £146 million to help fund new manufacturing centres for vaccines, cell and gene therapy and medicines manufacturing, in addition to announcing increasing R&D investment, to 2.4% of GDP, to ease cooperation between academia and industry in this area.

Funding through the Industrial Strategy Challenge Fund is being used

by NPL to establish the UK measurement infrastructure for medical imaging technologies, to deliver new testing capabilities supporting the development, translation and adoption of these imaging technologies.

The project will ensure acceleration of the development and adoption of the latest measurement techniques and best practices. Additionally, NPL is working to identify and engage with medical imaging companies to improve competitiveness, support the access to new markets, and help deliver higher revenues and job creation.

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NPL is also working to discover, screen and validate new classes of antimicrobials with Ingenza, a world leader in the application of industrial biotechnology and synthetic biology, and the University of Plymouth, through an Innovate UK grant, to tackle antimicrobial resistance, a problem that could cause up to 10 million deaths each year by 2050.3 The project will use a class of antimicrobials, called epidermicins, which naturally target superbugs like MRSA, to enhance the range of bacteria they can kill as well as the potency at which they can do the strategy this. The project will also look to scale up production of outlines the need these antimicrobials for further testing and clinical trials, to make the best helping to accelerate their development.

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use of data and digital tools to support research and better patient care.

Data and digital health

Finally, the strategy outlines the need to make the best use of data and digital tools to support research and better patient care. This is also highlighted in the recently published Industrial Strategy white paper and the Life Sciences Sector Deal. The UK is unique in having a long-running national health service. With this comes long-term data sets, which can be helpful in finding trends, co-morbidities and effectiveness of treatments to improve healthcare.

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To realise this opportunity both industry and biomedical researchers need high quality data and longitudinal samples at scale, with longterm follow up, and scope to explore multiple technologies. This also requires standardisation and regulation to be embedded to ensure different systems can be correlated and combined such as radiology and pathology systems. Through high quality, validated and standardised data, AI and machine learning tools can be developed. NPL is also exploring how metadata around data quality might be stored at a machine-readable level, to make this information more accessible and is developing data standards to ensure the integrity of data, accelerate its use in critical applications and ease the integration of non-medical datasets, such as those from wearables, into a clinical setting.

The vision The vision of the Life Sciences Industrial Strategy and the process initiated through the Life Sciences Sector deals is to make the UK a world leader in this sector — and this should only be welcomed. To get there, progress is required across the research, technology, manufacturing and regulatory landscapes, and measurement is critical to achieving this. We look forward to working with partners in industry, academia and government to realising this vision.

References: 1. https://www.gov.uk/government/publications/industrial-strategy-building-a-britain-fit-forthe-future 2. http://www.pharmaceutical-journal.com/publications/tomorrows-pharmacist/drugdevelopment-the-journey-of-a-medicine-from-lab-to-shelf/20068196.article 3. https://amr-review.org/background.html

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OPINION

Sowing the seeds of consistency In this article, Hervé Sibillat, general manager, ADM-SIO, discusses the important considerations in managing the natural variability of plant-based pharmaceutical ingredients.

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V

ariations in the composition and physicochemical properties of pharmaceutical ingredients can have a significant impact on the safety and performance of the final drug product. A failure to properly manage the process has been the root cause of several recent recalls by the US Food & Drug Administration (FDA). Indeed, ‘variability reduction’ is identified as a key objective of the ICH Q10 Pharmaceutical Quality System.

Process management is of critical importance in controlling the variability of naturally derived pharmaceutical ingredients.

Meanwhile, manufacturers are continuing to innovate with active pharmaceutical ingredients (APIs) and excipients for pharmaceutical products. Highly purified, injectable-grade oils from vegetable origins, for instance, hold promise in applications ranging from large volume emulsions for parenteral nutrition, to use as excipients to address the solubilisation hurdles associated with lipophilic drugs.

However, the safety, quality and stability of vegetable oils is not easy to control. With the starting materials subject to diverse cultivation techniques, weather conditions and soil characteristics, a full risk assessment should always be carried out to identify the attributes that could impact the performance of the final dosage form. From material sourcing and categorisation, through to purification process design and stability studies, managing variability across the supply chain is critical to ensuring consistent plant-based pharmaceutical ingredients.

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Starting with the source Highly purified pharmaceutical oils are normally derived from either crude (solvent-extracted, such as soybean oil) or virgin oil (pressure-extracted, such as olive oil). Right from sourcing of the raw material, there are a number of product variability parameters to take into consideration when working with naturally-derived substances for use in pharmaceutical

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applications. Taking vegetable oils as an example again, the fatty acid composition is influenced by factors as challenging as sowing density, rainfall levels and soil structure. The way the crop is stored can also impact on quality, with poor conditions leading to the presence of mycotoxins, while an inappropriate drying environment may result in the formation of polycyclic aromatic hydrocarbons such as benzo(a)pyrene.

To guarantee a certain fatty acid profile, it is important to select a supplier that works with the correct crop cultivar. Limiting sourcing to some months of the year, nonetheless, can help to achieve characteristics including a specific UV absorbance. However, ensuring quality and consistency does not stop there. Systems need to be in place throughout the extraction and production processes to avoid issues such as cross-contamination.

Purification process design When working with vegetable oils, potential contaminants include pesticides, heavy metals and residual solid particles — all of which could negatively impact the quality attributes of the refined product. Conversely, some compounds — such as tocopherols, the antioxidants that naturally occur in most vegetable oils — are beneficial and need to be preserved as much as possible during processing.

It is for this reason that — in line with a good manufacturing practice (GMP) approach — the starting material received from the supplier for purification should always be tested to identify the different substances present. A careful analysis of the vegetable oil at this stage also allows the purification process to be adjusted depending on the variability of each batch. In-process controls (IPC) and real-time monitoring can then be used to fine tune conditions and guarantee the best batch-to-batch consistency. Out of trend (OOT) stability results will also immediately identify any process deviation.

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Alongside a knowledge of the critical product parameters, understanding the link to the process parameters is the key to minimising fluctuations in the quality of nature-based pharmaceutical ingredients. External contamination, for instance, can be avoided by conducting the purification steps in a closed environment with a high vacuum, which will remove residual oxygen and limit oxidation of the fatty acids. Nitrogen blanketing, meanwhile, can prevent oil oxidation and improve shelf life stability, while maintaining the optimal process temperature will help to avoid oil degradation and maintain the natural antioxidant content.

Completing the supply chain Once the highly-purified vegetable oils have been produced, stability studies are essential to provide evidence of how the quality of an API or excipient varies with time. During storage and transport, performance can be influenced by environmental factors, such as temperature, humidity and light. Here, ICH Q1A gives useful guidance, for instance, it recommends that tests are conducted with pharmaceutical ingredients kept in storage conditions similar to the climate of the region where the final drug product will be shipped.

Process management is of critical importance in controlling the variability of naturally derived pharmaceutical ingredients. The major challenge for pharmaceutical laboratories is to carefully select suppliers that have the capacity to apply strict criteria throughout the sourcing, manufacturing and transportation of products.

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As a global supplier of highly purified pharmaceutical oils, ADM-SIO, has a network of cGMP compliant manufacturing facilities, enabling it to implement full management of the natural variability of plant-based pharmaceutical ingredients across the value chain, including from the sourcing of the raw materials. Additionally, it is working with both the European and US Pharmacopoeias to establish new monographs and develop advanced analytical techniques, in particular for injectable oils.

...managing variability across the supply chain is critical to ensuring consistent plant-based pharmaceutical ingredients.

”

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REGULATORY AFFAIRS

Brexit update Here, Vikash Patel, senior regulatory specialist for ELC Group, gives us an update on the regulatory developments impacting the pharma industry as a result of Brexit.

