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Contents

head office

March/April 2015 | Volume 15 Issue 2

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

Regulars

Features

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NEWS ANALYSIS

THINKING AHEAD

Including the potential of graphene potential as novel anticancer therapeutic strategy

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REGULATORY AFFAIRS

EPM focuses on the innovation in the pharma sector including Patheon, Capsugel and Natoli

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28

GRAND DESIGNS Drug delivery from 3M, Owen Mumford and Aptar Pharma

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OPINION

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CHEMICAL REACTION N4 Pharma in the spotlight

I Holland discusses the importance of innovation

publishers mark blezard, duncan wood

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editorial group editor lu rahman, lu.rahman@rapidnews.com

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TAKING A SAMPLE

Sector views including this issue’s Q&A with Colin White, Penn Pharma

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from the editor

Love is the drug The advances made in the pharma sector are well documented. Whether we are looking at drug development for stopping smoking or the latest cancer fighting formulations, the range of groundbreaking pharmaceutical products continues to increase improving the health and well-being of us all. The routes to and behind the latest drug developments are highly interesting, especially when they come from sources close to home.

A study from Edinburgh University recently highlighted that new discoveries about what helps bacteria thrive in soil could aid the search for new drugs to fight infections.

Researchers have found that bugs’ ability to prosper in the earth is more complex than previously thought and the study challenges the existing theory that bacteria can only thrive in their natural environment. According to scientists, bacteria in soil produce potential biological agents for defence that kill fungi and other bugs and these can be developed as antibiotic drugs. How factors in soil interact dictates where bacteria are found and understanding them better could provide researchers with a clearer picture of how soil ecosystems function. This could help scientists increase yields from crop harvest and enable researchers to identify antimicrobial agents that could be developed as new antibiotics.

Researchers at the Universities of Edinburgh and Ottawa found that bacteria can also thrive in non-native environments. The team collected bacteria and soil samples from a forest in Western Quebec, Canada. They grew bacteria in soils from each of the sites sampled and found that they could prosper in a variety of different environmental conditions. Importantly, the study casts doubt on the belief that bacteria are only able to survive only in their natural environment.

Of course, the outcome and findings will be of extreme importance but in this case the fact that we have gone back to nature in order to tackle ongoing health issues, is a key point.

Similar research from the Universities of Sydney and Regensburg in Germany, have also uncovered similar findings in their discovery that the ‘love hormone’ oxytocin may have a sobering effect on alcohol intoxication.

The research may lead to the use of oxytocin as a drug for the treatment of alcohol dependence and withdrawal.

Oxytocin occurs in a range of situations – it increases during childbirth to ease labour and is shared between mothers and babies during breastfeeding. According to Dr Michael Bowen, from the University of Sydney’s School of Psychology, while alcohol impairs coordination by inhibiting the activity of the brain regions that

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provide fine motor control, oxytocin prevents this effect to the point where, when tested on rats, we can’t tell the behaviour of drunk rats from ones whose brains have been infused with the hormone. This is only the beginning of the process as scientists need to uncover a safe drug delivery method to ensure that adequate amounts of oxytocin reach the brain.

The fact that these two examples highlight the application of natural findings to find cures for modern illness is fascinating. Of course, we shouldn’t hang too tightly to the coat tails of the natural world in the belief that it holds all the answers as we need science to help us advance. Innovation in the scientific world is key to the way in which we treat disease and view the way we can make advances in medicine.

However, it brings home the need for us to look at every potential source of inspiration when we seek new ways of innovating.

Lu Rahman

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NEWS ANALYSIS

Graphene potential as novel anti-cancer therapeutic strategy

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his new development opens up the possibility of preventing or treating a broad range of cancers, using a non-toxic material.

Writing in the journal Oncotarget, the team of researchers led by Professor Michael Lisanti and Dr Aravind Vijayaraghavan has shown that graphene oxide, a modified form of graphene, acts as an anti-cancer agent that selectively targets cancer stem cells (CSCs).

In combination with existing treatments, this could eventually lead to tumour shrinkage as well as preventing the spread of cancer and its recurrence after treatment. However, more pre-clinical

studies and extensive clinical trials will be necessary to move this forward into the clinic to ensure patient benefit.

Professor Lisanti, the director of the Manchester Centre for Cellular Metabolism within the University’s Institute of Cancer Sciences, explained: “Cancer stem cells possess the ability to give rise to many different tumour cell types. They are responsible for the spread of cancer within the body – known as metastasis – which is responsible for 90% of cancer deaths.

“They also play a crucial role in the recurrence of tumours after treatment. This is because conventional radiation and

chemotherapies only kill the ‘bulk’ cancer cells, but do not generally affect the CSCs.” Dr Vijayaraghavan added: “Graphene oxide is stable in water and has shown potential in biomedical applications. It can readily enter or attach to the surface of cells, making it a candidate for targeted drug delivery. In this work, surprisingly, it’s the graphene oxide itself that has been shown to be an effective anti-cancer drug.

“Cancer stem cells differentiate to form a small mass of cells known as a tumoursphere. We saw that the graphene oxide flakes prevented CSCs from forming these, and instead forced them to differentiate into non-cancer stem-cells.

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Dr Federica Sotgia, one of the co-authors of the study, concluded: “These findings show that graphene oxide could possibly be applied as a lavage or rinse during surgery to clear CSCs or as a drug targeted at CSCs. “Our results also show that graphene oxide is not toxic to healthy cells, which suggests that this treatment is likely to have fewer side-effects if used as an anticancer therapy.”

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“Naturally, any new discovery such as this needs to undergo extensive study and trials before emerging as a therapeutic.

We hope that these exciting results in laboratory cell cultures can translate into an equally effective real-life option for cancer therapy.”

The team prepared a variety of graphene oxide formulations for testing against six different cancer types – breast, pancreatic, lung, brain, ovarian and prostate.

The flakes inhibited the formation of tumour sphere formation in all six types, suggesting that graphene oxide can be effective across all, or at least a large number of different cancers, by blocking processes which take place at the surface of the cells. The researchers suggest that, used in combination with conventional cancer treatments, this may deliver a better overall clinical outcome.

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Graphene has the potential to revolutionise a vast number of applications, lighter, stronger composites to flexible, bendable electronics. Graphene oxide can be used to create membranes that can coat surfaces to prevent corrosion, or filter clean water in real time. Demonstrating the remarkable properties of graphene won a university team of researchers the Nobel Prize for Physics in 2010.

Cancer and materials advanced materials are among The University of Manchester’s research beacons – examples of pioneering discoveries, interdisciplinary collaboration and crosssector partnerships that are tackling some of the biggest questions facing the planet.

NEWS ANALYSIS

NEW

Market needs new approach to drug development Patient friendly systems can offer new options for competing says Claus Feussner, Vetter Pharma-Fertigung Forward thinking: Progressive companies have been looking beyond the traditional methods of drug delivery in clinical phases, says Claus Feussner, Vetter, Pharma-Fertigung

(Bio)-pharmaceutical companies are under enormous pressure to compete in new ways if they are going to survive.

The drug development model of today is far more sophisticated than the model of just a few years ago. This is mainly due to the greater degree of complexity of new compounds being developed. In order to compete companies need to take an innovative approach to the way they manage their drug development business. This is especially true in their early development work.

Traditionally, companies have relied on drug development almost only in vials for good reason. They are ‘well known’ and the initial set-up work is simpler. Vials also make best sense for dose-ranging studies. With the overall high cost of drug development, it is understandable that in the early stages of the development process, companies are hesitant to add extra costs and complexity upfront, due to the risk of trial failure.

In the past years, more progressive companies have been looking beyond the traditional methods of drug delivery in clinical phases. A reason for this includes several syringe market reports which show the global prefilled syringe market expected to show continued positive growth due to rapidly increasing development of biologic drugs and other suitable compounds. One additional reason for this positive trend is the rising demand for greater ‘friendly’ patient and caregiver administration, both in the clinical as well as in the market stage.

A user-friendly system may actually improve trial appeal, making it easier to recruit medical clinics for clinical trials that use prefilled syringes instead of traditional vials. When available, the user-friendly nature of prefilled syringes contributes to patient compliance and consistency. Additional clinical and commercial advantages of using syringes include precision single-unit dosing which better meets the requirements of today’s more complex compounds. And, the use of syringes also reduces overfilling, thus saving valuable API compared to vials.

However, when a (bio-)pharmaceutical company is looking to differentiate their product, the delay of inclusion of a prefilled syringe delivery system into the development process until just before market entry can actually result in significant costly and competitive consequences. That is because syringe development requires various steps and tests, including stability and functionality/bioavailability tests. In subsequent development, the transition from vial to syringe is being realised sequentially, starting at, or near the end of phase lll. This approach means that it will typically take up to two years to complete the transition to syringes, from packaging selection through validation/ registration runs.

Companies starting syringe development earlier, in full or partial parallel with vial development, can actually cut transition time by as much as 18 months, depending upon when syringe work begins and the complexity of the compound. This shift in thinking can enable not only an immediate start with the advanced primary packaging device, but also a smoother and quicker market entry. Consequently (bio-)pharmaceutical companies can gain an earlier return on investment.

With more biologics competing in the same therapeutic space, launching directly in a syringe can set a drug product apart from the competition and offer an advantage that other companies may not be able to beat. Partnering with a CDMO can make it both easier and faster to start syringe development earlier in the development process, thus benefiting from the described advantages early on. Such a partner, being equipped with the necessary experience in this field, can help design a robust development process that both meet a compounds specific requirements, and already mirrors commercial production for a smooth scale-up to subsequent large-scale production.

For many indications, prefilled syringes seem to be the way of the future. And, being part of the future with clinical syringe development provides an innovative approach for innovative companies to gain an early advantage.

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NEWS ANALYSIS

Heating cancer drugs improves uptake Heating targeted cancer drugs increases uptake in tumour cells, say scientists at Manchester University Manchester scientists have found that gentle heating of targeted nano-sized drug parcels more effectively boosts delivery to tumour cells – resulting in an improvement in survival rates.

Professor Kostas Kostarelos who led the research, said: “We have previously seen promising results from this combination approach on a petri dish, but no study had yet investigated its potential in living tissue.”

One of the clinically-established methods for the delivery of cancer chemotherapy drugs has been to package the drug inside nano-sized containers, known as liposomes. This allows the drug to more effectively localise into cancer tissue and reduces side-effects by limiting drug-infused liposome uptake in healthy cells.

The team compared liposomes with and without the ability to actively target cancer cells. They found that in combination with mild heating, the actively targeted liposomes showed greater uptake in tumour tissue in mice than those without targeting ability. This resulted in a moderate improvement in the animals’ survival.

The effectiveness of these liposomes has been further improved by engineering them to contain molecules (monoclonal antibodies) on their surface that allow them to better target cancer cells in combination to making them temperaturesensitive so that they release their therapeutic drug content upon mild heating.

“We have successfully developed heat-activated and antibody-targeted liposomes to show that they are chemically and structurally stable. This approach may help us develop novel mechanistic strategies to improve targeted drug delivery and release within tumour tissue, while better sparing normal cells,” added Professor Kostarelos.

Researchers from the Nanomedicine Laboratory at the University of Manchester – part of the Manchester Cancer Research Centre looked at the benefits of combining both active targeting and temperature-triggered release.

Cancer is one of the University of Manchester’s research beacons - examples of pioneering discoveries, interdisciplinary collaboration and cross-sector partnerships that are tackling some of the biggest questions facing the planet.

Increasing regulations and cutbacks in healthcare funding are causing the United Kingdom’s pharmaceutical industry to look to emerging markets for growth. However, regulatory compliance issues are also problematic in those territories, according to a recent study from Maetrics, a full-service life science consulting firm.

Emerging markets offer potential to UK pharma

Spending cuts and increased requirements for pharmacovigilance at home are causing pharmaceutical firms to look abroad.

With the National Health Service forecasting a potential £30bn funding gap by 2020, more than half of surveyed businesses (57%) confirmed that healthcare spending by governments will be a major challenge in 2015. In addition, that same percentage said keeping up with escalating regulatory demands are primary concerns for the coming year.

Increased demands for pharmaceuticals are drawing companies into emerging markets, though more than half of respondents said they had concerns about regulatory compliance in those territories. In addition, some 43% expressed concern about finding qualified staff for such ventures.

“Emerging market expansion offers an appealing solution for businesses that are feeling under pressure in mature markets, but ensuring compliance with different regulations is going to be tough,” said Peter Rose, managing director at Maetrics.

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Additional key findings include: • 36% of pharma respondents view the need for increased testing in pediatric medicines as a challenge for 2015.

• 20% are concerned about the 2015-2020 change in prescribing patterns – from standard pharma to products of biological origin – and the implementation of the Falsified Medicines Directive.

• A majority report inadequate investment in compliance at their firms, citing either lack of resources (68%), time (67%) or budget (65%).

• 61% report difficulties with implementing regulations to their specific environment.

• 60% say that regulations are hard to interpret and change too often.

“Having a strong quality and compliance team, whether internally or externally through a consulting partner, is more important now than ever before,” Rose continued. “It’s clear that the key to fully leveraging the opportunities in emerging markets is confidence in interpreting and implementing regulations.”

The study, conducted by leading business analyst MindMetre, surveyed more than 50 compliance and quality management professionals from four life sciences sectors, including pharmaceutical, medical device, biotechnology and nutrition – with participants from both large corporations and small to medium enterprises (SMEs) – to determine the industry outlook, examine growth drivers and provide insight into planning and buying behaviours

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REGULATORY AFFAIRS

Counting the cost Inna Demidova, regulatory affairs manager, Russia and CIS, looks at the Russian market in 2015 and the impact of sanctions on prices of medicines

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n 12 September 2014 the second package of EU sanctions was adopted, affecting the Russian economy in particular.

Another major world event of 2014 was the sharp fall in oil prices – one of the main financial sources for the Russian economy. The combination of these factors eventually led to the collapse of the RUR on 16-17 December 2014.

As a result, the prices of medicines in Russian pharmacies grew by 12.7% in 2014 and growth reached 20% in the last 1.5 months of the year, according to analysis by DSM Group.

The Russian pharmaceutical market is divided into two large segments: medicines with prices regulated by the Ministry of Health (MoH) ie the drugs included in the Essential Drugs List (EDL) and drugs with an unregulated price.

Under the influence of sanctions the RU government initiated a number of restrictions for the state purchasing of medical drugs and devices, if analogues or similar goods are produced in Russia.

On 5 February 2015, prime minister Dmitry Medvedev signed a decree #102 on the restriction of procurement of foreign medical devices, excluding devices manufactured by Belarus, Kazakhstan and Armenia – members of the Eur�Asian Economic Union (EAEU) Additionally, the Ministry of Industry and Trade developed a draft decree on the restriction of admission of foreign drugs to state procurement if there are two or more applications on their supply from manufacturers from country members of the EAEU, applying to all medicines purchased for state needs, including EDL drugs.

September 2015. Moreover, the RU MoH does not intend to reduce state purchasing of foreign EDL drugs, which have no analogues in the Russian Federation.

Now, about 20,000 International Nonproprietary Names (INNs) are marketed in Russia. However, the share of budget funds on the Russian pharmaceutical market is only 35%. Most drugs are purchased by patients whose income is limited. So, since the retail pharmaceutical market in Russia is actually a market of generics, patients still have a choice – there are often 10-20 analogues with a huge price difference in the different pharmacies.

Going forward, the Russian pharmaceutical market will be more focused on the Russian manufacturer and, Russian manufacturers also will receive significant support from the government, eg the decree of the RU government No. 98-R (approved 27 January 2015) includes a numerous of measures to support import substitution.

In 2009 the Ministry of Industry and Trade successfully implemented a Federal Program of development of the pharmaceutical industry (Pharma-2020) and in Russia there are now effective local generics which, in tenders and auctions, receive a 15% price preference. However, there is one nuance: two years ago Russia joined the WTO. Since then it has been prohibited to produce local generics of foreign drugs, as these drugs do not stay in the RU market for six years. But it should be noted that big pharma companies – including Astellas, AstraZeneca, Gedeon Richter, Novo Nordisk, Novartis, Servier, Stada, Takeda, and Teva – have built manufacturing sites in Russia, and more than 2.5 billion US dollars was invested in localisation in recent years (source: II International Forum “Drug Manufacturing Russia and CIS” conference).

