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Contents September 2015 | Volume 15 Issue 6

Regulars 5

21

Features 21

European union Spotlight on European Research

COMMENT Lu Rahman looks at the importance of digital technology in pharma

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6

YOU WEAR IT WELL

NEWS ANALYSIS

27

10 REGULATORY AFFAIRS

The significance of wearables & digital health from West and Qualcomm

32

12

SPANISH STEPS What this year’s CPhI has in store

OPINION

18

37

COVER STORY

SAFETY AT WORK

Catalent in focus

High potency manufacturing Capsugel, Aesica and Extract Technology highlighted

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editor ellie valero, ellie@rapidnews.com group editor lu rahman, lu.rahman@rapidnews.com editorial assistant emily hughes, emily.hughes@rapidnews.com associate editor dave gray david.g@rapidnews.com contributing editor aleksandra jones, ola@rapidnews.com publishers mark blezard, duncan wood

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from the editor Intelligent thinking The digital revolution is everywhere and the life sciences sector is no exception.

The pharmaceutical sector is experiencing significant influence via digital technology. The concept of the market moving ‘beyond the pill’ has been well documented and we are now seeing the way in which digital innovation is impacting positively within pharma in clinical trials, for example.

Key players in the pharmaceutical world are embracing the benefits that digital technology can provide. Recently we learned that Bayer Healthcare has launched the Grants4Apps Accelerator 2015 program in Berlin which will be awarding grants to five digital health start-ups.

The EPM team is also part of the digital revolution with its Let’s Get Digital campaign which aims to support companies looking to take advantage of digital technology to improve the way information is received and analysed. This ultimately impacts on the way in which medication is developed and formulated. The digital revolution is an integral part of the way in which the industry needs to proceed to ensure the future of pharma is as streamlined and competitive as possible.

way they market themselves. Eularis recently released E-VAI, a marketing analytics solution based on artifical intelligence, which is designed to allow pharmaceutical companies to understand and get value from marketing data. The company says it saw the opportunity to bring this type of technology into pharma marketing to reverse the trend of poor marketing and sales results and decreasing budgets.

Using digital technology is crucial within the pharma sector in order to retain competitiveness and a leading edge. The industry is at the forefront in terms of breakthroughs and cutting-edge developments. It is the companies that are using digital innovation to further boost their position in the market, that will steal a march in the coming years. Whether for marketing purposes or clinical trials, digitisation is becoming increasingly crucial for stake holders looking to maintain their lead in a sector where innovation rules.

Lu Rahman

The effect of the digital revolution also extends to the way in which companies do and increase business. One area often overlooked by many companies is the

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5

NEWS ANALYSIS

Industry pays further £209 million to underwrite medicines bill T

he ABPI and the Department of Health have announced a payment of £209 million from industry to underwrite growth of the medicines bill for the second quarter of 2015 under the 2014 Pharmaceutical Price Regulation Scheme (PPRS).

Industry has contributed a total of £416 million in PPRS payments so far in 2015 to help support the use of branded medicines by the NHS. However, the growth rate of branded medicines in the scheme for the second quarter of 2015 was 2.41% - half the rate seen in 2014.

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David Watson, director of pricing and reimbursement for the ABPI said: “As an industry, we want to see patients getting access to the best high value medicines across all therapy areas. This scheme provides the NHS with a unique opportunity to give patients in the UK greater access to new and innovative treatments at minimal cost.

“We are deeply concerned that the reduced growth rate shown in the second quarter suggests that patients in the UK are still losing out. Whilst industry is underwriting the medicines bill, patients are still not getting access to the right medicines at the right time. The UK already lags behind the rest of Europe in investing in medicines, based on the expenditure on pharmaceuticals per person. Today’s figures suggest that this could be worsening.

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“This is bad news for patients – we urge the NHS to ensure the PPRS payments allow clinicians to prescribe the medicines that they believe are right for their patients.”

During 2014 industry paid a total of £310 million to the Department of Health under the PPRS and it is anticipating payments totalling £800 million for 2015.

NEWS AN NEWS ANALYSIS

Digital health takes pharma beyond the pill Digital health has a major role to play in the pharma sector, from moving ‘beyond the pill’ to revolutionising clinical trials

A

Let’s Get Digital will be inviting readers of Digital Health Age, Medical Plastics News and European Pharmaceutical Manufacturer to join the campaign.

s patients become empowered, treatment providers will need to move fast to retain a competitive advantage. One new project aims to expedite and support the transition for all stakeholders.

Let’s Get Digital is a campaign which kicks off a conversation between all life science stakeholders The campaign, launched by media group Rapid Life Sciences, includes a newly established accreditation which will be awarded to pharmaceutical firms who can demonstrate a commitment to making digital health a reality.

Team spirit: Dave Gray and Lu Rahman, Rapid Life Sciences, the duo behind the Let’s Get Digital scheme

This means proving that data can be used to revolutionise the way treatments are formulated and prescribed. Digital health is an increasingly significant element of these sectors and Let’s Get Digital will provide a focal point for business, doctors and manufacturers to provide thought leadership, news and views on digital health.

“Anyone with a vested interest in the digital health sector can join our campaign – this could be manufacturers, doctors, pharma companies or technology suppliers. We will build a community within the life science sector to discuss issues anyone is facing in digital health and to promote best practice going forward,” she said.

Companies will need to identify their role in the digital health sector and will be accredited by Let’s Get Digital offering them the opportunity to provide content or thought leadership pieces on their digital health experience which will be posted on the Digital Health Age, Medical Plastics News and European Pharmaceutical Manufacturer websites.

“It is becoming increasingly evident that digital health will have a serious impact on the life science sector. From the devices being manufactured, the way in which pharma is collecting and using data, to the way doctors are interacting with patients, digital health is big news.

“This is an important and exciting campaign and we are hoping to use the industry support we receive via our publications to let government know the issues the digital health sector is facing. What does it need to be successful? Is the 2018 date realistic? What needs to be done to make business more aware of the part it needs to play in this up-andcoming market?

“Let’s Get Digital is a campaign to bring together everyone involved in digital health. Joining the campaign means you are serious about digital health and want to help push it forward to ensure it becomes as successful as it can possibly be,” said Lu Rahman, group editor, Rapid Life Sciences.

“No company is better placed to do this than Rapid Life Sciences as we have a foothold in manufacturing, pharma and digital health itself giving us real leverage to make ministers aware of the challenges and achievements taking place in this area,” added David Gray, deputy group editor, Rapid Life Sciences.

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7

NEWS ANALYSIS

Novo Nordisk researches new generation drug delivery devices N

There are many challenges of developing and producing a reliable peptide delivery vehicle. They include avoiding premature degradation in the body, overcoming poor peptide transport over epithelial barriers, limiting variability of absorption (caused, for example, by interaction with food in the stomach) and producing both peptide and the delivery vehicle in sufficient scale and numbers cost-effectively. If these challenges can be overcome, as recent research suggests, drug delivery devices hold great therapeutic promise for a plethora of diseases where patients need devices hold great to take frequent injections.

ovo Nordisk has announced a research collaboration with the Langer Laboratory at the Massachusetts Institute of Technology (MIT) for the next generation of drug delivery devices for the administration of peptides.

The aim of the research collaboration, which is conducted at both MIT in Boston, US and at Novo Nordisk’s research facilities in Måløv and Hillerød, Denmark, is to develop the next generation of drug delivery devices as an alternative to parenteral or injection-based delivery of peptides.

“

Drug delivery potential and I am looking forward to this exciting research collaboration with one of the world’s leading drug delivery laboratories,’ Peter Kurtzhals

Professor Robert Langer’s laboratory has expertise in creating new approaches for delivering drugs such as peptides and proteins across complex barriers in the body such as the blood-brain barrier, the intestine, the lung and the skin. Together with Dr Giovanni Traverso, a gastroenterologist and biomedical engineer at Harvard Medical School, and research affiliate of MIT, they will lead a team in the development of a platform enabling the oral delivery of peptides.

8

”

“Drug delivery devices hold great potential and I am looking forward to this exciting research collaboration with one of the world’s leading drug delivery laboratories,” said Peter Kurtzhals, senior vice president and head of global research at Novo Nordisk.

Robert Langer, professor and head of the Langer Laboratory at MIT, said: “We are very excited to be doing research sponsored by Novo Nordisk to address one of the current greatest challenges in drug delivery”.

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REGULATORY AFFAIRS

Immune response ELC’s Dr Parvinder Punia and Dr Siddharth Chachad discuss global and regional vaccine programmes

Global and regional programmes exist for vaccines. Each region has its own mandate of how and when vaccines are administered, especially in the paediatric population. Apart from the regional programmes run by the FDA, EMA (and its local authorities), TGA and other such large health agencies, the WHO is additionally running the Global Vaccine Action Plan (GVAP) endorsed by the 194 member states of the World Health Assembly. It is a framework targeted to prevent millions of deaths by 2020 through better access to vaccines.

Immunisation is one of the most successful and cost-effective health interventions known. Over the past few decades, immunisation has achieved many things, including the eradication of smallpox, an accomplishment that has been called one of humanity’s greatest triumphs. Vaccines have saved countless lives, lowered the global incidence of polio by 99% and reduced illness, disability and death from diphtheria, tetanus, whooping cough, measles, Haemophilus influenzae type b disease and epidemic meningococcal A meningitis.

The GVAP is the catalyst for health agencies and regulators worldwide to consolidate the regulations for vaccines. At the moment, regulations are agency (or regional agency)-dependent or from the pre-qualification of the WHO. By law, regulators are restricted to access or use information from other regions to determine the safety, efficacy and quality of a vaccine based on evaluation from other regulators. Moreover, there is a limited pool of regulators worldwide that are able to assess vaccines based on these parameters as well as compliance to GMP and manufacturing standards. However, it is well-accepted that the regulators pre-qualifying vaccines for the WHO are drawn from national regulatory authorities (NRAs), for example, the TGA, FDA and so on.

10

Therefore, it would only stand to reason that a pre-qualified WHO vaccine should be widely accepted by other regulatory authorities. In cases where distribution of pre-qualified vaccines has been extremely broad (millions of doses administered, effective immunisation achieved), it may be justified that further regulatory scrutiny could be minimised. Safety is well-established from wide usage in the population without any significant concerns or adverse events; although still questioned under the remit of a controlled clinical trial with a noninferiority study design. Moreover, the vaccination programmes remain unharmonised. Dosing schedules of the vaccines in infants may differ significantly, as mandated by different immunisation programmes in different countries, which can lead to confusion in clinical study planning and its future acceptability by regulators. For instance, while 22 out of 29 EU/EEA countries have implemented a universal vaccination programme for hepatitis B vaccine in infants and adolescents as per WHO recommendation, seven countries (Denmark, Finland, Iceland, the Netherlands, Norway, Sweden and the UK) have opted for only selective vaccination programmes targeting risk groups such as neonates born to HBsAg-positive mothers (21/29), haemodialysis patients (22/29) and household contacts of HBsAg-positive patients.

Inputs have arrived from a wide range of regulators, and the scientific opinion is changing now on a global scale. Current regulatory science is improving methods to measure vaccine potency to minimise trials and maximise assay outcomes. Moreover, post-marketing surveillance is being similarly enhanced to evaluate the risk/benefit of a vaccine at registration and throughout its global lifecycle.

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OPINION

Forward thinking: According to Dr Neil Murray, drug discovery and development is key to achieving improvements in cancer diagnosis and treatment

T

he molecular revolution over the last decade has done much to help turn cancer into an illness that can be managed, as opposed to as disease that prematurely ends lives.

Counting the cost Breakthroughs in cancer pose the ‘who pays?’ question, says Dr Neil Murray, Redx Pharma.

Cancer immunotherapy is at the frontier of this change, challenging tumour cells’ ability to hide from the body’s immune system. By provoking the immune system into attacking tumour cells, immunotherapy has achieved a meaningful step-change in terms of saving lives. In those patients where it’s effective, it’s a smart alternative to the highly invasive approach of surgery, radiation or chemotherapy. And yet, immunotherapy, in common with other breakthroughs in cancer, is not without its own issues — in particular, the cost of treatment.

As a result of these advances in therapy, the best chance of surviving any form of cancer today may well involve a cocktail of different drugs. The associated costs of using these treatments, however, present a profound financial challenge to all public health systems.

The question of who pays is only ever going to become more acute — ironically because of the good news that we are all living longer. Across the board, advances in modern medicine have made a big impact on life expectancy. As cancer is predominantly a disease of older people, these improvements mean our society faces an ever-burgeoning bill for combating cancer.