These days there doesn’t seem to be a moment that goes by where there isn’t some snippet of news on the great Brexit plan. As to be expected, something of such magnitude will have ramifications across all sectors of life.

Naturally the regulatory aspects of drug registration and life cycle management are both areas that will require very careful planning and implementation, as well as constant revision of such plans as more clarity is fed down from the EMA. What is becoming abundantly clear is that, despite the best efforts of all parties involved, Brexit will be anything but smooth. There will be a huge amount of frustration, lack of clarity and shifting of the goalposts as we hurtle towards March 2019.

The story so far…

What we know thus far is that on 20 November, the EMA decided to relocate its offices from London to Amsterdam. The move has to be executed by the 30 March 2019 at the latest, and there will be expected bumps along the way regarding transition.

The EU commission has also stood firm in insisting that the UK pay the anticipated £400 million-plus bill for the relocation. So, we can see the mood from the EU commission and the EMA is a frosty one at best.

This recent development has been followed up by two new documents. Firstly, the EMA

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has released updated procedural guidance on Brexit-related changes. This guidance includes how to classify variations, what supporting documents are required and whether variations can be grouped, as well as many more items.

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With the clock ticking for Brexit, it is imperative if you are an MAH, manufacturer or involved in the supply chain that you should be actively preparing and planning for all Brexit-related changes.

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Subsequently, the EMA has just released an updated Q&A document giving organisations further guidance related to Brexit submissions, specifically covering situations where the UK is part of the MA registration in various aspects such as API, batch release, QPPV, MAH and so on. Some of the main points raised in these two documents are as follows: generic/hybrid applications for which marketing authorisations will be granted after 29 March 2019 should refer to a RefMP (reference product) that is or has been authorised in an EU-27 Member State or a contracting state of the EEA (European Economic Area); any bioequivalence studies conducted with a medicinal product sourced in the UK can be used in generic/hybrid

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marketing authorisation applications (MAAs) only if the marketing authorisation is granted before 30 March 2019; and batches of the RefMP released by the UK after 29 March 2019 will not be considered as a Union (EEA)authorised comparator. Moreover, for any orphan designation applications submitted after 29 March 2019, patients in the UK should no longer be taken into account in the calculation of the prevalence of the disease in order to meet the requirements for orphan drug designation as set out in Regulation (EC) No 141/2000, i.e., a condition affecting no more than 5 in 10 thousand persons in the Union (EEA).

The clock is ticking With the clock ticking for Brexit, it is imperative if you are an MAH, manufacturer or involved in the supply chain — and some or all of your operations rely on UK supply — that you should be actively preparing and planning for all Brexit-related changes. There are only 16 months remaining and the regulatory landscape is expected to develop further, so it is vital that a robust regulatory impact analysis is undertaken on your product portfolio.

There are many CROs out there that can provide fluid support on what will be a regulatory intense time. Whether that means acting as local QPPV, or as MAH or batch release site, helping to look for a new API supplier or FP manufacturer or updating your PSMF, CROs can be a useful tool in your action planning and execution.

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REGULATORY AFFAIRS

Here, Dan Anslow, UK sales manager with Crest Solutions, shares some key tips and insights, learned through partnering with pharmaceutical manufacturers that have already successfully implemented solutions for serialisation, aggregation and Track & Trace.

Effective in Europe from February 2019, EU directive 2011/62/EU, also referred to as EU FMD, aims to reduce counterfeiting of prescription drugs by tracking and tracing the passage of drugs through the entire supply chain.

Under the directive, all new packs of prescription medicines placed on the market in Europe from February 2019 onwards will have to bear two safety features: a verifiable unique identifier (serialised code) and an anti-tamper device.

Serialisation is the process by which the pharmaceutical manufacturer, using country specific regulations and GS1 standards, must assign and apply a unique serial number (in both a 2D data matrix barcode and human readable form) to an individual item to be sold to a consumer, this product identifier is recorded on the outer packing.

As someone who has worked at the coal face of the design and implementation of Track & Trace systems, I have seen first-hand the realities of achieving compliance with regulations including the FMD. Below I have outlined some key tips and insights that I have learned when partnering with pharma manufacturers that have already successfully implemented solutions for serialisation, aggregation and Track & Trace.

For those that are beginning or in the process of implementation, use the below guide to avoid common pitfalls and benefit from identified areas of good practice on your journey to compliance.

Serialisation and the EU-FMD • To avoid both product contamination and product counterfeiting, many countries have introduced regulation, typically referred to as ‘Track and Trace’ or ‘serialisation’ which protects the integrity of a bone fide pharmaceutical carton or bottle.

• In the case of the European Falsified Medicines Directive, the regulation deadline is the 9 February 2019.

• The EU-FMD pertains specifically to the lowest saleable item of prescription medicine, which requires a unique reference number or ‘serialisation number’ which is displayed as human readable text and embedded within a 2D matrix.

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• The carton or bottle must also must contain anti-tamper evidence.

• The unique codes will be transferred to the EMVO, commonly known as the European Hub, which will then transfer the codes to the relevant national hubs where the product will be sold.

• At the end of the supply chain a pharmacist will scan the 2D bar code and in real time check with the National Hub that the code is bone fide before releasing to the patient.

The three components of a successful serialisation implementation There are three key components of serialisation, and they might not be what you expect: • Stakeholder engagement • Vendor selection & relationship • Staff training

Things to watch out for • Ensure your team is on board from the very beginning. The relevant stakeholders and teams must have a clear understanding of the scale and impact of the project to be undertaken and what will be required of them.

• When selecting a vendor, consider experience and their ability to support your site on the ground.

• As regulations in this sector are evolving, technology can be immature and, with the best of intentions, vendors can over-promise. Ensure you complete due diligence and test the systems in any possible environment (demo or reference sites) for weaknesses throughout the development process.

• Visits to reference sites where solutions have already been implemented are a must!

• Your team of line operators will appreciate an understanding and training in this technology.

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LEGAL - REGULATORY

Potential impacts of Brexit In this article, NSF International goes into detail about what the potential ramifications of Brexit may be on the regulatory landscape in pharma.

T

he only thing that is certain following the UK’s momentous decision to leave the European Union (EU), so called Brexit, is that the pharmaceutical industry, as all others, is facing at least two years of unprecedented uncertainty.

may be perceived by the EU as the UK wanting to ‘have its cake and eat it’. The Commission is already seeing EU Member States pushing their national agendas on a range of issues and they will likely not want to be too accommodating of the UK in future trading relationships.

One possibility is that the UK will seek to join Norway, Lichtenstein and Iceland in the European Economic Area (EEA). If this were to happen, If the UK does comparatively few practical not join the EEA, changes would be required for it will become medicinal products. However, a third country politically it would appear to be very unlikely that the UK will seek as far as the EU to join the EEA. is concerned

On 21 September the UK Parliament’s Commons Select Health Committee announced the launch of an inquiry into the regulatory arrangements needed to guarantee safe and effective supply of medicines, medical devices and products post-Brexit. Written submissions were made by many companies and industry associations. Public hearings were expected to be held in December 2017.

and this will lead to much more profound changes.

European Medicines Agency (EMA) relocation

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If the UK does not join the EEA, it will become a third country as far as the EU is concerned and this will lead to much more profound changes.

The UK government published a Brexit position paper, Continuity in the availability of goods for the EU and the UK, in late August 2017 and an industrial strategy white paper in December 2017. Its position for medicinal products and medical devices appears to be that it would like the UK to continue working with the EU as though Brexit hadn’t happened. However, the UK’s proposals

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The EMA is moving its headquarters from London to Amsterdam. The choice of Amsterdam has generally been well received by industry and the EMA, but the move will have resource implications for both the EMA and the UK’s Medicines & Healthcare products Regulatory Agency (MHRA), which has provided the EMA with up to 40% of its scientific expertise.