Since 1 September 2010, the maximum manufacturers’ selling price for EDL drugs must be registered. Moreover, this price must not exceed the maximum price for comparable drugs already marketed in Russia.

Cost calculation for such drugs is also regulated by government decree #865 of 29 October 2010, with different methods of calculation for local and foreign manufacturers.

These measures should mean rising drug prices will not have a dramatic impact on the socio-economic situation in the country. In the extreme case there is a procedure of ‘compulsory licensing’ – when patent owners have to transfer the license to use their rights in exchange for some compensation.

At the end of 2014, the prices of EDL drugs had risen minimally; retail prices increased by 0.35%, and in the hospital segment, by slightly more than 4% (source: http://www.rosminzdrav.ru/news). However, in January 2015, the growth of the hospital segment was 15%, and growth of EDL drugs was 6%. In October 2014, seeing the worsening economic situation, the RU MoH held additional auctions and managed to provide our patients with all the required expensive drugs up to

Sanctions will not force the MoH to reduce the purchase of foreign EDL drugs, which have no analogues in the Russian Federation. It is equally obvious that the support of government and private investments are actively developing RU pharmaceutical companies. It is further obvious that the market abhors a vacuum, and if European and American pharmaceutical companies will leave a RU market, others will come from Asia, India, China.

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NEWS ANALYSIS

East meets West As India leverages European technology to become a world manufacturing hub, the global ambitions of its pharma industry provides lessons for US and European big brands, says Abhishek Bardhan, M+W Products Growth tactics: Abhishek Bardhan, based at M+W Group’s India office, has experienced the growth of pharmaceutical manufacturing over the past decade With Europe’s acknowledged role as pioneers, longstanding experience and reputation in cleanroom manufacturing, businesses are working together with emerging markets to help create a broader marketplace for pharmaceutical manufacturing.

The opportunities for win/win in best practice and cost control for global players in the pharma industry are substantial especially for one such emerging market India. It is well documented as an attractive place for businesses looking to invest in due to its recent growth, strong democracy and growing standards as well as its high numbers of skilled staff. What’s more India itself is fast tracking its presence on the global pharmaceutical manufacturing scene, and deploying smart strategies.

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According to figures cited by the Indian government last year globally, the Indian pharmaceutical industry is ranked third largest in volume terms and 10th largest in value terms. The sector is highly knowledge-based and its steady growth is positively affecting the Indian economy. In addition to the relatively low cost-base, the organised nature of the Indian pharmaceutical industry is attracting several companies that are finding it viable to increase their operations in the country. In terms of value, exports of Indian pharmaceutical products increased at a CAGR of 26.1% to touch US$ 10.1 billion during FY06-13.

Currently, the Indian pharmaceutical industry is highly fragmented with about 24,000 players (330 in the organised sector).

The top ten companies make up for more than a third of the market.

the order of the day with emerging markets keen to learn from years of experience.

In 2012, Europe’s pharmaceutical trade surplus was estimated at �80 billion .

Already major manufacturers based in the sub-continent have flexed their muscles with a flurry of M&A activity, with clearance to enter North America. The US market alone accounted for nearly 30% of India's medicine exports of $15 billion in the fiscal year through March 2014.

The advantage that India has over other emerging markets is a plethora of highly skilled engineers and technology graduates providing a ready-made low cost labour market. They cover the most sophisticated of manufacturing processes from R&D to world-leading production regimes. This is in sharp contrast with Europe where the skills gap for engineers has placed a premium on such as a precious resource.

Europe’s reputation for quality and precision finished products, and German engineering excellence in particular, is still

Times are changing, however, with emerging markets gaining a foothold. For many BRICS economies, the question is

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how they manage to compete on a world stage with the developed regions such as Europe. The answer is simple – through partnerships. Indian pharmaceutical manufacturers are leveraging the expertise and brand strength of European engineering organisations to build cleanroom facilities that provide environments for the manufacture of pharmaceuticals that meet stringent regulations across the globe.

GMP standards which are essential for their products to be acceptable globally.

M+W Products’ experience in India is demonstrating that European/Indian partnerships are proving beneficial to both sides.

The strength of the pharmaceutical market in India is gaining traction and growing with investments continuing to pour in, largely through mergers and acquisitions. With many Indian drug companies investing outside of India as well, confidence in the market is growing from both sides. The benefits for European engineering organisations to partner with Indian pharmaceutical manufacturers lies largely in the cost benefits. Due to availability of skilled labour, India has the ability to deliver cost efficient programmes. Pharmaceutical manufacturing projects can cost between 30 and 40% of manufacturing projects in the U.S, a significant reduction in costs leaving cash left over for investment or future projects. One of the main reasons why India’s pharma market has catapulted to become a significant player is the amount of government support it has received. With the implementation of ‘PharmaVision 2020’ the Indian government is aiming at making India a global leader in end-to-end drug manufacture.

I am general manager at M+W Group’s India office, and have experienced the growth of pharmaceutical manufacturing over the past decade. One of the key challenges is the lack of readily available advance technology products for facilities which are needed in order for India to deliver its pharmaceutical manufacturing at global standards.

European engineering and products have strong reputations of engineering excellence and pharmaceutical companies in India are cottoning on to the benefit of partnering with such organisations. There is an incredible amount of research and development already taking place in the Americas and across Europe. Rather than follow the same route yet remain 50 to 100 years behind many organisations, businesses are realising that a combined approach to building up the Indian pharmaceutical manufacturing industry is ideal. Furthermore, these partnerships help Indian pharmaceutical companies deliver global levels of safety and quality while adhering to the levels of FDA and

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11.03.15 09:15

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OPINION

Trust fund Today’s pharma industry is suffering a crisis of trust, say Bart Sayle and Nick Hawker, The Breakthrough Group.

They discuss creating a culture of trust and breakthrough in the industry

P

harma is grappling with a variety of issues that are affecting the industry’s performance and value and require an adjustment to the traditional business model. To thrive in this new environment top leaders will not only have to develop innovative patient-centered models, they will also need to achieve enterprise-wide culture change and facilitate breakthrough innovation.

According to PWC’s Report ‘From Vision to Decision Pharma 2020’, the pharma industry faces three fundamental challenges.

First, rising customer expectations as payers are imposing new cost constraints on providers and are scrutinising the value of medicines more carefully.

Secondly, low scientific productivity. Pharma’s output has flatlined for the past decade.

And thirdly, cultural sclerosis. The prevailing management culture, mental models and strategies on which the industry relies are the same ones it’s traditionally relied on, even though they’ve been eclipsed by new ways of doing business.

Against this background, the results of a recently published article from PatientView Quarterly cannot be a surprise. Only 34% of patient group respondents gave pharma a “good” or “excellent” rating.

So what can the industry’s senior figures do to rebuild public trust and build healthy, innovative, high-performing companies to successfully meet pharma’s fundamental challenges of the future? They would be well advised to start by focusing on their culture.

According to 84% of the more than 2,200 global participants in the 2013 Culture and Change Management Survey by Booz & Company,

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culture is critically important to business success. However, less than half of participants saw their companies effectively managing culture, and more than half said a major cultural overhaul was needed.

Interestingly.

Even more remarkable were the findings of Kotter and Heskett’s landmark study. It documented that companies managing their cultures well saw stock price increases of 901% versus 74% for the companies that did not.

Strong cultures don’t happen by accident or are only achievable by organisations with exceptional leaders or extraordinary products. What many companies don’t realise is that there are a number of practical ‘tools’ (concepts and techniques designed to change the way individuals think and act) and processes that are proven to increase both individuals and the company’s future success and levels of innovation and to build and sustain a strong customer-centric culture.

This year’s Global Innovation 1000 study shows that spending more on R&D is not what drives results in innovation. The most crucial factors are strategic alignment and a culture that supports innovation.

Companies with strong innovation cultures think innovatively in everything they do and are constantly searching for better or more effective ways of doing things. The optimal outcomes are achieved when each person in the organisation channels their creativity and actions toward: business growth, people development, an empowering and supportive culture and providing innovative tools and processes for effectiveness and executional excellence.

Strengthening customer focus and trust, accountability for results, teamwork, and a sense of urgency along with instilling an entrepreneurial, winning spirit are the key to achieving success.

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An innovative culture cultivates engagement, enthusiasm, challenges people to take risks in a safe environment, fosters learning and encourages independent thinking.

We try to foster a culture of innovation and creativity, and this includes how we continue to improve as a more responsible and sustainable company.”

Former Lilly executive Bernard Munos has analysed industry data to ascertain which pharma R&D operations have been most productive, and why. His analysis confirms Novartis has been one of the best performers over the last 15 years, and he believes that the company’s leadership and culture were instrumental in this success.

Another leader who understands the impact of culture is Pascal Soriot who has overseen an increase in AstraZeneca’s share price by nearly 60% since he took over as chief executive. In his words: "We have fostered a culture of innovation where science is at the heart of what we do.”

“At Novartis we are driven by our mission of caring and curing. We strive to attract and retain talented associates who are passionate about improving patients’ lives," says Novartis’ current CEO Joseph Jimenez.

"Believing in a higher purpose for the organisation builds strong associate engagement, and is critical to building a world-leading culture.

The upshot: A culture can make or kill a company. If, as a business leader, managing your culture isn’t already at the top of your priorities, it should be. Breakthrough discovery comes from a breakthrough culture.

Getting the corporate culture right can transform businesses and unleash explosive breakthrough innovation and growth of the enterprise.

“

Strong cultures don’t happen by accident or are only achievable by organisations with exceptional leaders or extraordinary products.

”

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OPINION

Preparatory school Sally du Toit and Katherine Hutchinson, Quanticate say prepare for the unexpected and examine the importance of integration throughout the entire product life cycle with pharmacovigilance

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analysis of the trial). Technological advancements give the ability to store password-protected unblinded data on the safety database. However, definition and documentation of the blinded and unblinded team and processes to maintain these are also helpful.

ince their introduction in the wake of the Thalidomide tragedy in the 1960s, international pharmacovigilance systems continue evolving to meet the changing requirements for the effective protection of public health. There is now a more proactive approach, not only to identify and evaluate potential safety issues, but also to minimise risks and promote the safe and effective use of medicines.

The driving factors behind the current trends in pharmacovigilance include pharmaceutical market globalisation. Effective pharmacovigilance systems need to quickly detect and manage potential safety issues. Another factor is innovative products development with unknown safety profiles, which require careful monitoring – for example products based upon new technologies, such as biologics, gene therapy and products which act on novel targets or work through mechanisms of action previously untested in humans. Pharmaceutical companies want to halt product development, which have an unacceptable risk-benefit profile early. Approximately 5% of hospital admissions in the EU is thought to be due to an adverse drug reaction1.

Integrated pharmacovigilance Pharmacovigilance traditionally concentrated on postmarketing safety surveillance. As recommended by the CIOMS V Working Group2, there is a recent shift towards systematic pharmacovigilance throughout the product life cycle.

While the post-marketing use of products involves the exposure of numerous patients, and may demonstrate previously unseen, rarer adverse drug reactions, there is much to learn about potential risks in clinical trial stage and preclinical studies. The development risk management plan (DRMP) and evaluation of clinical trial safety data on an ongoing basis is more apparent.

Pharmacovigilance systems should integrate input from internal and external stakeholders. Internal stakeholders are many and diverse, as illustrated in Figure 1.

These include the clinical operations, clinical data management (CDM) and statistics teams, with their role in running clinical trials and managing and evaluating clinical trial data. Regulatory affairs, medical writing and public relations provide key roles in the implementation of labelling updates and communication of safety information.

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Figure 1: Pharmacovigilance stakeholders within a sponsor or licence holder organisation Many pharmacovigilance activities handled by affiliate or partner companies, or outsourced to CROs, require integration to provide clearly documented, coherent, life cycle pharmacovigilance system; comprehensive safety data exchange agreements (SDEAs) can ensure this.

From the regulatory perspective, the implementation of the development safety update report (DSUR) in September 2011 harmonises clinical safety reporting across international conference on harmonisation (ICH) regions, in addition to coordinating safety reporting across the product life cycle. Through its overlap with the periodic safety update report (PSUR), it was updated in January 2013, to the periodic benefit-risk evaluation report (PBRER) in the re-vamped post-authorisation Guideline on Good Pharmacovigilance Practises (GVP) Module VII .

The use of data safety monitoring boards (DSMBs) for the monitoring and assessment of data during clinical trials is increasing due to its provision of unbiased review, which may be unblinded without affecting the trial integrity. One consideration is the inclusion of members with knowledge of areas associated with potential risks, in addition to the therapeutic indication of the product.

Data management and statistics expertise in safety data management and evaluation is becoming apparent.

Signal detection methodologies using statistical techniques adapted from manufacturing are generally applied to large post-marketing surveillance databases.

CIOMS VIII guidelines on signal detection, published in 2010, enabled some further pragmatic solutions and guidance for effective signal detection to be integrated into the recent GVP Module IX on Signal Management.

With various safety data being held on different clinical and safety databases, effective data flow and reconciliation is vital to ensure the integrity of the databases (see Figure 2).

Data integration for analysis and evaluation and inclusion in documents such as the integrated summary of safety (ISS) for a new drug application (NDA) is important and requires pooling of adverse event (AE) data across studies. Avoid introducing biases due to inappropriate pooling, such as different treatment regimens or differing lengths of treatment. Centralisation of case report form (CRF) and safety data provides efficiencies and a high quality global safety database.

Safety data Pharmaceutical companies are challenged with managing substantial safety data from numerous sources. This volume is increasing due to growing global clinical trials and postmarketing studies. The requirement for unblinding of suspected unexpected serious adverse reactions (SUSARs) prior to reporting to EU competent authorities and ethics committees necessitates careful planning and safety data management. To maintain trial integrity, companies must decide which personnel will have access to unblinded data (such as members of the pharmacovigilance group) and who will not be permitted access (such as clinical and biostatistics personnel involved with the conduct and

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Figure 2: Data ow and reconciliation between sources of safety data and clinical trial and safety databases

One of the more significant changes in the new post-authorisation GVP legislation is the goal to strengthen safety data collection by regulators, with the EudraVigilance database becoming the single point of receipt of individual case safety reports within the community. As each Member State works to ratify the new legislation, marketing authorisation holders must comply with a complicated set of transitional measures to ensure regulatory case reporting compliance. The US FDA is proposing to amend postmarketing safety reporting regulations and mandate electronic safety reporting.

Transparency & communication

help achieve the ultimate shared goal of delivering the safest and most effective medicines possible and maximising its contribution to public health.

References 1. Proposal for a directive of the European Parliament and of the Council amending as regards pharmacovigilance, Directive 2001/83/EC on the community code relating to medicinal products for human use.

2. CIOMS V, Current Challenges in Pharmacovigilance: Pragmatic Approaches, 2001.

3. Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, Yamaguchi Y and Handa H, Identification of a Primary Target of Thalidomide Teratogenicity, Science 327(5971): pp1,345-1,350, 2010.

Transparency and communication has become paramount. Recent changes to pharmacovigilance EU legislation (Regulation 726/2004 and directive 2001/83/EC) were developed in consultation with stakeholders, including pharmaceutical companies, regulatory authorities, healthcare professionals (HCPs) and consumers. These changes will strengthen consumer reporting and help involve consumers more in pharmacovigilance.

EU legislation proposed changes in GVP Module XV could introduce an EU web portal, a main platform for medicinal safety announcements including links to member state web portals. Education on monitoring and prescribing use of medicines helps identify any issues with the product name, labelling, packaging or potential medication errors.

Proactive risk management The trend is for proactive risk management.

Pharmacovigilance systems deliver the key elements of an effective risk management system. These are risk identification and evaluation, development of risk minimisation and mitigation strategies, and the communication of those strategies to all relevant parties.

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EU regulatory changes promote proactive risk management and require RMP for MAAs involving new active substances.

EU PSURs focus on risk-benefit and the frequency of reporting is specified in the marketing authorisation (MA), depending on the risk-benefit profile of the medicine.