A BUPA study recently estimated that costs will soar by 65% by 2021. It found that the total cost of cancer diagnosis and treatment in the UK, incorporating the NHS, the private sector and the voluntary sector, was in the region of £9.4 billion in 2010, the equivalent of an average of £30,000 per person diagnosed with cancer. It estimates that the UK’s ageing population is likely to see the number of new cancer cases rise by 20% from a level of 318,000 cases per year in 2010 to 383,000 cases per year in 2021.

It follows that rising incidence levels will increase demand for cancer diagnosis and treatment. This increase, combined with advances in technologies and treatments mean that the total cost to the NHS, the private sector and the voluntary sector for treating cancer is projected to be almost £15.3 billion in 2021, an average of £40,000 per person diagnosed with cancer.

As a country it’s abundantly clear to everyone in healthcare that we need to invest more in cancer services and to work harder as a society to educate people about healthier lifestyles. At the same time, given the soaring costs there’s an obvious imperative to get the right treatment to the right patient.

12

This is where the era of ‘personalised medicine’ using new diagnostics offers hope, improving the cost effectiveness of our care. Increased efficiency by better use of expensive equipment, targeting expensive drugs to those that will really get benefit and keeping patients out of hospital has to be part of the plan.

Cancer immunotherapy research is one of the areas of expertise at our Redx Oncology subsidiary — one of the best bets modern medicine has when it comes to delivering what in simple terms might be described as maximum cost-benefit. Following on from recent successes in the nomination of development candidates for blood cancers and autoimmune diseases (Btk programme) and basal cell carcinoma (SMO programme), Redx Oncology has two programmes that directly look to stop tumours using evasive mechanisms to escape the body’s natural immune defences.

The first of these programmes targets a type of white blood cell called a macrophage; the name comes from the Greek meaning ‘big eater’. These macrophages are present in the tumour microenvironment. They can exist as both anti-inflammatory ‘M1’ macrophages, which will help clear the cancer cells from the body and inhibit tumour growth, or as pro-inflammatory ‘M2’ macrophages, which can actually promote growth of the cancer.

Inhibition of the cFMS receptor ensures healthy balance between the macrophage types and hence prevents accumulation of undesired M2-like macrophages in the tumour microenvironment. This provides the rationale for the use of cFMS inhibitors in cancers such as glioblastoma and pancreatic cancer as a combination with other cancer killing therapies.

The second Redx programme focusses on inhibiting an enzyme called IDO. Tumours have evolved mechanisms that weaken the immune system or render them invisible to it. By blocking IDO, we can release the breaks on the immune system and allow it to find and destroy growing tumours.

The combination of IDO with targeted chemotherapies and other immune-promoting therapies has been shown pre-clinically to have a synergistic effect. It can mean better efficacy than existing treatments. A race is now on within the scientific community to identify an IDO inhibitor that can demonstrate this in the clinic.

As a society we understand that drug discovery and development is key to achieving improvements in cancer diagnosis and treatment. And whilst new resources will need to be directed towards meeting the future cost of fighting cancer, we also need to find ways to use the resources we have more efficiently. Immunotherapy provides the very real hope of putting a brake on cancer.

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13

OPINION

Think tank Peter Sheppard, Genpact, explains how reimagining operations helps pharmaceutical companies refocus resources

T

oday’s pharmaceutical companies face mounting pressures across several fronts that dictate a need to reimagine business models and transform operations.

Channelling collaboration

Research and development (R&D) needs to build a pipeline that delivers new therapeutic options. The emergence of clinical-grade self-serve applications not only allow patients to manage their own medical conditions but also increase the amount of real-time data available to evaluate when developing new drugs.

Commercial needs to build new capabilities to succeed in an increasingly competitive marketplace of healthcare options, as digital technologies are transforming the way companies interact with healthcare professionals and patients.

Talking point: According to Peter Sheppard R&D needs to build a pipeline that delivers new therapeutic options

The cost of meeting regulatory compliance is growing in double digits as companies respond to new requirements across whole value chain, including product identification and traceability through to healthcare professional transparency.

To respond to these pressures and take advantage of the opportunities, C-suite executives need to identify how to redirect resources to invest in strategic capabilities while creating an enterprise that is fundamentally less complex and better able to compete in a rapidly evolving industry.

Intelligent operations Pharmaceutical companies need to evolve their business models and technology architecture quickly and efficiently, linking the strategies of both to deliver transformative change without compromising execution.

One area often not explored effectively is how restructuring finance and accounting (F&A) processes can deliver not only cost savings but also bring greater operational efficiencies for the enterprise as a whole. By using advanced technologies that can sense, act, and learn, companies can achieve intelligent F&A operations that simplify processes and reduce non-value-added steps, optimise working capital, and increase productivity.

Genpact’s work with UCB is an innovative example or how a global pharmaceutical company can transform its F&A processes to reallocate resources to more strategic growth areas, while improving the effectiveness of the Finance function. We reimagined operations and introduced new automation technology in such areas as source to pay (S2P), record to report (R2R), and order to cash (O2C) delivering efficiencies while providing senior management with better quality information on which to base key decisions. The end results led to increased customer satisfaction, greater efficiencies, and cost savings.

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Collaboration is paramount when embarking on restructuring F&A, both among internal corporate groups and with an external strategic service provider.

Various company stakeholders must learn to put aside their inherent biases that may have favoured disparate processes due to departmental silos. They need to agree on a common framework, learning to leverage strengths and best practices across the enterprise. An effective approach is to start the transformation initiative with a well-defined structural organisation. Teams work together to co-design projects, and team leaders agree on precise, transparent goals, and own responsibility for certain tasks. It also is vitally important that all teams set achievable and measurable metrics and monitor the projects’ effectiveness throughout the transformation.

Partnering closely together, UCB and Genpact designed and implemented a transformation roadmap with three mutual goals: drive efficiencies, enhance compliance, and improve customer satisfaction, all of which we successfully achieved together as a team. We introduced Value Stream Leads (Global Process Owners) who were responsible for the end-to-end S2P, R2R, and O2C operations, including both retained and offshored processes in UCB’s locations around the world. This approach enabled excellent coordination built on shared experience and best practices. We also established a strong governance team with clear targets, timelines, roles, and responsibilities. As a result, we implemented more than 20 projects across 25 countries in less than 12 months.

The future Businesses must spend time and focus carefully to identify the right strategic partners and internal mechanisms to achieve their desired results. With more effective collaboration – similar to how the GenpactUCB team worked – pharmaceutical companies can successfully transform processes and implement intelligent operations that can help redirect resources to strengthen R&D as well as increase profitability.

In addition to back-office opportunities, advanced operating models are increasingly relevant to core business processes. Companies also must drive change across marketing and sales, medical, and supply chain operations. This comes with a number of challenges such as breaking down additional barriers among internal functions, requiring tighter integration, and an overhaul of other existing processes. Yet by achieving such enterprise-wide transformation, pharmaceutical companies can compete more effectively and strategically in an everevolving dynamic marketplace, while continuing to keep quality patient outcomes and increased satisfaction as their top priority.

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Q

Perfect partners Dr David Roblin, chief operating officer and director of scientific translation at the Francis Crick Institute in London, talks to EPM about the Institute’s recent partnership with GSK that will address a number of disease areas

OPINION

&A

Q: What are the key objectives of this partnership and how will these be achieved?

A: The principle aim of this groundbreaking relationship is to derive accelerated insights into the basic biology of health and disease.

In something we call ‘Close Distance Translation’, scientists from each organisation will work side-by-side in integrated teams at the Crick’s worldleading centre of biomedical discovery in the heart of London and GSK’s global R&D hub in Stevenage. The close proximity of these two sites and the institutions’ complementary areas of expertise will create a fertile ground for collaborative, innovative research – exposing scientists to new ways of thinking and building capability within each organisation. Increased interactions between Crick and GSK scientists will benefit both sides, introducing new ways of working and stimulating the development of novel approaches to problems. GSK and the Crick believe that this fluid interchange of skills and ideas could lead to significant discoveries in the basic scientific understanding of human disease, which could ultimately improve the success rate for discovering new medicines.

This represents a landmark agreement in open science. In the Crick we aim to have industrial scientists embedded in our laboratories and fully integrated with our existing scientific groups. Together the scientists will accelerate breakthroughs in the understanding of human health and disease. GSK is an outstanding partner to commence this effort and I am excited to see what we deliver together.

Q: What is the long-term vision for this partnership?

Q: There are a number of projects in the immediate pipeline, can you please tell us a bit about these?

A: A number of projects within this collaboration are expected to start in 2015, building up to a steady state of around 10 projects in 2016.

The first four projects involve work in crystallography, viral accessory proteins, small molecule covalent binder collections, and the identification of compound and protein tools relating to immunity and cancer.

By the end of 2016, once the Crick is operational in its new laboratories, all 10 projects should be underway.

The ongoing nature of the Crick-GSK collaboration is expected to foster strong links between the organisations, as well as providing an excellent channel for the training and development of talented staff.

A: In the spirit of open innovation, research findings from the collaboration will be shared with the broader scientific community, via joint publication in peer-reviewed journals. This will enable important discoveries to be applied across the research community, maximising the potential for the collaboration to progress scientific understanding and accelerate the development of treatments for patients.

Q: This is the first alliance between the Institute and a pharmaceutical company, do you think it could pave the way for further collaborations with industry?

A: This is the first of what the Crick hopes will be multiple open science collaborations with many companies with an interest in health and the life sciences.

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NEWS PROFILE

Working knowledge: One of the company’s divisions is in Knowsley, UK. For 90 years, Manesty has been supplying tablet presses and coaters to the pharmaceutical industry

Pressing engagement Lu Rahman speaks to Marcus Behrens, Bosch Packaging Technology, to find out the company’s latest innovations to the market

With headquarters near Stuttgart, Germany, Bosch Packaging Technology operates in 30 locations across the globe offering process and packaging technology.

One of the company’s divisions is based in Knowsley, UK. For 90 years, Manesty has been supplying tablet presses and coaters to the global pharmaceutical and process industry. Today the brand operates under the Bosch Packaging Technology name and together with Hüttlin, this completes Bosch’s process technology portfolio for solid pharmaceuticals.

Around 120 employees develop tailor-made solutions at the site in Knowsley. All Manesty tablet presses and coaters have been designed to offer transferable parameters, easy scale-up and flexible batch changeovers – from laboratory to production scale. They are manufactured to meet the rising market requirements for flexibility, efficiency and reduced life-cycle costs The company is keen to continually offer innovative products and the TPR range has been developed specifically with the customer in mind.

According to Bosch Packaging Technology general manager, Marcus Behrens, these machines now offer higher yields with a more flexible design.

Behrens says that this range is what pharmaceutical manufacturers have been waiting for. Last year the company released the TPR 500 on to the market - this year the TPR 200 for small to medium size batches and the TPR 700 for high production volumes have also been added to the range.

“The TPR 500 can produce 400,000 tablets an hour using standard tooling and a small footprint,” says Behrens. The machine has been designed to be suited for multiple unit pellet systems without the need for any extra equipment.

“These machines come with an integrated die option, modular powder feeding system and an easy-tooperate Human Machine Interface (HMI), which is what pharmaceutical manufacturer have told us they need,” says Behrens.

The TPR 200 is designed for small to medium batches with outputs of up to 230,000 tablets per hour. One of its key features is its hygienic and easy to clean design as well as a compact footprint. A modular data acquisition system means that tabletting formulations can be developed and evaluated. It also comes with options for R&D configuration, containment applications and bi-layer tablets.

The TPR 700 is the largest tablet press of the series.

“This machine is capable of producing more than one million tablets an hour,” boasts Behrens. “As well as pharmaceutical products, it can be used for products such as vitamins and because it has been ergonomically designed, the production and technical areas of the tablet press are easily accessible.”

A two-level production zone means production and technical areas are kept separate even when removing the exchangeable turret.

All three tablet presses have been developed to significantly improve overall equipment effectiveness (OEE) in terms of availability, quality and output. Combined with an exchangeable turret, the patented integrated die plate offers increased flexibility, fast, safe and easy changeover, as well as reduced cleaning times.

“Obviously it depends on the machine model and the type of tablets, but we are seeing output capacities being improved by up to 40%,” explains Behrens.