The MHRA has said it can envisage two possible futures post-Brexit: continue working in partnership with the EMA or operate as a standalone agency.

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Brexit implications In late May 2017 the EMA and European Commission published the first in a series of guidance documents to help pharmaceutical companies responsible for both human and veterinary medicines prepare for Brexit. Potential changes that would be required with the UK leaving the EU and becoming a third county are:

Pharmaceutical legislation Most EU pharmaceutical legislation has been issued as directives, which have already been transposed into UK legislation; mostly in The Human Medicines Regulation 2012 (Statutory Instrument 2012–1916). However, this statutory instrument (SI) will be part of the UK government’s grand bill to repeal the European Communities Act 1972, which will transpose the existing provisions unchanged, at least initially, into UK law.

GMP and other regulatory guidance The MHRA has had significant input into the development of GMP and other medicinal product guidance, and the EU GMP guide has been heavily influenced by UK inspectors.

However, the European Commission has published plans and draft text that fragments EU GMPs, with separate GMPs for marketed

products, IMPs and ATMPs. This has been opposed by all EU inspectors, but the Commission appears to be pressing ahead. It’s possible the UK will not follow this breakup of GMP, especially if the Pharmaceutical Inspection Co-operation Scheme (PIC/S) also chooses to depart from the EU model.

The MHRA will want to continue to influence via organisations such as PIC/S, where it recently had chairmanship, and the International Council for Harmonisation (ICH), where it would likely become a member.

MRAs, regulatory inspections and imports If a mutual recognition agreement (MRA) or an agreement on conformity assessment and acceptance (ACAA) is agreed prior to Brexit, not much will change between the UK and the EU. Without MRAs or ACAAs, UK companies would be subject to inspections by EU authorities and the MHRA would be required to inspect in EU Member States, which it is not currently staffed to do.

The UK will need to agree its own MRAs with countries that currently have MRAs with the EU. This will add to the MHRA’s work in the short term if there is a lag between the UK leaving the EU and the signing of UK MRAs. If MRAs are not place when the UK leaves the EU, product exported from the UK would need to be re-tested on importation to the EU. The UK could choose to also test product coming from the EU, which could mean transferring hundreds of analytical methods.

The MHRA could lose its access to the EudraGMDP database, so its inspection outcomes would no longer be entered.

Qualified persons (QPs) The role of the QP is already UK law via SI 2012-1916, so if the UK agrees to mirror EU legislation, there should be no change in the requirements to become a QP in the UK or in their role in batch certification.

When the UK is no longer in the EU, UK QPs will no longer be able to accept certification of products by EU QPs and vice versa. This is likely to increase the workload for QPs in the UK and in the EU for product coming from the UK. Hopefully QPs who became eligible in another EU Member State and are named on UK manufacturing or importation authorisations (MIAs) might be grandfathered, but it is possible they may no longer be eligible. The reverse is also true with UK-origin QPs no longer being able to be named on MIAs in the EU.

Marketing authorisations MHRA will likely have to mutually recognise centralised (EU) authorisations and introduce a process to issue a national marketing authorisation (MA), much like Norway and Iceland currently do.

In May 2017, the European Commission and EMA issued the Notice to marketing authorisation holders of centrally authorised medicinal products for human and veterinary use, and followed this in late November with more detailed practical guidance, to remind companies of the actions they need to take before the UK becomes a third country:

the UK is the Reference Member State (RMS), the role of the RMS will need to migrate to another EU Member State, which requires the initial RMS to prepare an assessment report. The MHRA will be hard-pressed to do this for every MRP/ DCP it leads, so an interim process is required.

Clinical trials Clinical Trials Regulation No. 536/2014 has not previously required translation into UK law, but would need to be translated when it becomes implemented in the second half of 2019 if the UK wishes to follow the new process. However, the UK is unlikely to be able to have access to the new submissions portal.

API imports The UK will need to apply to go on to the commission’s white list of non-EU acceptable active pharmaceutical ingredient (API) exporting countries. If the UK is not added to the list, the MHRA will have to issue written confirmation of GMP compliance for every API exported from the UK into the EU.

Pharmacovigilance “…marketing authorisation holders of centrally authorised medicinal products… are reminded of certain legal repercussions, which need to be considered: • EU law requires that marketing authorisation holders are established in the EU (or EEA) • Some activities must be performed in the EU (or EEA), related for example to pharmacovigilance, batch release etc.

Marketing authorisation holders will need to act sufficiently in advance to avoid any impact on the continuous supply of medicines for human and veterinary use within the European Union.”

For decentralised and mutual recognition procedures (MRPs/DCPs), companies will probably begin moving away from the UK. For existing MAs linked to an EU procedure, where

The current process depends on access to several EU databases and centralised systems, e.g., EudraVigilance. The UK may no longer have access to these post-Brexit, so it may need its own system. Also, UK-based QPs responsible for pharmacovigilance (QPPVs) will probably no longer be eligible in the EU.

Pharmacopoeia The European Pharmacopoeia (PhEur) is prepared, published and distributed by the European Directorate for the Quality of Medicines and Healthcare which is part of the Council of Europe, not the EU. If the UK remains a member of the Council of Europe, not too much should change.

Summary • If the UK joins the EEA (which is highly unlikely), impact is minimal.

• If the UK becomes a third country, changes will likely be profound.

• Agreeing MRAs/ACAAs and being on the EU API white list will help reduce some impacts.

• The UK’s position of wanting to continue as if it hadn’t left the EU may not be acceptable to the EU. • We will not know the full impact of Brexit until a detailed exit strategy is agreed at the highest political level, which could take several years.

• We are entering a period of significant uncertainty and companies must start planning for Brexit now!

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COVER STORY

The next level…

About a year ago, Schott set out to elevate pharmaceutical glass quality to a new level with its perfeXion initiative. EPM sat down with Dr Patrick Markschläger, executive vice president, Schott Tubing, to discuss the impact of glass tubing on future packaging challenges.

Q. Why should the pharmaceutical industry give special consideration to pharma glass?

It’s widely accepted that pharma packaging has become an integral part of the drug product.

Yet any primary packaging can only be as good as the basic material it is made of. As the pharma industry is striving to optimise its cost/performance ratio, our goal is to provide a material which is highly inert and comes with a high dimensional and cosmetic quality from the very beginning.

Q. Are you referring to borosilicate glass?

Indeed. Borosilicate glass has the big advantage of exhibiting excellent characteristics without further treatment, which allows for the reduction of risk and complexity in the process. Also, it has a longstanding track record of over 100 years.

Q. Looking at the challenges that lie ahead — what current trends in the pharmaceutical industry can you support on the part of glass tubing?

To give you two examples: We see a strong trend towards highly concentrated

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drug formulations, which are often more viscous and require high-dosage accuracy.

Furthermore, there is an increasing number of higher dosage volumes, which leads to longer administration times. Here, a pharma company would be looking for optimal device integration. Both calls for the container to have very accurate dimensions, especially regarding the inner diameter and length. If you use precise tubing, half the battle is already won.

Or vice versa — without accurate tubing you are much less likely to end up with a highquality container. This is exactly why we have introduced our perfeXion process.

Q. Can you briefly explain the concept of perfeXion? perfeXion is a big data approach to reach a zero-defect tubing. We can examine 100% of the glass with lasers, cameras and infrared systems on-line during the production process. The data is analysed immediately, and the system precisely allocates imperfections allowing for the differentiation of corresponding individual tubes, which can then be sorted out later.

The result is a glass tube that has been

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completely evaluated. We also use the data to improve our own production process, and it enables downstream post-processing steps to be efficiently aligned with the tubing quality.

Q. Conducting automated controls seems logic, why is this not yet a standard in the glass tubing industry given the rising quality demands?

I believe this will definitely become a standard.