Pharmacovigilance has a vital part to play in public health. Pharmacovigilance systems must evolve to quickly detect and minimise risks for unexpected or inexplicable adverse drug reactions.

The primary mechanism by which Thalidomide causes birth defects was only discovered recently, nearly 50 years after the link was first made3. Current trends are shifting towards integrated pharmacovigilance throughout the product life cycle, involving input from all stakeholders. Pharmacovigilance systems can be improved to allow more effective management of the risk-benefit profile of medicinal products. It will

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1/20/2015 11:17:41 AM

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COVER STORY Tip top: C-up of tips from I Holland

Old and the new: A pill machine from yesteryear

Key to success I Holland explains why innovation is key to ensuring tablet production is fast, precise and accurate

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he manufacture of oral solid dosage forms has come a long way since the procedure of hand rolling pills used in previous centuries. Innovations introduced by leading tablet tooling and pharmaceutical manufacturers have advanced in order to keep pace with the ever growing demand driven by developing markets in order to produce tablets for the masses.

Originally a pill would be rolled into a ball, then into a long pipe shape which was divided into lengths to roughly calculate dosage. This later progressed into using tiles with graduations so that the pipe could be rolled to a specific length equal to a more accurate dose.

One of the first innovations the industry could truly call a ‘machine’ was the pill machine. This allowed for the pipe to be measured and cut into accurate pieces. With careful manipulation it could produce quite rounded portions which were then put under a pill rounder to make the cut portions spherical. 1

From these early days, tablet production has advanced thanks to the research and development undertaken by companies like I Holland, one of the world’s foremost tablet tooling manufacturers.

The vision of I Holland has always been, “to be the customer’s preferred choice as the market leading provider of innovative tablet tooling and complimentary equipment, underpinned by our understanding of tabletting science.”

Pharmaceutical manufacturing is an ever-changing environment and to produce tablets cost-effectively, investment in new technologies and processes must be developed, I Holland has introduced a number of innovative product developments and studies 16

that continue to transform the way pharmaceutical manufacture is undertaken, making it a process that is fast, precise, reliable and a far cry from the days of the hand-rolled tablet.

Early innovations One of the first notable punch and die innovations to have had an impact on tablet manufacture in the last 70 years, was the introduction of ‘hobbed tips’ which I Holland pioneered in 1964. This process uses an extremely high precision metal master of the desired tablet design to cold form the punch tip detail. I Holland led the way in the precision cold forming of tablet punch heads, resulting in the company patenting the process for tablet tooling manufacture. This method has now become the standard for quality punch manufacture and is used by leading tablet tooling producers across the world. This unique technique ensures the production process is accurate, quicker, cheaper, and most importantly repeatable.

It was also during this period, and into the 70s, that I Holland began using Computer Numerical Controlled machines, again increasing precision and repeatability, all of which have helped to establish the company as one of the leading authorities in tablet compression tooling as it is today.

Changing manufacturing performance With the increase in strict regulations and standards during the manufacture of tablets, the adoption of tried and tested protocols are important. It was the introduction of these exacting procedures that bought in the next step in I Holland’s history.

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The I Holland Eurostandard technical document (in existence since 1992) advises tablet manufacturers on tablet tooling terminology, configuration and procurement and includes the latest technical specification compatible with ISO 18084:2005(E) – ‘Press Tools for Tablets’. There are also a number of guides including tablet design, troubleshooting and treatments and coatings. Used world-wide for many different type of tablet press, it has helped customers to accurately specify tablet punches and dies, answering commonly occurring questions found during tablet production. All the information included is a result of research and findings that have been documented over the years.

Another technological advancement in tooling which must be observed are multi-tipped punches. Although it is not a new technology (I Holland has been producing multi tip tooling for over 30 years) it has only been adopted fully in the pharmaceutical industry during more recent years.

Multi tip tooling has transformed the quantity of tablets produced and it is now considered the most productive form of tablet manufacture where it can be applied.

Successful implementation of multi tipped tooling can reduce the need to invest in expensive tablet presses, therefore reducing the overall capital spend. The number of tool set-ups required per production batch can also be reduced and product batches are completed quickly decreasing the overall production time. It also benefits tablets which need to be compressed within a very short time of the formulation being prepared.

The modern tabletting process is an exacting one, and wherever possible tooling materials need to be optimised

for the task. To this end, I Holland first developed Rotahead punches which allow the head to rotate independently to the punch body, providing a ‘bearing’ between the punch head and cams. This enables the head and body to be manufactured from different optimised materials, resulting in an extended tool life Another notable process and innovative addition to the company’s portfolio is the PharmaCare 7-Step Process, a program of professionally planned maintenance which has been adopted as a SOP by companies world-wide.

The key factors required in tablet manufacturing include the need to increase production and accuracy, with the requirement to do it cost-effectively and quickly. This has always been a challenge since mass tablet production was introduced, but processes have been developed to help, including the PharmaCare 7-Step Process.

Tablet manufacturing problems and tablet tooling failures are generally the result of one, or a combination things including; ● Difficult product/granule ● Inappropriate tablet design ● Incorrect tablet press set up and operation ● Inadequate tablet press maintenance ● Poor condition of tablet tooling

The ’7 step’ process helps to reduce these problems through seven simple procedures.

STEP 1: Clean – Ensure tooling is free from contamination.

STEP 2: Assess – Following cleaning, punches and dies must be inspected for general condition.

STEP 3: Repair – Rectify any damage to the tooling i.e. light corrosion.

STEP 4: Measure – Essential after polishing and repair to ensure critical tooling dimension have stayed within tolerance.

STEP 5: Polish – Automated polishing is recommended for an even polish and consistent finish.

STEP 6: Lubricate – It is important to protect, preserve and aid the smooth operation of tooling.

STEP 7: Store – The final step is important to protect and minimise damage of tooling.

Application of the 7 Step Process will usually have a direct impact on the reduction of many common tablet and tooling problems, resulting in a better quality end product, and provide direct cost saving for the tablet manufacturer.

The latest innovation from I Holland, is TSAR-Predict, which has helped in reducing time consuming and expensive field trials by offering a solution to stop tablet tooling sticking problems.

An important advancement in tabletting history is the implementation of continuous tablet production.

This form of manufacture made an impact on the way tablets were produced, with significant benefits from increased productivity to quality. Large pharma companies have seen the benefit in this method compared to the batch process technique, and innovation in continuous tablet production is still ongoing today. Even with this innovation the problem of ‘sticking’ still remained, and

it was because of this that I Holland focused on finding an answer. After eight years of tablet tooling coating development I Holland has built up a range of anti-stick coatings. It’s due to the depth of this range and its many different anti-stick properties that the company embarked on the project that was later to become known as TSAR (Tabletting Science Anti-Stick Research).

Investigation into the cause of formulation sticking to punch tip faces was undertaken with a predictive tool developed to recognise the correct punch or die coating solution for sticky formulations without carrying out the long and expensive process of in-the-field testing.

It is not just research and standards that really make a difference in tablet production, it is also the tooling and technology behind it that makes a huge impact.

For any tablet tooling manufacturer it is important to always move forward in the design of tooling that leads to a better end product. There have been developments from a number of manufacturers over the years, which has seen tablet tooling progress to meet the demands of modern medicine. Most recently the implementation of metallised bellows and drip cups to help prevent tablet and punch guide contamination during the

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tablet compression process have been introduced.

This pioneering advancement ensures that tiny fragments of material will not reach the end user, another insurance of a quality end product.

This innovative thought-process continues in 2015 with major product developments to be announced by I Holland at ACHEMA in Germany later this year.

The company will showcase its latest innovative products using the show as a platform to introduce new and ground-breaking developments to help customers run the best possible tablet manufacturing processes.

Capturing new technologies and adding to them through pioneering and novel introductions, I Holland sees itself as an innovator in its field, and with the continuation of constantly developing, improving and collaborating with its customers, this innovation will continue.

Reference 1. Royal Pharmaceutical Society 2. http://knowledge.insead.edu/innovation/the-dna-of-the-worldsmost-innovative-companies-1020#oTf0zripyvsoRPgS.99

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Q

Growth spurt Colin White, general manager, Penn Pharma, A PCI company, PCI talks to EPM about the company’s recent expansions and its core business strengths going forward

EPM: PCI acquired both Penn Pharma and Biotech in 2014, what does this now mean to customers?

CW: We are committed to providing an unparalleled customer experience with our clinical and commercial services, and such services require world-class facilities.

The innovation and vision of the PCI board has created an exceptional pharmaceutical outsourcing company, offering solutions that increase speed to market and deliver commercial success. Each of the three companies has specialist expertise providing bespoke and select services to their respective customer base. By combining the expertise and resources we are able to deliver a company with global reach, offering both general and where needed, specialist services in line with ever changing customer demand. The recent acquisitions bring PCI’s global footprint to 16 facilities across North America and Europe. PCI remains a forward thinking company and there is no reason to believe that it has any intention of slowing down. It’s fair to say that now is an exciting time for all.

OPINION

&A

EPM: Penn Pharma has a history of providing a full outsourcing service, but more recently invested in innovative manufacturing capabilities, can you tell us more?

CW: Under new management, Penn Pharma formulated a manufacturing strategy based on customer need. In 2013 Penn opened a purpose-built contained manufacturing facility in direct response to the significant growth in the number of highly potent molecules in development. These molecules require specialist handling and contained processing to protect both operators and the environment. Penn Pharma has led the market in contained manufacturing and in 2014 we were awarded ISPE Facility of the Year, Facility Integration for our new facility and will see us host an ISPE regional event in March 2015. Then, in 2014 and in line with the strategy, we completed a service expansion programme to offer large-scale manufacturing. This investment increased capacity for both current and future clients and improved our ability to service the growing market need for large-scale commercial outsourcing solutions. Most recently we have invested in roller compactor technology which will become operational in 2015. Roller compaction is a process that provides a granulation method for materials that are heat and moisture sensitive. It avoids the use of liquid and high temperatures associated with wet granulation and subsequent drying methods. Our decision to invest in this technology was again in direct response to customer demand.

EPM: PCI is seen as a packaging expert, can you tell us more about this?

CW: In 2014, PCI completed the expansion of its packaging facilities in Rockford, IL, one of three locations in the United States. This Rockford location features nine PCI facilities totalling over a 1,000,000 square feet, supporting both commercial contract packaging services and clinical trial services, including packaging and labelling as well as global logistics services for investigational studies including storage, distribution, and management of returned drug product. The new 97,000 square foot site functions as PCI’s North American logistics centre and depot, offering extensive capacity for a variety of cold chain temperature ranges for global studies including controlled ambient, 2-8C, -20C, and -80C. In addition, the newly constructed site supports controlled substances II – V.

EPM: The original Biotec business has very specialist expertise in cold chain storage and distribution; can you tell us more about this?

CW: With innovative technology solutions, flexibility and a commitment to customer service, Biotec’s expertise supports global projects across a range of temperature conditions including controlled room temperature, 2 - 8°C, -20°C, -40°C, -80°C, and specialization in products requiring -196°C. A recent expansion quadrupled the capacity to store, package and ship cold chain products, and includes a second purpose built facility for the storage of Advanced Therapeutic Medicinal Products (ATMP) at -196°C. ATMPs include gene therapies, somatic cell therapies (stem cells) and tissue engineered products.

EPM: Finally, there was recent press activity relating to an exemplary safety record at the PCI Penn Pharma Tredegar site, can you elaborate on this?

CW: In January 2015, we achieved the milestone of being four years accident free which is something we are extremely proud of. This is even more remarkable given the backdrop of the building and expansion programmes all of which have been delivered within this four year timeframe. This achievement in safety does not just happen; we have created a safety focused culture by developing robust processes. These include a very effective ’near miss’ system as well as employing the principles of Lean Six Sigma.

When we talk about safety within the business, there is a real sense of pride evident and it is the commitment of our staff that has led to this incredible achievement.

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SPOTLIGHT ON INNOVATION

Thinking ahead

Innovation is essential

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ccording to Patheon’s Mike Mencer, innovation is essential to the pharmaceutical industry. “Advancements are made every day to ensure the products being delivered to patients are of the best quality and best suited to meet their medical needs. From softgel technologies to solubility enhancers to integrated supply chains, many innovations have evolved in recent years yet the pace of innovation is likely to only increase. The need for customised medications and greater speed to market is a principal component currently driving innovation in the industry. The recent global Ebola crisis speaks to the demand for making needed medications available quickly and how fast the pharmaceutical industry can respond to such outbreaks. Potential Ebola vaccines are currently undergoing clinical trials led by a joint Liberian-US clinical research partnership and sponsored by the National Institute of Allergy and Infectious Diseases (NIAID),” he says.

Mencer adds that according to the National Institutes of Health (NIH), the average time to market for a new drug is 14 years, with six of those years dedicated to ensuring drug safety during clinical trials. However, research surrounding treatments and vaccines for the Ebola virus seem to be moving at a much faster pace in the last six to nine months.

“In order to continue this trend of reacting to crises in real time, there needs to be consistent focus on innovative solutions that improve speed to market, not only for vaccines, but also for new drugs and drug-device combinations.

“Patheon meets this need for maximised speed and innovation through the Patheon OneSource service solution. This offering links both drug substance (small and large molecules) supply with drug product manufacturing spanning a range of oral and injectable dosage forms for products in both development and commercial stages.

With an integrated service, customers gain value in four areas – speed, simplification, harnessing global expertise and choice. This service gets product to clinic more quickly, so can lead to faster product to market,” he says.

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Speed is the essence: According to Mike Mencer, Patheon, there needs to be consistent focus on innovative solutions that improve speed to market, not only for vaccines, but for new drugs and drug-device combinations

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SPOTLIGHT ON INNOVATION

Implications driven by regulations

Driven by the need to improve efficiency

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ichard Nemesi, Videojet Technologies says that for suppliers of serialization equipment to the pharmaceutical industry, there are several trends driving innovation in technology.

He says: “Demand is increasing for coding technologies that can mark a wider range of substrates and handle more complex data management responsibilities, without compromising product safety or legislative compliance. Optimal coding solutions are part of a holistic approach to pharmaceutical manufacturing, with the printer playing a small but integral role in addressing industry regulations.

“One key trend is the heightened need for intelligent data management. One example of this is asynchronous communication, where the printer can decouple its print function from the data management activities going on simultaneously. This enables higher throughput which is required on some production lines. Another example is effective buffer management. Some track and trace solutions send many serialization codes to the printer at once, where they reside in a buffer until placed on the package. In the event of an unexpected line stoppage, codes can be left unused unless an intelligent coding device can communicate which numbers are still available for use. This is especially relevant in countries where manufacturers may have to purchase serial numbers, enabling manufacturers to reclaim unused codes and protect their investment.

“New regulation also demands more information to be printed on a wider variety of substrates, including traditionally challenging materials. One example of a difficult substrate to code is high-density polyethylene (HDPE). Recent innovations in laser printing technologies leverage UV wavelengths to create crisp, indelible black marks on HDPE, including serial number and bar codes.

“Effectively addressing regulations is a collective effort for all production line technologies, with coding playing a central role. Innovative coding solutions will integrate with other technologies upstream on the production line and also convey information effectively throughout the supply chain ultimately protecting brand reputation, and the consumer from substandard products.”

Trend hunter: Richard Nemesi, Videojet Technologies, highlights several trends driving innovation in technology

atoli’s Dale Natoli believes that innovation in the pharmaceutical industry, where manufacturing is concerned, is almost always driven by the need to improve efficiency – to produce more, faster.

“We’ve seen it with inquiries about continuous manufacturing in facilities, and with the advent of functionality being added to the electronic components on tablet presses. However, a very simple way to improve efficiency during tablet manufacturing is to consider multiple tip punches and dies.

“Although multi-tip tooling has been available for years, this configuration has had a quiet adoption by the pharmaceutical industry. Multi-tip has become a popular option for manufacturers in the United States, and we have begun to see an uptick in interest from customers in other parts of the world.