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COVER STORY

Optimum performance Matt Mollan and Julien Meissonnier, Catalent provide expertise on strategies to optimise API performance for oral delivery dosage forms

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ccording to a recent report[1], the average drug development cost today is around $1.4 billion. If time costs or expected returns that investors forego while a drug is in development are further added into the costs, the total cost to develop a drug rises to $2.6 billion.

An additional $312 million is spent on post-approval R&D activities such as new formulations, new dosage strengths and regimens and monitoring safety and longterm side effects in patients. The higher drug development costs could be explained by the increasingly challenging nature of drug candidates due to the inherent complexity of activating the target receptors, increased focus on chronic and degenerative diseases, as well as rigorous regulatory requirements and the drive towards patient-centric drugs.

What challenges does this cause in the development process? A recent drug delivery landscape survey by the Catalent Applied Drug Delivery Institute shows that drug development cost, lengthier development cycles and identifying a suitable delivery platform are the top three business challenges faced by formulation scientists and R&D managers. The key challenge mentioned was that the majority of the compounds entering the development stage are poorly soluble[2]. Their insight echoes the current biopharmaceutics classification system (BCS), according to which

~70% of new chemical entities (NCEs) are either poorly soluble in water, have low cell permeability or both. Safety, therapeutic efficacy, and stability also dominated as the top drug formulation challenges currently faced by R&D. Specifically, dissolution issues, API degradation and crystallisation/precipitation issues were found to be the top stability challenges faced by the formulation scientists.

How can the industry respond to these challenges and make the drug development process more efficient to create better therapies while maintaining quality? A crucial step in this process can be addressing these challenges at the early stage of drug development.

Recent innovations have provided techniques and tools to address all the biopharmaceutical challenges including bioavailability, stability, manufacturability and safety challenges faced by development scientists in today’s industry. The need is to better design the drug development process so that it is both scientifically rigorous and data driven; is simultaneously more efficient and effective in systematically examining all the relevant techniques available (in parallel to save time) and is then immediately followed by conducting feasibility studies and rapid prototyping to select the best possible formulation and delivery system match to overcome each molecule’s unique set of challenges.

The table below describes the biopharmaceutical challenges and the tools available to resolve them.

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CHALLENGES

SOLUTIONS

Biopharmaceutical / Bioavailability Challenges

• Particle size reduction • Solid dispersion/solution formulations (i.e. hot melt extrusion) • Lipid based drug delivery systems • Salt/co-crystal formation • Controlled and / or modified release formulations

Stability challenges (physical and/or chemical)

• Change formulation compositions (i.e. excipients nature and/or quality) • Optimise API crystal form • Tighter control of manufacturing process parameters • Excipient selection based on compatibility with API form change • Manufacturing process optimisation • Selection of an optimal packaging system

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Industry experts agree that a single approach cannot resolve the challenges for all drug molecules in R&D today. These issues have to be addressed on a case by case basis, keeping in mind the unique physicochemical and biopharmaceutical characteristics of the API. High throughput salt, crystal-form and co-crystal screening can be an enabler in speeding up drug development at the early stages. To optimise the API’s stability and solubility, these screening platforms, along with pre-formulation studies, can be an efficient and practical way to evaluate and select the most suitable solid-form for an API. Needless to say, the selection of appropriate formulation approach during the early stage of product development involves several challenges, including limited API supply, the need for rapid turnaround, and finite development time. These constraints have triggered the need for new modelling and predicting techniques. For example, a thermodynamic solubility modeling approach can provide the required correlation between experimental and predicted solubility data that can be useful in selecting vehicles for initial formulation design faster[3] . This novel approach can help overcome challenges in labour and material requirements during traditional dosage formulation experiments, resulting in the opportunity to perform dosage form selection in the early phases of drug development.

New techniques have also been developed to improve small batch size handling processes to resolve the challenges posed by the low amount of API often available in early drug development. One of the approaches adapted to lipid based drug delivery systems involves adapting the input parameter values, such as process parameters and tooling on the industrial scale machine[4].

These results in manufacturing early development batches (ie preclinical) applying from the very beginning of a project the adequate quality process parameters while maintaining adequate yield for each unit operations. This solution avoids cost-intensive scale-up steps, enables developing Quality by Design settings at the very early stage of a programme (ie Phase I) and yields faster and better outcomes for the drug product. The development of a new project with only a low amount of API available is possible because product losses have been identified for each step of the process and an optimisation of the tooling involved in this kind of small production has been successfully performed.

With all the new drug formulation tools and better understanding of the target receptors, it is expected there will be a reduction in the demise of molecules during the development process and more molecules proceeding to the pre-clinical animal pharmacokinetics (PK), toxicity or first-in-human (FIH) studies. However, integrating a suite of drug development tools under the same umbrella, to enable the selection of the most stable and effective ‘developability’ form, will further enhance the current approach. This will result in creating an efficient process that will give each molecule the best chance to succeed. This multidisciplinary platform can be based on a threepronged approach.

• High throughput screening technologies to configure the most stable and efficient drug form: This will be crucial to optimise API performance initially and will provide the much needed data on stability, hygroscopicity, particle attributes such as shape and sizedistribution, and bulk attributes including density and flow • Bringing in industry experts from different areas: A team of scientists with diverse expertise in physical chemistry, analytical chemistry, automation, synthetic chemistry, physical pharmacy, crystal engineering and informatics driven by a science based developability assessment methodology[5] would address the drug development challenges early on in the process • Feasibility studies to select the most suitable delivery technology for the molecule: This will ensure that API form will be compatible with the drug delivery vehicle and remain stable during the manufacturing operations.

Employing this scientific Developability Classification System strategy in the early drug development process can significantly reduce potential risks and contribute to overall time and cost savings. To summarise, an all-inclusive, cross-functional, multi-discipline approach will optimise the API performance, enabling robust manufacturing with the goal of putting a cap on the ever increasing cost of drug development.

REFERENCES: [1] Tufts CSDD 2014 Cost Study, Tufts Center for the Study of Drug Development. http://csdd. tufts.edu/news/complete_story/pr_tufts_csdd_2014_cost_study [2] The 3rd annual drug delivery landscape survey was sponsored by Catalent Applied Drug Delivery Institute. For more information, visit www.drugdeliveryinstitute.com [3] FORMULATION DEVELOPMENT - Overcoming Early Phase Development Challenges & Optimizing Formulations With a Minimal Amount of API, Irena McGuffy, Drug Development & Delivery, June 2015. http://www.drug-dev.com/Main/Back-Issues/FORMULATIONDEVELOPMENT-Overcoming-Early-Phase-Dev-939.aspx#sthash.quHrNccB.dpuf [4] Softgel Capsules Low Batch Size Optimization on Industrial Equipment, Vincent Plassat & Guillaume Enderlin, Catalent Pharma Solutions, CRS Annual Conference, 2015 http://www.catalent.com/index.php/thinking/science/Softgel-Capsules-Low-Batch-SizeOptimization-on-Industrial-Equipment [5] The Developability Classification System: Application of Biopharmaceutics Concepts to Formulation Development, James M. Butler, GSK R&D Harlow, JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99 (4940-4954), NO. 12, DECEMBER 2010

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Müller GmbH - 79 618 Rheinfelden (Germany) Müller GmbH - 79 618 Rheinfelden (Germany) Industrieweg 5 - Phone: +49 (0) 76 23 / 9 69 - 0 - Fax: +49 (0) 76 23 / 9 69 - 69 Industrieweg 5 - Phone: +49 (0) 76 23 / 9 69 - 0 - Fax: +49 (0) 76 23 / 9 69 - 69 A company of the Müller group A company of the Müller group info@mueller-gmbh.com - www.mueller-gmbh.com info@mueller-gmbh.com - www.mueller-gmbh.com

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EUROPEAN RESEARCH

European union The European Federation of Pharmaceutical Industries and Associations discusses the importance of its Partners in Research initiative to boost research in healthcare

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n the search for new medicines partnering between pharmaceutical manufacturers has become commonplace in recent decades. This is in part because companies learned long ago that working in silos represents an inefficient way of developing innovative medicines, helping to support the sustainability of national healthcare systems and improving public health.

In fact, it has become increasing obvious that in order to develop a new therapy we often need to look beyond the established models, to include biopharmaceutical and technology companies, universities, hospitals, venture capital firms and governments.

By working in collaboration with continued focus on the patient at the centre of research and development paradigm, we are together witnessing a revolution in the way in which therapies are created.

Healthcare stakeholders have embarked upon a concerted drive towards the creation of precision medicines that will eventually lead to highly personalised care.

The pharmaceutical industry understands that in order to maximise the potential of this new ecosystem, it is vital to establish strategic alliances and enter into collaborations with other sectors including imaging, devices, IT, diagnostic and animal health industries. Increased collaboration could help reduce high rates of attrition in drug R&D, speed patient access to innovative therapies and ultimately lead the way to improved patient outcomes.

Partners in Research was set up as a constituent entity of the European Federation of Pharmaceutical Industries and Associations with the aim of supporting the evolution of the life science sector and with the considered ability to act upon policies that allow for the integration of a

range of technologies and sciences that are needed to address unmet medical needs and exploit the vast health potential offered by science.

It is open to non-(bio)pharmaceutical companies and pharmaceutical R&D companies that are not eligible to be EFPIA corporate members or members of its specialised groups.

Part of Partners in Research’s raison d’etre is its intended contribution to attaining the objectives set out under the Strategic Research Agenda of the second phase of the world’s largest public-private health research partnership, the innovative Medicines Initiative (IMI/IMI 2).

Today the Partners in Research initiative has nine members from the fields of medical diagnostics and molecular imaging; genome exploration; advanced data management, connectivity, and analytics technologies; optics and optoelectronics and animal health.

These members have access to EFPIA activities under IMI 2 and also benefit from the support that EFPIA provides its members in their relationships with the IMI-2 Joint Undertaking between the European Commission and the pharmaceutical industry.

There are a number of well-placed examples that serve to highlight the mutually beneficial collaboration between IMI/EFPIA and Partners in Research.

Based in Montpellier, France, Alcediag creates innovative approaches for medical diagnostics and predictive toxicology. Its principal field of activity is personalised medicine for psychiatric disorders. To achieve its goals within this field, it focuses on two main areas of application – the predictive neuropsychiatric toxicology test of drugs and the diagnostic test.

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THE DIFFERENCE BETWEEN A SOLUTION AND

THE RIGHT SOLUTION.

Breadth and depth of proven technologies and capabilities. Technology selection and formulation methodologies based on deep science. Through the integration of Capsugel, Bend Research and Encap Drug Delivery, we give you the expertise needed in bioavailability enhancement, modified release and other key formulation applications to meet your problem statement and target product profile. Our strengths span design, development and manufacturing – an integrated process to take your product from start to finish, all under one point of contact, to minimize costs, time and risk. Capsugel, the company that pioneered polymer science to develop the widest portfolio of hard capsules, delivers the right solution.

To find your solution visit www.Capsugel.com/DFS or call +1.541-312-CAPS.

Better medicines through science and engineering.

The company is developing two key enabling technologies (KETs) called Editox and Editdiag en route to providing diagnostic solutions for the psychiatric disorder field. Alcediag is keen to share Editox and Editdiag with pharmaceutical industry and says this collaboration will enable the development of drugs for personalised treatment with no neurotoxic side effects and suicide risk. It will also allow for the validation of Alcediag’s biomarkers and the associated technologies to help stratify patients for more effective treatment and design of clinical trials as well as prepare the regulatory path for acceptance of Alcediag’s biomarkers and the associated technologies.

Illumina specialises in disciplines that are relevant to IMI 2 including genomics, bioinformatics, cancer research, molecular diagnostics and human genetics.

The company aims to provide leadership and guidance around protocols to generate genomic data as well as to provide informatics leadership around aggregation and synthesis of molecular and other clinical data.

In an age where the idea of generating big data to improve therapies is of supreme importance, Illumina provides the pharmaceutical industry with a valuable partner in this process.

Zoetis discovers, develops, manufactures and commercialises animal health medicines and vaccines. In terms of the IMI 2 Scientific Research Agenda its work in vaccines, small molecule therapeutics, large molecule therapeutics and biotherapeutics, platform technologies, diagnostics, biomarkers, genetic tests, digital and data analytics and services and bio-devices are important.

The company has been keen to cooperate with the pharmaceutical sector to developing research alliances. The hope is that they will deliver additional value to new discoveries either in the human or animal health fields. Zoetis also seeks to share experiences on the identification of biological targets, mechanisms, screening techniques, biomarkers, formulations and other technologies.