One has to take into account, though, that the analysis of a curved tube surface at high drawing speeds is difficult to perform. Hence, many still rely on sample-based testing to control the quality of glass tubing. With perfeXion, the cornerstone is set to replace statistical control by 100% on-line analyses.

Q. Can perfeXion also help to eliminate glass breakage?

It is the basis to provide containers with a flawless surface, and this in turn helps to maintain the naturally high breakage resistance of glass.

“

Using glass with a flawless surface will maintain the natural break resistance of the glass

”

Q. Can you explain that further?

Borosilicate glass is a very strong material, unless you weaken the surface by causing scratches or chips. This sometimes happens during production or transport. If this weakened spot then experiences too much stress later on — for example, during the filling process — the glass will break. Using glass with a flawless surface will maintain the natural break resistance of the glass, and this should normally be sufficient for the vast majority of pharmaceutical applications.

The key for us is to provide pre-damage free glass tubing, and we will significantly increase our efforts in this field.

Q. How about cases that call for a higher breakage resistance? Do they require a different type of glass?

I think it is safe to assume that pharmaceutical companies are not explicitly looking for a new glass composition. What they are ultimately interested in are the characteristics of the container — break resistance and a superior extractables & leachables (E&L) profile. Both can be achieved with existing and already authorised Type I glass. Higher breakage resistance can be achieved with an industry-standard ion exchange process, which compresses the glass and makes it more stable. Several packaging providers have such solutions in their portfolio.

Superior E&L profiles for biotech applications are sufficiently addressed with highly-functional SiO2 plasma coatings. Better control of a vial’s delamination propensity can be reached with an improved and tightly controlled converting process so that no re-registration is required.

We favour this route because it keeps down the regulatory hassle for pharma companies.

Q. Can you explain the difference between borosilicate and aluminosilicate glass?

First, I would like to say that Schott is in a good position to comment on both glass types as they have been part of our portfolio for many years. We supply aluminosilicate glass mainly to the electronics industry, where it is widely used, and this glass type also plays a role for glassceramic cooktops known under the brand name SCHOTT CERAN. Glass in general consists of network formers (e.g., silicon, boron, aluminium) as well as network modifiers (e.g., sodium, calcium).

A borosilicate glass contains significant amounts of boron, whereas aluminosilicate glass does not contain this element. The presence of boron is known to increase the chemical stability of glass, hence borosilicate glass bears a high hydrolytic resistance due to its chemical composition, making it a Type I glass.

In contrast, an untreated aluminosilicate glass vial would probably only meet the Type III requirements.

Thus, intense further treatment is necessary to produce a container of aluminosilicate glass which meets regulatory requirements. Plus, there is no scientific track record to assess the interaction between drug components and the glass surface.

needed first to do justice to the complexity of pharmaceutical products.

Q. For companies that experience breakage problems, what do you suggest?

Again, big data comes into play. Normally, there are only few passages on the filling line where the glass is set under stress. If you can identify these crucial spots, this will bring you a major step forward.

A system we think is very interesting is provided by a Canadian company called Smart Skin Technologies. They send drones on the line, which mimic the shape of the container and are equipped with sensors, to measure the movement, forces and stress. We heard from leading pharmaceutical companies that they were able to significantly reduce breakage by conducting such analyses and performing simple adjustments to the line afterwards. To us, this is a pretty straightforward approach.

Of course, we are highly interested in an open discussion, and are ready to adjust to market requirements.

However, solid data is

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21

DRUG DELIVERY

End-to-end solution We sit down with Dirk Leister, technical marketing manager, process and pharma extruders for Thermo Fisher Scientific, to find out more about hot melt extrusion and the company’s new automated, integrated system designed for continuous production of drug implants.

Q. What is hot melt extrusion (HME) in a nutshell?

delivery systems such as co-extrudes and subcutaneous implants.

Based on well-established screw technology that transports and compounds material ingredients to the point of extrusion, melt extrusion has been in use for several decades in the formulation of plastics, rubbers, foods and many other materials. Regarding the possibilities of pharmaceutical processing using twin-screw instrumentation, not only is HME an option, with its range of possible applications, but wet extrusion and granulation processes can also be accomplished with today’s modern twinscrew extruders.

HME has become a versatile tool for modern formulation scientists. If we consider that continuous manufacturing is the next big development step in pharmaceutical processing, the role of pharmaceutical twin-screw processes will significantly increase for certain applications, such as continuous granulation.

Q. Can the physical properties of compounds throw up challenges in HME? Some materials being used in the HME process can be sticky, cohesive or sensitive to electrostatic. Preventing segregation and ensuring precise dosing of those compounds is key for a high-quality endproduct.

Q. How is HME advantageous in drug development?

In the 1980s, HME was considered a promising new technology used to overcome solubility issues for newly developed drug molecules. Soon after market introduction, the first commercially available medicine manufactured with HME became available for immunodeficiency treatment. Since then, the technology has developed further and solved many formulation challenges in the fields of controlled and modified release, taste-masking, prevention of drug abuse and, more recently, for drug

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With extensive experience enabling our customers to develop pharmaceutical extrusion processes, Thermo has successfully completed a number of projects involving ‘challenging’ compounds. We have been able to help our customers design robust processes, even when one or two of the ingredients of the formulation exhibit demanding physical properties.

Q. Could you briefly run through the essentials of the new Pharma mini implant line and how it will benefit pharma manufacturing?

Based upon our proven and successful Thermo Scientific Pharma mini HME twin-

screw micro compounder, the Thermo Scientific Pharma mini implant line is an automated end-to-end solution for developing and commercial manufacturing of injectable drug delivery systems that meet cGMP and FDA requirements.

A closed-loop control and recording system ensures precise, secure operation and a compliant product as well as process documentation. A laser-based measuring and monitoring device and high-precision

“

The Pharma mini implant line is designed to help pharmaceutical manufacturers improve product quality while minimising development time.

manufacturing enables product release without further testing or analysing — the equivalent of real-time release of a product. This is a huge advantage for drug producers.

The Thermo Scientific Pharma mini implant line encompasses all necessary technical features to support end-to-end manufacturing. If the process designed by a drug producer also complies with the regulations, the drug producer can realise much faster time-to-market for new formulations.

Q. What advantages can manufacturers expect from an implantable drug delivery system over more conventional delivery forms?

”

Implantable drug delivery systems offer several advantages over conventional oral dosage forms. Implants allow sitespecific drug administration where the drug is needed most. Examples include implants used in the treatment of prostate or breast cancer. This also allows for lower doses of the drug, minimising unwanted side effects.

Q. What is the significance of end-toend manufacturing?

As implantable devices allow for sustained release of an API, it removes the burden to take multiple pills or injections per day. Perhaps the most important advantage is patient compliance, as some clinical patterns make it difficult or impossible for the patient to adhere to the treatment schedule.

cutting are designed to ensure that all manufactured implants are fully in spec.

The Pharma mini implant line is designed to help pharmaceutical manufacturers improve product quality while minimising development time.

When used for commercially manufactured drug delivery devices, precisely controlled end-to-end manufacturing is important because it documents all relevant parameters for compliant manufacturing.

When carefully applied, end-to-end

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DRUG DELIVERY

Needle in a haystack

M

any people ask: “What new and emerging technologies will shape the future of drug research, development and delivery?”

From research and development (R&D) through to manufacturing the final drug product, the range of processes that take place before medicines are administered to a patient are extensive, expensive and time consuming.

Yet, early data suggests these timelines are beginning to shorten and, in some cases, costs are beginning to lessen. So, what is causing this trend — and how can it be replicated?

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The problem in drug research is often associated with the ‘finding the needle in a haystack’ conundrum.