“Multi-tip tools can provide a drastic increase in output and reduction in operating costs. Running a tablet press with multi-tip tooling produces more tablets per compression cycle, while reducing run time for the machine. There are clear advantages to receiving more tablets in less time, but multi-tip also provides the same production capacity using fewer presses – which increases usable space in the compression room, reduces set up and cleaning time and the amount of operators needed to run the equipment. Multi-tip punches and dies can be produced in the same shapes, with embossing, etc. as standard, single tip tooling.

“We believe the tabletting industry will increasingly adopt these simple tooling configuration enhancements, in addition to the technological enhancements that are becoming available.

“Improvements to efficiency will always be a goal for pharmaceutical manufacturers.

Increased production can help consumers by getting the drug to market sooner, and manufacturers benefit by cutting costs and overhead. Multi-tip tooling can be one solution among a host of options to help the pharmaceutical industry innovate.”

Breakthrough technology for drug delivery needs According to Jim Coward, Capsugel dosage form solutions, the functionality and flexibility of lipid multiparticulate (LMP) technology offers an attractive formulation option for pharmaceutical and nutraceutical products, including pediatric and geriatric treatments.

“The innovative, lipid-based drug delivery platform has multiple applications, including taste-masking, extended release, immediate release and improved bioavailability.

Because LMPs are truly spherical, matrix multiparticulates, they bring the benefits of multiparticulate delivery, which include gut distribution, less intra- and inter-patient GI transit time variability and potential improvement in ease of swallowing with the functionality of lipid-based formulations. But unlike other multiparticulate formulation options, LMPs offer intrinsic taste-masking properties and have a smooth texture when taken, simple processing with no solvents and high drug loading capacity (up to 5060%). LMP technology is also very flexible in terms of multiparticulate size (50-1000 microns) and finished dose representation (capsule, sachets or orally dissolving tablets).

“Recently, Capsugel Dosage Form Solutions announced the broad commercial availability of its proprietary LMP technology, adding to its bioavailability enhancement technologies, including LBF options in liquid-filled hard capsules (LFHC) and softgels (SGC) for oral delivery. The LMP technology brings additional flexibility vs. LFHC or SGC lipid options in terms of release profile, drug combination delivery and ability to coat for additional functionality, such as targeted release.”

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SPOTLIGHT ON INNOVATION

Mark Offerhaus Micreos

Dr Bjorn Herpers

Resistance training

According to a UK Impact on government-commissioned pharmacoeconomics report, the total number As new antibacterial agents of deaths as a result of emerge which are viable antimicrobial resistance is Deaths from antibiotic resistance are an increasing threat. as long-term maintenance projected to rise to 10 million therapies, or as prophylaxis, Dutch biotech company Micreos has launched what is said to the first per year globally by 20501 they will alter the clinical value – more than the number bacteria-killing enzyme (endolysin) registered for human use against MRSA. and the pharmacoeconomic currently dying from cancer.

Mark Offerhaus Micreos and Dr Bjorn Herpers clinical microbiologist, explain model for antibacterial The threat of antibiotic treatments. With reduced fear resistance is not new, the first A working mechanism unrelated to antibiotics). It, therefore, has potential to be of resistance, and removal of negative reports of Staphylococcus sp. bacteria 1) that of antibiotics, meaning even the first antibacterial compound suitable side-effects associated with broader resistance to penicillin occurred in 1947, antibiotic-resistant strains of bacteria, for longer-term maintenance therapy of disruption of the body’s natural flora, just four years after penicillin was first S. aureus-related skin conditions and for the remit of these drugs can expand, such as MRSA, are susceptible. mass-produced, and Methicillin-resistant and their development will represent a Staphylococcus aureus (MRSA), was 2) Phages have co-evolved with bacteria large-scale prophylaxis. better investment for pharmaceutical discovered over 50 years ago. over billions of years; therefore, 3 companies.

The latest trials on rosacea and acne endolysins target highly-conserved indicate a significant reduction in symptoms Despite the size of the problem, areas of the bacterial cell wall, greatly investment in research and development reducing the likelihood of bacterial after Staphefekt use in the Gladskin gel Phage and endolysin or cream formulation. Compared with is limited; the acute nature of bacterial adaptation. technology in other areas symptom severity scores before use, infections makes trail design complex, Endolysins target specific bacterial 3) significantly less pustules, burning, itch, Phage technology also has great potential and antibiotics are not particularly species; commensal (beneficial) eye symptoms and dry skin were reported outside of the pharmaceutical industry. lucrative compared with treatments bacteria are not killed, reducing the after six weeks in 112 people with Phages are already used for food safety. for chronic conditions. Also, fear of chance of opportunistic infection rosacea, with a significant positive effect FDA-approved phage culture, Listex, resistance has encouraged conservative following treatment, as is often seen on the dermatological quality-of-life score. specific to Listeria monocytogenes, is usage of new agents. after courses of antibiotics.

Similar results were found with acne, with used during the production of meat, significant reductions reported in lesions cheese, fish, vegetables, fruit and Endolysins Micreos’ endolysin, Staphefekt, is the and pain in 59 people. Trials on eczema other food products, and Salmonelex, With these challenges in mind, the holy first endolysin registered for human are ongoing, as S. aureus is known to be is used against Salmonella in poultry grail is an agent which can sidestep use against bacterial infections, and highly involved in this skin disease too. processing. Micreos’ pipeline also bacterial resistance, or is viable for exemplifies the practical benefits of the Furthermore, case observations in patients includes R&D projects in agriculture long term or prophylactic (preventative) characteristics of endolysins listed above. with recurring skin infections due to S. and animal health. These areas see therapy. The use of endolysins is one aureus suggest that long-term suppression heavy usage of antibiotics, and are seen innovation which has this potential. Staphylococcus aureus is the most of S. aureus carriage on the skin with as breeding grounds for resistance, so Endolysins are an essential part of the common cause of skin and soft tissue Staphefekt could have a preventive effect even here, the availability of antibiotic reproduction process of phages. Phages infections.2 Besides these more invasive on the frequency of local invasive infections alternatives will have a positive impact are common micro-organisms which infections, S. aureus can cause local like furunculosis. on human health. can replicate only through a bacterial symptoms like skin irritation, itch or host. When a bacterial cell is infected, inflammation. Staphefekt is currently the phage takes over its DNA and starts used for treatment of skin conditions producing new phages. The phage uses associated with S. aureus, like eczema, References endolysins, which are also produced acne and rosacea. It’s effect is specific 1. Review on Antimicrobial Resistance. Tackling a Global Health Crisis: Initial Steps. 2015 inside the bacterial cell, to destroy the to Staphylococcus aureus, leaving the http://amr-review.org/sites/default/files/Report-52.15.pdf bacterial cell wall, releasing the new skin’s beneficial bacteria unharmed.

2. Moet, G et al. Contemporary causes of skin and soft tissue infections in North America, Latin America, and Europe: Staphefekt has also not been shown to phages and killing the host bacterium.

Report from the SENTRY Antimicrobial Surveillance Program (1998–2004) Diagnostic Microbiology and Infectious Disease; 57(1): 7-13 induce resistance in vitro, and does not 3. Micreos data on file Endolysins have three characteristics that have systemic side-effects when applied to the skin (unlike corticosteroids and assist in fighting antimicrobial resistance:

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engineering for a better world

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SPOTLIGHT ON INNOVATION

Data centre Robert Gleave, intellectual property consultant at Coller IP, advocates making optimum use of available data to underpin business strategy

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It is good practice for businesses to regularly monitor the publication of new patent applications from key competitors

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The pharmaceutical and biotech industries have undergone rapid change in recent years, partly in response to well documented challenges facing the industry, but also due to shifts in technology - such as from small molecule development to biologics - and the ever increasing amounts of data available to research organisations.

It is of key importance for research companies, and those supporting aspects of the drug development process, to be aware of longer term trends in technological, clinical and regulatory environment within the industry. This enables strategic plans to be put in place and to make sure that future product offerings are aligned to market or industry needs. One strategy to increase industry awareness and to support business planning is to have a structured approach to analysis of emerging patent literature.

It is good practice for businesses to regularly monitor the publication of new patent applications from key competitors. This can help to rapidly identify new potentially disruptive technologies and therefore enable a response strategy to be developed. Emerging patent literature can also help point to areas of synergistic research and identify potential collaborators or new markets. Once identified, potentially high impact patent applications should be monitored to assess progress in patent prosecution and to determine strategies for opposition if necessary.

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It is also important to monitor and analyse broader trends in patent filings across the industry, for example with by picking out areas of high research activity, and therefore those areas where others are investing their time and money. This broader analysis can be a significant challenge in the pharmaceutical sector due to the sheer quantity of patent filings. For example, the top 25 pharmaceutical companies (by 2013 sales) and their subsidiaries have filed over 17,000 new patent families in the last five years.

There are a number of complementary ways in which an experienced patent analyst can extract trends from such data sets.

Patent classification codes are used by patent examiners to link new applications to one or more technical fields. Some classification schemes, such as the Cooperative Patent Classification system used by the European and US patent offices, offer a high degree of granularity, and therefore enable the stratification of large patent sets into specific technical fields of interest. As a simple example, the 17,000 patent families identified above can be split using classification codes to show that approximately 37% of the families relate to small molecules, 24% to biologics, 11% to medical devices and 8% to methods of diagnosis. continued overleaf:

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17:

SPOTLIGHT ON INNOVATION

The analysis of classification codes can also extract information relating to emerging areas of interest in the pharmaceutical sector and the key players involved. For example, the use of location-based services is an area of increasing interest for patient engagement, remote monitoring and collecting real time patient data. An analysis of relevant patent classification codes indicates that the top pharma companies have filed over 300 families in this area in the last five years, with Roche being the most active patenting entity.

Large patent sets can also be analysed to look for those patents which have been highly cited by other patent applicants or examiners.

These documents can represent important or breakthrough technologies which have been used as a basis for the development further technological advances, although it is important to for a patent analyst to carefully analyse the results such a citation analysis. Amongst the most highly cited patent families from the top pharma set include patents relate to HCV inhibitors and blood glucose measurement devices.

A useful tool in the broader analysis of patent sets is the generation and analysis of patent landscape maps. These maps are typically generated through term frequency analysis and other algorithms

“

to cluster documents relating to shared themes. The output is a visualisation of the patent space with patents arranged in map ‘contours’ which indicated the density of the cluster patents. Such maps can be useful to identify key areas of patenting activity, the major patenting entities in a particular technology space, and can be time-sliced to show trends in patent filing over a set period.

One way to achieve this kind of insight is to appoint an external expert, who can work with a business who can develop a focussed patent search and analysis strategy, the results of which can enhance strategic business planning.

While most businesses are unlikely to be interested in a whole sector analysis, the techniques discussed above can readily be applied to a focussed set of patent families within an industry sub-sector or particular research field.

In summary, it is vital for businesses in high tech industries such as pharma and biotech to keep track of both their competitor’s activities as well as trends more generally within the market. It is therefore important to develop a structured approach to the identification and analysis of emerging patent data.

Emerging patent literature can also help point to areas of synergistic research and identify potential collaborators or new markets

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PLEASE MARK YOUR CALENDARS AND PLAN TO ATTEND!

MAY 5 - 8, 2015 Palais des Congrès d’Antibes Nice, FRANCE

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DRUG DELIVERY

Grand designs Craig Thompson and Clive Nicholls, Owen Mumford, discuss design for modern drug formulations

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Pharmaceutical manufacturers need to think beyond the drug itself, and consider the various aspects of delivery and administration

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t’s predicted there will be continued growth in biologics and that this will be a key driver for the emergence of large volume injectors, with around 50% of the top 100 selling drugs expected to be biologics by 2016. Biologics are estimated to contribute 27% of the total drugs market by 2020, causing pharmaceutical companies to focus on developing drug delivery devices that allow self-administration of high viscosity, large volume drugs and/or biologics.

The challenges introduced from the increase in new drug formulations, such as higher viscosity formulations requiring a slower, prolonged delivery places greater emphasis on pharmaceutical and biopharmaceutical companies to add value through the delivery method. Pharmaceutical manufacturers need to think beyond the drug itself, and consider the various aspects of delivery and administration that bring value to the end-user, health care professional and/or care giver, helping to differentiate in a crowded market.

Owen Mumford is a major medical device design and manufacture company, developing diagnostic and self-injection devices such as pen injector systems and auto-injectors for multiple therapy areas including diabetes and multiple sclerosis.

Craig Thompson, OEM sales manager at Owen Mumford commented: “There are multiple ways in which you can add value to the end user; alterations can be made to the injection devices to change the method of administration, making it more of a comfortable experience when injecting. Involving human factors experts during the design and development stages can help steer the design to make the process of injecting less intimidating for the user and can provide insights to improve adherence.

“For example, the Autoject Micro disposable auto-injector is designed to deliver a variety of volumes and high viscosity drugs whilst also being

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designed to improve adherence. Features such as keeping the needle hidden from the user at all times, clear sequencing of user steps to prevent incorrect use and sharps injury prevention help overcome the barriers to self-injection. The device is compact, visually pleasing and easy to use, adding to end-user comfort, which, as always, remains a priority for us.”

In response to the predicted growth in higher drug viscosities, the industry is going to see a similar growth in the development of injection devices that meet this need.

Owen Mumford, a company with both design and manufacture capabilities, understands that such devices will become more advanced, Clive Nicholls, product design and development manager at Owen Mumford added: “The industry is likely to see an increase in both wearable devices and more traditional injection devices specifically designed to deliver higher viscosity drugs. Device developers need to get the right balance between the conveniences of a quick, simple injection with the more comfortable absorption benefits of a slower, prolonged delivery method to ensure the best device for the end user.

Whilst traditional injection devices offer the former; being quick and simple, they can struggle to deal with the discomfort of injecting a large, viscose volume into a patient in a short period of time. Wearable devices deal with the issue of discomfort of injection, but the user has to remain in contact with the device for a far longer period often compromising convenience.”

In summary, it’s fair to say the developments in modern drug formulations are seeing key changes in the design of injection devices, taking into account both the delivery method of the drug and the end-users comfort. Along with this, there is going to be a rise in the manufacture and use of wearable devices, but with further requirement for development, considering the end-users convenience and comfort.

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DRUG DELIVERY

Making a point Microneedles breakthrough brings 3M one step closer to introducing new alternative drug delivery method which should offer new opportunities for pharma companies

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etting an injection at the doctor’s office typically does not rank highly on many people’s wish list. Thanks to 3M scientists’ know-how, the day is getting closer when patients may be receiving their prescription medications at home via microscopic needles. Pharmaceutical and biotechnology companies can now partner with 3M on development and conduct clinical trials using its 3M Hollow Microstructured Transdermal System (hMTS). Designed to be patient-friendly and easy to use, 3M hMTS should also open new opportunities for pharmaceutical companies and patients.

The device’s availability for clinical trials comes after conducting a number of studies and design verification tests. Based on 3M microreplication technology, pharmaceutical and biotech companies can take advantage of this patient-friendly hollow microneedle device for difficult-to-deliver biologics.

To reach this current stage of clinical readiness with the hMTS device, 3M has undertaken a rigorous process, including finalising the device design, manufacturing critical components from medical grade materials, establishing GMP array manufacturing and device assembly, as well as filing documentation with FDA. 3M conducted a human tolerability study with the goal of selecting the appropriate microneedle array for use in clinical studies. The outcome of this study found very good delivery times for 2 mL (less than two minutes on average). These results provide foundational data in assessing the safety of the device. Clinical supplies are now available for assessment in potential development partners’ trials.

Home delivery: 3M says that the day is getting closer when patients may be receiving their prescription medications at home via microscopic needles

“From the foundation laid by our recent human study, we are excited to extend our hollow microneedle device and expertise to companies who are ready for clinical studies. Pharma companies can now evaluate 3M hMTS in their clinical trials as a delivery system for a new drug product or a product line extension,” said Ingrid Blair, vice president, business and marketing, 3M Drug Delivery Systems. “Keeping patient preference top of mind is key and with this new system, pharmaceutical companies have more options to satisfy patients.”

“3M Hollow Microstructured Transdermal System continues to demonstrate a number of unique benefits, including reproducible intradermal delivery, a proven ability to deliver formulations up to 2 mL with various viscosities, and API-dependent PK profile benefits,” continued Blair. “Its patient-friendly features and the ability for patients to easily self-administer open new opportunities to move treatments out of the clinic and into the patient’s own home. We are looking forward to working with pharmaceutical partners to provide this microneedle drug delivery alternative.”