These three company examples showcase the range of skill that bring value to the Partners in Research agenda. They also underscore the renewed emphasis on a collaborative effort to discover and progress the therapies of tomorrow. Other important Partners in Research are GE Healthcare (medical imaging and information technologies, medical diagnostics, patient monitoring systems, drug discovery and biopharmaceutical manufacturing technologies); InterSystems (advanced data management, connectivity, and analytics technologies); Piramal Life Sciences (molecular imaging); PMB Alcen (medical diagnosis, scientific research); Siemens (medical diagnostics); and Zeiss (biomedical research and medical technology).

It is the vast array of skills and expertise, coupled with the synergies that can be achieved that will help to streamline clinical trials, provide extra stimulus in the drive to harness big data and ultimately deliver more targeted treatments to benefit patients.

“

Increased collaboration could help reduce high rates of attrition in drug R&D, speed patient access to innovative therapies and ultimately lead the way to improved patient outcomes.

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”

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EUROPEAN RESEARCH

Bridging the gap Without competent researchers, innovation processes in European medicines’ development will not be sustainable, say Klaus Wassermann and Christa Janko, EMTRAIN

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MTRAIN is a European publicprivate consortium, offering tools and services for improving the infrastructure for education in European medicines research and development.

EMTRAIN’s core argument is that to meet the needs of future medicines research and development, in order to boost innovation, it will be necessary to leave the traditional disciplinary silo approach Research process: Klaus Wassermann and Christa Janko, EMTRAIN believe that competent researchers for innovation behind and adopt fundamental crossand development in European medicines are vital disciplinary thinking and collaboration.

This change in culture is profound in that In the past decade, the environment for medicines research and development has undergone it requires both the academic and the business worlds to change wellunprecedented change. Core structures shifted from big pharma established routines and work together much more closely. to extensive collaborations between industry, academia and small and medium enterprises. Novel scientific discoveries have Identifying obstacles been made, with greater emphasis on the molecular basis of disease for stratified and personalised medicine. And the overall In Europe a number of hurdles have been identified in the fields of focus of the business is shifting to needs and priorities of patients biomedical education and training which hold back innovation processes in medicines research on the whole. For example, highly qualified and society. biomedical professionals wishing to move to another European country Within all these dynamics however, the pharmaceutical industry in order to advance their careers might have to undergo re-training. A continues to see a lack of new product emerging from its research broadly agreed procedure to recognise scientific training across Europe and development departments. Licences for blockbuster medicines would improve this situation considerably. are phasing out, and there are currently not enough new product lines to fully compensate. For these reasons, making the time- Another issue is disruptive changes in science and technology, consuming and resource-intensive research and development challenging mechanisms of maintaining professional competency by processes both more efficient and effective is a major concern. To rendering hitherto well-established methods and routines obsolete. provide patients and society with novel innovative medicines and With ever greater complexity in research and manufacturing, increasing equally sustain prosperity for the business in the future, something specialisation of individual professionals and thus ever bigger multidisciplinary teams working together on solving a specific problem, needs to be done. there is a substantial need for collaboration and communication across EMTRAIN, the European Medicines Research Training Network, disciplinary boundaries. tackles these challenges. The consortium addresses a crucial factor for sustainable innovation in European medicines research: educating and Finally, the number of postgraduates employed in the private sector has training biomedical professionals for them to stay optimally competent been shown to have a significant positive effect on company as well as national economic performance. However, a major cause for concern is in their job. widely seen in the fact that traditional academic institutions are not effectively The EMTRAIN project is supported by Europe’s public research preparing their biomedical sciences students for careers in private industry. community and the European pharmaceutical industry in the form of a Today only about 20% of newly graduated PhDs in the biomedicial sciences public-private partnership. In short, its central services support students, are able to pursue a career in academia because there are not enough early stage researchers and established professionals in advancing their tenure track jobs. Thus, catering for the remaining 8%, a majority of which will take up a job in industry, is of the highest importance. careers in medicines development.

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Preparing academics for jobs So traditionally, pharma companies need to invest heavily in newly employed young research staff. The main issue here has not so much been mastering up-to-date biomedical research methods and procedures, but rather familiarising newly employed PhDs with the implications and challenges of working in the business environment.

Raising PhD students’ awareness early on about how pharmaceutical industry works would help significantly to reduce this initial effort and improve collaboration between the industry and academia.

The EMTRAIN project has established tools to cater for this. It runs annual workshops for PhD students who are interested in gaining in-depth understanding of how the pharma industry works. The PhD workshops are hosted by pharmaceutical companies who are themselves part of the EMTRAIN consortium. Students attending the EMTRAIN PhD Workshop learn about the medicines development process, entrepreneurship, intellectual property and ethics, to name but a few. Besides that, the PhD students practice presenting their research work to a critical expert audience. The company hosting the workshop brings the students in close contact with their senior research staff and provides guided tours of their local premises. The EMTRAIN PhD workshops have been met with students’ interest and enthusiasm and have reportedly been very successful in terms of attendance and benefit to the participants.

“

In Europe a number of hurdles have been identified in the fields of biomedical education and training which hold back innovation processes in medicines research

”

Biomedical web portal Students and experienced professionals who require training are faced with the problem of how to find appropriate courses that match their requirements of time, location, cost and quality. EMTRAIN offers another tool to meet this need - a web search platform containing a comprehensive list of courses and other education and training opportunities in the biomedical sciences from all across Europe.

On-course (www.on-course.eu contains details of close to 6,800 biomedical masters, PhD and short courses. A team of dedicated curators are working on entering courses, updating existing entries and giving support course providers on a daily basis. Course seekers benefit from a sophisticated variety of customisable search functions.

Course providers profit from the opportunity of advertising their courses on a platform that is specifically targeted to their audience. Registered providers have access to the backend of the system, enabling them to maintain their own course entries by themselves. In addition to its advanced search and editing functions, On-course also provides elaborate tools for statistical analyses of information in the database which monitor trends and gaps, as well as patterns of usage.

Competency as currency Maintaining optimal competency doesn’t stop once research staff are trained and fully established in the company business. Skills, knowledge and competencies required to fulfil a specific role in the medicines development value chain are changing constantly, with new concepts, research technologies and market trends emerging continually.

Planning for additional training to maintain innovation rates, as well as to advance the researchers’ careers, requires a systematic approach.

A third part of EMTRAIN’s activities has been building and maintaining an extended network of stakeholders in continuing professional development. Under the umbrella of the LifeTrain initiative (www. lifetrain.eu) is an open community of employers, professional bodies, course providers and individual professionals exchange ideas and develop concepts and tools to better organise continuing professional development for research staff in the biomedical sciences.

LifeTrain’s core concept is the notion of competency. Competencies are observable factors which can be documented and compared against formalised requirements. Competency not only includes knowledge acquired by formal trainingcbut also factors like skills, values and attitudes. To implement the competency concept in everyday running of medicines development LifeTrain invites employers and professional bodies to define the requirements of a specific role in specially conceived competency profiles. The researchers in turn demonstrate how well they match a profile with their competency portfolios which they are invited to maintain by themselves. The competency concept is a major step in supporting mobility across national and disciplinary boundaries, significantly facilitating both employers’ staff management and professionals’ career planning across Europe.

Currently, LifeTrain has more than 80 dedicated signatories who have agreed on a set of core principles for optimally conducting continuing professional development. LifeTrain’s signatories, as well as about 200 other stakeholders, meet up at the annual LifeTrain Workshop to discuss recent developments in continuing professional development for biomedical sciences, resulting in developing further concepts, strategies and tools.

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VITAL EXPERTISE.

Vital expertise for safe and secure pharmaceutical transportation Pharmaceutical products require precise handling at every stage of transport to ensure patient protection.

That’s why Thermo King PharmaSolutions offers precise temperature control and air distribution throughout the supply chain, and a wide range of GDP-validated equipment and services to enhance your quality system. Easy access to service history, advanced monitoring, 24/7 assistance, and training are also available.

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DIGITAL HEALTH

Make the connection: Wearable drug delivery technology includes West Pharmaceutical Services’ SmartDose electronic wearable injector system

You wear it well Graham Reynolds, West Pharmaceutical Services, looks at embracing the connected health movement and werables in the management of chronic diseases

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or patients with many chronic conditions, such as diabetes, haemophilia and autoimmune diseases such as rheumatoid arthritis and multiple sclerosis, the use of injectable biologic therapies is on the rise.

These drugs present several challenges for both drug manufacturers and patients. In particular, many biologics require a high concentration, so an effective dose may be highly viscous, or require large doses to be injected slowly over time. This can make it difficult to deliver a consistent dose every time, potentially impacting patient adherence to a given therapy.

According to estimates from the World Health Organisation, patient adherence with chronic medication therapies is remarkably low – about 50% internationally[1].

This is a major health issue, as non-compliance can lead to a number of complications, including poor clinical outcomes, increased costs for many healthcare stakeholders (including the patients themselves) and lost revenue for pharmaceutical companies.

Treatment options are not the only evolving element in the care of chronic diseases. The delivery of healthcare for chronic conditions is shifting from doctors’ offices and hospitals into the patient’s home in an effort to provide patients with more independence and control over their treatment while helping to stem growing healthcare costs. This, coupled with increased use of biologics, is making it increasingly important to provide patients with novel approaches to drug delivery.

One of the most promising options is wearable drug delivery technology. For example, West Pharmaceutical Services’ SmartDose electronic wearable injector system

is a single-use, electronic wearable injector that adheres to the patient’s body, usually on the abdomen and is pre-programmed to deliver high volumes of viscous or complex drug products. The system incorporates a polymer-based drug container system with a drug delivery device that controls the delivery of large doses over time, making it easier for patients to self-administer medication outside of the clinical setting.

The industry is now taking the wearable technology concept one step further by connecting injectable drug delivery systems with tools that can improve the user experience and drive adherence. The connected health movement has helped the pharmaceutical industry realise the potential of using consumer technology and electronic devices to further engage patients in their care and address the issue of non-compliance.

As one example, West has joined with HealthPrize to develop apps in conjunction with self-injection drug delivery to enhance the patient experience and help those managing chronic diseases stick to their medication regimens. In the first offering from the West/HealthPrize collaboration, patients will manually scan barcodes or otherwise enter data about their medication compliance into the smartphone/tablet app (or on an Internet browser from a computer if they don’t have a wireless device). Connected health offerings such as this provide numerous benefits for all parties within the health ecosystem. For patients, this provides a better experience around tracking self-treatment schedules, including education, gamification and rewards for adherent behaviour.

The ultimate goal is to boost adherence and improve

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outcomes. For the healthcare system – burdened by approximately $25 billion in preventable readmissions annually[2] – there is significant opportunity for the use of outcomes and adherence data to help generate potential savings in avoidable hospital stays and subsequent interventions triggered by non-adherence to prescribed medications. Lastly, pharmaceutical companies can recapture the revenue lost annually due to non-compliance, which has been estimated to be over $564 billion (insert reference).

Looking ahead to the future of chronic disease management it’s imperative that the pharmaceutical industry remains focused on collaboratively improving medication adherence and improving patient outcomes, as this will have a positive impact on some of the most significant and costly issues in healthcare delivery. As patients and healthcare providers are increasingly looking to technology in pursuit of improved wellness – especially to manage chronic diseases – providing new, innovative approaches, such as connected health applications will be critical to truly impacting the way patients receive their care and the effective treatment of chronic conditions.

[1] World Health Organization. (2003). Adherence to long-term therapies: evidence for action. Retrieved August 5, 2015 from http://www.who. int/chp/knowledge/publications/adherence_full_report.pdf [2] PriceWaterhouse Coopers’ Health Research Institute. (2008). The Price of Excess: Identifying Waste in Healthcare. Retrieved August 6, 2015 from http://www.pwc.com/us/en/healthcare/publications/the-priceof-excess.jhtml

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More than meets the eye With one of the widest ranges of cleanroom wipes and mops available, plus a newly completed range of alcohols, disinfectants and detergents, there is definitely more to Contec than meets the eye. From patented Anticon wipes with particle attraction technology, or market leading presaturated wipes in a variety of substrates, Contec has a cleanroom wipe to suit every budget, application and facility. Contec has launched three new innovative mopping products, adding a curtain cleaner and sealed edge mops to their extensive mopping range.

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What to wear?