Drug research

The problem in drug research is often associated with the ‘finding the needle in a haystack’ conundrum. There are so many ‘targets’ within the human physiology system — such as receptors, enzymes, proteins, pathways — and so many potential variables that can interact with these targets, that both the intended and unintended effects give rise to the needle in a haystack simile. With so many variables it can become almost impossible to identify how a drug works and what pathway it is affecting.

”

The development of artificial intelligence (AI), in all its possible guises, can go a long way towards solving the problem. There are currently several endeavours that are seeking to exploit the massive computing and pattern analysis capabilities of modern AI platforms. These also include the analysis of historical data of potential candidate compounds that were

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Drug research and development is often likened to finding a needle in a haystack with multiple targets and many potential variables with which they can interact. So, what technological advancements are impacting development timelines and how can they be applied on a wider scale? Paul DennyGouldson, vice president strategic solutions, IDBS, goes into more detail…

previously ‘canned’, with the aim of repurposing them for other diseases.

Further exploits are also sighted towards the analysis of complex data sets to elicit new information about a given drug target or pathway — where connecting massive disparate data sources, both internal and external, is a key requisite for success. Other areas of interest lie in the area simulation of drug properties and effects on the human body. Whilst this has been done for many years, the type and size of data feeding the simulations are growing rapidly.

Lastly, we are also seeing emerging trends where scientists are being supported in their daily work with augmented intelligence. This is where the decision is still made by the scientists, but the data and support for that decision is as automated as possible. The request for an AI platform to flag information, as and when it is needed, is a natural extension of AI’s offering, as it sits squarely in the arena where AI can have the greatest impact.

Drug development The problem faced by many R&D organisations when developing new drugs is in finding the shortest, quickest and most cost-effective path to the finished product. This is due to the extremely stringent regulations and quality directives that drug development processes must adhere to.

Yet the commercial pressure on companies is always there — whether improving competitive advantage, improving market share or being first to a new market — each drives behaviour. A single day’s delay of a drug to market costs a company an average of $1 million in lost revenue.

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“

Whilst AI cannot offer a silver bullet or a single answer, automated tools can greatly improve the speed of data aggregation, greatly improve the surfacing of the relevant data to the right person or group at the right time, and thus speed up the discovery process.

”

Automating decisions and aggregating data that is relevant to decisions is an area of great interest to the application of AI technology, and can go a great way towards solving this problem. Whilst AI cannot offer a silver bullet or a single answer, automated tools can greatly improve the speed of data aggregation, greatly improve the surfacing of the relevant data to the right person or group at the right time, and thus speed up the discovery process.

The automated control of manufacturing processes is also an area of great potential for AI, given its ability to monitor many variables and interrogate data at a speed that is not feasible for humans. All this leads to earlier identification of either unwanted, or desired, trends in the process and a self-learning system that can optimise and make decisions based on inputs. This operates in the same way as autonomous cars — via machine learning and pattern identification — but the environment in the pharma process space is not as well defined as the automotive industry, and so may take a little longer to develop.

Drug delivery Following the R&D phase, the next challenge in the process is the need to get the right drug to the right patient at the right time. This, like other issues earlier in the process, is a multi-layered problem, where there are many variables at play. The advent of ‘-omic’ medicine (such as genomics, proteomics, metabolomics), alongside our continued ability to look at the fundamental and underlying reasons why diseases manifest, is going a long way towards improving the process, allowing scientists to tailor the drugs that patients are given.

However, the amount of data and its complexity means that AI and associated methods are critical to both understanding the disease (related

to the first discovery problem statement) and using it to make treatment decisions. Coupled with this data deluge comes the added complexity of individual patients — a drug that might work at one time for a given patient/disease might not work in another instance.

Another area of clinical research that is well underway in identifying delivery issues is the monitoring of adverse events once a drug is released.

Here AI comes into its own, as it can help analyse the terminologies used to describe events and learn how to categorise those based on previous understanding and training undertaken by scientists. All this can be done on both social media and hospital data (with the correct security in place) allowing drug companies to get an almost real-time view on the status and performance of a drug as it is administered to patients.

Some work still to do The implementation of these new technologies described, such as deep learning, machine learning and augmented intelligence — all delivered via the cloud — is allowing greater global collaboration, faster research decisions and more effective crunching of increasing amounts of data.

All of this is going a long way to finding hard to identify problems within complex ‘haystacks’.

The trick now, as these technologies continue to develop, is to really understand what they can offer outside of the small, niche areas of application they currently serve. Without such general potential applicability, it will become necessary to reign in the industry’s expectations of impact, and tailor them to be far more realistic, as there is very rarely a silver bullet for problems.

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25

33rd International Exhibition for Fine and Speciality Chemicals

The industry’s premier sourcing and networking event

Some 400 international exhibitors offer bespoke solutions and specific substances to enhance products or develop new chemical solutions.

s Top conference s p o and worksh insights offer valuable &D projects! into ongoing R

e Lecture Theatr Agrochemical ic eers Clin Chemspec Car e Theatre Pharma Lectur eatre ices Lecture Th Regulatory Serv eatre RSC Lecture Th t-ups Innovative Star

Fine and speciality chemicals for various industries: • pharmaceuticals • agrochemicals • petrochemicals • cosmetics • adhesives & sealants • paints & coatings • polymers • biotechnology • colourants & dyestuffs • food & drink • industrial cleaning • reprography & printing • water treatment and much more.

Koelnmesse Cologne, Germany

20 – 21 JUNE 2018 www.chemspeceurope.com

Organisers:

20 – 21 June 2018 | Koelnmesse Cologne, Germany

CASE STUDY: PACKAGING Who:

Schubert-Pharma

What:

Automated handling of sensitive products with novel 3D technology

How:

Schubert TLM modular platform

Better safe than sorry The company Schubert-Pharma develops and implements packaging solutions for the pharmaceutical industry — ranging from primary packaging through to finished product pallets. The team comprises 20 pharmaceutical experts including specialists in cross-disciplinary consulting and internationally certified project managers.

The request A large biotechnology firm in the Netherlands — which provides patients with medicines for cancer therapy or severe chronic diseases and metabolic disorders — was looking for a new system to pack vials and pens in different configurations in order to expand its capacities and modernise its packaging line.

To ensure simplicity, safety and overall patient compliance, the manufacturer not only offers vials, but also pens for a precisely dosed administration of a drug to battle high cholesterol. The delicate products need to be handled with extra-special care during the packaging process. Apart from glass breakage, the pens should not be activated prematurely during the packaging process.

Automating this small-component packaging task would open up the possibility of increasing efficiency and saving production costs. At the same time, the chosen packaging solution needed to offer a high level of flexibility and precise handling.

Perfect picking out of the bulk box — the newly developed 3D camera from Schubert makes it possible. It detects the exact position and layer height of the pens by scanning the complete top layer in the bulk box after each pick of the robot. This image allows the pens to be taken out of the box with high-level precision.

The solution On meeting with Karin Kleinbach, sales account manager at Schubert-Pharma, the biotech firm decided that the Schubert TLM modular platform was the most advantageous option for the packaging task.

For this challenging task, Schubert-Pharma developed a combination of efficient robot technology and advanced 3D image recognition — both of which were key to the decision to partner with Schubert.

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The F4 pick and place robot picks up one vial from the belt and pre-groups the vials on the Transmodul.

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CASE STUDY: PACKAGING (continued) The erected cartons are placed on a Transmodul and forwarded to the next processing phase, where they are loaded with trays or partitions.

Just like in the first packaging phase, the blanks are fed into the machine via a magazine.

The benefits Designed for safety In the design of the machine, gentle, product-friendly handling was top priority: special attention was paid to avoiding glass-to-glass contact.

To meet this requirement, the vials and pens are placed into fluted cardboard dividers or pre-formed trays within the cartons. Furthermore, only extremely low forces could be exerted upon the products during this process. A force of 60 N was the limit set by the customer to ensure that the sensitive products would not be damaged and that unnecessary production downtime would not occur. Should this value be exceeded, the machine stops to enable checking of the problem source and removal of the products from the working area.