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DRUG DELIVERY

Well adjusted When administering liquid medicines for domestic use, a ratio of 10% to 15% of the dosage is too high or too low. In case of an underdose of eg antibiotics, children may develop resistances; if they overdose on the medication this can result in poisoning, so exact dosing is extremely important.

Raumedic has developed innovative dosing systems. The dosing syringe with external dose adjustment ensures better accuracy for the exact dosing of liquid drugs.

Precise operation and easy handling for the user are top priority. This is why the RauDose has a visible, coloured, raised adjustment mechanism. The medication dosage can be preset precisely with one hand by means of an external fixing bracket and a scale graduation. Gradual adjustments of 0.5 ml trigger off a haptic and acoustic feedback to the user. This means the dosing deviation is less than 3%.

Well adjusted: Raumedic has developed a dosing syringe with external dose adjustment to ensure better accuracy for the exact dosing of liquid drugs.

Smart work Aptar Pharma’s Prohaler is a smart DPI that has been developed with the patient in mind. This, says Aptar Pharma, makes it intuitive and simple to use by all asthma and COPD patients.

Prohaler features a novel powder dispersion technology enabling consistent lung deposition even when operating at relatively low patient inhalation flow rates. According to Aptar Pharma, the results of recent research showed that Prohaler has excellent ergonomics, providing intuitive and constant handling characteristics. It is easy to use, only three simple steps are needed: open the device, inhale and close it; inhaling triggers the release of a full dose of medication. And a dose counter reminds the patient how many doses are left in the device.

Prohaler also offers visual and audible feed-back systems to facilitate ease-of-use and patient compliance.

User interface: Aptar Pharma’s Prohaler is a smart DPI that has been developed with the patient in mind.>>

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INNOVATION

Single source: The development of SampleGenie technology enables samples to be dried or concentrated, directly into a single vial

Taking a sample

This, and the automation SampleGenie 4 is the offered by Genevac latest version of Genevac’s evaporators simplifies the technology for direct protocol before storage or concentration of large sample volumes into vials, designed Genevac explains how its latest technology allows large analysis. SampleGenie has for use in the Rocket Synergy sample volumes to be dried directly into vials helping cut been designed to remove time consuming manual steps as Evaporator.

SampleGenie down on both time and errors well as lowering labour costs technology enables large and improving data reliability. sample volumes to be dried directly into vials, eliminating a number of time-consuming sample handling steps and the attendant SampleGenie technology, in conjunction with Genevac evaporators, risk of errors. The latest generation SampleGenie is designed to enhance is finding widespread use in applications including chemical / life science research. the exceptional capabilities of the original design.

Accommodating sample volumes of up to 250ml, and featuring a new vial adapter insert to suit a range of vials from 12mm to 28mm diameter and up to 70mm tall. SampleGenie 4 has been precision engineered to reduce the risk of vial breakage.

Traditionally protocols for concentration of chromatographic fractions has involved drying multiple fractions in an evaporator, re-suspending pooled fractions into a single vial and then re-drying before storage and analysis. Even with modern centrifugal evaporators such processes typically take two to three days to complete. The development of SampleGenie technology has, said Genevac, revolutionised this process enabling samples in Genevac Rocket Synergy, HT and EZ-2 series evaporators to be dried or concentrated, directly into a single vial eliminating the need for reformatting of samples after drying.

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FOLIO

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GRANULATION, MILLING & MIXING

A miller’s tale Claude Lefebvre, Frewitt, looks at how production bottlenecks with the milling of solids and difficult-toprocess API products can be overcome easily and economically

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customer of Frewitt was confronted with a manufacturing bottleneck in processing solids and this became a major obstacle to achieve the production capacity needed. The situation occurred at pharmaceutical manufacturer Sanovel.

Sanovel manufactures final (oral solid dosage) OSD forms of anti-diabetic drugs formulated with metformin as one of the active ingredient. The Sanovel manufacturing site in Istanbul receives metformin packaged in 25-80 kg bags which, due to the hygroscopic properties of the product, become hard solid blocks during transport and storage. For the metformin to be processed, the blocks need to go through a time consuming grinding step which disagglomerates the product into a fine powder of 200300µm.

Requiring several hours to process a 275 kg batch in the high shear mixer, this dissaglomeration step was clearly a bottleneck of the whole wet granulation process for Sanovel. A sound technical solution to that issue would shorten the cycle of the high-shear mixer allowing a balanced process flow between all components of the whole wet granulation process and as a result substantial gains in terms of global manufacturing capacity.

Jürgen Abel made an interesting comparison in his article about flexible production: "The bottleneck can be compared to the weakest link in a chain that breaks if the load is too great."

Sanovel's weakest link in this case was processing metformin using the time-

Smooth operation: Claude Lefebvre, Frewitt, explains how production bottlenecks can be overcome easily and economically>>

consuming disagglomeration in the high-speed mixer. Production throughput through the weakest link had to be significantly increased in order to increase overall system performance.

Since Frewitt had already dealt with the problem with other customers, it didn't have to reinvent the wheel for Sanovel.

The solution was readily available: the DelumpWitt.

Metformin blocks are manually charged to a high-shear mixer, initially dissaglomerated to 250 micron powder before being processed in a wet granulation suite.

Compared with the conventional approach, which consists of a two-step process lump breaker and a mill the DelumpWitt is is a one process step breaking big lumps and fine milling them to target particle size. This integration into one system also means low height, low weight and small footprint.

Back in 2011, the dissaglomation of a 275 kg metformin batch was a timeconsuming step taking several hours.

Sanovel's target was to reduce this to 20 minutes.

To find a solution to this challenge, Frewitt, a long-time partner to Sanovel, was contacted so as to benefit from the expertise and years of experience with milling systems.

The DelumpWitt consists of a conical feed funnel for product blocks up to a size of 60 x 30 x 20cm, a crusher and a conical sieve mill which can be used with different type of sieves or rasps for fine grinding of the product. The rotor and sieve can be easily changed and cleaned.

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Installed at Sanovel, the DelumpWitt has since totally achieved its objectives: Metformin blocks are manually charged to the feeding hopper, pre-broken, and milled to the final particle size of 250µm. A batch of 275kg today is disagglomerated in 10 minutes, crushed and processed to a fine, free-flowing powder easily conveyed by vacuum to a high-speed mixer. From there the product is ready for processing and transfers to downstream operations of the wet granulation suite.

No longer does it takes several hours to dissaglomerate. Today, the high-shear mixer can deliver its full capacity.

Ersin Ünal, Sanovel's production equipment maintenance executive, said: "Our collaboration with Frewitt provided the sound solution to our bottleneck challenge. The DelumpWitt gives us the manufacturing flexibility and capacity increase paramount to our success.”

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New York times This year’s Interphex – April 21-23 – in New York, promises a selection of the latest technologies and expertise on offer to the pharma sector Interphex takes place on 21-23 April at the Javits Center, New York. It’s billed as the single source for complete biopharmaceutical development and manufacturing solutions to safely and cost effectively process all dosage forms for life-enhancing drugs with a unique combination of exhibition, education, workshops, partnering opportunities, and networking events.

According to the show organisers, more than 12,000 global pharmaceutical and biotechnology industry professionals together with 600 suppliers will be at the event. Pharmaceutical industry leaders and subject matter experts from more than 48 countries will be offering the opportunity to share their knowledge and discuss the latest technologies.

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Lesson plan >>

Micro management >>

The Rockwell Automation Center for The Connected Enterprise will be offering educational sessions. Experts will demonstrate how the latest automation and information technology, accelerated by advances in enabling technologies – including the Internet of Things, data analytics, remote monitoring and mobility – is improving collaboration and real-time decision making as well as driving profitability in life sciences manufacturing.

PSL USA will be exhibiting one of its latest innovations on its stand. It has been heavily involved in developing microsphere filtration solutions designed to produce microspheres used for long lasting drug delivery. New applications for microspheres are discovered every day especially in the field of cancer research and biopharmaceutical industry. PSL developed innovative solutions for the downstream formulation of microspheres used as drug delivery devices: Polymer microspheres can work as miniature time release drug capsules within the patient body.

"Interphex attracts producers at the leading edge of their industry and manufacturing in general," said John Genovesi, vice president and general manager, information software and process, Rockwell Automation.

Stand Crystal Palace Stand 3

PSL’s process experts developed the MicroSphere Refiner in response to the challenges faced by drug manufacturers with other techniques such as mesh blocking, lengthy drying and Steam-In-Place (SIP) difficulties. The MicroSphere Refiner is a piece of process equipment combining filtration, cake washing, classification and drying, all in one step, with sterile product recovery.

Stand 2232

Quality counts >> Ensuring that drug manufacturers maximise product quality and ensure patient safety is a topic that Crane ChemPharma & Energy will address during this year’s exhibition.

Pressing news >> Fette Compacting America, supplier of tablet press equipment for pharmaceutical and nutritional applications, has announced the North American launch of the FE75 tablet press, a double-sided rotary press that can be equipped with up to 115 punch stations to produce more than 1.6 million tablets per hour. Ideal for the premium production of large batches, the FE75’s control system architecture allows for the potential incorporation of all four compression stations into one compression cycle, for direct compression of challenging products requiring maximum dwell time. The FE75 will make its North American debut along with the first-ever look at the complete line of FE series tablet presses at Interphex.

The company says its line of Saunders aseptic diaphragm valves form an integral part of the pharmaceutical manufacturing process and enable drug manufacturers to effectively control the manufacturing process.

Among a new generation of products designed to increase accuracy and maximise diaphragm life are the Saunders S360 stainless steel actuator and the I-VUE smart sensor. These products are said to deliver the twin benefit of having advanced technology to drive better performance and at the same time obtain an accurate footprint of the valve’s performance.

Stand 3622

Another dimension >>

Sharing several novel technologies with the other FE-series models, the FE35 and FE55, the FE75 features a new, patent-pending conical filling unit, highly accurate manually adjustable filling table, innovative compression rollers, trouble-free, corner-mounted tablet discharge, a highly intuitive, 19-inch operating terminal, and the connection of process equipment via a standardized plug-and-play interface. While the FE35 single-sided rotary press is optimised for quick changeovers and the FE55 offers maximum flexibility in diverse production scenarios, the FE75 has been specifically tailored to high-volume output for large batch production.

Stand 2505C

Fraser Advanced Information Systems is leading the 3D Printing Education and Demonstration Forum for the pharma and biopharma Industries.

The goal of the inaugural Fraser 3D Printing Pavilion is to introduce Interphex attendees to 3D printing equipment, materials and applications that leverage this emerging business model for the pharmaceutical and biopharmaceutical industries.

“The Fraser 3D Print Pavilion is a perfect example of Interphex’s commitment to bringing cutting edge technologies to the pharma and biopharma industries that we serve,” said Ed Several, senior vice president and general manager, Interphex. “We are delighted to join with Fraser as it shares its extensive knowledge and experience in seven different 3D printing technologies that are ideal for professional, lab and production environments. This effort brings together 3D and bio printing thought leaders to share their insights and expertise with key decision makers and engineering professionals regarding the promise of 3D printing in pharma as well as the potential pitfalls.”

Cover story >> L B Bohle, provider of high efficiency processing technologies and OCS Checkweighers, a partner for efficient checkweighers, catchweighers, in-motion scales as well as X-ray scanners, will be showcasing a range of technologies at Interphex.

“We have set the standard in pharmaceutical production with our high precision coaters”, said Martin Hack, vice-president and general manager, L B Bohle.

“We are proud to showcase our fleet of industry leading tablet coaters from laboratory through pilot to production scale at Interphex. Our innovative process concepts and cleaning methodologies improve coater functionality and deliver outstanding results for our customers.”

3D Printing Pavilion

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Stand 2811

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potent compounds. potent compounds. potent potent potent compounds. compounds. compounds. potent compounds. potent compounds. potent potent potent compounds. compounds. compounds. potent compounds. potent compounds. potent potent potent compounds. compounds. compounds. potent compounds. integrated solutions. integrated solutions. integrated solutions. integrated integrated solutions. solutions. solutions. integrated solutions. potent compounds. integrated solutions. integrated solutions. integrated integrated solutions. solutions. solutions. integrated solutions. potent compounds. potent potent potent compounds. compounds. compounds. potent compounds. integrated solutions. integrated integrated integrated solutions. solutions. solutions. integrated solutions. reliably supplied. reliably reliably supplied. reliably reliably supplied. supplied. supplied. reliably supplied. integrated solutions. reliably reliably supplied. reliably reliably supplied. supplied. supplied. reliably supplied. integrated solutions. integrated integrated integrated solutions. solutions. solutions. integrated solutions. reliably supplied. reliably reliably reliablysupplied. supplied. supplied. supplied. reliably reliably supplied. reliably supplied. reliably reliably reliablysupplied. supplied. supplied. supplied. reliably

+ +++++++++++++++ + ++++++ ++++++++++++++++ ++ +++++ ++++++++++++++++ + +++++

10 10 10 10 10 10 10 10 10 10 10 10 10 10 20 20 20 20 20 20 20 20 20 20 20 20 20 20 300 300 300 300 300 300 300 300 300 300 300 300 300 300 300