DIGITAL HEALTH

Rick Valencia, Qualcomm Life, explains how wearable technologies enhance the effectiveness of clinical trials

Rick Valencia, Qualcomm Life says that adopting wearables and connectivity platforms will be the next advancement in the industry’s evolution

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earables have grown in popularity in the last two years and are primarily known for smartwatches and fitness bands. But this new technology could save the US health care industry hundreds of billions of dollars.

One emerging area in which connected wearable devices may have the biggest potential impact is in the clinical trial space. As Kevin Patrick, a professor of family and preventive medicine at the UC San Diego School of Medicine, discussed in a recent Xconomy piece, clinical trials are growing into a multi-billion dollar global market for wearable health trackers and other related technologies and pharmaceutical companies are the primary customers.

At present time, trials are costly, time-consuming, demanding and come with an extremely high rate of failure. Because data during these trials is typically collected in paper form, much of it is lost; the remainder that isn’t lost is susceptible to concerns with accuracy and analysis. The industry needs an easier, more efficient and more reliable method of collecting data from clinical trials. Connected wearable devices could be the solution.

When it comes to wearables, there's no one-size-fits-all answer.

A variety of devices can be attached to your body in a multitude of ways, and each one comes with an advanced array of sensors and monitoring equipment. These devices are continuously measuring your body's data and syncing that information to the cloud, at which time they can easily be collected, aggregated and used by clinicians conducting the clinical trial.

Continuous care and passive data collection may sound like a faroff dream for patients and doctors, but through Connected Therapy Management (CTM) it's quickly becoming a reality. Technologies such as glucose monitors, remote injectors and patches are now capable of providing real-time, secure data capture and transfer. Clinicians can analyze and troubleshoot trial design, address potential adverse events and improve outcomes while reducing the risk of data loss. Connected Therapy Management also allows for remote monitoring of patients, aligned incentives and the ability to combine therapeutic data with

diagnostic data. Connected health technologies also improved patient engagement and medication adherence by making data collection more seamless, moving care to more convenient settings like the patient’s home and providing digital engagement tools that encourage patients to participate in their health.

While the advantages of connected health technologies in clinical trials are well understood, we will not stand to reap the benefits without a scalable, interoperable platform that allows the array of devices, applications and services to integrate. Earlier this year, Qualcomm Life collaborated with Novartis to provide 2net, a global connectivity platform that seamlessly collects and aggregates medical device data during trials to improve the convenience and speed of capturing study participant data and test results.

The 2net platform is a cloud-based system that's designed to be universally interoperable, meaning that it can connect with a wide range of different medical devices and apps. The 2net Hub is a plug-and-play gateway that acts as the information highway for collecting data from home-based medical devices like weight scales and blood pressure monitors, while 2net Mobile can transform a smartphone or tablet into a secure gateway for capturing biometric data from devices while on the go. By liberating medical device data, 2net enables health care providers to remotely monitor their patient’s health status in a more comprehensive, timely manner.

Clinical trials have inherent risk and complicated by nature, but the risk of not adopting digital technologies to advance the industry is too great.

Wearables are not just the latest consumer trend in technology; they have the potential to save the health care industry billions of dollars and help bring new treatments and innovations to market, not to mention aid in the advancement of scientific discoveries.

Modern health care may be focused on finding new treatments and advancing medical knowledge, but it has taken longer than most industries to evolve and adapt to the digital age. Adopting the latest medical-grade wearables and connectivity platforms will be the next advancement in the industry's evolution.

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THROUGH THE DOORS

Made in Denmark Medical packaging group Gerresheimer has sites all around the world, but from one facility in Denmark, the group produces vast quantities of innovative packaging solutions for some of the biggest names in pharma. EPM takes a look through the doors at Gerresheimer

This year a new product was launched which re-thinks the Duma concept altogether Innovation is a major part of Gerresheimer’s operation

In fact Düring revealed that the group has developed 12 new dispensing solutions. He added that 40% of all prescribed medicines do not achieve their full effect, either because they are taken at the wrong time, at the wrong dose, or not taken at all.

The healthcare system is driving innovation here, as it becomes increasingly intolerant of the cost and waste of misused medicines.

Situated on the outskirts of ‘wonderful, wonderful Copenhagen’ in a small town called Vaerloese, the Gerresheimer facility stands at 12,000m2, having been built back in 1964, before the company was known as a specialist supplier to the medical sector. Back then the group had operations in many different packaging markets.

Last year the Danish arm of Gerresheimer celebrated its 50th anniversary. Originally called Dudek Plast, it was founded in 1964 by Peter Dudek, who is now 86.

From one facility in Denmark, the group produces vast quantities of innovative packaging solutions for some of the biggest names in pharma

There are currently 100 employees at the two Danish production facilities in Vaerloese and Haarby.

Today though, the Vaerloese site is used for the manufacture of the group’s Duma and Dudek branded portfolios for pharmaceutical packaging.

Duma Twist-Off, was first launched way back in 1992 – notable for its cap design. Over the years the portfolio has seen many variations, and this year a new product was launched which re-thinks the concept altogether.

Improvements include more uniform wall thickness, optimised closure design and compatibility with all other high quality Duma Twist-Off and Duma OneLiner closures. But most noticeable change is the new closure which is designed to be user-friendly for the elderly (it can be easily opened using the side of a coffee table or with a biro pen) and yet maintains child-resistance.

As an example, Düring demonstrated DropAid – a delivery solution for eye drops.

The design is simple but clever.

Not only does it make the dropper bottle easier to open, it also allows the user to position the bottle so that the eye drops end up in the eye rather than around the edges.

Above it all though, quality is key for the group. “Quality is crucial in our business,” explained Our tour is concluded by Charlotte Borgensgaard, chairman of the group’s quality council. “Quality is crucial in our business. Quality is something that affects us all, because we all take medications at some time or other.”

The company operates a global quality initiative which involves a close collaboration with all quality managers around the world.

“We want to ensure that elderly citizens who aren’t as strong as they used to be can still open their tablet containers,” said Niels Düring, global executive vice president, plastic packaging. “But we also want to prevent curious children in the family from being able to swallow their grandparents‘ tablets.”

Walking around the factory, it’s clear that Gerresheimer has a strong emphasis on design quality. But speaking with Niels Düring, it also becomes apparent that innovation still has a major role to play. He explains that dispensing is one key area where the group sees potential for development.

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The DropAid design is simple but clever

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Spanish steps

CPhI

This year’s CPhI takes place on 13-15 October 2015, IFEMA, Feria de Madrid, where some of the leading names in the pharmaceutical sector will be highlighting their latest expertise and innovation

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here are many reasons to make a trip to Madrid in October. CPhI allows you to meet 36,000 senior pharma professionals from more than 150 countries in one setting. Over 2,500 exhibitors in 20 dedicated zones will becovering ingredients, APIs, excipients, finished dosage, contract services, packaging, machinery and more.

For many global companies the show offers an efficient and effective way to meet suppliers from major markets such as China, India and the US as well as emerging markets including Turkey, Russia and Malaysia.

Organisers of the event say that CPhI allows visitors to keep abreast of the latest industry developments and stay up-todate on market news and trends during the Pre-Connect conference.

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Highlights Pharma Forum The Pharma Forum aims to provide a range of business opportunities to pharmaceutical professionals in one central place. The forum is billed as the go-to space for pharmaceutical professionals looking to explore specialist niche areas, new business opportunities, as well as sourcing non biased information on trends, innovations, developments, and the latest regulatory insights.

Pharma Forum includes: access to the latest innovative products and services in the Innovation Gallery, free high value content at the Pharma Insight Briefings and the chance to share your experiences and recharge your batteries at the Pharma Insight Lounge.

Located within the Pharma Forum, the Pharma Insight Briefings are a series of in-depth, specialist seminars on topics to enhance your time at the show.

Exhibitor showcases

Tweet chat Returning for its second year, the second day of CPhI Worldwide will host an industry wide tweet chat broadcasting a conversation between the CPhI expert panellists and the attendees. With the release of the annual report, attendees will be able to analyse the contributions of the panellists and contribute to a live discussion displayed throughout the screens at the show.

Join the conversation at @cphiww using #cphiww

Pre-Connect congress The 7th Annual Pre-Connect Congress takes place the day before CPhI Worldwide on 12 October. This event features six modules, over 10 hours of content from 40-plus speakers and an audience of more than senior executives from the global pharma industry.

Previously speakers’ corner, this is the commercial platform for pharma professionals to highlight their expertise and services. These 25 minutes speaking slots provide companies with an invaluable opportunity to present perspectives on their key products, innovations, services to visitors and the press. Additionally, it provides an open platform for speakers to directly interact with attendees and help with networking.

Innovation tours Across each of the three days at CPhI, top industry experts will guide attendees through innovation tours. These hourlong bespoke events give a brief overview of industry trends and recent innovations within the pharmaceutical industry. Starting from the innovation gallery, the tours travel throughout CPhI, ICSE & P-MEC and InnoPack providing perspective across the entire pharmaceutical supply chain.

“

For many global companies the show offers an efficient and effective way to meet suppliers

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CPhI

Twist and shout At this year’s CPhi, Gerresheimer will be focussing on usability.

“More and more people are self-medicating,” said Jessica Kreher, a graduate designer specialising in usability and sales engineer at Gerresheimer Medical Systems. She added that the demographic changes taking place in many countries around the world have contributed to the self-medication trend, as has the rapid increase in access to medical care in developing nations.

Kreher will be highlighting the advantages of usability in a presentation entitled ‘Usability Engineering for Drug Delivery Devices’ on October 13.

Usability affects both patients and health professionals such as doctors and nurses. Gerresheimer Medical Systems’ product portfolio includes easy-open tablet bottles and an application aid that helps eye drop users to position the bottle properly to syringes, injection pens, asthma inhalers and an optimised heart catheter delivery device.

One of Gerresheimer’s longstanding best-selling products, the Duma Twist-Off plastic container, is designed for usability and functionality. It offers senior-friendly, child-resistant and tamper-evident features in one single closure.

Plastic fantastic

Perfect partners

Global Closure Systems – provider of plastic closure solutions for the global FMCG market will be showing its Clic-Loc, Mediloc, CapePharma, PharmaSafeTM and Vistop ranges. The company offers expertise child-resistant closures, tamper evident closures, droppers and medical devices in Europe.

Alongside its large portfolio of more than 230 pharmaceutical standard closures for liquid and solids pharmaceutical products, GCS has extended its closures range (Fliploc, Lite-Loc) and developed a bi-injected TPE closure for large volume parenteral (LVP) using BFS technology.

Clariant will be demonstrating its commitment to customer collaboration and innovation in the pharmaceutical and healthcare market.

The company’s industrial and consumer specialties business unit will present innovative and sustainable solutions including Polyglykol universally applicable pharmaceutical polymers plus a range of Macrogols with various molecular weights – all of them supported by CEP certification and DMF. Clariant Healthcare Packaging manufactures controlled atmosphere-packaging that helps to protect healthcare products from humidity and oxygen. Its portfolio includes desiccant canisters and packets; tubes and desiccant stoppers; Tubairless1, an airless packaging system for protecting and dispensing sensitive pharmaceutical semi-solids and creams; EQ-Can and EQ-Pak humidity regulators.

Clariant Healthcare Polymer Solutions will feature the MEVOPUR and the REMAFINEP brands of colour and performance masterbatches and compounds developed specifically for the medical device and pharmaceutical packaging sector.

Solid performance Nolato has been working on a new addition to the Cerbo Solid container range. The Cerbo Solid W has a similar design as the Cerbo Solid range however this new pack has a new neck opening.

Glenn Svedberg, head of Nolato Medical Pharma Packaging: “In response to further needs from our customers, we have been able to advance this standard range into something that will add value for both our customer and the end-user. With the optimised closure and thick wall container, it ensures extra security and superior tightness for solid dose pharmaceutical products it’s been designed for. As well as the increased neck opening that improves efficiency on filling lines.”

The new Cerbo Solid W and Cerbo Solid standard range will be exclusively on display at CPhI in Madrid, as part of the offering of plastic packaging solutions from Nolato Medical Pharma Packaging.

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FOLIO

Capital ideas CPhI can really take it out of you, but save some energy and time . . .we’ve handpicked five essential things to do in Madrid during the show

OPHTHAL

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Gran Via Meaning ‘great way’, the Gran Via is a major shopping street in the centre of Madrid. It’s also a great way to pack several sights into one attraction, as it’s home to several notable buildings including the Metropolis Building, the Edificio Grassy and the Telefonica Building – Europe’s first skyscraper.