A combination consisting of F2 and F3 robots folds the partitions before they are placed into the product cartons. Sensors on the robot tool ensure that each carton has been provided with a partition or tray respectively.

Then the pre-grouped products — pens or vials — are placed into the cartons. In order to ensure safe shipping, the vials and pens are securely snapped into the trays or partitions of the cartons.

Precise and gentle product handling through spatial control During the packaging process of the pens, a new 3D camera from Schubert, which was especially developed for this project, is applied.

Transport boxes with 120 pens are placed on a table in front of the picking robots. The F4 robot takes the pens directly from the transport boxes and places them in pre-grouped formations. After each product is taken, the 3D camera scans the contents of the boxes and determines the exact position and layer height of each individual pen. These data are passed on to the F4 pick and place robot and ensure that each product, even if its position has changed following removal of a pen, can be precisely targeted at the next product intake. Empty shippers are automatically discharged from the machine.

The packaging process Gentle, product-friendly handling — the product is exposed to the maximum force begins with the feeding of 60 N. of the standing vials on a conveyor belt which transports them to the F4 robots. A camera detects their position on the belt and simultaneously controls the presence of the caps. The F4 robot then respectively grips one vial from the belt and groups it horizontally on the Transmodul. The pens, however, are fed to the F4 robots in transport crates with 120 pens each on a separate conveyor belt.

In the carton erecting station, the blanks for the vials or the pens are denested from a magazine and erected. During this process, the pharmacode on the blanks is controlled and verified. Blanks with incorrect codes are rejected beforehand and do not even enter the packaging process.

Folding box with inside preformed tray: glass-to-glass contact of the vials during transport is successfully prevented.

Exact placement of the pens in the folding boxes — here as well, gentle handling is top priority.

In the next module, F2 robots pick the product leaflets from a magazine and place them in the product cartons. Prior to inserting the leaflets, the pharmacode on the leaflets is controlled and verified. Leaflets with incorrect codes are rejected beforehand and do not enter the packaging process.

In the final step of the packaging process, the cartons are closed and the latches are controlled. Incompletely filled and not firmly closed cartons are detected and ejected. A conveyor belt forwards all the controlled products to the downstream process.

The customer was especially convinced by the sophisticated technical concept as well as the scalability and resulting flexibility of the TLM line.

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What is the link between a smartphone and a drug delivery device?

Folding box for pens with patient-friendly ‘flip-top’ closure

“Feedback from the customer confirms that we are on the right track with our efforts: the vertical start-up, which Schubert was able to demonstrate on-site, impressed them greatly,” confirmed Kleinbach.

Last but certainly not least, the Schubert-Pharma team succeeded in meeting the high demands placed on project management and the high-end pharmaceutical company’s challenging FAT and SAT conditions.

Facts & Figures: A TOTAL OF 13 FORMATS (PENS & VIALS)

Discover how to improve nasal and ophthalmic compliance with e-Advancia® and e-Novelia®

PENS: • As one-count and two-count packages • 75 cartons per minute for both 1ct and 2ct formats VIALS: • 300 products per minute infeed from the upstream labelling machine, up to 100 cartons per minute depending on the format • Two different vial sizes (3 cc and 5 cc); option: 50 cc and 100 cc

Booth D30

END-PACKAGING PRODUCT CONFIGURATION: • 1ct: 100 cartons per minute • 3ct: 100 cartons per minute

Paris, 7-8 February 2018

• 4ct: 75 cartons per minute • 5ct: 60 cartons per minute • 6ct: 50 cartons per minute

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29

THE YEAR AHEAD

Pharma’s Fantastic...

What to watch out for over the coming 12 months that should have an impact on the pharma landscape, according to some industry leaders…

A

s we are now (just about) settling back into our everyday routines, it’s time to look towards the potential trends we may expect over the coming months. In this prediction feature, we put forward some questions to a few industry leaders to discern what they believe should be on our radars for the year ahead and have come up with a list of our ‘Fantastic Four’ for the pharma industry.

Contributors: • Michael Avraam is the global product manager at ChargePoint Technology

• Dr Andrew Rut, CEO and founder of MyMeds&Me

• Daniel Piekarz, SVP DataArt Solutions, Healthcare & Life Sciences practice leader

• Mark Quick, executive vice president — Corporate Development, Recipharm

• Marianna D’Onghia – I Holland marketing assistant

• Jean-Marie Aulnette, vice president of EMEA sales, TraceLink

TECHNOLOGY TANGENT It’s no surprise that technology will have a certain amount of influence in the future but as we move further into 2018 what technological advances and trends can we expect to witness in the pharma sector.

For Daniel Piekarz, SVP DataArt Solutions, Healthcare & Life Sciences practice leader, blockchain will be of interest to many more hospitals and pharma companies. “We expect to start seeing more real-world solutions being piloted leveraging blockchain,” he said. “The moonshot being a longitudinal view of patient data that can be used to incentivise the patient to do things, like make healthier choices.”

This view of assisting the patient and helping with patient adherence marries well with technological advancements, particularly in the wearable space. The array of new technologies available to pharma has the potential to truly transform the clinical trial space, according to Dr Andrew Rut, CEO and founder of MyMeds&Me.

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“Technology will be a catalyst to the transformation of clinical trials,” he asserted.

“Implementing truly real-time data observation, capture and collection, systemised processing and analysis, significantly improves the quality and efficiency of clinical studies and technology is emerging as the catalyst that drives these new efficiencies for the benefit of clinical trials and people’s lives.”

Manufacturing is also set for a change through the adoption of wireless monitoring technology. “As the demand for high potency drugs increases and the biotechnology sector continues to flourish, the industry will look to technological advances to drive future change in manufacturing facilities,” explained Michael Avraam, global product manager at ChargePoint Technology. “Incorporating wireless monitoring technology will allow operators to receive vital equipment performance data as well as generating an audit trail; allowing for maintenance, health and safety and compliance teams to make informed decisions to proactively manage their maintenance programmes.”

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EXCELLING IN EFFICIENCY Various factors are converging within pharma, meaning there is more need to increase efficiencies across the board. An ageing population, more demand from the end user and governments to reduce drug prices, along with increasing pressure to reduce the time to market, to name but a few.

“With the drive for demand and rising cost pressures there has to be manufacturing solutions that are more effective,” stressed Marianna D’Onghia – I Holland marketing assistant. “What we are seeing is an increased need for efficient monitoring processes and management systems which allow manufacturers to undertake in-depth scrutiny of tablet production. During 2017 we saw an increased interest in software and technology that effectively manages tablet production and we see this continuing in 2018.”

“Pharmaceutical companies are facing a lot of pressure to reduce the costs of medicines for the end user and they’re looking for ways to reduce both costs and time to market by improving efficiencies throughout the supply chain,” added Mark Quick, executive vice president — Corporate Development, Recipharm.

“As a result, many companies are seeking to automate certain processes to reduce errors and increase throughput.”

Avraam concurred with Quick, explaining that in many drug manufacturing facilities automated systems are already in operation. “This is likely to increase rapidly as the potential for more efficient integration of processes and Industry 4.0 are fully realised,” he said.

Besides automating processes in the manufacturing space, technology may have another role to play in improving efficiencies. “Further opportunities are presented by the prospect of incorporating smartphone technology to enable more direct patient engagement,” explained Jean-Marie Aulnette, vice president of EMEA sales, TraceLink. “This could lead to the first of its kind in patient data collection and advance the efficiency of the healthcare industry in an unprecedented way.”