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solutions solutions solutions solutions from from from from sites in tHe gloBal netwoRk sites sites sites sites in in tHe in in tHe tHe tHe gloBal gloBal gloBal gloBal netwoRk netwoRk netwoRk netwoRk optimization through supply Integrated solutions from optimization optimization optimization optimization through through through through supply supply supply supply sites in tHe gloBal netwoRk optimization through supply optimization through supply Integrated solutions from Integrated Integrated Integrated Integrated solutions solutions solutions solutions from from from from optimization through supply Integrated solutions from optimization through supply optimization optimization optimization optimization through through through through supply supply supply supply Integrated solutions from Integrated Integrated Integrated Integrated solutions solutions solutions solutions from from from from optimization through supply Integrated solutions from sites in tHe gloBal netwoRk optimization through supply optimization optimization optimization optimization through through through through supply supply supply supply optimization through supply optimization through supply optimization optimization optimization optimization through through through through supply supply supply supply optimization through supply Integrated solutions from sites tHe gloBal netwoRk sites sites sites sites inin in tHe in in tHe tHe tHe gloBal gloBal gloBal gloBal netwoRk netwoRk netwoRk netwoRk sites in tHe gloBal netwoRk optimization through supply Integrated solutions from Integrated Integrated Integrated Integrated solutions solutions solutions solutions from from from from YeaRs exPeRtise Integrated solutions from in HigH YeaRs exPeRtise in HigH optimization through supply optimization optimization optimization optimization through through through through supply supply supply supply optimization through supply Potent Handling YeaRs exPeRtise HigH YeaRs YeaRs YeaRs YeaRs exPeRtise exPeRtise exPeRtise exPeRtise inin in HigH in in HigH HigH HigH YeaRs exPeRtise in HigH YeaRs exPeRtise in HigH Potent Handling YeaRs exPeRtise in HigH 80+ years providing drug delivery solutions YeaRs exPeRtise in HigH YeaRs YeaRs YeaRs YeaRs exPeRtise exPeRtise exPeRtise exPeRtise in in HigH in in HigH HigH HigH YeaRs exPeRtise in HigH Potent Handling Potent Handling Potent Potent Potent Potent Handling Handling Handling Handling Potent Handling 80+ years providing drug delivery solutions YeaRs exPeRtise in HigH Potent Handling YeaRs YeaRs YeaRs YeaRs exPeRtise exPeRtise exPeRtise exPeRtise in in HigH in in HigH HigH HigH YeaRs exPeRtise in HigH Potent Handling YeaRs exPeRtise in HigH Potent Potent Potent Potent Handling Handling Handling Handling YeaRs YeaRs YeaRs YeaRs exPeRtise exPeRtise exPeRtise exPeRtise in in HigH in in HigH HigH HigH 80+ years providing drug delivery solutions 80+ years drug delivery solutions Potent Handling YeaRs exPeRtise in HigH 80+ 80+ 80+ 80+ years years years years providing providing providing providing drug drug drug drug delivery delivery delivery delivery solutions solutions solutions solutions 80+ years providing drug delivery solutions 80+ years providing drug delivery solutions Potent Handling Potent Potent Potent Potent Handling Handling Handling Handling Potent Handling 80+ years providing drug delivery solutions 80+ 80+ 80+ 80+ years years years years providing providing providing providing drug drug drug drug delivery delivery delivery delivery solutions solutions solutions solutions Potent Handling YeaRs exPeRtise in HigH Potent Potent Potent Potent Handling Handling Handling Handling 80+ years providing drug delivery solutions Potent Handling 80+ years providing drug delivery solutions 80+ 80+ 80+ 80+ years years years years providing providing providing providing drug drug drug drug delivery delivery delivery delivery solutions solutions solutions solutions 80+ years providing drug delivery solutions 80+ years providing drug delivery solutions 80+ 80+ 80+ 80+ years years years years providing providing providing providing drug drug drug drug delivery delivery delivery delivery solutions solutions solutions solutions Potent Handling 80+ years providing drug delivery solutions YeaRs exPeRtise HigH YeaRs YeaRs YeaRs YeaRs exPeRtise exPeRtise exPeRtise exPeRtise inin in HigH in in HigH HigH HigH YeaRs exPeRtise in HigH 80+ years providing drug delivery solutions Potent Handling Potent Potent Potent Potent Handling Handling Handling Handling Handled Potent CoMPoUnds Potent Handling Potent CoMPoUnds Handled 80+ years providing drug delivery solutions 80+ 80+ 80+ 80+ years years years years providing providing providing providing drug drug drug drug delivery delivery delivery delivery solutions solutions solutions solutions Potent, hghly potent, hormones 80+ years providing drug delivery solutions Potent CoMPoUnds Handled Potent CoMPoUnds Handled Potent Potent Potent Potent CoMPoUnds CoMPoUnds CoMPoUnds CoMPoUnds Handled Handled Handled Handled hghly potent, hormones Potent, highly potent, hormones Potent CoMPoUnds Handled Potent CoMPoUnds Handled and cytotoxics Potent CoMPoUnds Handled Potent, hghly potent, hormones Potent Potent Potent Potent CoMPoUnds CoMPoUnds CoMPoUnds CoMPoUnds Handled Handled Handled Handled Potent, hghly potent, hormones Potent CoMPoUnds Handled cytotoxics Potent, Potent, Potent, Potent, hghly hghly hghly hghly potent, potent, potent, potent, hormones hormones hormones hormones and cytotoxics Potent, hghly potent, hormones Potent, hghly potent, hormones Potent CoMPoUnds Handled Potent Potent Potent Potent CoMPoUnds CoMPoUnds CoMPoUnds CoMPoUnds Handled Handled Handled Handled Potent CoMPoUnds Handled Potent, hghly potent, hormones and cytotoxics Potent, Potent, Potent, Potent, hghly hghly hghly hghly potent, potent, potent, potent, hormones hormones hormones hormones Potent CoMPoUnds Handled Potent Potent Potent Potent CoMPoUnds CoMPoUnds CoMPoUnds CoMPoUnds Handled Handled Handled Handled and cytotoxics Potent, hghly potent, hormonesHandled and and and cytotoxics and cytotoxics cytotoxics cytotoxics Potent CoMPoUnds and cytotoxics and cytotoxics Potent, hghly potent, hormones Potent, Potent, Potent, Potent, hghly hghly hghly hghly potent, potent, potent, potent, hormones hormones hormones hormones Potent, hghly potent, hormones and cytotoxics Potent CoMPoUnds Handled and and and cytotoxics and cytotoxics cytotoxics cytotoxics Potent, hghly potent, hormones Potent, Potent, Potent, Potent, hghly hghly hghly hghly potent, potent, potent, potent, hormones hormones hormones hormones and cytotoxics Potent, hghly potent, hormones and cytotoxics and and and cytotoxics and cytotoxics cytotoxics cytotoxics and cytotoxics Potent, hghly potent, hormones and cytotoxics and and and cytotoxics and cytotoxics cytotoxics cytotoxics

and cytotoxics Potent CoMPoUnds Handled Potent Potent Potent Potent CoMPoUnds CoMPoUnds CoMPoUnds CoMPoUnds Handled Handled Handled Handled Potent CoMPoUnds Handled and cytotoxics Potent, hghly potent, hormones Potent, Potent, Potent, Potent, hghly hghly hghly hghly potent, potent, potent, potent, hormones hormones hormones hormones Potent, hghly potent, hormones and cytotoxics and and and cytotoxics and cytotoxics cytotoxics cytotoxics and cytotoxics

Potent Handling exPeRtise Potent Handling exPeRtise

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Proven trackHandling record with 20+ years of potent Integrated analytical, development and Robust engineering and PPE controls. integRated seRviCes safelY & sUPPlied Potent exPeRtise integRated seRviCes safelY & ReliaBlY ReliaBlY sUPPlied Potent Handling exPeRtise Proven track record with 20+ years of potent Integrated analytical, development and Robust engineering and PPE controls. handling experience and 80+ years providing supply solutions with recent investments Comprehensive risk assessment processes. integRated seRviCes safelY &ReliaBlY ReliaBlY sUPPlied Potent Handling exPeRtise integRated integRated integRated integRated seRviCes seRviCes seRviCes seRviCes safelY safelY safelY safelY &ReliaBlY && & ReliaBlY ReliaBlY ReliaBlY sUPPlied sUPPlied sUPPlied sUPPlied Potent Potent Potent Handling Handling Handling exPeRtise exPeRtise exPeRtise Potent Handling exPeRtise integRated seRviCes safelY & sUPPlied Potent Handling exPeRtise Proven track record with 20+ years of potent Integrated analytical, development and Robust engineering and PPE controls. handling experience and 80+ years providing supply solutions with recent investments Comprehensive risk assessment processes.

Proven track record with 20+ years of potent Integrated analytical, development and Robust engineering and PPE controls. innovative pharmaceutical delivery solutions. in high potency seRviCes clinical packaging, Micron Highly-trained, experienced team with deep integRated seRviCes safelY & ReliaBlY sUPPlied Potent Handling exPeRtise integRated integRated integRated integRated seRviCes seRviCes seRviCes seRviCes safelY safelY safelY safelY & ReliaBlY & & & ReliaBlY ReliaBlY ReliaBlY sUPPlied sUPPlied sUPPlied sUPPlied Potent Potent Potent Handling Handling Handling exPeRtise exPeRtise exPeRtise Potent Handling exPeRtise integRated safelY & ReliaBlY sUPPlied Potent Handling exPeRtise handling experience and 80+ years providing supply solutions with recent investments Comprehensive risk assessment processes.

Proven track record with 20+ years of potent Integrated analytical, development and Robust engineering and PPE controls.

Proven Proven Proven Proven track track track track record record record record with with with with 20+ 20+ 20+ 20+ years years years years ofpotent potent of of of potent potent potent Integrated Integrated Integrated Integrated Integrated analytical, analytical, analytical, analytical, development development development development and and and and Robust Robust Robust Robust engineering engineering engineering engineering and and and PPE and PPE PPE controls.

PPE controls. controls. controls. innovative pharmaceutical delivery solutions. in high potency clinical packaging, Micron Highly-trained, experienced team with deep integRated seRviCes safelY & ReliaBlY sUPPlied Potent Handling exPeRtise Proven track record with 20+ years of analytical, development and Robust engineering and PPE controls. integRated integRated integRated integRated seRviCes seRviCes seRviCes seRviCes safelY safelY safelY safelY & ReliaBlY & & & ReliaBlY ReliaBlY ReliaBlY sUPPlied sUPPlied sUPPlied sUPPlied Potent Potent Potent Handling Handling Handling exPeRtise exPeRtise exPeRtise Potent Handling exPeRtise handling experience and 80+ years providing supply solutions with recent investments Comprehensive risk assessment processes.

300+ potent and highly-potent compounds, Technologies particle size engineering, and expertise in special handling protocols integRated seRviCes safelY & ReliaBlY sUPPlied Potent Handling exPeRtise integRated seRviCes safelY & ReliaBlY sUPPlied Potent Handling exPeRtise integRated integRated integRated integRated seRviCes seRviCes seRviCes seRviCes safelY safelY safelY safelY & ReliaBlY & & & ReliaBlY ReliaBlY ReliaBlY sUPPlied sUPPlied sUPPlied sUPPlied Potent Potent Potent Handling Handling Handling exPeRtise exPeRtise exPeRtise Potent Handling exPeRtise integRated seRviCes safelY & ReliaBlY sUPPlied Potent Handling exPeRtise Proven track record with 20+ years of potent Integrated analytical, development and Robust engineering and PPE controls. integRated seRviCes safelY & ReliaBlY sUPPlied Potent Handling exPeRtise Proven Proven Proven Proven track track track track record record record record with with with with 20+ 20+ 20+ 20+ years years years years of potent of of of potent potent potent Integrated Integrated Integrated Integrated analytical, analytical, analytical, analytical, development development development development and and and and Robust Robust Robust Robust engineering engineering engineering engineering and and and PPE and PPE PPE controls.

PPE controls. controls. controls. innovative pharmaceutical delivery solutions. in high potency clinical packaging, Micron Highly-trained, experienced team with deep handling experience and 80+ years providing supply solutions with recent investments risk assessment processes.

Proven track record with 20+ years of potent Integrated analytical, development and Robust engineering and PPE controls. handling handling handling handling experience experience experience experience and and and 80+ and 80+ 80+ 80+ years years years years providing providing providing providing supply supply supply supply supply solutions solutions solutions solutions with with with with recent recent recent recent investments investments investments investments Comprehensive Comprehensive Comprehensive Comprehensive risk risk risk assessment risk assessment assessment assessment processes. processes. processes. processes.

300+ potent and highly-potent compounds, Technologies particle size engineering, andsolids. expertise in across special handling protocols handling experience and 80+ years providing solutions with recent investments Comprehensive risk assessment processes. innovative pharmaceutical delivery solutions. in high potency clinical packaging, Micron Highly-trained, experienced team with deep as well as hormones and cytotoxics. expanded manufacturing services for oral inComprehensive 10+ sites our global network.

Proven track record with 20+ years of potent Integrated analytical, development and Robust engineering and PPE controls.

Proven Proven Proven Proven track track track track record record record record with with with with 20+ 20+ 20+ 20+ years years years years of potent of of of potent potent potent Integrated Integrated Integrated Integrated analytical, analytical, analytical, analytical, development development development development and and and and Robust Robust Robust Robust engineering engineering engineering engineering and and and PPE and PPE PPE controls.

PPE controls. controls. controls.

Proven track record with 20+ years of potent Integrated analytical, development and Robust engineering and PPE controls. handling experience and 80+ providing supply solutions with recent investments risk assessment processes. handling handling handling handling experience experience experience experience and and and 80+ and 80+ 80+ 80+ providing providing providing providing supply supply supply solutions solutions solutions solutions with with with with recent recent recent recent investments investments investments investments Comprehensive Comprehensive Comprehensive Comprehensive risk risk risk assessment risk assessment assessment assessment processes. processes. processes. processes.

300+ potent and highly-potent compounds, Technologies particle size engineering, expertise inengineering special handling protocols Proven track record with 20+ years of potent Integrated analytical, development and Robust engineering and PPE controls.

Proven track record with 20+ years of potent Integrated analytical, development and Robust engineering and PPE controls.

Proven Proven Proven Proven track track track track record record record record with with with with 20+ 20+ 20+ 20+ years years years years of potent of of of potent potent potent supply Integrated Integrated Integrated Integrated analytical, analytical, analytical, analytical, development development development development and and and and Robust Robust Robust Robust engineering engineering engineering and and and PPE and PPE PPE controls.

PPE controls. controls. controls. innovative pharmaceutical delivery solutions. in high potency clinical packaging, Micron Highly-trained, experienced team with deep handling experience and 80+ providing with recent investments Comprehensive risk assessment processes. innovative innovative innovative innovative pharmaceutical pharmaceutical pharmaceutical pharmaceutical delivery delivery delivery delivery solutions. solutions. solutions. solutions. inhigh high insupply in insolutions high high high potency potency potency potency clinical clinical clinical clinical packaging, packaging, packaging, packaging, Micron Micron Micron Micron Highly-trained, Highly-trained, Highly-trained, Highly-trained, experienced experienced experienced experienced team team team team with with with with deep deep deep deep as well as hormones and cytotoxics. expanded manufacturing services for oral solids. inComprehensive 10+ sites across our global network.

Proven track record with 20+ years of potent Integrated analytical, development and Robust engineering and PPE controls. innovative pharmaceutical delivery solutions. in potency clinical packaging, Micron Highly-trained, experienced team with deep 300+ potent and highly-potent compounds, Technologies particle size engineering, and expertise in special handling protocols handling experience and 80+ years providing supply solutions with recent investments Comprehensive risk assessment processes. handling handling handling handling experience experience experience experience and and and 80+ and 80+ 80+ 80+ years years years years providing providing providing providing supply supply supply supply solutions solutions solutions solutions with with with with recent recent recent recent investments investments investments investments Comprehensive Comprehensive Comprehensive Comprehensive risk risk risk assessment risk assessment assessment assessment processes. processes. processes. processes. handling experience and 80+ years providing supply solutions with recent investments Comprehensive risk assessment processes. innovative pharmaceutical delivery solutions. in high potency clinical packaging, Micron Highly-trained, experienced team with deep as well as hormones and cytotoxics. expanded manufacturing services for oral solids. in 10+ sites across our global network. innovative innovative innovative innovative pharmaceutical pharmaceutical pharmaceutical pharmaceutical delivery delivery delivery delivery solutions. solutions. solutions. solutions. in high in in in high high high potency potency potency potency clinical clinical clinical clinical packaging, packaging, packaging, packaging, Micron Micron Micron Micron Highly-trained, Highly-trained, Highly-trained, Highly-trained, experienced experienced experienced experienced team team team team with with with with deep deep deep deep handling experience and 80+ years providing supply solutions with recent investments Comprehensive risk assessment processes. handling experience and 80+ years providing supply solutions with recent investments Comprehensive risk assessment processes. handling handling handling handling experience experience experience experience and and and 80+ and 80+ 80+ 80+ years years years years providing providing providing providing supply supply supply supply solutions solutions solutions solutions with with with with recent recent recent recent investments investments investments investments Comprehensive Comprehensive Comprehensive Comprehensive risk risk risk assessment risk assessment assessment assessment processes. processes. processes. processes.

300+ potent and highly-potent compounds, Technologies particle size engineering, and expertise in special handling protocols innovative pharmaceutical delivery solutions. in high potency clinical packaging, Micron Highly-trained, experienced team with deep 300+ 300+ 300+ 300+ potent potent potent potent and and and highly-potent and highly-potent highly-potent highly-potent compounds, compounds, compounds, compounds, Technologies Technologies Technologies Technologies particle particle particle particle size size size engineering, size engineering, engineering, engineering, and and and and expertise expertise expertise expertise in special in in in special special special handling handling handling handling protocols protocols protocols protocols handling experience and 80+ years providing supply solutions with recent investments Comprehensive risk assessment processes. integRated seRviCes safelY & ReliaBlY sUPPlied Potent Handling exPeRtise 300+ potent and highly-potent compounds, Technologies particle size engineering, and expertise in special handling protocols as well as hormones and cytotoxics. expanded manufacturing services for oral solids. in 10+ sites across our global network. integRated integRated integRated integRated seRviCes seRviCes seRviCes seRviCes safelY safelY safelY safelY & ReliaBlY & & & ReliaBlY ReliaBlY ReliaBlY sUPPlied sUPPlied sUPPlied sUPPlied Potent Potent Potent Handling Handling Handling exPeRtise exPeRtise exPeRtise Potent Handling exPeRtise integRated seRviCes safelY & ReliaBlY sUPPlied Potent Handling exPeRtise innovative pharmaceutical delivery solutions. in high potency clinical packaging, Micron Highly-trained, experienced team with deep innovative innovative innovative innovative pharmaceutical pharmaceutical pharmaceutical pharmaceutical delivery delivery delivery delivery solutions. solutions. solutions. solutions. inTechnologies inhigh high in in inhigh high high potency potency potency potency clinical clinical clinical clinical packaging, packaging, packaging, packaging, Micron Micron Micron Micron Highly-trained, Highly-trained, Highly-trained, Highly-trained, experienced experienced experienced experienced team team team team with with with with deep deep deep deep innovative pharmaceutical delivery solutions. potency clinical packaging, Micron Highly-trained, experienced team with deep 300+ potent and highly-potent compounds, Technologies particle size engineering, and expertise in special handling protocols 300+ 300+ 300+ 300+ potent potent potent potent and and and highly-potent and highly-potent highly-potent highly-potent compounds, compounds, compounds, compounds, Technologies Technologies Technologies particle particle particle particle size size size engineering, size engineering, engineering, engineering, and and and and expertise expertise expertise in special in in in special special special handling handling handling handling protocols protocols protocols protocols innovative pharmaceutical delivery solutions. in high potency clinical packaging, Micron experienced team with deep innovative pharmaceutical delivery solutions. in high potency clinical packaging, Micron Highly-trained, experienced team with deep innovative innovative innovative innovative pharmaceutical pharmaceutical pharmaceutical pharmaceutical delivery delivery delivery delivery solutions. solutions. solutions. solutions. Technologies high in in inhigh high high potency potency potency potency clinical clinical clinical clinical packaging, packaging, packaging, packaging, Micron Micron Micron Micron Highly-trained, Highly-trained, Highly-trained, Highly-trained, experienced experienced experienced experienced team team team team with with with with deep deep deep deep as well as hormones and cytotoxics. expanded manufacturing services for oral solids. in 10+ sites across our global network.