EAR, NOS

ROAT TH

E,

Plaza Mayor

PULMONA R Y

Another central attraction, the Plaza Mayor is a great place to stop for a coffee or try some tapas. And you’ll be sitting in the middle of some of Spain’s most important history, having been home to markets, bullfights, football matches, and even public executions.

PARENTER AL DERMAL/ T RA NS

Flamenco!

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For a great night out, head to one of Madrid’s many flamenco restaurants. This traditional dancing is loud, lively and colourful, and should revive you after a day in the halls.

Exhibitor & Speaker

Tapas When you’re travelling in a large group it can be hard to please everyone when it comes to choosing somewhere to eat. That’s why tapas is perfect, and where better to try it than Madrid? Small portions, big variety and lots of flavour. Ten minutes by taxi after the show will take you to La Castela, where you get a free dish with every drink.

Temple of Debod You don’t have to be a history fan to find this impressive. An ancient Egyptian temple in the middle of one of Europe’s most cosmopolitan cities, the temple was once situated in Aswan, near the river Nile. However, due to the construction of a nearby dam, Egypt gifted the temple to Spain in 1960.

Booth 4C40 Nemera provides solutions for the pharmaceutical industry, including standard innovative products, development of custom devices and contract manufacturing.

ophthalmic

pulmonary

dermal/ transdermal

parenteral

nasal/ buccal/ auricular

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

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HIGH POTENCY

Safety at work Stephen Brown, Encap Drug Delivery, a division of Capsugel Dosage Form Solutions describes why the safe manufacturing of high potency drugs requires a specialised approach

H

ighly potent active pharmaceutical ingredients (HPAPIs), including both small molecules and biologics, continue to increase as a share of the drug development pipeline facilitated by high throughput screening. More than 25% of total drugs worldwide today contain HPAPIs, and projections show that the global market for HPAPI drugs will grow by an estimated compound annual growth rate of nearly 10% between 2012-2018.

Growth in HPAPI use is largely driven by advances in clinical pharmacology and oncology research, including antibody drug conjugate applications.

When compared with traditional active pharmaceutical ingredients, HPAPIs have properties that enable them to target disease more selectively at significantly lower dosages with reduced side effects. Compounds are generally classified as highly potent due to an occupational exposure limit (OEL) of ≤10 µg/ m3, a daily therapeutic dose of ≤10mg/day or if a 1mg/kg/day dose produces serious toxicity in laboratory animals.

HPAPIs are highly toxic compounds until they reach finished solid or liquid form. This poses an occupational risk to R&D and manufacturing employees. High potency formulations are also low dose applications by definition and as such, can require specialised approaches to ensure accurate dosing throughout the development cycle.

Because of the exposure risk, handling of HPAPI requires facilities with specialised equipment, infrastructure and expertise from pre-clinical development through commercial manufacture to protect employees. It also necessitates the development of innovative dosage form technologies that can help reduce occupational risk during the manufacturing process. As a result, pharmaceutical companies are increasingly seeking partners with specialised and proven HPAPI handling capabilities to help them develop and manufacture their HPAPI medicines in the safest possible conditions.

Stephen Brown, Capsugel, explains the approach needed for safe manufacturing of high potency drugs

Specialised expertise

Innovative dosage form technologies

Specialised HPAPI manufacturers are addressing toxic exposure risk to their employees and the environment by implementing advanced capabilities in facility design, equipment, containment, air handling, monitoring and operational scale. Best practice facilities feature:

In addition to containment facilities, specialised HPAPI development and manufacturing organisations continue investing in innovative dosage form technologies that address the dose and handling challenges associated with HPAPI-based formulations.

• Room pressure cascades designed for containment within the main HPAPI handling area.

• Airlocks and vestibules around laboratory and manufacturing suites to provide gowning and degowning areas and proper pressure differentials. Additionally, misting showers may be a part of degown and exit vestibules to allow for rinsing of personal protective equipment.

• HVAC systems designed for single-pass air (no return) with necessary controls for temperature, humidity and particulates.

These systems must allow for filtration and capture of contaminants in the point source within the isolator and the general HVAC system.

• A good industrial hygiene programme to ensure that equipment and systems operate properly, meeting design specifications and demonstrating the effectiveness of the containment for the specific compound being handled.

• Restricted access to ensure that only properly trained employees who are well versed in HPAPI operating protocols enter designated HPAPI-handling spaces.

By outsourcing HPAPI manufacturing, pharmaceutical companies avoid the need to develop specialised infrastructure, engineering controls, and employee training and protocols that are expensive to implement, especially for the low volumes typically associated with HPAPI products. At Capsugel, we have invested in and maintain high containment capabilities across our technologies from design through commercialisation up to OEL <1 µg/m3.

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Liquid fill hard capsules (LFHC) and soft gelatin capsules are examples of such technologies and minimise the risk of airborne contamination to being only possible at the initial powder handling stages of the manufacturing process. Following the initial wetting or dissolution of HPAPIs, the bulk formulation can be further processed through the capsule filling and sealing stages of the manufacturing processes with a significantly reduced risk of contamination to the operators and manufacturing environment. The finished dosage form also has a reduced risk of surface contamination with HPAPI and provides a product that can be safely processed and packaged with minimal risk to employees.

Dose homogeneity and fill accuracy are also more easily assured through liquid and semisolid fill compared to dry ingredient-based dosage forms.

[1] HPAPIs and Cytotoxic Drugs Manufacturing Market, Roots Analysis, August 2014, http://www.rootsanalysis. com/reports/view_document/hpapis-and-cytotoxicdrugs-manufacturing-market/64.html [2] Transparency Market Research, High Potency Active Pharmaceutical Ingredients (HPAPIs) Market - Global Industry Analysis, Size, Growth, Share And Forecast 2012 – 2018, November 25, 2012, http://www. transparencymarketresearch.com/high-potency-activepharmaceutical-ingredients-market.html [3] Molly Bowman, Development in high potency API manufacturing, Specialty Chemicals Magazine, July 2013, http://lifesciences.thomsonreuters.com/m/pdf/ Bowman_SCM_Jul13.pdf

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O’Hara Tablet Coating System Small O’Hara Laboratory Coating Systems, up to 100 kg

O’Hara Labcoat series are compact selfcontained Laboratory coating systems.

• • • • • •

Aqueous & solvent designs Interchangeable pans Portable & self-contained CE declaration & conformity Tablet pellet pans Anti bearding spray nozzles

O’Hara Technologies Inc. 20 Kinnear Court, Richmond Hill Ontario, Canada, L4B 1K8

Medium

O’Hara Containment Coating Systems, 95 to 100 kg

The Containment Labcoat is a product line of multi-pan laboratory and production coating systems with containment for highly potent API’s.

• • • •

High Volume O’Hara Continuous Coaters, aters, 10 to 1200 (kg/hr)

FastcoatTM continuous Coater is a product line of continuous/fast batch tablet coating systems.

• • • • • • •

Up to OEB5 Rigid isolator door seals Reverse tablet discharge Flex containment option

Tel: +1-905-707-3286 Fax: +1-905-763-6749

Rapid coating speeds Wash in place (WIP) Zero wastage Adjustable bed depth Anti-bearding spray nozzles Recipe control Less product damage

Email: sales@oharatech.com Web Site: www.oharatech.com

Please visit our Stand #325 at 2015 AAPS Annual Meeting & Exposition in Orlando Convention Centre to get more information on O’Hara New Coating Technology

Nest & Tub Container feeding

Clean, sterile glass containers, ready to be filled

Washing Vials

Depyrogenation (for vials and cartridges)

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Nesting, tub insertion & Tyvek sealing

Y

CM

Cartridges

MY

CY

CMY

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Double bagging in Steribag

Syringes

Tray Final sterilization Vials

www.ez-fill.com 38

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HIGH POTENCY APIS

Handle with care Dr Mike Battrum, Aesica Pharmaceuticals describes the art of safely tableting potent APIs

Safe as houses: Employers are legally required to ensure that employees are not subjected to concentrations of substances above the occupational exposure limit

I

n recent years an increasing number of pharmaceuticals and intermediates have been developed that are classed as potent materials. As employers are legally required to ensure that employees are not subjected to concentrations of substances above the occupational exposure limit (OEL), the facilities, equipment and operational procedures for handling potent materials on a commercial scale must therefore, be designed, constructed and proven to be safe prior to manufacturing.

The fundamental basis of design is to provide primary protective equipment (PrPE) that is fully contained and prevents human contact with potent materials. It is then necessary to locate the equipment in a facility that provides secondary containment to ensure that airborne particles cannot reach the outside world should the equipment fail.

PrPE The choice of contained system depends on a containment performance target, less than or equal to the OEL. This performance target must be given to an equipment vendor when specifying equipment.

The handling or manufacture of potent materials will centre around a piece of process equipment (for example, mills or tablet presses) in which dry powders are processed. Other types of equipment, such as coaters, can have a lower, but still quantifiable, risk.

During design, it is essential to examine how leak tight the equipment is and under what pressure it will operate.

Technical advances such as inflatable door seals warrant serious consideration. Usually equipment should be operated under negative pressure.

The weak points of process equipment are the systems for transferring powder into and out of the unit. Barrier isolators are the most common equipment. Isolators can

be stand-alone, fully enclosing the necessary production equipment or integrated with other process units.

Secondary containment

Isolators can be fixed-wall or flexible-walled. Hardwalled isolators are convenient in API environments where potential damage is a factor. Flexible-walled isolators are frequently mobile stand-alone units, with stainless steel bases and tubular frames.

PrPE is only part of the overall solution. Unfortunately, there is always a risk that the systems may fail or be operated incorrectly. Contamination at these low levels cannot be seen or detected and therefore it is essential that possible contamination cannot exit the building. This is known as secondary protection.

Both types can be operated either at atmospheric pressure or under negative pressure (at least -30 Pa). Negative pressure isolators deliver much better containment performance.

Facilities designed for the manufacture or handling of potent materials should follow clear guidelines, including, entry via an airlock that is at a higher pressure relative to the rest of the facility.

Split butterfly valves (SBVs) are another common method of transferring solids from a fixed contained unit to another mobile unit.

All facilities are different and may be subject to different influences based on the complexity of the process. This means that a number of factors should be considered such as how decontaminated PPE will be disposed of; and how materials will be made safe before they are removed from the area.

Alternatively, for processes that require the handling of less potent powders or tablets in the 0.5â&#x20AC;&#x201C;10 kg range, the Hycoflex bag system is simple and easy to use and relies on the Hycoflex coupling â&#x20AC;&#x201D; a plastic and metal device that can be docked and de-docked using a specialist tool[1].

The containment equipment must be designed so that the appropriate cleaning methodology can be performed.

The main three stages of cleaning are wash-in-place (WIP), wiping down and dismantling.

An automatic clean-in-place (CIP) or WIP system is preferred as it should reduce gross contamination to an acceptably low level.

For wiping down it is important in the design phase to ensure that all surfaces can be reached using the glove ports though occasionally, specialist cleaning tools are required.

For dismantling in phase 3, it is sensible to do swab tests to confirm the cleanliness of equipment.

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Performance testing It is vital to prove the efficacy of containment equipment by testing with surrogate powders. A methodology for the testing is provided in the ISPE Good Practice Guide.

Testing is usually performed over three runs of normal operation. Sample analysis can take as long as two weeks before results are available.

It is wise to ensure full training prior to testing as containment performance can often be operator dependent. Performance testing should be repeated after the first and second years of operation thus providing three data points against which to fully evaluate the containment performance of the PrPE systems.

REFERENCE 1. www.niroinc.com/pharma_systems/hicoflex.asp

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HIGH POTENCY

High five According to Extract Technology there are five questions you need to ask yourself before purchasing a high potency containment system

C

reating a safe environment for people working with highly potent substances is not an easy task. It’s not just a matter of buying a readily made solution. It has to be operated and maintained properly to ensure the people working with the hazardous materials will not be exposed.

Institutions have to invest a fair amount of money in their containment systems – that’s why, if you’re considering purchasing one, these five questions below will help you specify your containment needs before contacting a containment system vendor.

1

WHY DO WE EVEN NEED CONTAINMENT?

The main and crucial reason organisations use containment systems is to make sure that their personnel is protected from the active compound; that they will not be sick or harmed in any way by the potent substance. The person responsible for ensuring that safety has to evaluate handling and producing processes of products such as certain powders, hormones, cyto-toxic or radio-pharmaceuticals.

Containment solutions are also needed because of legal requirements and the obligation to comply with Health and Safety at Work regulations.