SERIOUS ABOUT SERIALISATION Prior to serialisation regulations there was extremely limited communication between manufacturers and the end users. As the deadlines for these regulations get ever nearer, we are approaching a time when this disconnect may be bridged, however, it is imperative, now more than ever, that companies get on top of their preparations for this regulatory implementation.

“2018 must remain track and trace focused,” asserted Aulnette. “The regulations cannot be avoided and if companies do not comply in time, their days will be numbered.

This year will be a ‘survival of the fittest’ situation with regards to compliance.”

In agreement with this sentiment, Quick added: “Those who haven’t prioritised developing a serialisation solution in 2017 (and many haven’t) are now in a race against time to ensure compliance ahead of the respective deadlines. Serialisation is a huge task and having underestimated the challenge in 2017 it’s important that companies adopt a proactive approach to these regulations this year.”

Obviously, these changes will be impactful on pharma on a global scale and as Quick emphasizes, it will be important to quickly mitigate the effects of serialisation so that it doesn’t impact too heavily on efficiency.

“With the recent US implementation of the Drug Supply Chain Security Act (DSCSA) regulations in November 2017, European companies should look ‘across the pond’ for advice, guidance and support with the tricky and at times onerous task of serialisation,” Aulnette commented.

“What is clear is that serialisation and new regulatory requirements across the globe will continue to be key market drivers over the next year, shaping the sector landscape,” he continued. “The gap across the industry regarding serialisation readiness needs to be closed, otherwise companies are going to be left behind in February 2019.”

MARKET MOVEMENTS Market trends, growth, expansions, acquisitions and developing sectors are always on the agenda when considering future possibilities. As we are witnessing an increase in the need for industry to adjust to new regulatory requirements, there will undoubtedly be a corresponding change to certain aspects of the pharma market, one in particular is anticipated to be the growth of the outsourcing sector.

“Outsourcing, in particular, will continue to grow over 2018,” said Aulnette.

“Finding the right outsourcing partner with the necessary serialisation capabilities will be an increasing trend over the next 12 months.”

“It is likely that, given the time constraints and the cost implications, we will see more and more companies look to well-prepared outsourcing partners to cater for their serialisation requirements,” agreed Quick. “The introduction of new serialisation regulations and the increasing demand for new, automated technologies is driving companies to take a more innovative approach to development and manufacturing. This combined with ever-increasing pressures to reduce costs across the board is driving companies to consolidate and collaborate with other members of the supply chain.”

It isn’t only outsourcing that is predicted to experience growth. With more interest in personalised medicine and biologics, this too should drive an increase in merger and acquisition activity.

“The pharmaceutical industry is seeing huge demand in oncological and immunesuppressant therapies, which is fuelling the increase in drug manufacturing using high potency active pharmaceutical ingredients (HPAPIs),” Avraam explained.

“This has serious implications throughout the supply chain, however the result for manufacturers is a growing need to look at more innovative containment strategies to meet high potency handling requirements.”

From I Holland’s perspective, there will be continued expansion in oral solid dosage forms, with a particular emphasis on the emerging markets. “The requirement for solid dosage continues to grow,” stated D’Onghia. “We have seen this specifically within Latin America. This region is the ‘fastest ageing in the world, and in 2055 there will be 130 million more Latin Americans over 60 than there are today’* this means a growing demand in medicine and over the counter products like solid dosage forms.”

These developing markets are being driven to comply with good manufacturing practices to ensure their products are compliant and can be marketing on a global scale. To this end, investment is required to enable facility upgrades, noted D’Onghia. *Pharmerging Fundamentals: Inside Latin America’s Expanding Medicine Cabinet — https://www.linkedin.com/pulse/pharmerging-fundamentals-inside-latin-americas-mariana-romero-roy/

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31

OSD MANUFACTURING

That’s a wrap!

Various aspects must be considered when deciding upon the best coating technology. Here, Thorsten Agnese, Florian Bang and Thorsten Cech (from BASF), along with Fiorenzo Cembali, Giusi Mondelli and Caterina Funaro (from IMA S.p.A., Active division) describe their recent study comparing three different coating technologies’ efficiency in a pellet coating process.

T

here are various aspects to consider when deciding on a coating technology. Process efficiency, content uniformity of the applied coat, and economical aspects are features of utmost importance, yet vary depending on the type of coating employed. These considerations are particularly vital when dealing with functional coating and/or drug layering.

Looking at the considerations in more detail, we performed a study, which was aimed at comparing three different coating technologies’ efficiency in a pellet coating process.

Below, we have provided an overview of our methods and results.

Materials and method Pellets (20–25 mesh, Emilio Castelli) consisting of sucrose and microcrystalline cellulose were used as substrate. As tracer, riboflavin (BASF) embedded in a film of poly(vinyl alcohol)-poly(ethylene glycol) graft copolymer (Kollicoat IR, BASF), ratio 1:2, was applied as aqueous formulation with a solid matter content of 15%.

The functional coat was based on poly(methyl methacrylate-co-(2-diethylaminoethyl) methacrylate) copolymer (Kollicoat Smartseal 30 D, BASF).1 Further components of the formulation (Table 1) were: FD&C Blue No. 1 (BASF), acetyl tributyl citrate (ATBC, Jungbunzlauer), buthylene hydroxy toluene (BHT, Lanxess), docusate sodium (DS, Cytec), and talc (Merck). The solid matter content of the formulated Kollicoat Smartseal dispersion was 20%.

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Table 1: Coating formulation for the functional coat.

Ingredient

Content

Polymer based

Kollicoat Smartseal 30 D

50.5%

Acetyl tributyl citrate (ATBC)

7.6%

15.0%

Buthylene hydroxy toluene (BHT)

1.3%

2.5%

Docusate sodium (DS)

1.0%

2.0%

Talc

39.0%

FD&C Blue No. 1

1.0%

Three different coating technologies were used in this study: a fluid bed coater (FBC) Mylab (Figure 1), with bottom spray configuration, a solid wall drum coater (SWC) GS Evolution Lab (Figure 2), and a side vented pan coater (SVP) Perfima Lab (Figure 3), with wedge wire screen drum. The latter drum has been specifically designed for coating small substrates, such as pellets. Small wedge wires are fitted into the drum wall to allow the passage of process air. The drum maintained the same drum shape, mixing baffles and spray system as the standard equipment for tablet coating. All machines were provided

by IMA Active division (Bologna). The coating trials were performed according to schema listed in Table 2.

Figure 1: Fluid bed coater (FBC), Mylab.

To allow a distinct investigation on the coating level, the individual amount of applied coat was determined by photometrical measuring of either riboflavin or the colorant FD&C Blue No. 1.2,3 For dissolution testing, a standard USP Dissolution Apparatus 2 (Paddle) from ERWEKA, equipped with continuous on-line UV measuring (Agilent 8453), was used. Since taste-masking functionality is to be delivered in the oral cavity, phosphate buffer (pH 6.8) was used as dissolution media (700 mL ±1%, 37°C ±0.5 K, n=13).

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Figure 2: Solid wall drum coater (SWC), GS HP 25.

Figure 4: SEM images (different resolution) of pellets coated in fluid bed coater (SE detector, 5 kV, 12 nm Pt).

Figure 3: Side vented pan coater (SVP), Perfima Lab.

Table 2: Parameter set for the different processes.

Parameter

Fluid bed coater (FBC)

Solid wall coater (SWC)

Side vented pan coater (SVP)

Batch size

2.5 kg

25 kg

25 kg

Batch volume

3.0 L

30 L

30 L

Inlet air temperature Air quantity Orifice diameter Spray rate Atomisation air pressure

55–68°C

65–70°C

75–80°C

140–170 m³/h

500 m³/h

600 m³/h

1.2 mm

1.2 mm

1.2 mm

25 mL/min

25–30 mL/min

50–70 mL/min

1.2 bar

1.2 bar

1.2 bar

Table 3: Comparison of the three processes regarding of weight gain and standard deviation.