300+ potent and highly-potent compounds, particle size engineering, and expertise in special handling protocols as well as as as well well well as hormones as as as hormones hormones hormones and and and cytotoxics. and cytotoxics. cytotoxics. cytotoxics. expanded expanded expanded expanded manufacturing manufacturing manufacturing manufacturing services services services services for for oral for for oral oral solids. oral solids. solids. solids.Highly-trained, in10+ 10+ inexpertise in in 10+ 10+ sites 10+ sites sites sites across across across across our our global our our global global global network. network. network. network. innovative pharmaceutical delivery solutions. in high potency clinical packaging, Micron Highly-trained, experienced team with deep as well as hormones and cytotoxics. expanded manufacturing services for oral solids. in sites across our global network.

Proven track record with 20+ years of potent Integrated analytical, development and Robust engineering and PPE controls.

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PPE controls. controls. controls.

300+ 300+ 300+ 300+ potent potent potent potent and and and highly-potent and highly-potent highly-potent highly-potent compounds, compounds, compounds, compounds, Technologies Technologies Technologies Technologies particle particle particle particle size size size engineering, size engineering, engineering, engineering, and and and and expertise expertise expertise expertise in special inin in special special special handling handling handling handling protocols protocols protocols protocols Proven track record with 20+ years of potent analytical, development and Robust engineering and PPE controls.

300+ potent and highly-potent compounds, Technologies particle size engineering, and expertise in special handling protocols as well as hormones and cytotoxics. expanded manufacturing services for oral solids. in 10+ sites across our global network. as well as as as well well well as hormones as as as hormones hormones hormones and and and cytotoxics. and cytotoxics. cytotoxics. cytotoxics. expanded expanded expanded expanded manufacturing manufacturing manufacturing manufacturing services services services services for for oral for for oral oral solids. oral solids. solids. solids. in 10+ in in in 10+ 10+ sites 10+ sites sites sites across across across across our our global our our global global global network. network. network. network.

300+ potent and highly-potent compounds, Technologies particle size engineering, and expertise in special handling protocols 300+ potent and highly-potent compounds, Technologies particle size engineering, and expertise in special handling protocols 300+ 300+ 300+ 300+ potent potent potent potent andhighly-potent and and highly-potent and highly-potent highly-potent highly-potent compounds, compounds, compounds, compounds, Technologies Technologies Technologies Technologies Technologies particle particle particle particle size size size engineering, sizeengineering, engineering, engineering, and and and and expertise expertise expertise in special inin inspecial special special handling handling handling handling protocols protocols protocols protocols as well as hormones and cytotoxics. expanded manufacturing services for oral solids. inexpertise 10+ sites across our global network.

300+ potent and compounds, particle size engineering, and expertise in special handling protocols handling experience and 80+ years providing supply solutions with recent investments risk assessment processes. as well as hormones and cytotoxics. expanded manufacturing services for oral solids. in 10+ sites across our global network. handling handling handling handling experience experience experience experience and and and 80+ 80+ 80+ 80+ years years years years providing providing providing providing supply supply supply supply supply solutions solutions solutions solutions with with with with recent recent recent recent investments investments investments investments Comprehensive Comprehensive Comprehensive Comprehensive risk risk risk assessment risk assessment assessment assessment processes. processes. processes. processes. well as as as well well well asas hormones as as as hormones hormones hormones and and cytotoxics. and cytotoxics. cytotoxics. cytotoxics. expanded expanded expanded expanded manufacturing manufacturing manufacturing manufacturing services services services services fororal for oral for for oral oral solids. oral solids. solids. solids. in 10+ inin in 10+ 10+ sites 10+ sites sites sites across across across across our our global our our global global global network. network. network. network. handling experience and 80+ years providing solutions with recent investments Comprehensive risk assessment processes. asas well as and cytotoxics. expanded manufacturing services for solids. inComprehensive 10+ sites across our global network. as well hormones and cytotoxics. expanded manufacturing services for oral in 10+ sites across our global network. as well as hormones and cytotoxics. expanded manufacturing services for oral solids. in 10+ sites across our global network. well as as as well well well ashormones hormones as as as hormones hormones hormones and and and cytotoxics. and cytotoxics. cytotoxics. cytotoxics. expanded expanded expanded expanded manufacturing manufacturing manufacturing manufacturing services services services services fororal for oral for for oral oral solids. oral solids. solids. solids. in 10+ inin in 10+ 10+ sites 10+ sites sites sites across across across across our our global our our global global global network. network. network. network. asas well as hormones and cytotoxics. expanded manufacturing services for solids. inHighly-trained, 10+ sites across our global network. innovative pharmaceutical delivery solutions. in high potency clinical packaging, Micron experienced team with deep innovative innovative innovative innovative pharmaceutical pharmaceutical pharmaceutical pharmaceutical delivery delivery delivery delivery solutions. solutions. solutions. solutions. ininhigh high inin inhigh high high potency potency potency potency clinical clinical clinical clinical packaging, packaging, packaging, packaging, Micron Micron Micron Micron Highly-trained, Highly-trained, Highly-trained, Highly-trained, experienced experienced experienced experienced team team team team with with with with deep deep deep deep innovative pharmaceutical delivery solutions. potency clinical packaging, Micron Highly-trained, experienced team with deep ™ 300+ potent and highly-potent compounds, Technologies particle size engineering, and expertise in special handling protocols 300+ 300+ 300+ 300+ potent potent potent potent and and and highly-potent and highly-potent highly-potent highly-potent compounds, compounds, compounds, compounds, Technologies Technologies Technologies Technologies Technologies particle particle particle particle size size size engineering, size engineering, engineering, engineering, and and and and treatments. expertise expertise expertise expertise special inin in special special special handling handling handling handling protocols protocols protocols protocols 300+ potent and highly-potent compounds, particle size engineering, and expertise inin special handling protocols Catalent.

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12/02/2015 16:53:28 12/02/2015 16:53:28

CLEANROOMS

Clean living WHP describes the facility it has completed for TC BioPharm’s (TCB), new clinical manufacturing facility in Glasgow WHP, cleanroom design, engineering and construction company, has recently completed TC BioPharm’s (TCB), new clinical manufacturing facility in Glasgow, which processes patients’ own cells in an innovative treatment to target and destroy cancer.

Angela Scott, TCB’s operations director, commented: “The team has done an amazing job building and commissioning our facility in record time. Not only have WHP built an impressive GMP facility in the heart of Scotland, they also ensured that costs were managed in a supportive and proactive manner.

“As TCB’s clinical outreach extends beyond the UK, WHP and TCB wil jointly evaluate logistics of facility expansion on a geographical basis, using a combination of modular and mobile clean room systems that can be located in strategic areas to support planned treatment regimes.”

Constructed to comply with stringent UK Good Manufacturing Practice (GMP) regulations, the 3,500sq ft facility took 12 weeks to build from start to finish. It includes two cleanrooms, quality control suites and development laboratories designed to support the manufacture of clinical grade product. The facility has just been granted a license to produce human cell therapy products by the Medicines Healthcare Products Regulatory Agency (MHRA).

WHP’s managing director, Nigel Hall, said: “We have gained a strong reputation for our cleanroom design and construction in the biotechnology industry and it is pleasing to demonstrate our expertise on a project as important as this one – especially so close to home.”

Clean sweep: The 3,500sq ft facility took 12 weeks to build and includes two cleanrooms, quality control suites and development laboratories

Fast mover Pepperl+Fuchs explains how its sterility compliant workstations mean less downtime and more production Pepperl+Fuchs’ newly enhanced sterility compliant workstations for aseptic installations provide a germ-free environment and offers minimal down-time for set-up and maintenance. The aseptic operator workstation is designed for use in MES, batch/process control, and building management functions. The unit features a flush 316L stainless steel enclosure, an ergonomically angled hygienic keyboard and an industrial-grade monitor with an FDA-grade silicone gasket.

While traditional OIT installations require six to eight hours of installation, Pepperl+Fuchs says its aseptic workstations’ caulk-free design can be installed in 30-minutes. This rapid installation removes the OITs from critical path in new installations and allows for shorter commissioning and operations to begin.

Pepperl+Fuchs aseptic workstations are certified for use in general purpose and Class I, Division 2 and Class II, Division 2 classified areas, satisfy Class 100 (ISO 5) requirements and are Grade A/B compatible.

Ideally suited to any wall, spring-loaded wall clamps anchor the unit housing in even the most shallow spaces, and the door simply mounts to internal hinges. The installation process provides an air/bacteria seal between the door and the shell, and between the door and the wall. Once installed, communication and power connected in minutes and operation can begin.

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39

sws lnoFwlo F n io

       

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    

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Biopharmaceutical

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Processes

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3/16/15 9:22 AM

20/03/2015 16:50:35

STERILISATION

Flexible friend Paolo Golfetto, Ompi discusses changing pharmaceutical operations for parenterals through a new flexible concept

Solution provider: Ompi aims to ease the problems pharma companies face developing new parenteral drugs

T

oday pharmaceutical companies face a high amount of costs for developing new parenteral drugs and there are many cases of patent losses. There is the need to offer them new manufacturing solutions as their target in this scenario is to lower cost pressure, increase flexibility and quality, reduce time to market and outsource non core activities.

Ompi aims to ease these problems providing a new filling platform based on a new flexible concept.

The manufacturing development process for new or existing drugs, especially for the emerging biotech needs or small batch needs, is often delayed due to the limited availability of filling options with an acceptable cost for the start up and formats of existing aseptic lines.

In a traditional pharmaceutical manufacturing process for parenterals, a pharmaceutical company deals with many phases, just for the proper preparation of the container system: washing, depyrogenation, sterilisation, filling, capping and crimping. This consolidated process allows them to benefit from a high speed and a high capacity but it also has some disadvantages – less flexibility, a larger footprint, high operating and validation costs and high glass-to-glass contact risk.

Everybody knows that glass-to-glass contact is responsible for a series of problems that result in costs increase and risk of recalls: cosmetic issues, scratches, breakage and particle generation.

As not all the phases indicated are core activities for the pharmaceutical companies, Ompi EZ-fill solution aims to ease this pharmaceutical manufacturing process. By providing pharmaceutical companies with already washed and sterile containers (both in tray and in nest and tub format), this new flexible concept allows them to reduce space required for operations and to avoid the need of cleaning glass packaging before filling because it outsources non core activities. Moreover, it enables processes which reduce or eliminate glass –to-glass contact. This is assured through the nest and tub solution, thanks to a specific design of the packaging material that should preserve both particulate and cosmetic aspects. This reduces filling line downtime linked to broken containers and particle generation both in the transportation phase and in the buffering/in-feeding operations.

The nest and tub format is provided for all sterile containers (vials, cartridges and syringes), so pharmaceutical companies can maximise flexibility in aseptic filling using a common filling platform (combi line). The Ompi EZ-fill is designed to be a flexible concept as it has been developed with the main fill and finish equipment manufacturers and can therefore be easily integrated into existing pharmaceutical manufacturing filling lines. Machine manufacturers have also been involved in the development of the packaging design and concept for the proper handling and machine-ability with a range of fill and finish units.

Ready-to-fill glass containers can be also packaged in tray format that can be processed in existing lines (adapted or revamped). This solution allows more containers for packaging unit and pharmaceutical companies can minimize manufacturing costs increasing efficiency.

THE OMPI EZ-FILL PROCESS HAS THE FOLLOWING PHASES: Incoming materials: containers are supplied to the Ompi EZ-Fill area (ISO7 and ISO5 under laminar flow).

Washing: containers are washed into the washing machine with WFI (Water For Injection).

Siliconisation: cartridges are siliconised with high performances layer distribution process (baked silicone).

Heating: drying and depyrogenation (only for vials and cartridges) in an oven. The cycle is optimised in order to reduce the timing and assure an optimal drying.

Packaging: the final steps place syringes, vials and cartridges into two final packaging solutions – tray: one piece box (only for vials) and nest and tub: nest and tub format (for all types of containers: syringes, vials, cartridges).

Both formats are sealed with a Tyvek lid, packaged in steribags and case-pack allowing for sterilisation. Key attention is given to the cleanliness of the packaging components as to the production of the glass container itself. Final configuration includes packaging in pallets.

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Final sterilisation: filled tubs/tray in steribags are sterilised by EtO or steam (steam sterilisation upon request).

Capping: cartridges can optionally (upon customers’ request) be pre-capped.

The Ompi EZ-fill process is GMP compliant and already approved by numerous pharmaceutical companies.

41

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Pharmaceuticals Research to Finished Product

Source Manufacture Outsource • Pharmaceutical Ingredients • Good Automated Manufacturing Practice (GAMP®) • Scale-up: Qualification & Validation • Supply Chain Risk Management • The Future of Pharma in the UK

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STERILISATION

Clean sweep Karl Barker, head of microbiology, Wickham Laboratories explains the challenges and solutions in sterility testing

M

edical devices or parenteral pharmaceuticals that are injected or implanted into the body are required to have a sterility test to confirm that there are no microorganisms present. The testing is governed by international standards eg USP, Ph Eur, JP, and ISO1-4.

There has been an increased focus on sterility testing recently given several high profile cases where medical products have been contaminated with microorganisms causing septicaemia and even death.

Sterility testing must be completed under strict aseptic conditions by well trained staff utilising documented verified procedures. The difficulty lies in that the test environment and test system are under a significant and constant microbial challenge. Used in combination, isolator technology and enclosed sterility test systems such as the industry standard Merck Millipore Steritest significantly reduce the risk of contamination during testing, but we must not become complacent and rely on technology alone.

There are two methods of sterility testing: membrane filtration and direct inoculation. With membrane filtration, product is filtered equally onto two sterile discs which are then washed and exposed to different broth media. Direct inoculation involves a product being placed directly into a volume of broth and can only be used where filtration is not possible. In both cases the broth media is incubated for a period of 14 days after which the broths are rated as growth or no growth based on turbidity; no growth indicating sterility.

Most parenteral products undergoing sterility testing are aqueous preparations which may be readily sampled and filtered requiring little in the way of special attention. However, not all pharmaceutical preparations are as simple to test.

The first category of difficult samples are those which filter slowly or those

in which the filtration rate slows due to filter blockage. Samples prone to such filtration difficulties include products containing proteins or methylcellulose.

Use of surfactants such as Tween or Triton x100 in the wash fluid may help as they lower interfacial tension and act by dispersing the agent. It is important to pre-wet the filter with the fluid and surfactant prior to sampling in order to minimise the potential for binding to the filter matrix. Additionally, warming the samples to reduce the viscosity may help with difficult products.