Organisations such as Medicines and Healthcare products Regulatory Agency (MHRA) or the FDA in US may require such systems depending on the type of products being handled.

2

There are several ways to achieve a controlled contained environment.

The main categories of possible containment strategies include: general ventilation, downflow booths – with or without barriers and Isolators that may – or may not – have transfer ports and valves.

Deciding which system is needed at your facility will require a risk assessment. Assess the type of products, how dusty they are, how long the operators will be exposed to them and the quantities that will be handled. Such evaluation will help determine whether there will be a need for a localised exhaust ventilation, additional barriers or even isolators.

The third main reason is control of migration. When weighing and dispensing a powder in one room, the containment solution you employ will help make sure the powder doesn’t travel into another room. Controlling the work environments will enhance the safety and protection of every employee.

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IS THERE A STRATEGY TO FOLLOW?

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3

4

HOW DO I SELECT THE RIGHT STRATEGY FOR OUR PROCESSES AND PRODUCTS?

IS IT A BOOTH’S JOB?

Downflow booths continually flow and filter the air inside to protect operators.

Extract Technology always recommends following the containment pyramid figure developed in the early 1990s. This pyramid is often used industry wide for this exact purpose – to determine the potential containment strategies.

Downflow booths are steel enclosures that operators will have to step into to work with products that need containment. Air circulates and protects the operator by pushing any dust clouds downward and away from their breathing zone, into filters. The dust is kept inside, whilst the booth operates at slightly negative pressure, continually cleaning, recirculating and pulling air in from outside the room.

Go with the flow: In a downflow booths air circulates and protects the operator by pushing any dust clouds downward and away from their breathing zone, into filters

Firstly, one has to incline the exposure potential – what are the quantities an operator would potentially have to handle? Grams are considered to be small quantities, kilograms – medium and large quantities are measured in tons. You will have to determine one key exposure factor.

The dustiness of the material is also crucial here. Sand-like products will have a low dustiness potential whereas products resembling finely granulated powdered sugar could blow around easily, placing them at the high end of dustiness level.

The last factor to consider in the upper section of the contamination pyramid is to measure the risk an operator will face is task duration.

Short task durations are around 15 minutes; when people work with a compound for hours at time you’d classify that as long durations.

Determining these factors will allow you to establish the exposure potential as EP 1, 2, 3, or 4 as seen in the pyramid.

After you established that you will have to determine the occupational limit (OEL) for the specific product. The limits are broken into bands corresponding with quantities allowed per cubic meter of space, labelled A-F. Usually the product itself will list its band level.

Now you can find the best and most suitable control strategy. Knowing the exposure potential and band level, you can read horizontally to find the recommended strategy.

Downflow booths vary in size, ranging from 1.5m to 8m wide and various depths. After the booth is installed in the field, the containment line can be measured, determined and marked. The containment depth between the line and the back wall is where the airflow is most effective at protecting the operator. Areas outside this depth are not considered safe for the personnel working inside – and all operations should be performed as close to the back wall as possible.

Choosing the right size requires determining the types of activities that will take place inside, the types and footprint of the processing equipment located within and number of operators working inside. For example, the size of any bulk containers inside the Booth, how products are weighed, packaged and delivered – all these factors have to be considered within the design process. Method of packaging affects sizing of the booth – eg. there is a big difference in handling containment between a product packaged in bucket size container and a product coming on a pallet.

The way that product moves from one piece of equipment to another matters as well – does it go through a small mill during weighing, does it land in other containers? Answering all these questions will influence the final design of the containment solution.

You might also have a requirement for manipulation devices inside a downflow booth, eg. conveyor systems or drum handling equipment.

Depending on the arrangement within your facility, filters can be accessed for safe change either from inside or outside. If located in a warehouse environment, your booth will need a positive pressure airlock installed on the front to keep the inside cleaner. As for booth’s own requirements, adequate utilities are necessary – chilled water is recommended for booth cooling and three-phase power is needed for the lights, high-efficiency fan drive motors, gauges, and for power inside the booth.

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5

OR IS IT AN ISOLATOR?

An isolator is an enclosure that contains a qualified controlled environment, sealed to a high standard of leak tightness. Used when products are so potent that a downflow booth couldn’t provide enough protection, isolators contain the product inside while the operator works with it by placing their arms through glove ports.

When deciding in favour of an isolator, a factor to consider is cleaning.

The Isolator has to be totally neutralised before it’s opened to maintain equipment kept inside. No powder residue can be left as this could cause cross contamination to the next batch.

Isolators are equipped with safe change HEPA filters and fans operating at slightly negative pressure as well as pressure sensors and gauges that monitor the system. If a glove is breached, the fan speeds up to maintain the desired air flow and negative pressure to protect the operator. Users should perform leak testing on a regular basis, following procedures and protocols. A glove testing device might have to be procured alongside the Isolator to ensure safety.

Space is less of a concern when deciding for Isolator in favour of downflow booth however, adequate ceiling height and space around the isolator is required for testing and maintenance. Another issue to consider beforehand is the size of doorway, room, and the pathway that would be taken during delivery if the isolator is going into an existing lab.

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isolators require 3-phase power and 15-25 amps (depending on size), compressed air and cleaning liquid (based on the product – provide water for water-soluble products and solvents for solvent-based products).

As Extract’s isolators are fabricated from 316L stainless steel and acrylic (complete with special coating), it proves cost-effective and reasonable to create a wooden mock-up construction to make sure the form and fit actually works, and operators can reach everything and perform all desired activities.

Gaskets and glove materials are selected based on the compounds to be used inside the isolator.

Answering the above five questions and considering all the mentioned factors influencing containment within your facility can help you improve the process of purchasing containment systems thus enhancing operators’ safety and the quality of the final product.

The X factor: When deciding in favour of an isolator one factor to consider is cleaning, says Extract Technology

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TOPICALS

Silver service Crawford Healthcare’s Richard Anderson discusses how new approaches to antimicrobial resistance and silver-based wound dressings could relieve the burden on the NHS

Silver bullet: US hospitals have taken to the reemergence of silver-based wound care products, in an effort to prevent infections topically

almost three decades, the advanced wound care market is seeing rapid growth and innovation, particularly in the privatised American healthcare system.

NHS waiting times have come under intense scrutiny in the press over the last 12 months and rightly so. While we may have seen an improvement in the situation since last Christmas — when the number of patients waiting 12 hours or more for a bed on a ward reached record levels — the NHS is sure to come under strain again in the near future.

US hospitals have taken to the re-emergence of silver-based wound care products, in an effort to prevent infections topically. The slower delivery of antibiotics to a wound through the blood often means that secondary infections are already too well established to be treated effectively. Treating a wound directly with an appropriate antimicrobial wound dressing may be the most appropriate treatment for dealing with that individual infection.

Labour hung its hat on the NHS in the general election for good reason — despite having failed to check the figures — and while David Cameron is pushing a seven-day service by 2020, continued austerity into 2016 suggests we won’t see an immediate upswing in resources.

Fast-forming biofilms have often been Meet and greet: Richard Anderson, Crawford Healthcare, meeting George Osborne. considered a hindrance to this approach December’s unprecedented bed shortage Anderson says new approaches to AMR could help with the burden on the NHS however, the US market is responding well may have been attributed to a lack of social to the use of powerful, silver-based wound care provision for the elderly but with that dressings. These dressings destroy biofilms situation unlikely to have drastically improved on contact, where previously nurses would be required within a 12-month window, the NHS could face similar bed to physically remove the layer of membrane, which shortages this winter. With that in mind, NHS Trusts must essentially serves to protect infection-causing bacteria. find more efficient methods of treatment, and it is up to healthcare companies to innovate to help them in that task. Treating a wound directly with an appropriate antimicrobial The use of silver in wound care has been declining in Europe since 2009 but with new technologies While the number of people admitted to hospital is wound dressing may be the most available in this area we could see an increase in dependent on a number of external factors, clearing beds appropriate treatment for dealing the topical treatment of wounds. This could reduce of long-term residents has to be a target for the NHS. with that individual infection. the risks of secondary infection, from bacteria such One of the main drains on resources is undoubtedly the as MRSA and subsequently reduce the length of a impact of secondary infections, encouraged by the everpatient’s hospital stay. growing resistance to modern antibiotics.

“

The pharmaceuticals market is at somewhat of a tipping point in relation to antibiotics. Years of oversubscription, combined with a slowing pipeline of new products, means that the likelihood of contracting secondary infections during hospital treatment is perilously high.

The recent Review on Antimicrobial Resistance, headed by former Goldman Sachs chair Jim O’Neill, suggested that international governments would need to provide a fund to stimulate pharma businesses to re-enter the generally unprofitable industry of antibiotics.

”

But while we await any concrete action in this area, medical practitioners must look at other ways of preventing infection — most notably wound care. Though the antibiotics market has been relatively stagnant for

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This, of course, is just one of the many areas of the healthcare industry that is making strides forward but one which provides a viable route to a stronger NHS. The difficulties faced by the NHS are unlikely to go away easily and it’s time the issue of antibiotic resistance was effectively dealt with. A superfund that ploughs more money into pharmaceuticals is of course one approach but to keep with the pace of innovation, our healthcare service might be better placed to embrace the many new technologies on the market.

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The worldâ&#x20AC;&#x2122;s leading companies in additive manufacturing technologies and highly specialized tool-making will show you their expertise at formnext powered by tct.

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CAPSULES

The hard line Fernando Diez, business development manager of Qualicaps, explains the advantages of the hard capsule dosage form in protecting drugs from light radiation The problem A drug substance or drug product can be exposed to natural or artificial light during production, storage, administration and use. The great majority of drug substances and pharmaceutical excipients absorb UV and visible radiation. Absorption is a first indication that a compound may participate in a photochemical process, i.e. be photoreactive, which can result in its own decomposition or that of other components of the formulation in vitro.

It is well known that optical radiation can change the properties of various materials and products. This is often manifested as discoloration of colourless products or bleaching of coloured compounds. The number of drugs identified as photo chemically unstable is steadily increasing. Some examples include ketoprofen (nonsteroidal antiinflammatory drug), fenofibric acid (hypolipidemic drug) and tiaprofenic acid (nonsteroidal anti-inflammatory agent).

Absorption of optical radiation may result in the formation of free radicals and/or reactive oxygen species, which are identified as the reactive species in the process. Following photoexcitation, the substrate will dissipate the excess energy in a chemical or physical process.

Competition between photochemical and photo physical events ultimately determines to what extent given excited state will undergo chemical reactions, or deactivate either radiatively or by heat dissipation.

Hard shell capsules Capsules, along with tablets, are the most common form of dosage for the oral administration of solid-state pharmaceuticals and nutraceuticals.

One of the main advantages of the capsule as dosage form is the timeto-market. In standard conditions, the time needed to develop the drug is shorter if the capsule is the option chosen. This is the reason why lately there is a growing demand for this dosage form.

Patented in the 19th century, two-piece capsules have played a prominent role in the pharmaceutical sector.

For much of that period, gelatin capsules, which contain fillings such as • • active pharmaceutical ingredients (APIs) and excipients, dominated as the market standard. However, in recent years, there has been a shift, with hydroxypropyl methyl cellulose (HPMC) capsules rising to the fore.

Figure 1: Pharma products approved by FDA. 2014 data ends October. Y axis in %

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40 35

30 25

20 15

10 5

0

Tablets

2007

Injection

Capsules

Others

2014

The switch has come on the back of substantial pharmaceutical research revealing that while gelatin allows for an overall decent powder release from the capsule shell, as a protein derived from animals, it also has the potential to become chemically unstable and carries the risk of transmissible spongiform encephalopathy, a group of neurodegenerative conditions.

Subsequently, HPMC, known for its chemical inactivity, lack of crosslinking and low moisture content, not to mention excellent microbiological qualities, has emerged as the market’s most viable alternative to gelatin in the manufacture of capsules.

Both capsule types have a low refractive index, 1.24 for gelatin and 1.34 for HPMC. Once a pigment with a high refractive index such as titanium dioxide (2.27—2.71) is added, a structure with high radiation barrier is formed.

When a ray of light passes from a substance of low refractive index to a substance of high refractive index, light is reflected at the boundary; the amount of light scattered is higher, and the difference between their respective refractive indices is greater. As a portion of the light reflects at the surface of each pigment particle, changes in the speed of light as it enters the pigment particle causes it to bend or refract. This part of the light is then impeded from passing through the particles, changing its path at the surface and thus reflecting out. This scattering of light by the many pigment particles is what causes opacity and ultimately creates a protective barrier to harmful radiation.