Coater

Weight gain

Standard deviation

Fluid bed coater (FBC)

6.02%

3.62%

Solid wall coater (SWC)

3.38%

2.43%

Side vented pan coater (SCP)

4.84%

3.87%

Figure 5: Dissolution profiles of pellets bearing three different functional coating levels applied in different coating technologies (values: mean ±SD, n=3).

Figure 6: SEM images (different resolution) of pellets coated in solid wall coater (SE= detector, 5 kV, 12 nm Pt).

Figure 7: SEM images (different resolution) of pellets coated in side vented pan coater (SE= detector, 5 kV, 12 nm Pt).

could be achieved with distinctively lower coating levels in all coaters. The reason was, most likely, the absence of the critical edge between band and cap, which every tablet bears inherently. Pellets with their spherical shape do not offer such crucial areas.

In the current study, side vented pan coating allowed high inlet air quantities resulting in higher spray rates compared to the solid wall one. The dedicated design of the wedge wire screen drum allows high process air volumes, consequently resulting in high spray rates and economical short process times; similar to conventional perforated drum coaters. Compared to the fluid bed processor, this technology provides two main advantages: firstly, it comes with a much smaller footprint, and secondly, the spray guns are readily accessible during the process. Additionally, drum coating processes can easier be controlled simplifying up-scaling procedures.

Pellets, which passed through a fluid bed coating process experienced hardly any mechanical stress.

In addition, to the cushioning effect provided by the processing air, the excellent accessibility of the whole product’s surface area allowed perfect drying. This produces coated substrates, with smooth surfaces (Figure 4), already delivering functionality at moderate coating levels (Figure 5). The mechanical impact on the substrate was higher in both drum coaters leading to the surfaces appearing slightly rougher (Figures 6 & 7).

Functionality was achieved at similar coating levels in both coaters. Differences were merely found regarding processing time, due to differences in the available inlet air quantities.

Solid wall coating generally allows a vast variety of different processes (e.g., tablet coating, powder layering). In order to gain this flexibility, one needs to sacrifice on the amount of inlet air that can be utilised. As a result, processing times were slightly longer but offer the advantage of gaining a higher coating uniformity.

Results Firstly, riboflavin was coated onto the pellets as a tracer for the later performance testing of the functional coat (dissolution). In all three coaters, the same coating formulation with the same solid matter content was sprayed onto the pellets for five hours, using optimised settings for each individual technology. The achieved weight gain revealed an excellent performance of the fluid bed coater. However, employing standard deviation as a scale for content uniformity, the solid wall coater presented best results (Table 3).

Typically, the coating formulation based on Kollicoat Smartseal needs to be applied with a coating level of 3.5 mg/cm² onto tablets to gain functionality.4 When applying the same coating formulation, onto pellets, full functionality

Conclusion Expectedly, fluid bed coating allowed the shortest possible processing time thanks to larger quantities of inlet air available. The fluidisation of the particles, inherently provides high drying capacity and mixing efficiency. Consequently, the coating formulations could be applied economically quicker and more homogeneously.

In contrast, both pan coaters offer the advantage of being a more compact installation (smaller footprint).

Additionally, access to the processing area is faster and easier. Furthermore, large batch sizes can be coated in smaller sized equipment.

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References: 1. Kolter, K., et al., ‘Physicochemical characteristics of a new aqueous polymer’, AAPS Annual Meeting, 14–18 November 2010, New Orleans, USA. 2. Agnese, Th., et al., ‘Developing a photometric method to determine the amount of film-coating material applied onto individual tablet cores’, 3rd PharmSciFair, 13–17 June 2011, Prague, Czech Republic.

3. Agnese, Th., et al., ‘Evaluating different methods to determine the amount of applied coating material onto a tablet’, 3rd PharmSciFair, 13–17 June 2011, Prague, Czech Republic.

4. Agnese, Th., et al., ‘Determining the minimum amount of functional coat to be applied to gain taste masking functionality and investigating whether shape or scale is influencing the results’, 3rd PharmSciFair, 13–17 June 2011, Prague, Czech Republic.

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TECH TALK

Seven tips to success In the first of the Tech Talk series, Novarum founder and BBI group head of mobile, Dr Neil Polwart, goes through his seven key tips that should be kept at front of mind when trying to implement a successful mHealth strategy. mHealth is a well-known industry buzzword these days, with both the clinical and commercial community looking to maximise the opportunities inherent in this fast-growing sector.

Many different factors affect the likely commercial success of new mHealth offerings, and while some product development aspects of bringing a new app to market are the same as in any sector — there are some elements that anyone embarking upon a new mHealth initiative should keep front of mind:

1

5

IS IT ‘ACTIONABLE’?

It seems obvious that measuring a biomarker or other indicator is only worth doing if there is some action the patient (or those who care for them) can take to change the potential outcome.

Good mHealth solutions not only track and record information but help patients, or clinicians, take actions to improve the situation. Actions that the user can perform themselves are more useful than actions that require the intervention of others.

2

The Minimum Viable Product is a concept widely used in software to help get a product to market quickly, get feedback and make iterative improvements.

The regulatory complexities in medical software can sometimes discourage people from using this approach, as it can create a huge list of demands from potential users.

Trying to develop and deliver a complex solution that addresses these straight away will almost guarantee failure: not only will the time to market be delayed, but your users may be confused by the complexity of the offering and struggle to learn its features. Focus on the key aspects that deliver maximum benefit first. Your users will soon tell you what-else they want to see included.

WHO WILL PAY?

Often in software development the question of who pays is ignored in the early stages. We have seen Twitter, Facebook and others become hugely successful on the back of business plans that largely ignored initial profit maximisation. Almost without exception, those products are now funded by advertising revenues, which may not be at all appropriate for privacy-sensitive medical applications.

It can often be challenging to convince a healthcare provider to pay for intangible capabilities like apps. While in many countries, the patient will not be accustomed to paying for treatments directly and may be reluctant to make a regular commitment.

Of course, a solution that reduces insurance premiums may be tempting for individuals, or an insurer might see sufficient cost savings to fund it themselves — if the right quantitative outcome data is in place. It is important to understand though, that just because it is a great idea doesn’t mean it will make money in healthcare.

3

6

BEWARE OF MAKING THE PROFESSIONAL’S LIFE HARDER

7

BE CLEAR ABOUT PRIVACY FROM DAY ONE

MAKE SURE THE SOLUTION EXPLOITS THE BEST OF MOBILE Mobility means that users will expect your solution to function without an internet connection. Users also appreciate it when sensors offer functionality not available on their desktop computer to either enhance usability or provide functions simply not possible from a traditional computer — like augmented reality, barcode scanning, etc.

If any part of your product model requires sharing data with others, be 100% clear about this: make it obvious who will see what. People are concerned about privacy — but they are mostly concerned about the unknown — so be upfront, transparent and succinct, don’t hide it in pages of small print. It is all too easy to lose the trust of your users if you appear to do anything with the data they were not aware of.

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DON’T TRY TO BUILD THE ENTIRE ECO-SYSTEM YOURSELF

There can be a temptation to provide all the systems and functions yourself, but most modern software and services have application programming interfaces (API) allowing you to share data or track activity. By providing your own API you can let others build capabilities on top of your core functions, letting users gain wider functionality without getting involved in every niche application.

mHealth apps are most widely adopted when clinicians and professionals recommend them. Even if they aren’t the primary user, give consideration to how your product will make their life better, and bear in mind that extra data often requires more time for each patient — not necessarily a bonus for busy clinicians trying to see as many people as possible. Tools which identify the highest risk patients, or process large quantities of data to make quick, robust and effective decisions can help these key people become product advocates.

4

DON’T FORGET THE MINIMUM VIABLE PRODUCT

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