Antibiotic preparations have a tendency to bind to the filter making them difficult to wash from the filter matrix. It is essential in testing these samples to use low binding filters and incorporate Lecithin and Tween in the wash fluid to aid washing and provide a neutralising capacity to the test system. As larger volumes may distort the filter matrix, the maximum amount of wash fluid allowed on a 47mm filter is 500mL, usually delivered as five separate 100mL washes.

Pharmaceutical preparations which contain oils or fats are also a challenge but they may be rendered soluble by the use of isopropyl myristate (IPM). The IPM is sterilised by filtration and stored in sterile bottles until required. When IPM is used, the product is aseptically transferred into the IPM, mixed thoroughly, and then introduced to a dry membrane filter to facilitate more rapid filtration. Filtration is generally slow but once complete, wash fluid containing up to 5% Tween can be used to wash the IPM and product mixture from the membrane. Again, filtration is slow, but gentle swirling of the filter can help the process along. In this process, up to 5 x 100 mL washes may be required.

For more difficult samples, warming the IPM and Tween wash fluid up to 37°C can aid the filtration process.

Another challenge that may arise in sterility testing is caused by the products which can impart a “haze� to the media, making it impossible to tell whether this is

Testing testing: Example of sterility testing in an isolator utilising Merck Millipore Steritest system

due to the sample or microbial growth.

The pharmacopoeias recommend a subculture of this media to establish whether the growth is microbial or not.

This additional testing requires at least another four days of incubation with a test now at least 19 days long.

In addition to these issues, the increasing level of sophistication in delivery devices may also present difficulties in testing.

Devices such as prefilled syringes or powder cassettes for inhalers which fit neatly into the device often require multiple manipulations and are therefore a greater risk during sterility testing as the chance of microbial contamination is increased.

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Obtaining a valid sterility test method requires significant time and effort in the method suitability stage of the procedure to ensure it is robust and repeatable thus reducing the potential for problems further down the line.

1. USP 37 <71> Sterility Tests.

2. Ph Eur 8.0 2.6.1 Sterility.

3. JP XVI 4.06 Sterility Test.

4. ISO 11737-2 2009 Tests of Sterility.

43

It’s safer InsIde

mo d e l 6 6 0

No need to walk on eggshells.

At Weiler Engineering, our ASEP-TECH® packaging machines produce shatterproof, aseptically packaged products in a closed environment—virtually eliminating contamination concerns.

What else would you expect from the world’s most advanced aseptic liquid packaging system?

Our Blow/Fill/Seal machines integrate blow molding, sterile filling, and hermetic sealing in one uninterrupted operation—a hands-free manufacturing process that ensures your company’s parenterals, ophthalmic solutions, respiratory drugs, and other pharmaceutical liquids reach the marketplace in the most cost-effective manner possible—every time.

For more than 40 years, we have set the industry standard for sterile processing development with a continuous commitment to quality and innovation for aseptic technology. We will work with your company to develop a customized approach for each of your products.

©2015 Weiler Engineering, Inc.

Learn more about our Blow/Fill/Seal ASEP-TECH® packaging solutions.

See ASEP-TECH® systems in action, visit www.asep-tech.com/epm

Safeguarding solutions through innovative packaging

CASE STUDY

Safety first Roche, pharmaceutical manufacturer, has optimised its critical solvent-handling operations using Almatec pumps.

By Harald Vogl, Almatec

E

“When a tank needs to be emptied, the tank truck uses a hose for the disposal of the waste solvent. The dangerous part is when we hook the hose onto the truck and begin pumping the waste solvent.”

stablished in 1896, Roche recognised that the industrial manufacture of standardised medicines would be a major advance in the fight against disease.

By 2013 the Swiss company had grown Indeed, many of the to compile revenues of solvents that Roche 46.8 billion Swiss francs uses in its production ($52.5 billion USD). process are classified as Its operations are divided hazardous or dangerous into two core businesses chemicals and must be – pharmaceuticals handled per the ATEX and diagnostics. The requirements of European Roche Diagnostics Union directive 94/9/EG facility in Penzberg, regarding the use and Germany, is home to disposal of potentially both pharmaceutical and Pumped up: Florian Habeck, assistant tank manager for Roche Diagnostics, likes the explosive liquids. diagnostics operations. reliability, efficiency and safe operation from the Almatec E80 Series AODD pump This makes it one of the largest biotechnology research centres in Europe and is also the The Solution only Roche facility that is engaged in the research, development and The characteristics of Roche’s solvent-handling operation — highproduction for both its diagnostics and pharmaceutical divisions. The volume transfer of potentially dangerous chemicals — require a pump facility is the scene for the production of the active ingredients that are that can perform the task reliably, efficiently and safely, for both the used in almost all of the important pharmaceuticals and reagents that environment and site personnel. Since the late 1980s, Roche has relied Roche manufactures. on plastic air-operated double-diaphragm (AODD) pump technology from Almatec, Kamp-Lintfort, Germany, part of US-based PSG, to The Penzberg facility has been in operation for 40 years, employs more conduct solvent transfer in the safest and most efficient manner possible. than 5,100 people and features about 60 buildings. Large volumes of raw ingredients and finished pharmaceutical products are constantly on “At this site, we’ve used Almatec pumps for more than 25 years,” the move. One of the most critical types of these fluids are the solvents said Habeck. “The pumps are very reliable, that’s the main that are used in the pharmaceutical-production process. reason why we’ve used them for 25 years, and we also like that the pump is self-priming, it’s dry-run safe and that we can pump “Roche Diagnostics produces lots of medicines and is a very big liquids with particles in them. The pumps also produce a smooth pharmaceutical factory,” said Florian Habeck, assistant tank manager flow, so nothing happens to the liquid and nothing happens to at Roche Diagnostics. “We must have solvents in order to produce our the pump.” products. We buy the solvents from manufacturers and after using them for production we send the used solvents to underground storage tanks.”

From the beginning, Roche had used Almatec A-Series AODD pumps for its solvent-transfer applications, but when a new hall for Specifically, Roche has four underground tanks where the used solvents the production operations involving solvents was built in 2013, the are transferred. These tanks are quite large, with storage capacities company decided to upgrade to the new E-Series AODD pump ranging from 60 to 100 cubic meters (15,800 to 26,400 gallons). The from Almatec. The E-Series pumps are a direct replacement for the tanks are monitored and controlled from a computer station that gives A-Series models and earned their name because they are designed to the operator real-time information concerning, for example, liquid level be economic, ecological, efficient and ergonomic in their operation. and overfill or leakage warnings.

So, in October 2013, an E80 model and several E25 models were installed and began handling Roche’s numerous solvents.

“We can look at all of the waste-solvent tanks, the underground tanks, and the system shows us all of the warnings, from the level of the tanks or when we have to order a tank truck for disposal,” said Habeck. continued overleaf>>

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45

CONTAMINATION CONTROL SPECIALISTS

OF ALL GROUND-LEVEL CONTAMINATION

The E-Series pumps ideally meet Roche’s solventhandling needs because they feature solid-block construction with abrasion-resistant polyethylene (PE) and polytetrafluoroethylene (PTFE/Teflon) materials. The PE conductive and PTFE conductive models meet all ATEX requirements, meaning that they are suitable for use when pumping hazardous and dangerous materials.

The pumps utilise stainless-steel ring technology — eliminating the need for mechanical seals—to increase protection from leaks through consistent compression around the ring’s exterior. The E-Series pumps also feature Almatec’s Perswing P air control system, which offers superior efficiency when comparing flow rates and air consumption needed with competitive brands.

The E80 pump—affectionately known to Roche personnel as ‘Big Bertha’— has a maximum flow rate of 48 m3/hr (12,600 gph). Since the piping runs, at 4-5 meters (13-16 feet), that connect the storage tanks to the truck-loading area are quite long, the E80 pump’s suction line is outfitted with a pulsation damper, which allows the pump to produce a virtually uniform flow. The result is a pump that satisfies all of the criteria that Roche has for pumping used solvents.

Class monitor: Roche Diagnostics’ used-solvent storage tanks are monitored from a dedicated on-site computer room that gives the operator real-time information regarding liquid levels and potential alarm conditions

Perfect performance:Florian Habeck, right, assistant tank manager for Roche Diagnostics, has been pleased with the solvent-handling performance of the Almatec E25 Series AODD

“We use the E80 to pump the waste solvent from the underground tanks to the tank truck,” explained Habeck.

“The truck has a capacity of 25 m3 (6,600 gallon) and we want to fill the tank very quickly. That’s why we bought this big pump, so we can do it in a short amount of time.

It’s all about efficiency, and we have this pump because it is very efficient.”

Indeed, with its maximum flow rate of 48 m3/hr, the E80 pump is able to fill a standard tank truck with a 25-cubicmeter capacity in around 30 minutes.

The smaller E25 pumps, with their maximum flow rates of 8 m3/hr (2,100 gph), and which feature the ET pulsation damper, are used to transfer certain classes of used solvents to Roche’s in-house recycling area, where they are treated before they are transferred to a wastewaterdisposal facility.

Roche also benefits from the simple maintenance that the E-Series pumps require—in the rare instances when they do need maintenance.

“One of the benefits of the Almatec pumps is that they are very easy to work on,” said Habeck. “We’ll have local technicians come in to perform maintenance and they like the Almatec pumps because the maintenance is very easy to perform.”

“Safety and efficiency are the two most important aspects here at the Roche Diagnostics site, and that’s why we choose the Almatec pump,” said Habeck. “We have a long relationship and the E-Series pump is the next step in our relationship with Almatec. I think that the E-Series pumps are very safe and reliable, and they are one thing that I never have to worry about.”

WWW.EPMMAGAZINE.COM

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Contact Contec at infoeu@contecinc.com or by calling 0845 652 2582 to request a sample. www.contecinc.com Use biocides safely. Always read the label and product information before use.

4 MINs

SHOW PREVIEW

Making Pharmaceuticals is a free of charge event taking place at the NMM Exhibition Centre, Birmingham. Dedicated to the detailed and complex issues associated with developing, sourcing, manufacturing, outsourcing and delivering consistent pharmaceutical products to the market, Making Pharmaceuticals is designed to help industry improve manufacturing processes, address product formulation / reformulation, reduce undesired variability, deliver consistent product quality, improve process robustness and enhance efficiency.

Make it a date

Free to attend

Making Pharmaceuticals From Research to Finished Product, is a free to attend two day event on 28-29 April that offering seminars alongside an exhibition

The event will also be a focus for outsourcing in the pharmaceutical industry featuring contract services for license holders, brand owners and manufacturers looking for outsourcing options from research and clinical trials to manufacture to packing to delivery.

The exhibition will offer visitors the opportunity to meet and discuss their business needs and requirements with companies that provide the full spectrum of products and services to the sector, from APIs, excipients and raw materials, through to analytical testing, contract manufacture, machinery, equipment and packaging and more.

The full seminar programme of over 70 presentations and exhibition are free to attend. The programme includes the contribution of the PQG as well as EXCiPACT, IMechE, ISPE UK, Pharmig, De Montfort University and University of Leeds.

The programme at Making Pharmaceuticals has been created to offer an opportunity for everyone designing, developing and manufacturing pharmaceuticals to get the latest information from leading experts, manufacturers, suppliers and industry figures in sourcing, manufacturing and outsourcing pharmaceuticals from research to finished product.

Making Pharmaceuticals is designed to bring together everyone involved in the development life cycle leading to and including commercial manufacture and provides an essential focus to the many different skills, technologies, techniques, concepts and range of expertise necessary to deliver consistent products.

WWW.EPMMAGAZINE.COM

www.makingpharma.com 49

CHEMICAL REACTION It’s important to stay 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...

Super drugs Nigel Theobald, N4 Pharma offers an insight into the company’s latest offerings to the pharma sector EPM: Who are you and what do you do?

NT: N4 Pharma is a drug reformulation company focused on developing and out licensing new versions of existing high value drugs with an unmet commercial or medical need.

N4’s commercial strategy is to advance a pipeline of products through clinical proof of concept and then partner to take the products through bio-equivalence studies to regulatory approval. This simplified regulatory pathway reduces development risk and results in faster market access. We also offers our Cocrys service (which uses hot melt extrusion to manufacture co-crystals) to pharmaceutical companies with their own molecules that have issues with solubility and need a commercially robust process to help take them into clinical trials and beyond to a commercially scalable formulation.

Q & A

EPM: What have you focussed on recently?

NT: Our initial focus has been on developing Cocrys. The co-crystals can be used to improve a drug’s solubility either to improve onset of action or increase bioavailability and can also be used to control the solubility to enable a sustained release effect.

Crucially the process uses standard twin screw extruders and is therefore capable of large volume efficient commercial production of the co-crystals.

We have also developed Nuvac a nano-carrier delivery system for antigens that improves both humoral and cell mediation effects for vaccines. It can be used to reduce vaccine dose or improve vaccine or antibody drug conjugate performance and our first program with Nuvac is a single dose version of the hepatitis B vaccine using the antigen HBsAg. EPM: What is you latest service/ innovation?

NT: Our latest product we are developing is a new improved version of Sildenafil (Viagra). Sildenafil base API is highly insoluble and has been formulated and marketed as Sildenafil Citrate, a salt to improve its solubility. Despite this improvement on the base product Sildenafil citrate still takes around an hour to take effect. This can lead to clinical problems for patients who are concerned that having taken the drug it has not worked and who subsequently ‘double dose’. It is also a problem and an opportunity for the drug as it becomes more widely available to consumers, assuming the current attempts to switch to OTC status are widely successful.

N4 is developing a patented co-crystal of Sildenafil that will have a faster onset of action (target 15 minutes) and improved bio-availability. Cocrys enables new cocrystals to be developed and manufactured that will meet the FDA requirements for this new version of the drug to be classed as a drug product intermediate so therefore it will only require 505(b)(2) approval in the USA and Article 10 in Europe.

EPM: How can you benefit the pharmaceutical sector?

NT: As well as developing our own products we offer our Cocrys system to pharma companies under license to develop more soluble versions of either generic molecules or their own molecules.

For companies wishing to investigate the potential of Cocrys we initially offer a simple screening service to identify the most appropriate co-crystal to use, produce a small quantity of this co-crystal using a 16mm hot melt extruder and test its dissolution profile.

Once we have approved the preferred co-crystal we then optimise the co-crystal to 100% purity and produce GMP quantities for small-scale clinical trials.

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Cocrys is set to revolutionise the approach to manufacturing co-crystals that can then be easily commercially scaled to large volume market requirements.

EPM: Future plans?

NT: After optimising the Sildenafil co-crystal we intend to undertake a small patient study to determine the faster acting pharmacokinetic profile and bioavailability of the new co-crystal. At this point we will be looking to partner with a pharmaceutical company to take the product through larger scale clinical work to get the required regulatory approval for launch.

In addition we are looking to develop improved versions of itraconazole (much lower cost of goods) and Alendronate with improved bioavailability to reduce associated gastric issues.

We are also strengthening our own internal hot melt capability to cope with the increased demand we expect for the use of our Cocrys system. All in all a very exciting and high growth time for N4 Pharma.

WWW.EPMMAGAZINE.COM

Cost-Effective Compression The New PERFORMA™ Lite from GEA

Enhanced with the latest, state-of-the-art automatic control system, which greatly enhances ease of operation and maintenance, the compact-yet-powerful PERFORMA™ Lite tablet press offers precise tablet weight control, the ability to adjust the pre-compression dwell time by up to 300% and run certain formulations at higher outputs when other presses fail.

Ideal for small- and medium-scale solid dosage form production, the PERFORMA™ Lite operates at rates of up to 320,000 tablets/h and features an exchangeable stainless steel turret and an intelligent powder feeding system. As standard, the machine is equipped with replaceable upper guides, removable scraper seals and die seats.

Flexible, robust, reliable and fully equipped, the press improves product output, overcomes compression issues and facilitates the pressing of small tablets.

Improve your price-performance productivity today with the PERFORMA™ Lite.

When performance, flexibility and process control really matter, the PERFORMA™ Lite is your tablet press of choice.

Tel: +32 2 363 8300

Meet the PERFORMA™ Lite at ACHEMA (Hall 4 Stand F46).

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