Without these changes in the refractive index between the pigment and the medium, light passes through it practically unaffected. The system is transparent.

In Figure 2 an UV/VIS spectra for gelatin and HPMC capsules is shown.

The light transmission is very low for TiO2 concentrations over 3.5%.

Protection is higher in the UV area (200–400 nm).

It is remarkable that protection can be obtained with low concentrations of TiO2. Adding a pigment to a system can affect mechanical properties such as stiffness and tensile and impact strength or rheology. Therefore, the use of higher quantities of this additive must be avoided.

Figure 2A: UV/VIS spectra for HPMC capsules Y: Light transmission (%)

4 3.5 3 2.5 2 1.5 1 0.5 0

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Figure 2B: UV/VIS spectra for Gelatin capsules Y: Light transmission (%)

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Conclusion There is a growing interest on developing drug products in capsules in the pharmaceutical marketplace. Apart from all the advantages: reduced time-to-market, possibility of filling liquids, inhalation platform, etc., this oral dosage form provides light radiation protection of the drug substance when a low concentration of pigment is added to the capsule shell.

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STERILSATION

Making a point Noxilizer’s Evan Goulet and Stephen Morley outline the advantages that nitrogen dioxide (NO2) technology is able to provide over more traditional methods in the sterilisation of prefilled syringes

Sterilisation of prefilled syringes today is predominantly accomplished Noxilizer’s advanced room temperature sterilisation process uses using steam, EO or gamma radiation. While these methods are well NO2, a well-researched gas, in combination with humidity to established, their limitations could impede innovation and progress in inactivate resistant microorganisms and deliver sterile product. The the pharmaceutical and biotechnology FDA recommends adding an adjunct industries. More than 60% of new drug process, or additional sterilisation step, to products being developed today are “increase the level of sterility confidence” biologics, such as protein therapies[1]. This when aseptic processing is used in drug rapid rise in biological drug development is Sterilisation of prefilled manufacturing[2]. This is especially true expanding the market for new sterilisation syringes today is predominantly for products that are intended for use in technologies that can overcome the accomplished using steam, ophthalmic applications or in the sterile limitations of current methods. field of the operating room. NO2 gas is EO or gamma radiation. a surface sterilant that does not penetrate No single sterilisation method will be the container closure system and results compatible with every product on the in low surface residuals. market. Steam sterilisation has been around for more than a century and is well understood in both industrial Noxilizer’s NO2 technology is especially well suited to, and can be and hospital settings. EO has a long track record with the broadest conveniently installed as, an adjunct process for products that require material compatibility, and gamma radiation offers a low-temperature surface sterilisation. By providing solutions to the challenges presented option. Each of these methods has specific weaknesses with respect by steam, EO and gamma sterilisation, NO2 can help broaden the to sterilisation of prefilled syringes. These weaknesses were the driving horizon for use of all types of prefilled syringes, including dual chamber force behind the development of NO2 sterilisation. and combination devices, as the drug delivery system of the future.

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Comparison of NO2 and EO for prefilled syringe sterilisation Estimated Average Cycle Time Capacity Pre-conditioning Estimated Aeration Time Relative Humidity Vacuum Operating Temperature PFS Material Compatibility Sterilant Ingress Residuals Operator and Environmentally Friendly Manufacturing to Release Time

NO2 Sterilisers

Typical EO System

120–180 minutes

12–18 hours

360–5,000 l

2,200 l

No

Yes

60 minutes

9 days [4].

Low to High (30-80%)

High (70%)

Minimal

Yes

Room Temperature

40–60 °C

Yes

Yes

Below WFI limit

Common Issue

Low non-cytotoxic non-carcinogenic

Low cytotoxic carcinogenic

Yes

No

On-site, immediate release

Off-site, 7–24 day turnaround

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NO2 works as an oxidiser that inactivates microorganisms through degradation of DNA, providing a sterility assurance level (SAL) of 10-6 at relatively low gas concentrations (typically 10 to 20 mg/l). Process validation and routine monitoring of NO2 sterilisation proceed per ISO 14937[3].Biological indicators for the NO2 sterilisation process consist of spores of Geobacillus stearothermophilus, which is the same organism used for steam sterilisation.

No single sterilisation method will be compatible with every product on the market.

Noxilizer’s demonstrated ability to sterilise the exterior surfaces of glass and polymeric prefilled syringes using a rapid cycle, minimal vacuum and a truly room temperature process suggests that NO2 sterilisation is an ideal solution for manufacturers of sensitive biopharmaceuticals. The table provides a comparison of NO2 sterilisation with EO. In addition to the advantages outlined in the table, the financial benefit of using NO2 instead of EO could also be substantial (up to 40 to 60% cost savings). NO2 sterilisation equipment is significantly less expensive and does not require extensive facility modifications to be installed.

This would allow manufacturers currently using contract sterilisation to move their sterilisation process in-house, thereby reducing costs and turnaround times.

”

REFERENCES: [1] Prefilled Syringes & Parenteral Contract Manufacturing — Product Differentiation Is Critical. Drug Development and Delivery. May 2014.

[2] Guidance for Industry — Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice. Draft Guidance.

US Department of Health and Human Services – Food and Drug Administration – CDER – CBER – ORA. August 2003.

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Noxilizer’s advanced room temperature sterilisation process uses NO2

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[3] ISO 14937:2009 — Sterilization of health care products — General requirements for characterization of a sterilizing agent and the development, validation, and routine control of a sterilization process for medical devices.

[4] Chien YC, Su PC, Lee LH, Chen CY. Emission characteristics of plastic syringes sterilized with ethylene oxide — a controlled study.

J Biomed Mater Res Part B Appl Biomater. 2009;91(2):579-86. Doi: 10.1002/jbm.b.31432.

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WEIGHING

Double screw loss-in-weight feeder made by Three-Tec with an accuracy of +/- 0.5 grams at a feeding rate of 200 grams per hour. The feeding device, which includes two motors, two screws and a hopper is directly placed on top of the PBK weighing platform.

Weigh In Three-Tec specialises in loss-in-weight feeders.

The company is using a Mettler Toledo PBK weighing platform for accuracy and increased performance

A

new weighing platform provides extraordinary accuracy, high-capacity weighing and fast signal processing. A machine manufacturer uses those advantages for designing customised double screw loss-in-weight feeders with excellent dispensing precision.

Loss-in-weight feeders are used for precise continuous dosing of solids and liquids in various industries. Their output ranges from 5 grams up to 50,000 kilograms per hour with accuracy from +/- 0.25 to +/- 5% depending on the properties of the material dispensed.

Swiss company Three-Tec specialises in designing customised highprecision loss-in-weight feeders. The company places its feeding device on top of a PBK weighing platform made by Mettler Toledo. This platform includes the high-precision electromagnetic force-restoration weighing technology which provides a combination of high-capacity weighing, excellent accuracy and fast signal processing.

The chart shows the dispensing volume over time of loss-in-weight feeders with PBK weighing platform versus a traditional scale. It illustrates that the electromagnetic force-restoration weighing technology of the PBK is more accurate than analog load cells in traditional scales.

Compliance with demanding requirements A characteristic of loss-in-weight feeders is the cyclical change between controlled gravimetric dispensing and uncontrolled volumetric dispensing during refilling. The uncontrolled volumetric dispensing during refilling has to be kept as brief as possible to achieve accurate results. Therefore, it is advantageous to have large hoppers for storing large quantities of material to keep the period of uncontrolled dispensing brief.

As a result, the PBK weighing platform from Mettler Toledo used by Three-Tec carries a heavy preload consisting of one screw feeder with two motors each plus a big hopper. In addition it hosts a large quantity of material for dispensing as net weight. However, the PBK weighing platform still provides excellent resolution for accurately dispensing even the smallest amounts of material. Its outstanding specifications for eccentric load and linearity help assure an accurate and continuous material flow over long time periods.

This chart shows the material stock in hopper over time with a loss-in-weight feeder with PBK against a traditional scale. It illustrates that the PBK offers longer feeding cycles.

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CHEMICAL REACTION It’s important to keep on top of the latest services, companies and innovations.

EPM’s Chemical Reaction highlights a technology, service or business we think would be worth keeping an eye on...

What’s the alternative?

Alastair Smith, Avacta Life Sciences, outlines the company’s work developing engineered alternatives to antibodies

Who are you and what do you do?

AS: Avacta Life Sciences was established in 2012 (as part of the Avacta Group) to develop and commercialise its Affimer technology. Affimers - an engineered alternative to antibodies – can be used in scientific research, diagnostics and in the development of therapeutics.

Up until now the Avacta Group has raised £37million to invest in the commercialisation of Affimers over the next few years. This investment is being used for a range of projects including product development and a 13,000 sq ft laboratory production and logistics space which is due for completion in April 2016.

Q & A

What have you focussed on recently?

AS: Affimers have been engineered to have all of the benefits of antibodies, without the limitations. They have high affinity, exquisite specificity, are small, stable, robust and new Affimers can be generated, expressed and validated just seven weeks after receipt of target material - compared to 6–12 months for equivalent high quality antibodies.

They can be used in a range of applications. However, our strategy is to address important gaps in life sciences where the right affinity reagents aren’t available and to provide life scientists with powerful tools to open up new avenues of research and discovery. At present our focus is on creating new tools to study the ubiquitin proteasome system and cell signalling, as well as providing a number of general toolkit Affimers.

What is you latest service / innovation?

We are currently focussing on creating tools to support research into ubiquitin and the ubiquitin proteasome system. The covalent addition of ubiquitin to a target protein is now known to modulate most key processes in a cell. This is a relatively new area of biology and the tools, specifically antibodies, are not yet available to allow researchers to do the fundamental biology research that is required. There are several classes of proteins involved in this system: Ligases that add the ubiquitin to a target protein (~300 different ligases), DUBs which remove ubiquitin chains and then the ubiquitin chains themselves. We now provide Affimer binders that recognise specific di-ubiquitin chains. There are seven of these types of di-ubiquitin and each type is thought to have a different function in terms of the fate of the protein they are attached to. For some of the chain types the function is quite well understood and this is the only chain to which a good quality antibody exists. We have Affimers in our catalogue that are entirely unique - no equivalent antibody exists – and customer feedback has been phenomenal. Our K33 and K6 ubiquitin binders, for example, have proved very popular.

How can you benefit the pharmaceutical sector?

AS: We are excited about the potential applications of Affimers as therapeutics. Having already signed an exciting licensing partnership with Moderna Therapeutics to provide exclusive access to Affimers against certain targets, the potential of Affimers is now being recognised by the industry.

One example of where Affimers are being used in an exciting application is around the modulation of blood clotting. Cardiovascular disease (CVD) remains the main cause of morbidity and mortality in the developed world. Fibrin clot structure and fibrinolysis can determine predisposition to CVD and manipulating the prothrombotic environment can reduce the risk of vascular events.

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Forward thinking: Alastair Smith, Avacta Life Sciences says the company’s strategy is to provide life scientists with tools to open up new avenues of research

Affimers have been created that bind to fibrinogen and have been shown to interfere with clot formation in some cases, and in other cases to promote clot lysis. Affimers that reduce clot formation could be used to treat thrombotic disorders and those inhibit clot lysis show promising potential for the treatment of pathological hemorrhagic disorders, or for stopping bleeding following trauma.

Future plans?

AS: We will continue our combined focus on research reagents and therapeutic applications. In the near term we will focus on providing tools for the study of the ubiquitin proteasome system and cell signalling. We are also about to launch an exciting data pack around PD-L1 inhibitors, which has huge potential for oncology.

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At Phillips-Medisize We’re All About Process

We know process is the absolute key to assuring that we deliver upon our customers’ expectations, the first time and every time.

That’s why our people are all about process. In fact, our process requirements apply not only to manufacturing and quality SOPs, but also to our customer facing operations such as Program Management and Design and Development engagements, ensuring our customers benefit from a repeatable and scalable model.

So, when you work with Phillips-Medisize, you can be certain we’ll exceed your highest expectations the first time and every time.

Visit us at Innopack Stand 4G50

Contact Phillips-Medisize: phillipsmedisize.com / eu_sales@phillipsmedisize.com

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At Natoli Engineering Co., weâ&#x20AC;&#x2122;re proud to engineer punches and dies of superior quality, but we also provide all the technical knowledge and support equipment that you need.

We have built an outstanding reputation for quality service and support and we are driven to exceed our own high standards for performance. Find out more at natoli.com.